Note: Descriptions are shown in the official language in which they were submitted.
CA 02649893 2009-01-15
LOWER DOSAGE STRENGTH IMIQUIMOD FORMULATIONS AND SHORT DOSING
REGIMENS FOR TREATING ACTINIC KERATOSIS
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical formulations and
methods
for the topical or transdermal delivery of 1-isobutyl-1H-imidazo[4,5-c]-
quinolin-4-amine,
also known as (aka) 1-(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine, aka
imiquimod, to treat actinic keratosis with shorter durations of therapy, than
currently
prescribed for the commercially available Aldara 5% imiquimod cream, as now
approved by the U.S. Food & Drug Administration ("FDA"). More specifically,
the
present invention is directed to lower dosage strength imiquimod formulations
to deliver
an efficacious dose for treating actinic keratosis with an acceptable safety
profile, but
with a dosing regimen that is shorter and more convenient for patient use than
the
dosing regimen currently approved by the FDA for Aldara 5% imiquimod cream.
BACKGROUND
[0002] Actinic keratosis (AKs) is a precancerous (premalignant) skin disorder
caused
by or associated with chronic exposure to radiant energy, such as sunlight.
Actinic
keratosis lesions are small, red, rough spots or lesions occurring on sun
exposed areas
of the skin. Actinic keratosis lesions possess many of the same cellular
changes
observed in a skin cancer called squamous cell carcinoma (SCC). Research shows
that a mutated version of the p53 gene is found in sun-damaged cells in the
body and is
present in more than about 90% of people who have AKs and squamous cell
carcinomas. Although most actinic keratosis lesions do not actually become
cancerous,
some lesions can become malignant.
[0003] It is believed that actinic keratosis develops in skin cells called
"keratinocytes",
which are the cells that constitute about 90% of the epidermis, the outermost
layer of
skin. Chronic sun exposure, over time, generates mutations in these cells and
causes
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CA 02649893 2009-01-15
the cells to change in size, shape, the way they are organized, and the way
they
behave. In addition, the cellular damage can even extend to the dermis, the
layer of
skin beneath the epidermis.
[0004] Actinic keratosis lesions generally measure in size between about 2 to
about 6
millimeters in diameter. AK lesions can range in color from skin-toned to
reddish and
often have a white scale on top. On occasion, AK lesions will form into the
shape of
animal horns. When this occurs, the AKs are known as "cutaneous horns."
[0005] People who are at higher risk for developing actinic keratosis tend to
be fair-
skinned and spend significant time outdoors, e.g., at work or at play, over
the course of
many years. AK lesions usually develop on those areas of the body that have
been
constantly exposed to the sun for years. Additionally, the skin often becomes
wrinkled,
mottled, and discolored from chronic sun exposure. Common locations for
actinic
keratosis include the face, ears, lips, balding scalp, back of the neck, upper
chest, the
tops of the hands and forearms. When AK lesions develop on the lips, the
condition is
known as actinic cheilitis. Actinic cheilitis can be characterized by a
diffuse scaling on
the lower lip that cracks and dries. In some cases, the lips will have a
whitish
discoloration on the thickened lip.
[0006] Actinic keratosis is generally more common after age 40, because
actinic
keratosis take years to develop. However, even younger adults may develop
actinic
keratosis when living in geographic areas that are exposed to high-intensity
sunlight
year round, such as Florida and Southern California.
[0007] Actinic keratosis has become a significant health care issue in the
United
States of America. It is estimated that over 20 million Americans suffer from
actinic
keratosis, and that that number continues to grow. In fact, actinic keratosis
is so
common today that treatment for actinic keratosis ranks as one of the most
frequent
reasons people consult a dermatologist.
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CA 02649893 2009-06-10
[0008] The compound characterized as 1 -isobutyl-1 H-imidazo[4,5-c]-quinolin-4-
amine
or 1-(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine, and known as
imiquimod, is
disclosed in U.S. Patent No. 4,689,338 and described therein as an antiviral
agent and
as an interferon inducer. A variety of formulations for topical administration
of imiquimod
are also described therein. This U.S. Patent No. 4,689,338.
[0009] U.S. Patent No. 4,751,087 discloses the use of a combination of ethyl
oleate
and glyceryl monolaurate as a skin penetration enhancer for nitroglycerin,
with all three
components being contained in the adhesive layer of a transdermal patch.
[0010] U.S. Patent No. 4,411,893 discloses the use of N,N-dimethyldodecylamine-
N-
oxide as a skin penetration enhancer in aqueous systems.
[0011] U.S. Patent No. 4,722,941 discloses readily absorbable pharmaceutical
compositions that comprise a pharmacologically active agent distributed in a
vehicle
comprising an absorption-enhancing amount of at least one fatty acid
containing 6 to 12
carbon atoms and optionally a fatty acid monoglyceride. Such compositions are
said to be
particularly useful for increasing the absorption of pharmacologically active
bases.
[0012] U.S. Patent No. 4,746,515 discloses a method of using glyceryl
monolaurate to
enhance the transdermal flux of a transdermally deliverable drug through
intact skin.
[0013] U.S. Patent No. 5,238,944, U.S. Patent No. 7,038,051, U.S. Patent No.
6,693,113, U.S. Patent No. 6,894,060 U.S. Patent Publication No. 2007/0123558,
U.S.
Patent Publication No. 2004/087614, U.S. Patent Publication No. 2002/1 472 1
0, and
W02008US53522 disclose topical formulations and/or topical and transdermal
delivery
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CA 02649893 2009-06-10
systems containing 1-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-
methylpropyl)-
1 H-imidazo[4,5-c]quinolin-4-amine.
[0014] Currently, the FDA has approved a 5% imiquimod cream, commercially
available under the brand name Aldara , to treat certain dermal and mucosal
associated conditions, such as (1) the topical treatment of clinically
typical,
nonhyperkeratotic actinic keratosis (AK) on the face or scalp in
immunocompetent
adults, (2) topical treatment of biopsy-confirmed, primary superficial basal
cell
carcinoma (sBCC) in immunocompetent adults, and (3) the topical treatment of
external
genital and perianal warts/condyloma acuminate in patients 12 years or older.
[0015] Aldara is the brand name for an FDA-approved 5% imiquimod cream, which
is an immune response modifier. Each gram of the Aldara 5% imiquimod cream
contains 50 mg of imiquimod in an off-white oil-in-water vanishing cream base
consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white
petrolatum, polysorbate
60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl
alcohol,
methylparaben, and propylparaben. The Aldara 5% imiquimod cream is packaged
in
single-use packets or sachets, each containing 250 mg of cream, equivalent to
12.5 mg
of imiquimod.
[0016] Chemically, imiquimod, as indicated above, is known as 1-(2-
methylpropyl)-
1 H-imidazo[4,5-c]quinolin-4-amine or 1 -isobutyl-1 H-imidazo[4,5-c]-quinolin-
4-amine.
Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3.
The
chemical structural formula for imiquimod is as follows:
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CA 02649893 2009-01-15
N H 2
N ~
~ ~
'~~.. \---< C H3
CH3
[0017] Notwithstanding FDA approval, Aldara 5% imiquimod cream treatment is
not
without limitation, including an unsimplified and lengthy dosing regimen.
Generally
speaking, the treatment regimen for actinic keratosis using FDA-approved
Aldara 5%
imiquimod cream consists of applying the Aldara 5% imiquimod cream two times
per
week for a full 16 weeks to a defined/limited treatment area on the face or
scalp (but not
both concurrently). The surface treatment area for Aldara 5% imiquimod cream
is
limited to approximately 25 cm2 (e.g., a 5 cm x 5 cm area, which may be of any
shape;
the treatment area does not have to be square ) and is defined as one
contiguous area.
The number of AK lesions treated with Aldara 5% imiquimod cream per treatment
area
is generally between about 4 and about 8. Because the treatment area is quite
small,
less than one single-use Aldara packet or sachet (250 mg of total cream, of
which 12.5
mg is imiquimod) is generally used per application. Inconsistencies in both
compliance
and therapeutic results frequently occur with the treatment of actinic
keratosis with FDA-
approved Aldara 5% imiquimod cream due to the lengthy treatment period, i.e.,
16
weeks, the complicated dosing regimen, i.e., twice weekly, and the high
incidence of
application site reactions.
[0018] Subsequent to FDA-approval of Aldara 5% imiquimod cream to treat
actinic
keratosis, a pilot study was conducted that was an open-label trial that
included 25
patients who had between 5 and 20 discrete AKs within a cosmetic unit of the
forehead,
scalp, or cheek. During this pilot study, treatment consisted of once-daily
application of
5% imiquimod cream, three times a week for four weeks to the entire cosmetic
unit,
followed by a rest period of four weeks. The cycle was repeated if any AKs
remained
CA 02649893 2009-01-15
after a complete eight-week cycle. A maximum of three cycles was permitted (24
weeks). Thirty-three sites (i.e., cosmetic units) in 25 subjects were
evaluated.
According to the authors, compliance was excellent with a very tolerable
safety profile.
Complete clearing of all AKs was noted in 82% (27/33) of anatomic sites in 25
study
subjects. Almost half the sites (15/33) were clear at the end of the first
cycle. A
"therapeutic interval" was noted during the rest period wherein clinical
inflammation
subsided but AKs continued to clear. An added effect, according to the
authors, was the
uncovering and clinical appearance and subsequent eradication of incipient
(subclinical)
AKs in the treatment area. As a result, the authors concluded that there was
excellent
compliance with the cycle therapy regimen utilized in this study and that the
identification of a therapeutic interval may prove to be beneficial in
formulating
individualized dosing regimens. The authors warned, however, that the findings
of the
study must be evaluated cautiously. The authors also cautioned that, because
this
study was an open-label trial in a small number of study subjects, safety,
efficacy and
duration of efficacy needs to be corroborated by controlled, randomized trials
with larger
study populations. See Salasche S.J., Levine N., and Morrison L.: Cycle
therapy of
actinic keratoses of the face and scalp with 5% topical imiquimod cream: An
open-label
trial. J Am Acad Dermatol. 47(4):571-7 (Oct. 2002).
[0019] Also subsequent to FDA-approval of Aldara 5% imiquimod cream to treat
actinic keratosis, a dual-center, randomized, double-blind, vehicle-controlled
study was
conducted to evaluate the safety and efficacy of short courses of therapy with
Aldara
5% imiquimod cream in clearing _75% of baseline solar keratoses ("SK") within
a field
of treatment. Subjects with 5-15 baseline SK within one treatment area (scalp,
forehead
and temples, or both cheeks) were randomized to apply imiquimod or vehicle
cream to
the entire treatment area three times a week for 3 weeks. Subjects were
assessed 4
weeks after completing the first course for clearance of lesions. Subjects
with <75%
clearance were commenced or, a second 3-week course of study cream. Subjects
with
_75% clearance were followed up until study completion without further
therapy. All
subjects were evaluated at the study endpoint of 14 weeks after initiating
therapy for
assessment of the primary outcome (_75% clearance of baseline solar
keratoses).
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According to the authors, twenty-one out of 29 (72%) imiquimod-treated
subjects
cleared ?75% of baseline lesions compared with 3/10 (30%) subjects using the
vehicle
cream (Fisher's exact test, P = 0.027) and the imiquimod was well tolerated.
Also
according to the authors, the results of this study suggest that 5% imiquimod
administered three times per week may offer a therapeutic alternative to
patients with
SK on the face, and scalp, and that one or two short courses may be an
alternative to
the continuous longer Aldara 5% imiquimod cream therapy approved by the FDA.
The
authors did caution, however, that, because the study had a relatively short
follow-up
endpoint, additional studies may be needed to evaluate if the therapeutic
outcome can
be sustained. See Chen K. et al.: Links Short-course therapy with imiquimod 5%
cream for solar keratoses: a randomized controlled trial. Australasian J
Dermatol.
44(4):250-5 (Nov 2005).
[0020] In addition, a multi-center, vehicle-controlled, double-blind study to
assess the
safety and efficacy of imiquimod 5% cream applied once daily 3 days per week
in one
or two courses of treatment of actinic keratoses on the head was conducted and
reported in 2007. According to the authors, a total of 259 patients diagnosed
with AK
were enrolled in twenty study centers in Europe and applied imiquimod for 4
weeks,
entered a 4-week rest period and if they did not have complete clearance, the
patients
then entered a second course of treatment. The area of treatment was confined
to
about 25 cm2. As reported by the authors, patients in the imiquimod group had
an
overall complete clearance rate of 55.0% (71/129) vs. a rate of 2.3% (3/130)
for the
vehicle group and that there was a high rate of agreement between the clinical
assessment and histological findings with respect to AK lesion clearance. The
authors
further reported that, at both 8-week post-treatment visits, the negative
predictive value
of the investigator assessment was 92.2% for clinical assessments vs.
histological
results. The authors concluded that a 4-week course of treatment with three
times
weekly dosing of imiquimod 5% cream, with a repeated course of treatment for
those
patients who fail to clear after the first course of treatment, is a safe and
effective
treatment for AK, and the overall complete clearance rate (complete clearance
after
either course 1 or course 2) is comparable to the 16-week Aldara 5% imiquimod
cream
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treatment regimen, while decreasing drug exposure to the patient and
decreasing the
overall treatment time. See Alomar, A., J. Bichel, et al.: Vehicle-controlled,
randomized, double-blind study to assess safety and efficacy of imiquimod 5%
cream
applied once daily 3 days per week in one or two courses of treatment of
actinic
keratoses or, the head. British Journal of Dermatology. 157(1): 133-41 (2007).
[0021] Another vehicle-controlled, double-blind, randomized study of imiquimod
5%
cream applied 3 days per week in one or two courses of treatment for actinic
keratoses
on the head was conducted and also reported in 2007. According to the authors,
patients with actinic keratosis lesions on the head applied imiquimod or
vehicle cream
3x/wk for 4 weeks (course 1), patients with remaining lesions received another
course
of treatment, and complete and partial clearance rates were evaluated after
course 1,
after course 2 (overall), and 1 year later. The authors concluded that
imiquimod 3x/wk
in one or two courses of treatment appears to be effective for the treatment
of actinic
keratoses on the head, providing long-term clinical benefits and that some
recurrences
do occur, so long-term follow-up is recommended. See Jorizzo, J., S. Dinehart,
et al.:
Vehicle-controlled, double-blind, randomized study of imiquimod 5% cream
applied 3
days per week in one or two courses of treatment for actinic keratoses on the
head.
Journal of the American Academy of Dermatology. 57(2): 265-8 (2007).
[0022] Another multicenter, open-label study using imiquimod 5% cream in one
or two
4-week courses of treatment for multiple actinic keratoses on the head was
conducted
and also reported in 2007. According to the authors, this was an open-label,
phase Illb
study involving 180 dermatology clinics and practices in Germany, and patients
were
eligible if they had clinically typical, visible AK lesions located anywhere
on the head,
excluding the upper and lower eyelids, nostrils, lip vermilion, and inside the
ears. The
authors reported that patients applied imiquimod study cream to the treatment
area
once daily 3x/week for 4 weeks (course 1) followed by a 4-week post treatment
period
and that patients with AK lesions remaining in the treatment area underwent a
second
4-week treatment course. Apparently, the treatment area was not restricted and
patients were allowed to use one or two sachets per application. The size of
the
treatment areas and number of sachets applied were not reported. The median
number
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of AK lesions at baseline was 7. The authors further reported that 829
patients entered
the study and that, overall, the complete clearance rate was 68.9% (571/829),
the
partial clearance rate (percentage of patients with ? 75% reduction in the
number of
baseline AK lesions) was 80.2%. The authors acknowledged that local skin
reactions
(LSRs) and application site reactions (ASRs) were the most commonly reported
adverse events, and that four patients discontinued from the study due to LSRs
or
ASRs. The authors concluded that a shorter treatment regimen of imiquimod 5%
cream, i.e., once daily 3x/week for 4 weeks for 1 or two courses, can produce
complete
clearance rates similar to those seen with 16 weeks of Aldara 5% imiquimod
cream
treatment and has the advantage of lower drug exposure, resulting in a better
benefit-
risk profile for the patient. See Stockfleth, E., W. Sterry, et al.:
Multicentre, open-label
study using imiquimod 5% cream in one or two 4-week courses of treatment for
multiple
actinic keratoses on the head. British Journal of Dermatology. 157 Suppl 2: 41-
6
(2007).
[0023] Another randomized study of topical 5% imiquimod vs. topical 5-
fluorouracil vs.
cryosurgery in immunocompetent patients with actinic keratoses, including a
comparison of clinical and histological outcomes including 1-year follow-up,
was
conducted. According to the authors, this study compared the initial and 12-
month -
clinical clearance, histological clearance, and cosmetic outcomes of topically
applied
5% imiquimod (IMIQ) cream, 5% 5-fluorouracil (5-FU) ointment and cryosurgery
for the
treatment of AK of patients who were randomized to one of the following three
treatment
groups: one or two courses of cryosurgery (20-40 seconds per lesion), topical
5-FU
(twice daily for 4 weeks), or one or two courses of topical imiquimod (three
times per
week for 4 weeks each). In this study, the treatment area was confined to one
anatomic
area of 50 cm2 or less. The authors reported that: (1) sixty-eight per cent
(17/25) of
patients treated with cryosurgery, 96% (23/24) of patients treated with 5-FU,
and 85%
(22/26) of patients treated with IMIQ achieved initial clinical clearance, P =
0.03; (2) the
histological clearance rate for cryosurgery was 32% (8/25), 67% (16/24) for 5-
FU, and
73% (19/26) in the imiquimod group, P = 0.03; (3) the 12-month follow-up
showed a
high rate of recurrent and new lesions in the 5-FU and cryosurgery arms; (4)
the
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CA 02649893 2009-01-15
sustained clearance rate of initially cleared individual lesions was 28%
(7/25) for
cryosurgery, 54% (13/24) for 5-FU and 73% (19/26) for imiquimod (p < 0.01);
(5)
sustained clearance of the total treatment field was 4% (1/25), 33% (8/24),
and 73%
(19/26) of patients after cryosurgery, 5-FU, and imiquimod, respectively (P <
0.01); and
(6) the patients in the imiquimod group were judged to have the best cosmetic
outcomes (P = 0.0001). The authors concluded that imiquimod treatment of AK
resulted
in superior sustained clearance and cosmetic outcomes compared with
cryosurgery and
5-FU and that imiquimod should be considered as a first line therapy for
sustained
treatment of AK. See Krawtchenko, N., J. Roewert-Huber, et al.: A randomized
study
of topical 5% imiquimod vs. topical 5-fluorouracil vs. cryosurgery in
immunocompetent
patients with actinic keratoses: a comparison of clinical and histological
outcomes
including 1-year follow-up. British Journal of Dermatology. 157 Suppl 2: 34-40
(2007).
[0024] Also subsequent to FDA-approval of Aldara 5% imiquimod cream to treat
actinic keratosis, an open-label study to assess the safety and efficacy of
imiquimod 5%
cream applied once daily three times per week in cycles for treatment of
actinic
keratoses on the head was conducted. During this open-label study, imiquimod
5%
cream was administered three times per week for four weeks followed by four
weeks of
rest (cycle 1) to AK lesions on the head. If AK lesions remained visible at
the end of
cycle 1, a second treatment cycle was instituted. According to the authors,
50% (30 of
60) of the subjects who experienced complete clearance of AK lesions, and 75%
(30 of
40) of the subjects who experienced partial clearance of AK lesions after
imiquimod
treatment at the end of cycle 2. The authors further reported that 77% of the
subjects,
who achieved complete clearance, had no visible AK lesions 12 weeks post-
treatment
and that the imiquimod was well tolerated. The authors concluded that 5%
Imiquimod
cycle therapy, when administered three time per week for four weeks followed
by four
weeks of rest (cycle 1) combined with a second treatment cycle repeat, may be
a safe
and effective alternative to continuous imiquimod therapy for the treatment of
AK
lesions. The authors cautioned, however, that while cycle therapy does not
affect the
short-term AK recurrence rate, long-term follow-up is required. The authors
also
cautioned that further randomized, vehicle-controlled trials are needed. See
Rivers J.K.
CA 02649893 2009-01-15
et al.: Open-label study to assess the safety and efficacy of imiquimod 5%
cream
applied once daily three times per week in cycles for treatment of actinic
keratoses on
the head. J Cutan Med Surg. 12(3):97-101 (May-Jun 2008).
[0025] In view of the above, there is a need for improved actinic keratosis
topical
treatment that overcomes the current limitations associated with the current
FDA-
approved topical treatment regimen for actinic keratosis, i.e., 16 weeks,
twice per week,
with FDA-approved Aldara 5% imiquimod cream.
SUMMARY OF THE INVENTION
[0026] The present invention overcomes the above-mentioned limitations
associated
with the treatment of actinic keratosis with FDA-approved Aldara 5% imiquimod
cream
through the discovery of novel and improved imiquimod treatment regimens of
short
duration, lower dosage strength imiquimod pharmaceutical formulations, and
simplified
dosing regimens to treat actinic keratosis.
[0027] Generally speaking, the present invention provides for new and improved
substantially less-irritating lower dosage strength imiquimod pharmaceutical
formulations,
which are suitable for daily application in connection with substantially
condensed
treatment regimens and substantially expanded treatment areas, for topical
and/or
transdermal administration of an effective amount of imiquimod to treat
subjects who are
diagnosed with clinically typical, nonhyperkeratotic actinic keratosis (AK),
preferably
on the face or balding scalp of immunocompetent patients. In addition, the
present
invention provides for new and improved actinic keratosis treatments, wherein:
(1)
treatment periods of the present invention are substantially shorter in
duration, i.e., up to
six weeks and preferably up to four weeks, than the current FDA-approved 16-
week
treatment regimen for actinic keratosis treatment; (2) dosing regimens of the
present
invention are substantially simpler, i.e., one application daily each day for
up to six weeks
and preferably up to four weeks, than the current dosing regimen, i.e., once-a-
day but
only twice per week for 16 weeks, for the current FDA-approved Aldara 5%
imiquimod
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cream for actinic keratosis treatment; (3) treatment areas of the present
invention are
substantially larger, i.e., up to about 250 cm2, than the current FDA-approved
treatment
area, i.e., up to about 25 cm2, for Aldara 5% imiquimod cream for actinic
keratosis
treatment; (4) number of AK lesions being treated in accordance with the
present
invention are substantially greater in number, i.e., between about 5 and about
20 or more
AK lesions per treatment area, than the number of AK lesions, i.e., between
about 4 and
about 8 AK lesions per treatment area, generally being treated with the
current FDA-
approved Aldara 5% imiquimod cream for actinic keratosis treatment; (5) less-
irritating
imiquimod pharmaceutical formulations of the present invention are formulated
with a
lower dosage strength, i.e., between about 1% and about 4.25% imiquimod, than
the
current FDA-approved Aldara 5% imiquimod cream for actinic keratosis
treatment; and
(6) lower subject incidence of application site reactions is experienced in
accordance
with the present invention, as compared with higher subject incidence of
application site
reactions experienced with the current FDA-approved Aldara 5% imiquimod cream
and
treatment regimen for actinic keratosis treatment.
[0028] In other words, the present invention provides for new and improved
actinic
keratosis treatments that cover larger treatment areas, have short durations
of therapies,
use lower imiquimod dosage strengths, have simplified daily dosing regimens,
and have a
lower incidence of application site reactions, as compared to treatment of
actinic keratosis
with Aldara 5% imiquimod cream, as currently approved by the FDA.
[0029] The present invention thus provides numerous surprising advantages over
current FDA-approved Aldara 5% imiquimod cream therapy for actinic keratosis
treatment. For example, the present invention provides for (1) an expanded
imiquimod
treatment area estimated to be approximately 200 - 250 cm2, e.g., the full
face or entire
balding scalp, (2) a shortened treatment regimen, i.e., up to about 6 weeks
and
preferably up to about 4 weeks, (3) a simplified dosing regimen, i.e., once
daily on
each day of the treatment period, (4) low systemic imiquimod blood levels even
though
the treatment area is vastly expanded and the dosing frequency is increased,
(5)
treatment of an increased number of clinical lesions per treatment period,
e.g., about 5
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to about 20 AK lesions or more, and (6) a lower subject incidence of
application site
reactions, even though there is an increase in imiquimod surface area
penetration due
to the expanded treatment area and increased applied amounts in accordance
with
the present invention, during the topical treatment regimen of actinic
keratosis, than
currently associated with FDA-approved Aldara 5% imiquimod cream therapy.
[0030] Thus, the present invention overcomes certain of the limitations
associated
with the treatment of actinic keratosis with FDA-approved Aldara 5% imiquimod
cream
and addresses current medical needs for (1) a larger treatment area (full face
or
balding scalp: >25 cm2 vs. up to 25 cmz for Aldara 5% imiquimod cream), (2) a
shorter treatment period, e.g., two 2-week or two 3-week treatment cycles with
an
interim 2-week or 3-week no-treatment period sandwiched between them,
respectively, vs. the full 16-week treatment regimen for Aldara 5% imiquimod
cream),
(3) a more intuitive dosing regimen (daily dosing vs. twice weekly dosing for
Aldara
5% imiquimod cream) and (4) less or a lower incidence of application site
reactions.
[0031] The less-irritating lower dosage strength imiquimod pharmaceutical
formulations
of the present invention may comprise:
a) a lower dosage strength of 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine
or 1 -(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine (imiquimod) for
delivering an
effective amount of imiquimod; and
b) a pharmaceutically acceptable vehicle for imiquimod, which vehicle
comprises a fatty acid, such as isostearic acid, palmitic acid, stearic acid,
linoleic acid,
unrefined oleic acid, refined oleic acid, such as Super Refined oleic acid NF
(e.g., a
highly purified oleic acid, i.e., an oleic acid which has low polar
impurities, such as
peroxides, a low peroxide value and is marketed by CRODA; see e.g.,
www.crodausa.com) and a combination thereof, in a total amount of about 3
percent to
about 45 percent by weight based on the total weight of the formulation.
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CA 02649893 2009-01-15
[0032] The lower dosage strength imiquimod formulations of the present
invention,
especially those wherein the vehicle comprises an isostearic acid as the fatty
acid, are
uniquely designed to have physical and chemical stability, solubility,
emollient properties
and dose proportionate delivery similar to or better than Aldara 5% imiquimod
cream.
More specifically, the lower dosage strength imiquimod formulations of the
present
invention, especially those wherein the vehicle comprises an isostearic acid
as the fatty
acid, are believed to generally have similar or improved skin emolliency at
the application
site and dose proportionate release rates as to both the release rates of the
imiquimod
and the total amount of imiquimod released, relative to the Aldara 5%
imiquimod cream.
In other words, the lower dosage strength imiquimod formulations of the
present invention
are concentration influenced and have similar release rates to the Aldara 5%
imiquimod
cream. Additionally, the greater the amount of imiquimod in the formulation,
the faster
and the greater the total amount of imiquimod is released, evidencing that the
amount in
and the rate of release from the formulations are imiquimod concentration
dependent.
Thus, while the lower dose strength imiquimod formulations of the present
invention
deliver different cumulative amounts to the stratum corneum and epidermis,
i.e., local skin
delivery, than the Aldara 5% imiquimod cream, such lower dosage strength
imiquimod
formulations are believed to have a proportional and linear relationship that
is similar with
the Aldara 5% imiquimod cream as to both the rate of imiquimod- release and
the total
amount of imiquimod released and delivered locally to the skin over time, so
that the
imiquimod concentrations in the formulations of the present invention, the
imiquimod
release rates and the amount of imiquimod unabsorbed and delivered to the
stratum
corneum and epidermis, which has been released from the formulations, are
generally
proportional and linear to the Aldara 5% imiquimod cream.
[0033] In addition, the lower dosage strength imiquimod formulations of the
present
invention, especially those wherein the vehicle comprises an isostearic acid
as the fatty
acid, are uniquely designed to be stable and fall within the range of the
specifications for
the commercially available Aldara 5% imiquimod cream, such as to viscosity,
pH, and
stability, including microscopic and macroscopic stability. More specifically,
the imiquimod
present in the lower dosage strength imiquimod formulations of the present
invention,
14
CA 02649893 2009-01-15
especially those wherein the vehicle comprises an isostearic acid as the fatty
acid,
(monograph range: 90 to 110%) and benzyl alcohol (monograph range: 50 to 105
%)
remain within limits at both about 25 C and about 40 C over about a one month
period
and within limits at both about 25 C and about 40 C over about a six month
period.
Furthermore, the lower dosage strength imiquimod formulations of the present
invention,
especially those wherein the vehicle comprises an isostearic acid as the fatty
acid, remain
stabile for about six months at about 25 C and about 40 C, and also remain
stable with
respect to macroscopic and microscopic appearance, viscosity (monograph range:
2,000 to 35000 cPs) and pH (monograph range 4.0 to 5.5). In addition, the
lower dosage
strength imiquimod formulations of the present invention are uniquely designed
to meet the
requirements specified in both United States Pharmacopeia ("USP") and the
European
Pharmacopeia ("EP") as to preservative efficacy and remain free of degradation
products
when stored at about 25 C/60%RH, about 30 C/65%RH and about 40 C/75%RH over
about one, about two, about three and about six months and analyzed at about
318 nm
wavelength.
[0034] The present invention also contemplates lower dosage strength imiquimod
formulations, that have unique pharmacokinetic profiles when used, for
example, in
connection with the short durations of therapy to treat actinic keratosis in
accordance
with the present invention. By way of example, a 3.75% imiquimod lower dosage
strength formulation of the present invention, when approximately 500 mg of
such a
formulation (about 18.75 mg imiquimod) or less is applied daily for 21 days to
a
treatment area of about 200 cm2 on the face or balding scalp, achieves steady
state by
about week 2, e.g., between about day 8 and day 14, and provides an in-vivo
serum
profile selected from the following (See FIG. 54):
(a) a Day 21 Tmax of from about 4 hours to about 16 hours and preferably a
mean Tmax of about 7.4 hours with a standard deviation ("SD") of about 3.5, a
median
Tmax of about 9 hours and a geometric mean Tmax of about 6.6 hours and a
coefficient of
variation ("CV") of about 48%;
CA 02649893 2009-01-15
(b) a Day 21 Cmax of from about 0.07 to about 0.6 ng/ml and preferably a
mean Cmax of about 0.3 ng/ml with a standard deviation of about 0.16, a median
Cmax of
about 0.35 and a geometric mean Cmax of about 0.27 ng/ml and a coefficient of
variation
of about 49%;
(c) a Day 21 T1/2 of from about 9.7 to about 84 hours and preferably a mean
T1/2 of about 29.3 hours with a standard deviation of about 17, a median TI/2
of about
25.6 hours and a geometric mean T1/2 of about 26 hours and a coefficient of
variation of
about 58%;
(d) a Day 21 AUCO-24 of from about 1.1 to about 12 ng-hr/ml and preferably a
mean AUCO-24 of about 6 ng-hr/ml with a standard deviation of about 3, a
median AUCo_
24 of about 7 ng,hr/ml and a geometric mean AUCO-24 of about 5 ng-hr/ml and a
coefficient of variation of about 52%;
(e) a Day 21 Az of from about 0.008 W to about 0.07 hr' and preferably a
mean Az of about 0.03 hr' with a standard deviation of about 0.01, a median Az
of about
25.6 hr' and a geometric mean Az of about 0.03 hr' and a coefficient of
variation of
about 49%;
(f) a Day 21 Cmin of from about 0.06 to about 0.4 and preferably a mean Cmin
of about 0.20 with an SD of about 0.11, a median C,õ;n of about 0.19 and a
geometric
mean Cmin of about 0.17 and a coefficient of variation of about 55%;
(g) at Day 14/7 (a ratio of the trough concentration at Day 14 over the trough
concentration at Day 7), a trough concentration geometric mean ratio of about
1.09 with
a 90% confidence interval ("Cl") within a range of between about 0.8 and about
1.5;
(h) at Day 21/14 (a ratio of the trough concentration at Day 21 over the
trough
concentration at Day 14), a trough concentration geometric mean ratio of about
1.33
with a 90% confidence interval ("CI") within a range of between about 0.9 and
about 1.9;
16
CA 02649893 2009-01-15
(i) at Day 22/21 (a ratio of the trough concentration at Day 22 over the
trough
concentration at Day 21) a trough concentration geometric mean ratio of about
0.93 with
a 90% confidence interval ("CI") within a range of between about 0.6 and about
1.3;
(j) a mean peak imiquimod serum concentration of about 0.323 ng/ml at Day
21;
(k) a Day 21 RAUC of from about 1 to about 7 and preferably a mean RAUC
of about 4 with a standard deviation of about 2, a median RAUC of about 3.5
and a
geometric mean RAUC of about 3.3 and a coefficient of variation of about 56%;
(I) a Day 21 RCmax of from about 0.5 to about 5 and preferably a mean RCmax
of about 3 with a standard deviation of about 1.5, a median RCmax of about 2.7
and a
geometric mean RCmax of about 2.4 and a coefficient of variation of about 54%;
(m) a Day 21 LAzeff of from about 0.006 hr' to about 0.08 hr' and preferably a
mean L,\zeff of about 0.02 hr' with a standard deviation of about 0.02, a
median LAzeff
of about 0.01 hr l and a geometric mean L/\zeff of about 0.16 hr l and a
coefficient of
variation of about 97%; and
(n) a Day 21 T'~2eff of from about 8 hr to about 110 hr and preferably a mean
T'zeff of about 55 hr with a standard deviation of about 36, a median T'2eff
of about 50 hr
and a geometric mean T'2eff of about 42 hr' and a coefficient of variation of
about 66%.
[0035] In accordance with the present invention, a mean peak serum
concentration is
achieved with a 3.75% lower dosage strength imiquimod formulation of Examples
23-
28. More specifically, a mean peak serum concentration of about 0.323 ng/ml is
achieved with a 3.75% lower dosage strength imiquimod formulation of Examples
23-
28 after about 18.75 mg of imiquimod is applied to a treatment area of about
200 cm2
on the face or balding scalp each day for 21 days.
17
CA 02649893 2009-01-15
[0036] In addition, the present invention contemplates lower dosage strength
formulations that are pharmaceutically equivalent, therapeutically equivalent,
bioequivalent and/or interchangeable, regardless of the method selected to
demonstrate
equivalents or bioequivalence, such as dermatopharmacokinetic and
pharmacokinetic
methodologies, microdialysis, in vitro and in vivo methods and/or clinical
endpoints.
Thus, the present invention contemplates lower dosage strength imiquimod
formulations
that are bioequivalent, pharmaceutically equivalent and/or therapeutic
equivalent,
especially, 2.5% and 3.75% lower dosage strength imiquimod formulations that
are
bioequivalent, pharmaceutically equivalent and/or therapeutically equivalent,
when
used daily in accordance with the short durations of therapy of the present
invention to
treat actinic keratosis, e.g., used on treatment areas, namely, full face or
balding scalp,
that are between greater than about 25 cm2 and about 250 cm2 on a daily basis
for up to
about six weeks, including the 3 x 3 x 3 weeks 2-cycle treatment regimen, and
preferably up to about 4 weeks, including the 2 x 2 x 2 weeks 2-cycle
treatment
regimen.
[0037] Thus, the present invention contemplates: (a) pharmaceutically
equivalent
lower dosage strength imiquimod formulations which contain the same amount of
imiquimod in the same dosage form; (b) bioequivalent lower dosage strength
imiquimod
formulations which are chemically equivalent and which, when administered to
the same
individuals in the same dosage regimens, result in comparable
bioavailabilities; (c)
therapeutic equivalent lower dosage strength imiquimod formulations which,
when
administered to the same individuals in the same dosage regimens, provide
essentially
the same efficacy and/or toxicity; and (d) interchangeable lower dosage
strength
imiquimod formulations of the present invention which are pharmaceutically
equivalent,
bioequivalent and therapeutically equivalent.
[0038] By the term "lower dosage strength(s)", as used herein, it refers to a
pharmaceutical formulation containing imiquimod in an amount of between about
1.0
percent and about 4.25 percent by weight based on the total weight of the
formulation
18
CA 02649893 2009-01-15
and preferably a pharmaceutical formulation containing imiquimod in an amount
of
about 2.5% or about 3.75%.
[0039] By the term "short duration(s)" of therapy, as used herein, it refers
to the daily
topical application of an effective amount of imiquimod to a defined treatment
area
diagnosed with AK lesions for a total on-treatment period of up to about 6
weeks,
depending upon which lower dosage strength imiquimod formulation of the
present
invention is selected for daily application, and more preferably a total on-
treatment
period of up to about 4 weeks, wherein an optional defined intervening rest
period (no
treatment) of up to about 3 weeks, and more preferably a rest period (no
treatment) of
up to about 2 weeks, may be taken at some point during the treatment period,
to treat
actinic keratosis. Thereby, the "short durations of therapy" may include, by
way of
example, a total duration of 9 weeks (3 weeks on, 3 weeks off, 3 weeks on),
and more
preferably 6 weeks (2 weeks on, 2 weeks off, 2 weeks on) from beginning of
dosing to
the end of dosing, inclusive of the rest period. Nevertheless, it should be
understood
by those versed in this art that the 2-cycle treatment regimens with a rest
period
sandwiched in between are preferred. In addition, the "short durations" of
therapy may
also include an 8 week examination period (no further treatment) following the
treatment period.
[0040] The term "short duration(s)" of therapy of the present invention also
refers to
a two-cycle treatment regimen that involves either a 4-week or 6-week
treatment
regimen, wherein each treatment cycle consists of two or three weeks of once-
daily
applications of an effective amount of imiquimod, for each day of the cycle,
separated
by a 2-week or 3-week no-treatment period, respectively, such as follows:
(a) applying an effective amount of imiquimod to a treatment area affected
with actinic keratosis once per day for fourteen (14) consecutive days or 2
weeks
(cycle 1 - treatment on), followed by no application for fourteen (14) days or
2 weeks
(treatment off), followed by again applying an effective amount of imiquimod
to the
affected area once per day for fourteen (14) days or 2 weeks (cycle 2 -
treatment on)
19
CA 02649893 2009-01-15
for a total of twenty-eight (28) doses or 4 weeks of application therapy to
effectively
treat actinic keratosis; or
(b) applying an effective amount of imiquimod to a treatment area affected
with actinic keratosis once per day for twenty-one (21) consecutive days or 3
weeks
(cycle 1- treatment on), followed by no application for twenty-one (21) days
or 3
weeks (treatment off), followed by again applying an effective amount of
imiquimod
once per day to the affected area for twenty-one (21) days or 3 weeks (cycle 2
-
treatment on) for a total of forty-two (42) doses or 6 weeks of application
therapy to
effectively treat actinic keratosis.
[0041] As indicated above, when the short durations of therapy are used in
combination with the lower dosage strength imiquimod formulations of the
present
invention, it is surprisingly found that (1) simplified daily dosing regimens
can be used,
(2) the treatment area can be expanded, e.g., to treat greater than about 25
cm2, e.g.,
areas as large as approximately 200 cm2 - 250 cm2 or more (e.g., full face or
balding
scalp) may now be treated, and (3) the number of AK lesions to be treated is
higher,
e.g., to between about 5 and about 20 AK lesions or more per treatment area.
Also
quite surprisingly, it is found that the expanded treatment area and increased
number
of AK lesions can be effectively treated with lower dosage strength imiquimod
formulations without inducing significant local skin reactions or irritation
in the
treatment area or treatment limiting adverse events which could result in
premature
therapy termination or significant voluntary rest periods of several days that
are
generally associated with higher concentrations of imiquimod therapy. It is
also
surprisingly found that as much as between about 250 mg and 500 mg or more of
a
low dosage strength imiquimod formulation may be used per application in
accordance
with the present invention, especially when the short durations of therapy are
used in
combination with the low dosage strength imiquimod formulations of the present
invention.
CA 02649893 2009-01-15
[0042] In comparison, the Aldara 5% imiquimod cream approved by the FDA for
actinic keratosis concerns a treatment area defined as one contiguous area of
approximately 25 cm2 on the face (e.g., forehead or one cheek) or the scalp,
treating no
more than about 4 to about 8 AK lesions per treatment area, a dosing schedule
of only
twice per week for a full 16 weeks to the defined treatment area on the face
or scalp
(but not both concurrently) and the application of no more than 250 mg of
Aldara 5%
imiquimod cream formulation to the treatment area per application.
[0043] Also quite surprisingly, local skin reaction sum scores and mean local
skin
reaction erythema scores that are generated during the short durations of
therapy with
lower dosage strength imiquimod formulations in accordance with the present
invention
create unique bimodal or camelback patterns which parallel the 2-cycle
imiquimod
treatments of the present invention, wherein (1) the highest local skin
reaction sum
score and the mean local skin reaction erythema score generally and
characteristically
occur or peak during or at the end of the first cycle of treatment, (2) the
local skin
reaction sum score and the mean local skin reaction erythema score return to
normal or
baseline or about normal or baseline at the end of the no treatment period
between
cycles, (3) the local skin reaction sum score and the mean local skin reaction
erythema
score are again experienced by the subject during or at the end of the second
cycle of
treatment at generally but not necessarily a reduced score, as compared to the
local
skin reaction sum score and the mean local skin reaction erythema score during
the first
cycle of treatment, and (4) the local skin reaction sum score and the mean
local skin
reaction erythema score generally return to normal or base line shortly after
the second
cycle of treatment. See, e.g., FIGS. 18, 18A-B, 20, 20A-B and 43-50 and
Example 28.
When the bimodal or camelback pattern of local skin reaction sum score and
mean local
skin reaction erythema score are plotted as 2-dimensional graphs, wherein the
local
skin reaction sum score and the mean local skin reaction erythema score are
measured
on the vertical axis and the subject visits during the imiquimod 2-cycle
therapy are
measured on the horizontal axis, the unique bimodal or camelback patterns are
observed. See, e.g., FIGS. 18, 18A-B, 20, and 20A-B. Given this unexpected
result
that the local skin reaction sum score and the mean local skin reaction
erythema score
21
CA 02649893 2009-01-15
are generally decreasing overall during the course of therapy and return to
about normal
or baseline at the end of the two-week no treatment period between the two
treatment
cycles and again return to normal or baseline at about the end of the second
cycle of
treatment, imiquimod therapy compliance should be significantly improved and
the
therapeutic results, e.g., complete clearance or partial clearance or
reduction of AK
lesions, more consistently achieved.
[0044] Also quite surprisingly, the efficacy achieved by the lower dosage
strength
imiquimod formulations when used in either of the short durations of therapy,
e.g., two-
week or three-week 2-cycle treatment regimens, of the present invention for
treatment
of actinic keratosis as to total clearance, partial clearance and a reduction
in the number
of AK lesions is statistically significant over placebo. See, e.g., FIG. 51.
It is also
surprising that the efficacy achieved for treatment of actinic keratosis as to
complete
clearance or partial clearance of AK lesions is basically statistically
equivalent between
the lower dosage strength imiquimod formulations two-week or three-week 2-
cycle
treatment regimens of the present invention when the same lower dosage
strength
imiquimod formulations are used in accordance with either 2-cycle treatment
regimen
and compared with one another between the two 2-cycle treatment regimens. See
,
e.g., FIG. 51. Even more surprising, however, the efficacy achieved by a lower
dosage
strength 3.75% imiquimod formulation when used in either a two-week or three-
week 2-
cycle treatment regimen of the present invention for treatment of actinic
keratosis as for
partial clearance of AK lesions is statistically significant over a lower
dosage strength
2.5% imiquimod formulation when used in either a two-week or three-week 2-
cycle
treatment regimen. See, e.g., FIG. 51. Nevertheless, it should be noted that
the
efficacies that are achieved for complete clearance and partial clearance for
either lower
dosage strength imiquimod formulation, i.e., 2.5% or 3.75%, when they are used
in
either a two-week or three-week 2-cycle treatment regimen in accordance with
the
present invention are at about a 95% confidence level and a P value of less
than about
.001 versus placebo. See FIG. 51. It should also be noted that the efficacy P
value that
is achieved for partial clearance for a 3.75% lower dosage strength imiquimod
formulation versus a 2.5% lower dosage strength imiquimod formulation that is
utilized
22
CA 02649893 2009-01-15
in accordance with a two-week or three-week 2-cycle treatment regimen of the
present
invention is about 0.047 or about 0.034, respectively. See, e.g., FIG. 51.
[0045] It is also quite surprising that the efficacy achieved by a lower
dosage strength
3.75% imiquimod formulation when used in a two-week 2-cycle treatment regimen
of
the present invention for treatment of actinic keratosis as to a reduction in
the number of
AK lesions is statistically significant over a lower dosage strength 2.5%
imiquimod
formulation when used in a two-week 2-cycle treatment regimen, but no
difference or
essentially equivalent when both lower dosage strength imiquimod formulations
are
used in a three-week 2-cycle treatment regimen, in accordance with the present
invention. See, e.g., FIG. 51. It should be noted that the efficacy P value
that is
achieved for a percent reduction in the number of AK lesions for a 3.75% lower
dosage
strength imiquimod formulation versus a 2:5% lower dosage strength imiquimod
formulation that is utilized in accordance with a two-week or three-week 2-
cycle
treatment regimen of the present invention is about 0.048 or about 0.133,
respectively.
However, the 0.133 P value is not statistically significant. See, e.g., FIG.
51.
[0046] It is also quite surprisingly found that it is believed that no
statistical
significance in efficacy is achieved between a three-week 2-cycle treatment
regimen
versus a two-week 2-cycle treatment regimen regardless of the lower dosage
strength
imiquimod formulation used to treat actinic keratosis. See, e.g., FIG. 52. In
other
words, there is believed to be no additional efficacy benefit with the longer
3 week 2-
cycle treatment regimen than the two week 2-cycle treatment regimen of the
present
invention to treat actinic keratosis, irrespective of which lower dosage
strength
imiquimod formulation is used in either of the 2-cycle treatment regimens in
accordance
with the present invention. See, e.g., FIGS. 52, 1-13G, 25-27, 36-38A and 42.
It
should be noted that the P values that are achieved for (a) complete
clearance, (b)
partial clearance and (c) a reduction in the number of lesions, for the two-
week 2-cycle
treatment regimens and the three-week 2-cycle treatment regimens of the
present
invention are (a) about 0.462 General Linear Model ("GLM") and about 0.499
(LA), (b)
23
CA 02649893 2009-01-15
about 0.233 (GLM) and about 0.164 (LA), and (c) about 0.635 (GLM),
respectively.
See, e.g., FIG. 52.
[0047] While it is believed that there is no greater efficacy achieved between
the two
2-cycle treatment regimens of the present invention, it is found that there is
generally a
greater incidence of side effects, e.g., local skin reactions, and rest
periods associated
with the three-week 2-cycle treatment period as compared with the two-week 2-
cycle
treatment period when the same lower dosage strength imiquimod formulation is
used
in each of the 2-cycle treatment regimens in accordance with the present
invention.
Even though there is an increase in incidence of side effects and rest periods
associated with the three week 2-cycle treatment regimen, it is believed that
an
acceptable safety profile is still maintained when using either the two-week
or three-
week 2-cycle treatment regimens in accordance with the present invention. See,
e.g.,
FIGS. 14A-23, 28, 28A-B and 39-42. Nonetheless, it is quite surprisingly found
that
there is a lower subject incidence of application site reactions associated
with either of
the 2-cycle treatment periods of the present invention than associated with
use of the
Aldara 5% imiquimod cream to treat actinic keratosis in accordance with the
FDA-
approved treatment regimen, even though the Aldara 5% imiquimod cream is
applied
only twice weekly to a treatment area of approximately 25 cm2 for 16 weeks.
See, e.g.,
FIGS. 28, 28A-B, 41 and 41A. Thus, it should be understood by those versed in
this
art that, while both 2-cycle treatment regimens of the present invention
provide
efficacious dosing regimens with acceptable safety profiles, that are short
and more
convenient for patient use than the dosing regimen currently approved by the
FDA for
Aldara 5% imiquimod cream, to treat actinic keratosis, the 2 week 2-cycle
treatment
regimen of the present invention is preferred. It should also be understood
that the
short durations of therapy and lower dosage strength imiquimod formulations of
the
present invention are believed to be optimized to treat actinic keratosis. By
"optimized",
it is meant herein that the short durations of therapy and lower dosage
strength
imiquimod formulations of the present invention are designed to achieve
efficacy,
stability and release rates profiles that are at least essentially equivalent
to and linear
24
CA 02649893 2009-01-15
with Aldara 5% imiquimod cream, respectively, but with an improved acceptable
safety
profile.
[0048] By the term "acceptable safety profile", it is meant herein to mean
that
treatment of actinic keratosis with a short duration of therapy and a lower
dosage
strength imiquimod formulation in accordance with the present invention,
including the
2-cycle treatment regimens, does not cause treatment limiting side effects or
rest
periods in an appreciable number of subjects undergoing actinic keratosis
therapy to a
level that causes premature termination of treatment. The term "acceptable
safety
profile" also refers to treatment of actinic keratosis with a short duration
of therapy and a
lower dosage strength imiquimod formulation of the present invention with a
lower
subject incidence of application site reactions as compared with treatment of
actinic
keratosis with Aldara 5% imiquimod cream.
[0049] Also quite surprisingly, it is found that, when a lower dosage strength
imiquimod formulation, i.e.., about 2.5%, is used in a 2-cycle, 2 x 2 x 2
weeks, treatment
regimen in accordance with the present invention, to treat actinic keratosis
diagnosed in
females, a clearance rate, inclusive of complete clearance and partial
clearance, of
about 60% is achieved. See FIG. 31. Equally su-rprising, it is found that when
a low
dosage strength imiquimod formulation, i.e., about 3.75%, is used in either a
2-cycle, 2
x 2 x 2 week or a 2-cycle, 3 x 3 x 3 weeks, treatment regimen in accordance
with the
present invention, to treat actinic keratosis diagnosed in male or female
subjects or in
subjects with Type I, II or I II skin, about 10 lesions or less at baseline,
or with lesions on
the face or scalp, equivalent or comparable clearance rates, inclusive of
complete
clearance and partial clearance, are achieved. See, e.g., FIGS. 31, 33, 33A,
34, 34A,
35 and 35A-B. Also surprising, it is found that when a low dosage strength
imiquimod
formulation, i.e., about 3.75%, is used in either a 2-cycle, 2 x 2 x 2 week or
a 2-cycle, 3
x 3 x 3 week, treatment regimen in accordance with the present invention, to
treat
actinic keratosis diagnosed in subjects who are 65 years of age or older or in
subjects
who have greater than 10 lesions at baseline, the 2-cycle, 2 x 2 x 2 week
treatment
regimen is more effective. See, e.g., FIGS. 32, 32A, 34 and 34A.
CA 02649893 2009-01-15
[0050] It is also surprisingly found that, when a lower dosage strength
imiquimod
formulation is used in connection with a short duration of therapy, e.g.,
either a two-
week or three-week 2-cycle treatment regimen, of the present invention for
treatment of
actinic keratosis, the Investigators Global Integrated Photodamage ("IGIP")
score is
significantly or much improved as compared with baseline. See, e.g., FIGS. 24
and 53.
For example, and as shown in FIG. 53, when the 3.75% imiquimod studies are
combined, approximately 44% (132 of 299) of the subjects under going treatment
show
significant improvement, approximately 25% (76 of 299) of the subjects under
going
treatment show much improvement and approximately 17% (51 of 299) of the
subjects
under going treatment show slight improvement in the IGIP score from baseline,
whereas when the 2.5% imiquimod studies are combined, approximately 32% (97 of
304) of the subjects under going treatment show significant improvement,
approximately
26% (78 of 304) of the subjects under going treatment show much improvement
and
approximately 23% (69 of 304) of the subjects under going treatment show
slight
improvement in the IGIP score from baseline.
[0051] The salient elements of a pharmaceutical formulation according to the
present invention are (a) imiquimod and (b) a fatty acid, e.g., isostearic,
palmitic,
stearic, linoleic, unrefined oleic acid or refined oleic acid, such as Super
Refined oleic
acid NF (e.g., a highly purified oleic acid, i.e., an oleic acid which has low
polar impurities,
such as peroxides, a low peroxide value and is marketed by CRODA; see e.g.,
www.crodausa.com) and mixtures thereof. A pharmaceutical formulation of the
invention
can be in any form known to the art, such as a cream, an ointment, a foam, a
gel, a
lotion or a pressure-sensitive adhesive composition, each form containing the
necessary
elements in particular amounts and further containing various additional
elements.
[0052] A cream of the invention contains an effective amount of imiquimod,
such as
between about greater than 1 percent and about 4.25 percent by weight of
imiquimod,
based on the total weight of the cream; about 5 percent to about 30 percent by
weight of
26
CA 02649893 2009-01-15
fatty acid, based on the total weight of the cream; and optional ingredients
such as
emollients, emulsifiers, thickeners, and/or preservatives.
[0053] An ointment of the invention contains an ointment base in addition to
imiquimod and fatty acid. An ointment of the invention contains an effective
amount of
imiquimod, such as between about greater than 1 percent and about 4.25 percent
by
weight of imiquimod; about 3 percent to about 45 percent, more preferably
about 3
percent to about 30 percent by weight fatty acid; and about 40 percent to
about 95 percent
by weight ointment base, all weights being based on the total weight of the
ointment.
Optionally, an ointment of the invention can also contain emulsifiers,
emollients and
thickeners.
[0054] A pressure-sensitive adhesive composition of the invention contains
imiquimod,
fatty acid, and an adhesive. The adhesives utilized in a pressure sensitive
adhesive
composition of the invention are preferably substantially chemically inert to
imiquimod. A
pressure sensitive adhesive composition of the invention preferably contains
an effective
amount of imiquimod, such as between about greater than 1 percent and about
4.25
percent by weight of imiquimod; about 10 percent to about 40 percent by
weight, more
preferably of about 15 percent to about 30 percent by weight, and most
preferably about
20 percent to about 30 percent by weight of fatty acid; all weights being
based on the
total weight of the pressure sensitive adhesive composition.
[0055] Optionally, pressure sensitive adhesive compositions of the invention
can also
contain one or more skin penetration enhancers. The total amount of skin
penetration
enhancer(s) present in a pressure sensitive adhesive composition of the
invention is
preferably about 3 percent to about 25 percent by weight, and more preferably
about 3
percent to about 10 percent by weight based on the total weight of the
pressure sensitive
adhesive composition.
27
CA 02649893 2009-01-15
[0056] A pressure-sensitive adhesive coated sheet material of the invention
can be
made from a pressure-sensitive adhesive composition of the invention in the
form of an
article such as a tape, a patch, a sheet, or a dressing.
[0057] A lower dosage strength formulation of the present invention may be
used to
topically and/or transdermally administer an effective amount of imiquimod to
effectively
treat actinic keratosis with short durations of therapy and with an acceptable
safety
profile. Thus, lower dosage strength formulations according to the present
invention can
be applied to any suitable location, for example, topically to dermal, lip
and/or mucosal
surfaces. In the case of dermal application, for example, depending on the
concentration,
formulation composition, and dermal surface, the therapeutic effect of
imiquimod may
extend only to the superficial layers of the dermal surface or to tissues
below the dermal
surface.
[0058] It should be understood that while lower dosage strength formulations
of the
present invention containing, by weight based on the total weight of the
formulation,
between about 1% and about 4.25% imiquimod are contemplated, preferably
between
about 1.5%, 1.75%, 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0%
and
4.25%, and even more preferably between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%,
3.25%, 3.5%, 3.75% and 4.0%, and still even more preferably between about
2.5%,
2.75%, 3.0%, 3.25%, 3.5% and 3.75% are contemplated. Lower dosage strength
formulations of the present invention that contain about 2.5% imiquimod or
about 3.75%
imiquimod by weight based on the total weight of the formulation are most
preferred. It
should also be understood that lower dosage strength imiquimod formulations of
the
present invention, which have dose proportionate release rates as to both the
release
rates of the imiquimod and the total amount of imiquimod released, relative to
the Aldara
5% imiquimod cream, are also preferred.
[0059] Thus, it should be understood by those versed in this art that an
amount of
imiquimod present in a formulation of the present invention will be an
effective amount
when a formulation of the present invention is applied daily in accordance
with a short
28
CA 02649893 2009-01-15
duration of therapy as described herein to a targeted area diagnosed with
actinic
keratosis and permitted following each individual application to remain in
contact with
the targeted area for a sufficient time to allow an effective amount of
imiquimod to
clear such a disease or lesions of the disease, to partially clear the number
of lesions
of such a disease, to reduce the number of lesions, to prevent the recurrence
of such
a disease without inducing treatment limiting local skin reactions or adverse
events,
including unscheduled rest periods caused by such treatment limiting local
skin
reactions or adverse events, in an appreciable number of people undergoing
treatment. For example, when treating actinic keratosis in accordance with the
present invention, an effective amount will achieve a partial clearance in AK
lesions as
a targeted endpoint, e.g., at least about 40% and preferably at least about
50% and
more preferably at least about 60% and still more preferably at least about
70% and
most preferably at least about a 75% reduction in the number of AK lesions in
the
treatment area compared with baseline, or at least about 60% and preferably at
least
about 70% and even more preferably at least about 80% and most preferably at
least
about 90% median reduction in the number of AK lesions in the treatment area
compared with baseline as a secondary endpoint, or at least about 25% complete
clearance and preferably at least about 30% complete clearance and even more
preferably at least about 35% complete clearance and most preferably at least
about
45% complete clearance of the AK lesions as a primary endpoint. See, e.g.,
FIGS. 36,
36A, 37, 37A, 38, 38A, 51 and 52. By "complete clearance", as used herein, the
term
means the absence of clinically visible or palpable AK lesions in the
treatment area.
[0060] Results from use of the lower dosage strength imiquimod formulations in
accordance with the short durations of therapy of the present invention
demonstrate
that lower dosage strength imiquimod formulations dosed once daily for two
week or
three week 2 cycle treatment periods are effective and well-tolerated
treatments for
actinic keratosis on the face or balding scalp. The condensed dosing regimens
of the
present invention allows for short treatment periods, minimizing exposure to
imiquimod
and further supporting an improved benefit-risk profile, as compared with FDA-
approved Aldara 5% imiquimod cream 16 week, twice-weekly therapy.
29
CA 02649893 2009-01-15
[0061] Benefits of treatment with the lower dosage strength imiquimod
formulations
in accordance with the short durations of therapy of the present invention
include
complete clearance or partial clearance (_ 66%, preferably _ 75%, even more
preferably >88% and even more preferably _95%) of AK lesions for a majority of
the
subjects that are treated. See Example 24 and FIGS. 51 and 52. More
particularly,
complete or partial clearances of AK lesions are achieved as follows: (1) _35%
(57 of
160 subjects) complete clearance is achieved for a 2-week 2 cycle treatment
using a
3.75% lower dosage strength imiquimod formulation of the present invention;
(2)
>30% (49 of 160 subjects) complete clearance is achieved for a 2-week 2 cycle
treatment using a 2.5% lower dosage strength imiquimod formulation of the
present
invention; (3) >_34% (55 of 162 subjects) complete clearance is achieved for a
3-week
2 cycle treatment using a 3.75% lower dosage strength imiquimod formulation of
the
present invention; and (4) _25% (41 of 164 subjects) complete clearance is
achieved
for a 2-week 2 cycle treatment using a 2.5% lower dosage strength imiquimod
formulation of the present invention; whereas (5) >_59% (95 of 160 subjects)
partial
clearance is achieved for a 2-week 2 cycle treatment using a 3.75% lower
dosage
strength imiquimod formulation of the present invention; (6) _48% (77 of 160
subjects)
partial clearance is achieved for a 2-week 2 cycle treatment using a 2.5%
lower
dosage strength imiquimod formulation of the present invention; (7) _53% (87
of 162
subjects) partial clearance is achieved for a 3-week 2 cycle treatment using a
3.75%
lower dosage strength imiquimod formulation of the present invention; and (8)
_42%
(70 of 164 subjects) partial clearance is achieved for a 2-week 2 cycle
treatment using
a 2.5% lower dosage strength imiquimod formulation of the present invention.
Although subjects who are treated with the lower dosage strength imiquimod
formulations in accordance with the short durations of therapy of the present
invention
may experience local skin reactions (LSRs), see, e.g., FIGS. 16A-20, 20A-B and
29
and 40, the treatment is well tolerated and there is a marked lower subject
incidence
of application site reactions, e.g., see FIGS. 14A-E, 28, 28A-B, 41 and 41A,
as
compared with the longer FDA-approved Aldara 5% imiquimod cream treatment
regimen, i.e., 16 weeks, twice weekly, for AK therapy.
CA 02649893 2009-01-15
[0062] This same larger "treatment area" of the present invention may be
defined as
an area of greater than 25 cm2 (e.g., a treatment area greater than a 5 cm x 5
cm area
in any shape) and up to between about 200 cm2 and 250 cm2 or more on the face
(e.g.
forehead or one cheek) or on the balding scalp, including the full face or
entire balding
scalp. The number of AK lesions to be treated in the treatment area may range
from
about 5 to about 20 or more. It should be also appreciated by those versed in
this art
that the present invention also affords the added benefit of the uncovering
and clinical
appearance and subsequent complete or partial eradication of incipient
(subclinical)
AK lesions in the treatment area. It is presently believed that, because the
treatment
area exceeds 25 cm2, the lower dose strength imiquimod formulations and the
short
durations of therapy, when practiced in accordance with the present invention,
will
increase subject tolerance and compliance, irriprove the therapeutic results,
e.g.,
complete clearance or partial clearance or reduction of AK lesions, lower
subject
incidence of application site reactions (see, e.g., FIGS. 28, 28A-B, 41 and
41A), and
reduce voluntary rest periods (see, e.g., FIGS. 39 and 39A) during therapy, as
compared to Aldara 5% imiquimod cream if applied to the same larger treatment
area
in accordance with the present invention. Moreover, it is believed that,
because the
expanded treatment area is so much larger than the smaller treatment area,
i.e., less
than or equal to approximately 25 cm2, currently treated with Aldara 5%
imiquimod
cream, the expanded treatment area of the present invention will be much more
weighted to non-lesional/normal skin than previously experienced with the
smaller
treatment area treated with Aldara 5% imiquimod cream. Preferably, the
concentration of imiquimod applied is between about 1 percent to about 4.25
percent
by weight based on the total weight of a formulation of the present invention.
Also, to
treat actinic keratosis in accordance with the present invention, an effective
amount of
imiquimod should be applied once per day for at least up to about 6 weeks,
e.g., once
per day for a full 2 or 3 weeks (14 or 21 days) to a diagnosed or defined
treatment
area on, for example, the face or balding scalp (cycle 1), then stopped or
discontinued
for 2 or 3 weeks (14 or 21 days), a scheduled rest period, followed by
application
again once per day for a full 2 or 3 weeks (14 or 21 days) to the defined
treatment
31
CA 02649893 2009-01-15
area (cycle 2) to achieve a secondary and more preferably a primary endpoint,
e.g., to
achieve at least about a 75% reduction in AK lesions as a targeted secondary
endpoint and more preferably complete clearance of the AK lesions as a primary
endpoint. Also when treating actinic keratosis in accordance with the two-week
or
three week 2-cycle treatment periods of the present invention, an effective
amount of
imiquimod applied to the treatment area will not only achieve a secondary or
primary
endpoint, but will also induce a lower subject incidence of application site
skin
reactions and a fewer number of voluntary rest periods taken by the subjects
under
going treatment, e.g., no more than about 11 % and more preferably no more
than
about 7% of the subjects will take one or more rest periods during the short
two-week
2-cycle treatment period or no more than about 17% and more preferably no more
than about 27% of subjects will take one or more rest periods during the short
three-
week 2-cycle treatment period. See, e.g., FIGS. 21, 39 and 39A.
[0063] While the present invention has identified what it believes to be
preferred
concentrations of imiquimod formulations, numbers of applications per week and
durations of therapy, it should be understood by those versed in this art that
any effective
concentration of imiquimod in a formulation that delivers an effective amount
of
imiquimod and any -numbers of application per week during a short duration of
therapy, as described herein, that can effectively treat actinic keratosis,
without causing
treatment limiting local skin reactions or related adverse events, including
too many rest
periods, is contemplated by the present invention.
[0064] The above summary of the present invention is not intended to describe
each
disclosed embodiment or every implementation of the present invention. The
description
that follows more particularly exemplifies illustrative embodiments. In
several places
throughout the application, guidance is provided through lists of examples,
which
examples can be used in various combinations. In each instance, the recited
list serves
only as a representative group and should not be interpreted as an exclusive
list.
32
CA 02649893 2009-01-15
BRIEF DESCRIPTION OF THE DRAWINGS
[0065] The foregoing and other objects, advantages and features of the present
invention, and the manner in which the same are accomplished, will become more
readily apparent upon consideration of the following detailed description of
the invention
taken in conjunction with the accompanying figure and examples, which
illustrate an
embodiment, wherein:
[0066] FIG. 1 shows efficacy measures of complete clearance rates by study for
studies GW01-0702, GW01-0703, GW01-0704 and GW01-0705 for the 2-cycle 2 x 2 x
2
(2 weeks) treatment regimen and for the 2-cycle 3 x 3 x 3 (3 weeks) treatment
regimen;
[0067] FIG. 1A is a summary of primary and secondary efficacy endpoints for a
two-
week treatment cycle regimen concerning ITT population for studies GW01-0702
and
GW01-0704. Complete clearance is defined as the absence of clinically visible
or
palpable AK lesions in the treatment area. Partial clearance is defined as at
least a
75% reduction in the number of AK lesions in the treatment area compared with
Baseline. P values are from Cochran-Mantel-Haenszel test, stratified by
analysis site,
taking 2 treatment groups at a time. The P values marked with ** are
statistically
significant using Hochberg's modified Bonferroni procedure. LOCF=Last
observation
that is carried forward. Confidence intervals are calculated using exact
binomial
statistics. As used in this FIG. 1A, "2.5%" refers to a 2.5% imiquimod lower
dosage
strength formulation of Examples 23-28 and "3.75%" refers to a 3.75% imiquimod
lower dosage strength formulation of Examples 23-28;
[0068] FIG. 2 shows efficacy measures of complete clearance, by time point,
for
studies GW01-0702 and GW01-0704 for the 2-cycle 2 x 2 x 2 (2 weeks) treatment
regimen. As used in this FIG. 2, "Complete Clearance" refers to the rate of
complete
clearance of AK lesions, "Cyc 2 Start" refers to the start of the second
cycle, "4 Weeks
Post" refers to 4 weeks post treatment, and "EOS" refers to End of Study;
33
CA 02649893 2009-01-15
[0069] FIG. 2A shows a rate of complete clearance vs. study week an ITT
population
for study GW01-0702. Points that are marked with ** shows statistically
difference from
placebo. As used in this FIG. 2A, "Rate of Complete Clearance" refers to rate
of
complete AK lesion clearance, "A" refers to a 2.5% imiquimod lower dosage
strength
formulation of Examples 23-28, "B" refers to a 3.75% imiquimod lower dosage
strength
formulation of Examples 23-28, and "C" refers to placebo;
[0070] FIG. 2B shows a rate of complete clearance vs. study week of an ITT
population for study GW01-0704. Points that are marked with ** shows
statistically
difference from placebo. Points marked with ## show statistically significant
difference
between active treatments. As used in this FIG. 2B, "Rate of Complete
Clearance"
refers to rate of complete AK lesion clearance, "A" refers to a 2.5% imiquimod
lower
dosage strength formulation of Examples 23-28, "B" refers to a 3.75% imiquimod
lower
dosage strength formulation of Examples 23-28, and "C" refers to placebo;
[0071] FIG. 3 shows efficacy measures of complete clearance, by time point,
for
studies GW01-0703 and GW01-0705 for the 2-cycle 3 x 3 x 3 (3 weeks) treatment
regimen. As used in this FIG. 3, "Complete Clearance" refers to complete
clearance of
AK lesions, "Cyc 2 Start" refers to the start of the second cycle, "4 Weeks
Post" refers to
4 weeks post treatment, and "EOS" refers to End of Study See also FIGS. 2A and
2B;
[0072] FIG. 3A shows a rate of complete clearance vs. study week of an ITT
population for study GW01-0703. Points that are marked with ** shows
statistically
difference from placebo. Points marked with ## show statistically significant
difference
between active treatments. As used in this FIG. 3A, "Rate of Complete
Clearance"
refers to rate of complete AK lesion clearance, "A" refers to a 2.5% imiquimod
lower
dosage strength formulation of Examples 23-28, "B" refers to a 3.75% imiquimod
lower
dosage strength formulation of Examples 23-28, and "C" refers to placebo;
34
CA 02649893 2009-01-15
[0073] FIG. 3B shows a rate of complete clearance vs. study week an of ITT
population for study GW01-0705. Points that are marked with ** shows
statistically
difference from placebo. Points marked with ## show statistically significant
difference
between active treatments. As used in this FIG. 3B, "Rate of Complete
Clearance"
refers to rate of complete AK lesion clearance, "A" refers to a 2.5% imiquimod
lower
dosage strength formulation of Examples 23-28, "B" refers to a 3.75% imiquimod
lower
dosage strength formulation of Examples 23-28, and "C" refers to placebo;
[0074] FIG. 4A shows rates of partial clearance at end of study of a two-week
treatment cycle regimen of an ITT population for studies GW01-0702 and GW01-
0704.
In this FIG. 4A, "Rate of Partial Clearance" refers to rate of partial AK
lesion clearance
(defined as at least about 75% reduction in the number of AK lesions in the
treatment
area as compared with Baseline), "L" refers to a 2.5% imiquimod lower dosage
strength
formulation of Examples 23-28, "H" refers to a 3.75% imiquimod lower dosage
strength
formulation of Examples 23-28, P=placebo, and that the bars marked with **
show
statistically significant difference from placebo, whereas the bars marked
with ## show
statistically significant difference from 2.5%. The vertical blue lines
indicate 95%
confidence limits;
[0075] FIG. 4B shows a rate of partial clearance at week 14 for an ITT
population for
study GW01-0702. Partial clearance is defined as at least a 75% reduction in
the
number of AK lesions in the treatment area compared with baseline. The bars
marked
with ** show statistically significant difference from placebo. Dark black
vertical lines
represent 95% confidence intervals on the rates. In this FIG. 4B, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
CA 02649893 2009-01-15
[0076] FIG. 4C shows a rate of partial clearance at week 14 for an ITT
population for
study GW01-0704. Partial clearance is defined as at least a 75% reduction in
the
number of AK lesions in the treatment area compared with baseline. The bars
marked
with ** show statistically significant difference from placebo. The bars
marked with ##
show statistically difference between active treatments. Dark black vertical
lines
represent 95% confidence intervals on the rates. In this FIG. 4C, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
[0077] FIG. 4D shows a rate of partial clearance at week 17 for an ITT
population for
study GW01-0703. Partial clearance is defined as at least a 75% reduction in
the
number of AK lesions in the treatment area compared with baseline. The bars
marked
with ** show statistically significant difference from placebo. Dark black
vertical lines
represent 95% confidence intervals on the rates. In this FIG. 4D, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
[0078] FIG. 4E shows a rate of partial clearance at week 17 for an ITT
population for
study GW01-0705. Partial clearance is defined as at least a 75% reduction in
the
number of AK lesions in the treatment area compared with baseline. The bars
marked
with ** show statistically significant difference from placebo. Dark black
vertical lines
represent 95% confidence intervals on the rates. In this FIG. 4E, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
36
CA 02649893 2009-01-15
28, and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
[0079] FIG. 4F shows a rate of partial clearance vs. study time point combined
studies
for an ITT population regarding the use of a 3.75% lower dosage strength
imiquimod
formulation of Examples 23-28. Note the following: L2=2.5% two-week treatment
cycle regimen, L3=2.5% three-week treatment cycle regimen, H2=3.75% two-week
treatment cycle regimen, H3=3.75% three-week treatment cycle regimen,
P2=placebo
two-week treatment cycle regimen, and P3=placebo three-week treatment cycle
regimen. In this FIG. 4F, "Rate of Partial Clearance" refers to rate of
partial AK lesion
clearance (defined as at least about 75% reduction in the number of AK lesions
in the
treatment area as compared with Baseline), "Start of Cycle 2" refers to the
start of the
second cycle, "4 Weeks Post" refers to 4 weeks post treatment, and "8 Weeks
Post"
refers to 8 weeks post treatment;
[0080] FIG. 5 shows efficacy measures of partial clearance, by time point, for
studies
GW01-0702 and GW01-0704. See also FIG. 37A. As used in this FIG. 5, "Partial
Clearance" refers to partial clearance of AK lesions (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"Cyc 2 Start" refers to the start of the second cycle, "4 Weeks Post" refers
to 4 weeks
post treatment, "EOS" refers to End of Study, and "2 x 2 x 2" refers to a two
week, 2-
cycle treatment, as through out the FIGS. and the specification;
[0081] FIG. 5A shows a rate of partial clearance vs. study week for an ITT
population
for study GW01-0702. The points marked with ** shows statistically difference
from
placebo. The points marked with ## shows statistically difference between
active
treatments. As used in this FIG. 5A, "Rate of Partial Clearance" refers to
rate of partial
AK lesion clearance (defined as at least about 75% reduction in the number of
AK
lesions in the treatment area as compared with Baseline), "A" refers to a 2.5%
imiquimod lower dosage strength formulation of Examples 23-28, "B" refers to a
3.75%
37
CA 02649893 2009-01-15
imiquimod lower dosage strength formulation of Examples 23-28, and "C" refers
to
placebo;
[0082] FIG. 5B shows a rate of partial clearance vs. study week for an ITT
population
for study GW01-0704. The points marked with ** shows statistically difference
from
placebo. The points marked with ## shows statistically difference between
active
treatments. As used in this FIG. 5B, "Rate of Partial Clearance" refers to
rate of AK
partial lesion clearance (defined as at least about 75% reduction in the
number of AK
lesions in the treatment area as compared with Baseline), "A" refers to a 2.5%
imiquimod lower dosage strength formulation of Examples 23-28, "B" refers to a
3.75%
imiquimod lower dosage strength formulation of Examples 23-28, and "C" refers
to
placebo;
[0083] FIG. 6 shows efficacy measures of partial clearance, by time point, for
studies
GW01-0703 and GW01-0705. As used in this FIG. 6, Partial Clearance" refers to
rate
percent of partial clearance of AK lesions (defined as at least about 75%
reduction in
the number of AK lesions in the treatment area as compared with Baseline),
"Cyc 2
Start" refers to the start of the second cycle, "4 Weeks Post" refers to 4
weeks post
treatment, and "EOS" refers to End of Study. See also FIG. 37A;
[0084] FIG. 6A shows a rate of partial clearance vs. study week for an ITT
population
for study GW01-0703. The points marked with ** shows statistically significant
difference from placebo. The points marked with ## shows statistically
significant
difference between active treatments. As used in this FIG. 6A, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"A" refers to a 2.5% imiquimod lower dosage strength formulation of Examples
23-28,
"B%" refers to a 3.75% imiquimod lower dosage strength formulation of Examples
23-
28, and "C" refers to placebo;
38
CA 02649893 2009-01-15
[0085] FIG. 6B shows a rate of partial clearance vs. study week for an ITT
population
for study GW01-0705. The points marked with ** shows statistically significant
difference from placebo. The points marked with ## shows statistically
significant
difference between active treatments. As used in this FIG. 6B, "Rate of
Partial
Clearance" refers to rate of partial AK lesion clearance (defined as at least
about 75%
reduction in the number of AK lesions in the treatment area as compared with
Baseline),
"A" refers to a 2.5% imiquimod lower dosage strength formulation of Examples
23-28,
"B" refers to a 3.75% imiquimod lower dosage strength formulation of Examples
23-28,
and "C" refers to placebo;
[0086] FIG. 7 shows efficacy measures of mean % change from baseline count, by
study, for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also
FIG. 9A;
[0087] FIG. 8 shows efficacy measures of mean% change from baseline count, by
time point, for studies GW01-0702 and GW01-0704. As used in this FIG. 8,"%
Count
Reduction" refers to the percent reduction in AK count from Baseline, "Cyc 2
Start"
refers to the start of the second cycle, "4 Weeks Post" refers to 4 weeks post
treatment,
and "EOS" refers to End of Study. See also FIG. 9A;
[0088] FIG. 8A shows a median percent change from baseline AK lesion count vs.
study week for an ITT population for study GW01-0702. The points marked with
**
shows statistically significant difference from placebo. The points marked
with ##
shows statistically significant difference between active treatments. As used
in this FIG.
8A, "Median Percent Change" refers to median percent change in AK lesion count
from
Baseline, "A" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-28, "B" refers to a 3.75% imiquimod lower dosage strength
formulation of
Examples 23-28, and "C" refers to placebo;
[0089] FIG. 8B shows a median percent change from baseline AK lesion count vs.
study week for an ITT population for study GW01-0704. The points marked with
**
39
CA 02649893 2009-01-15
shows statistically significant difference from placebo. The points marked
with ##
shows statistically significant difference between active treatments. As used
in this FIG.
8B, "Median Percent Change" refers to median percent change in AK lesion count
from
Baseline, "A" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-28, "B%" refers to a 3.75% imiquimod lower dosage strength
formulation
of Examples 23-28, and "C" refers to placebo;
[0090] FIG. 9 shows efficacy measures of mean % change from baseline count, by
time point, for studies GW01-0703 and GW01-0705. As used in this FIG. 9, "Mean
%
Change from Baseline Count" refers to the mean percent reduction in AK count,
"Cyc 2
Start" refers to the start of the second cycle, "4 Weeks Post" refers to 4
weeks post
treatment, and "EOS" refers to End of Study. See also FIGS. 8A and 8B;
[0091] FIG. 9A shows a summary of AK lesion Count for an ITT population
regarding
GW01-0703. As used in this FIG. 9A, "2.5%" refers to a 2.5% imiquimod lower
dosage
strength formulation of Examples 23-28 and "3.75%" refers to a 3.75% imiquimod
lower dosage strength formulation of Examples 23-28. The P values are from the
Cochran-Mantel-Haenszel test, that is stratified by analysis site, taking two
treatment
groups at a time. The P values marked with '"* are statistically significant
using
Hochberg's modified Bonferroni procedure. Lesion counts which are recorded as
`indeterminate' are excluded from analysis;
[0092] FIG. 9B shows a summary of AK lesion Count for an ITT population
regarding
GW01-0705. As used in this FIG. 9A, "2.5%" refers to a 2.5% imiquimod lower
dosage
strength formulation of Examples 23-28 and "3.75%" refers to a 3.75% imiquimod
lower dosage strength formulation of Examples 23-28. The P values are from the
Cochran-Mantel-Haenszel test, that is stratified by analysis site, taking two
treatment
groups at a time. The P values marked with ** are statistically significant
using
Hochberg's modified Bonferroni procedure. Lesion counts which are recorded as
'indeterminate' are excluded from analysis;
CA 02649893 2009-01-15
[0093] FIG. 10 shows efficacy measures of clearance rates, by subject sex, for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in this FIG.
10, "Rate of Clearance" refers to the rate of complete AK lesion clearance;
[0094] FIG. IOA shows a summary of primary and secondary efficacy endpoints
for
male and female subpopulations for combined two-week treatment cycle studies
GW01-
0702 and GW01-0704 for an ITT population using either a 2.5% or a 3.75% lower
dosage strength imiquimod formulation of Examples 23-28. The P values for
clearance rates are from a generalized linear module (GENMOD), assuming a
multinomial distribution (DIST=MULT) and a cumulative logit link function
(LINK=CLOGIT), including effects of dose, subpopulation, and interaction. The
P
values for percent change in AK lesion count are from the analysis of variance
(GLM)
including effects of dose, subpopulation, and interaction; -
[0095] FIG. 10B shows a summary of primary efficacy variable, rate of complete
clearance at week 17 (end of study) subgroup analysis n/N (%) for study GW01-
0703
using either a 2.5% or a 3.75% lower dosage strength imiquimod formulation of
Examples 23-28;
[0096] FIG. 10C shows a summary of primary efficacy variable, rate of complete
clearance at week 17 (end of study) subgroup analysis n/N (%) for study GW01-
0705
using either a 2.5% or a 3.75% lower dosage strength imiquimod formulation of
Examples 23-28;
[0097] FIG. 11 shows efficacy measures of clearance rates, by subject
treatment
area, for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in
this FIG. 11, "Rate of Clearance" refers to the rate of complete AK lesion
clearance;
[0098] FIG. 12 shows efficacy measures of median percent change from baseline
between 0 and -100 for studies GW01-0703, GW01-0702, GW01-0704 and GW01-
0705. As used in this FIG. 11, "Percent Change" refers to the median percent
by which
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CA 02649893 2009-01-15
there is a change in the number of AK lesions using either a 2.5% or a 3.75%
lower
dosage strength imiquimod formulation of Examples 23-28 in either a two, 2-
cycle or a
three week, 2-cycle treatment;
[0099] FIG. 12A shows a median percent change from baseline in number of AK
lesions vs. study timepoint for combined studies for an ITT population using
either a
2.5% or a 3.75% lower dosage strength imiquimod formulation of Examples 23-28.
Note the following: L2=2.5% two-week treatment cycle regimen, L3=2.5% three-
week
treatment cycle regimen, H2=3.75% two-week treatment cycle regimen, H3=3.75%
three-week treatment cycle regimen, P2=placebo two-week treatment cycle
regimen,
and P3=placebo three-week treatment cycle regimen. As used in this FIG 12A,
"Median
Percent Change" refers to the median percent change in number of AK lesions
from
baseline, "Start of Cycle 2" refers to the start of the second cycle, "4 Weeks
Post" refers
to 4 weeks post treatment, "8 Weeks Post" refers to 8 weeks post treatment,
and "P"
refers to placebo;
[0100] FIG. 13 shows efficacy measures of mean percent change from baseline
between 0 and -80 for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705
using either a 2.5% or a 175% lower dosage strength imiquimod formulation of
Examples 23-28. As used in this FIG 13, "Percent Change" refers to the mean
percent
change in number of AK lesions from baseline, "Cyc 2 Start" refers to the
start of the
second cycle, "4 Weeks Post" refers to 4 weeks post treatment, and "EOS"
refers to
End of Study (8 weeks post treatment);
[0101] FIGS. 13A-G show a summary of percent change from baseline in number of
AK lesions by visit for combined studies for an ITT population using either a
2.5% or a
3.75% lower dosage strength imiquimod formulation of Examples 23-28. The P
values
are from the Cochran-Mantel-Haenszel test, that is stratified by analysis
site, taking two
treatment groups at a time. The P values marked with ** are statistically
significant
using Hochberg's modified Bonferroni procedure;
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CA 02649893 2009-01-15
[0102] FIGS. 14A-E show a summary of treatment-emergent adverse events n(%) of
subjects in descending order of incidence in a 3.75% or 2.5% two-week or three-
week
treatment cycle group where the adverse events are considered treatment
related by
the investigator for combined studies for an ITT population using either a
2.5% or a
3.75% lower dosage strength imiquimod formulation of Examples 23-28. The
counts
reflect number of subjects in each treatment group reporting one or more
adverse
events that map to the MedDRA system organ class. A subject may be counted
only
once in each row of the table. Treatment-related includes Probably Related and
Related. A treatment-emergent AE is an AE with onset date on or after day 1 of
treatment;
[0103] FIG. 15 shows safety measures of incidence of treatment-related adverse
events for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in
this FIG. 15, "H" refers to a 3.75% lower dosage strength imiquimod
formulation of
Examples 23-28 and "L" refers to a 2.5% lower dosage strength imiquimod
formulation
of Examples 23-28, and "V" refers to vehicle. See also FIGS. 14A-14E;
[0104] FIGS. 16A-C show a summary of local skin reactions (LSR) for most
severe
reaction grade during study overall for combined studies for an ITT population
using a
2.5% or a 3.75% lower dosage strength imiquimod formulation in 2 week or 3
week two-
cycle therapies in accordance with the present invention. Because a subject in
the two-
week 3.75% treatment group, a subject in the three-week 2.5% treatment, a
subject in
the 3.75% treatment group and two subjects in the three-week placebo group do
not
have post-baseline visits, they are excluded from the analysis;
[0105] FIG. 17 shows safety measures of LSR AUC sum score for studies GW01-
0703, GW01-0702, GW01-0704 and GW01-0705. As used in this FIG. 17, "H" refers
to
a 3.75% lower dosage strength imiquimod formulation of Examples 23-28 and "L"
refers to a 2.5% lower dosage strength imiquimod formulation of Examples 23-
28.;
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[0106] FIG. 17A shows a summary of local skin reactions (LSR) area under the
curve
of sum of LSR scores (days) for combined studies for an ITT population using
either a
2.5% or a 3.75% lower dosage strength imiquimod formulation of Examples 23-28.
The P values are from the analysis of variance (GLM) including effects of
dose,
regimen, and analysis center within regimen. The time period for the AUC
extends to
eight weeks after the end of treatment for both the two-week treatment cycle
regimen
(week 14) and the three-week treatment cycle regimen (week 17). Only subjects
who
receive treatment in both treatment cycles are included in this analysis;
[0107] FIG. 18 shows safety measures of LSR sum score, by time point, for
studies
GW01-0703, GW01-0702, GW01-0704 and GW01-0705;
[0108] FIG. 18A shows a mean LSR sum score vs. study time point for two-week
treatment cycle regimens for an ITT population using a 3.75% lower dosage
strength
imiquimod formulation of Examples 23-28. Note the following: Bsl=baseline,
EoCl=end of cycle 1, SoC2=start of cycle 2, EoC2=end of cycle 2, 4WP=4 weeks
post-
treatment, 8WP=8 weeks post-treatment, L2=2.5% two-week cycle regimen,
H2=3.75%
two-week treatment cycle regimen, P2=placebo two-week treatment cycle regimen;
[0109] FIG. 18B shows a mean LSR sum score vs. study time point for three-week
treatment cycle regimens for an ITT population using a 3.75% lower dosage
strength
imiquimod formulation of Examples 23-28. Note the following: Bsl=baseline,
EoCl=end of cycle 1, SoC2=start of cycle 2, EoC2=end of cycle 2, 4WP=4 weeks
post-
treatment, 8WP=8 weeks post-treatment, L3=2.5% three-week cycle regimen,
H3=3.75% three-week treatment cycle regimen, P32=placebo three-week treatment
cycle regimen;
[0110] FIG. 19 shows safety measures of incidence of severe LSR erythema for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in this FIG.
19, "H" refers to a 3.75% lower dosage strength imiquimod formulation and "L"
refers to
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a 2.5% lower dosage strength imiquimod formulation of Examples 23-28, and "V"
refers
to vehicle. See also FIGS. 16A-C;
[0111] FIG. 20 shows mean LSR erythema score, by time point, for studies GW01-
0703, GW01-0702, GW01-0704 and GW01-0705;
[0112] FIG. 20A shows LSR mean score vs. study week for erythema for an ITT
population for study GW01-0702. As used in this FIG. 20A, "A" refers to a 2.5%
lower
dosage strength imiquimod formulation, "B" refers to a 3.75% lower dosage
strength
imiquimod formulation of Examples 23-28 and C refers to Placebo;
[0113] FIG. 20B shows a LSR mean score vs. study week for erythema for an ITT
population for study GW01-0704. As used in this FIG. 20B, "A" refers to a 2.5%
lower
dosage strength imiquimod formulation, "B" refers to a 3.75% lower dosage
strength
imiquimod formulation of Examples 23-28 and C refers to Placebo;
[0114] FIG. 21 shows safety measures of incidence of rest periods for studies
GW01-
0703, GW01-0702, GW01-0704 and GW01-0705. See also FIG. 30;
[0115] FIG. 22 shows safety measures of rate of study discontinuation, for
safety
reasons, for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used
in this FIG. 22, "H" refers to a 3.75% lower dosage strength imiquimod
formulation of
Examples 23-28, "L" refers to a 2.5% lower dosage strength imiquimod
formulation of
Examples 23-28 and "V" refers to vehicle;
[0116] FIG. 23 shows a summary of select safety parameters associated with
applications of the 2.5% and 3.75% imiquimod cream formulations of Example 23
that
are used in 2 x 2 x 2 week, 2-cycle regimens and used in 3 x 3 x 3 week 2-
cycle
regimens. The results demonstrate the overall acceptable safety profile of
both the
2.5% and 3.75% imiquimod formulations of Example 23 according to either of the
2 or 3
week cycle regimens. Of note, the safety results suggest a preferable safety
profile
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when either the 2.5% or the 3.75% imiquimod formulation is used in a 2 x 2 x 2
week, 2-
cycle regimen versus a 3 x 3 x 3 week, 2-cycle regimen.
[0117] FIG. 24 shows improvement in the Investigator Global integrated
photodamage
score from baseline for a two week 2-cycle treatment period (2 x 2 x 2 weeks).
In this
FIG. 24, Study 1 refers to the GW01-0702 study and Study 2 refers to the GW01-
0704
study herein through-out. As used in this FIG. 24, "Pbo" refers to placebo and
"Imiq"
refers to imiquimod;
[0118] FIG. 25 shows meta-analysis efficacy of pooled clearance rates for
studies
GW01-0703, GW01-0702, GW01-0704 and GW01-0705;
[0119] FIG. 25A shows a summary of primary and secondary efficacy endpoints
for
combined studies, analysis within regimen for an ITT population using a 3.75%
lower
dosage strength imiquimod formulation of Examples 23-28. Complete clearance is
defined as the absence of clinically visible or palpable AK lesions in the
treatment area.
Partial clearance is defined as at least a 75% reduction in the number of AK
lesions in
the treatment area compared with Baseline. P values are from Cochran-Mantel-
Haenszel test, stratified by analysis site, within regimen, taking 2 treatment
groups at a
time. The P values marked with ** are statistically significant using
Hochberg's modified
Bonferroni procedure. LOCF=Last observation that is carried forward.
Confidence
intervals are calculated using exact binomial statistics;
[0120] FIG. 26 shows an efficacy comparison of complete clearance rates, by
study,
for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in this
FIG. 26, "2 x 2 x 2" refers to a two week, 2-cycle therapy and "3 x 3 x 3"
refers to a three
week, 2-cycle therapy. See also FIG. 25A;
[0121] FIG. 27 shows efficacy comparison of partial clearance rates, by study,
for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. As used in this FIG.
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27, "2 x 2 x 2" refers to a two week, 2-cycle therapy and "3 x 3 x 3" refers
to a three
week, 2-cycle therapy. See also FIG 25A;
[0122] FIG. 28 shows safety comparison of incidence of adverse events for
studies
GW01-0703, GW01-0702, GW01-0704 and GW01-0705, as compared with Aldara 5%
imiquimod cream. As used in this FIG. 28, "2 weeks" refers to a two week, 2-
cycle
therapy, "3 weeks" refers to a three week, 2-cycle therapy, "Pbo" refers to
placebo,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28 and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
[0123] FIGS. 28A-B show a number (%) of subjects in phase 3 studies with
treatment-emergent adverse events with incidence greater than 1% in the 3.75%
imiquimod two-week treatment cycle group for an ITT population. Counts reflect
number of subjects in each treatment group reporting one or more adverse
events that
map to the MedDRA system organ class. A subject may be counted once only in
each
row of the table. A treatment-emergent AE is an AE with onset date on or after
day 1 of
treatment. As used in these FIGS. 28A-B, "2.5%" refers to a 2.5% imiquimod
lower
dosage strength formulation of Examples 23-28 and "3.75%" refers to a 3.75%
imiquimod lower dosage strength formulation of Examples 23-28;
[0124] FIG. 29 shows a comparison of the incidence of severe erythema [(a
local skin
reaction (LSR)] for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705, as
compared with Aldara 5% imiquimod cream. As used in this FIG. 29, "H" refers
to a
3.75% lower dosage strength imiquimod formulation of Examples 23-28, "L"
refers to a
2.5% lower dosage strength imiquimod formulation of Examples 23-28 and "V"
refers to
vehicle, and "2 x 2 x 2" refers to a two week, 2-cycle treatment regimen and
"3 x 3 x 3"
refers to a three week, 2-cycle treatment regimen. See also FIG. 16A;
[0125] FIG. 30 shows safety measures of incidence of rest periods for studies
GW01-
0703, GW01-0702, GW01-0704 and GW01-0705, as compared with Aldara 5%
47
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imiquimod cream. As used in this FIG. 30, "H" refers to a 3.75% lower dosage
strength
imiquimod formulation of Examples 23-28, "L" refers to a 2.5% lower dosage
strength
imiquimod formulation of Examples 23-28 and "V" refers to vehicle, and "2 x 2
x 2"
refers to a two week, 2-cycle treatment regimen and "3 x 3 x 3" refers to a
three week,
2-cycle treatment regimen. See also FIG. 21;
[0126] FIG. 31 shows efficacy measures of clearance rates, by subject sex, for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also FIGS. 10A-
10C;
[0127] FIG. 32 shows efficacy measures of clearance rates, by subject age, for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also FIGS. 10B-
10C;
[0128] FIG. 32A shows a summary of primary and secondary efficacy endpoints
for
age subpopulations over and under 65 for combined two-week treatment cycle
studies
(GW01-0702 and GW01-0704) for an ITT population for active treatment only
using a
3.75% lower dosage strength imiquimod formulation of Examples 23-28. The P
values
for clearance rates are from a generalized linear module (GENMOD), assuming a
multinomial distribution (DIST=MULT) and a cumulative logit link function
(LINK=CLOGIT), including effects of dose, subpopulation, and interaction. The
P
values for percent change in AK lesion count are from the analysis of variance
(GLM)
including effects of dose, subpopulation, and interaction. As used in this
FIG. 32A,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation of
Examples 23-28, "<65" refers to an age population that is less than 65 years
old and
">=65" refers to an age population that is 65 years old or older;
[0129] FIG. 33 shows efficacy measures of clearance rates, by subject skin
type, for
studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also FIGS. 10B-
10C;
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[0130] FIG. 33A shows a summary of primary and secondary efficacy endpoints
for
Fitzpatrick skin type subpopulations for combined two-week treatment cycle
studies
(GW01-0702 and GW01-0704) for an ITT population for active treatment only
using a
3.75% lower dosage strength imiquimod formulation of Examples 23-28. The P
values
for clearance rates are from a generalized linear module (GENMOD), assuming a
multinomial distribution (DIST=MULT) and a cumulative logit link function
(LINK=CLOGIT), including effects of dose, subpopulation, and interaction. The
P
values for percent change in AK lesion count are from the analysis of variance
(GLM)
including effects of dose, subpopulation, and interaction. As used in this
FIG. 33A,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation of
Examples 23-28, and "I", "II", "III", "IV" "V" or "VI" refer to Fitzpatrick
skin type;
[0131] FIG. 34 shows efficacy measures of clearance rates, by subject Baseline
count, for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also
FIGS. 10B-10C;
[0132] FIG. 34A shows a summary of primary and secondary efficacy endpoints
for
baseline lesion count subpopulations for combined two-week treatment cycle
studies
(GW01-0702 and GW01-0704) for an ITT population for active treatment only
using a
3.75% lower dosage strength imiquimod formulation of Examples 23-28. The P
values
for clearance rates are from a generalized linear module (GENMOD), assuming a
multinomial distribution (DIST=MULT) and a cumulative logit link function
(LINK=CLOGIT), including effects of dose, subpopulation, and interaction. The
P
values for percent change in AK lesion count are from the analysis of variance
(GLM)
including effects of dose, subpopulation, and interaction. As used in this
FIG. 34A,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28 and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28;
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[0133] FIG. 35 shows efficacy measures of clearance rates, by subject
treatment
area, for studies GW01-0703, GW01-0702, GW01-0704 and GW01-0705. See also
FIGS. 10B-10C;
[0134] FIG. 35A shows a summary of primary and secondary efficacy endpoints
for
location of treatment area (face or balding scalp) subpopulations for combined
two-
week treatment cycle studies (GW01-0702 and GW01-0704) for an ITT population
for
active treatment only using a 3.75% lower dosage strength imiquimod
formulation of
Examples 23-28. The P values for clearance rates are from a generalized linear
module (GENMOD), assuming a multinomial distribution (DIST=MULT) and a
cumulative logit link function (LINK=CLOGIT), including effects of dose,
subpopulation,
and interaction. The P values for percent change in AK lesion count are from
the
analysis of variance (GLM) including effects of dose, subpopulation, and
interaction. As
used in this FIG. 35A, "2.5%" refers to a 2.5% imiquimod lower dosage strength
formulation of Examples 23-28, "3.75%" refers to a 3.75% imiquimod lower
dosage
strength formulation of Examples 23-28, and "Face" and "Balding Scalp" refer
to the
treatment area;
[0135] FIG. 35B shows a summary of primary and secondary efficacy endpoints
for
location of treatment area (face or balding scalp) subpopulations for combined
two-
week treatment cycle studies (GW01-0702 and GW01-0704) for an ITT population
using
a 3.75% lower dosage strength imiquimod formulation of Examples 23-28. The P
values for clearance rates are from a generalized linear module (GENMOD),
assuming
a multinomial distribution (DIST=MULT) and a cumulative logit link function
(LINK=CLOGIT), including effects of dose, subpopulation, and interaction. The
P
values for percent change in AK lesion count are from the analysis of variance
(GLM)
including effects of dose, subpopulation, and interaction. As used in this
FIG. 35B,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28, "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation of
Examples 23-28, and "Face" and "Balding Scalp" refer to the treatment area;
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[0136] FIG. 36 shows percent complete clearance compared with Aldara 5%
imiquimod cream. In this Fig. 36 and throughout the specification, study 1
refers to
GW01-0702 study and study 2 refers to GW01-0704 study. As used in this FIG.
36,
"Pbo" refers to placebo, "Imiq" refers to imiquimod, and "Aldara" refers to
Aldara 5%
imiquimod cream. See also FIG. 1;
[0137] FIG. 36A shows percent complete clearance compared with placebo. In
this
Fig. 36 and throughout the specification, study 1 refers to GW01-0702 study,
study 2
refers to GW01-0704 study, study 3 refers to GW01-0703 study and study 4
refers to
GW01-0705 study. As used in this FIG. 36A, "Pbo" refers to placebo and "Imiq"
refers
to imiquimod;
[0138] FIG. 37 shows percent partial clearance compared with Aldara 5%
imiquimod
cream. In this Fig. 37 and throughout the specification, study 1 refers to
GW01-0702
study and study 2 refers to GW01-0704 study. As used in this FIG. 37, "Pbo"
refers to
placebo, "2.5% Imiq" refers to a 2.5% imiquimod lower dosage strength
formulation of
Examples 23-28, "3.75% Imiq" refers to a 3.75% imiquimod lower dosage strength
formulation of Examples 23-28, and "Aldara" refers to Aldara 5% imiquimod
cream.
See also FIG. 4A;
[0139] FIG. 37A shows a partial clearance compared with placebo. In this Fig.
37A
and throughout the specification, study I refers to GW01-0702 study, study 2
refers to
GW01-0704 study, study 3 refers to GW01-0703 study and study 4 refers to GW01-
0705 study. As used in this FIG. 37A, "Pbo" refers to placebo, "2.5% lmiq"
refers to a
2.5% imiquimod lower dosage strength formulation of Examples 23-28, and "3.75%
Imiq" refers to a 3.75% imiquimod lower dosage strength formulation of
Examples 23-
28;
[0140] FIG. 38 shows AK median % reduction compared with Aldara 5% imiquimod
cream. In this Fig. 38 and throughout the specification, study 1 refers to
GW01-0702
study and study 2 refers to GW01-0704 study As used in this FIG. 38, "Pbo"
refers to
51
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placebo, "2.5% Imiq" refers to a 2.5% imiquimod lower dosage strength
formulation of
Examples 23-28, "3.75% Imiq" refers to a 3.75% imiquimod lower dosage strength
formulation of Examples 23-28, and "Aldara" refers to Aldara 5% imiquimod
cream;
[0141] FIG. 38A shows AK median % reduction compared with placebo. In this
Fig.
38A and throughout the specification, study 1 refers to GW01-0702 study, study
2 refers
to GW01-0704 study, study 3 refers to GW01-0703 study and study 4 refers to
GW01-
0705 study. As used in this FIG. 38A, "Pbo" refers to placebo, "2.5% Imiq"
refers to a
2.5% imiquimod lower dosage strength formulation of Examples 23-28, "3.75%
lmiq"
refers to a 3.75% imiquimod lower dosage strength formulation of Examples 23-
28,
and "Aldara" refers to Aldara 5% imiquimod cream;
[0142] FIG. 39 shows rest periods for the 2-cycle, 2 x 2 x 2 (2 week)
treatment
regimen, as compared with Aldara 5% imiquimod cream. As used in this FIG. 39,
"Pbo" refers to placebo, "2.5% lmiq" refers to a 2.5% imiquimod lower dosage
strength
formulation of Examples 23-28, "3.75% Imiq" refers to a 3.75% imiquimod lower
dosage strength formulation of Examples 23-28, and "Aldara" refers to Aldara
5%
imiquimod cream;
[0143] FIG. 39A shows selected safety parameters for combined two-week, two-
cycle
studies (GW01-0702 and GW01-0704) or three-week, two-cycle studies (GW01-0703
and GWOI-0705). As used in this FIG. 39A, "2.5% Imiq" refers to a 2.5%
imiquimod
lower dosage strength formulation of Examples 23-28, "3.75% lmiq" refers to a
3.75%
imiquimod lower dosage strength formulation of Examples 23-28 and "Tx" refers
to
treatment;
[0144] FIG. 40 shows local skin reactions ("LSRs"); % of subjects with severe
LSRs
for the 2-cycle, 2 x 2 x 2 (2 week) treatment regimen, as compared with Aldara
5%
imiquimod cream. As used in this FIG. 40, "Pbo" refers to placebo, "2.5% Imiq"
refers to
a 2.5% imiquimod lower dosage strength formulation of Examples 23-28, "3.75%
lmiq"
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refers to a 3.75% imiquimod lower dosage strength formulation of Examples 23-
28,
and "Aldara" refers to Aldara 5% imiquimod cream. See also FIG. 16A-C;
[0145] FIG. 41 shows a comparison regarding the incidence of selected common
adverse events for the 2-cycle, 2 x 2 x 2 (2 week) treatment regimen, as
compared with
Aldara 5% imiquimod cream. As used in this FIG. 41, "Pbo" refers to placebo,
"2.5%
lmiq" refers to a 2.5% imiquimod lower dosage strength formulation of Examples
23-28,
"3.75% lmiq" refers to a 3.75% imiquimod lower dosage strength formulation of
Examples 23-28, "Aldara" refers to Aldara 5% imiquimod cream, and "NS" refers
to
not specified;
[0146] FIG. 41A shows incidence of most common (greater than 1%) treatment-
related adverse events for combined two-week studies (GW01-0702 and *GW01-
0704)
or three-week studies (GW01-0703 and GW01-0705);
[0147] FIG. 42 shows benefit/risk for the 2-cycle, 2 x 2 x 2 (2 week)
treatment
regimen, as compared with Aldara 5% imiquimod cream; In this FIG. 42, "Severe
ery"
refers to severe erythema, "App site rxns" refers to application site
reactions, "Rest
Periods" refers -to the percent of patients who took rest periods during the
study in
addition to the two week rest period (no treatment period) sandwiched between
the 2-
cycles of two week treatments, "Complete Clear" refers to the rate of complete
AK
lesion clearance, "Partial Clear" refers to the rate of partial AK lesion
clearance (defined
as at least about 75% reduction in the number of AK lesions in the treatment
area as
compared with Baseline), "%Reduction" refers to median percent reduction in AK
lesions, "2.5%" refers to a 2.5% imiquimod lower dosage strength formulation
of
Examples 23-28, "3.75%" refers to a 3.75% imiquimod lower dosage strength
formulation of Examples 23-28, and "Aldara" refers to Aldara 5% imiquimod
cream;
[0148] FIG. 43 shows a clinical case study of a 39 year old white male in
which a
2.5% imiquimod (IMIQ) formulation is used in a 2 cycle, 2 x 2 x 2 weeks, to
treat actinic
keratosis;
53
CA 02649893 2009-01-15
[0149] FIG. 44 shows a clinical case study of a 74 year old white male in
which a
2.5% imiquimod (IMIQ) formulation is used in a 2 cycle, 2 x 2 x 2 weeks, to
treat actinic
keratosis;
[0150] FIG. 45 shows a clinical case study of a 66 year old white female in
which a
3.75% imiquimod (IMIQ) formulation is used in a 2 cycle, 2 x 2 x 2 weeks, to
treat actinic
keratosis;
[0151] FIG. 46 shows a clinical case study of a 73 year old white male in
which a
3.75% imiquimod (IMIQ) formulation is used in a 2 cycle, 2 x 2 x 2 weeks, to
treat actinic
keratosis;
[0152] FIG. 47 shows a clinical case study of a 70 year old white male in
which a
2.5% imiquimod (IMIQ) formulation is used in a 2 cycle, 3 x 3 x 3 weeks to
treat actinic
keratosis;
[0153] FIG. 48 shows a clinical case study of a 65 year old white female in
which a
2.5% imiquimod (IMIQ) formulation is used in a. 2 cycle, 3 x 3 x 3 weeks to
treat actinic
keratosis;
[0154] FIG. 49 shows a clinical case study of a 79 year old white male in
which a
3.75% imiquimod (IMIQ) formulation is used in a 2 cycle, 3 x 3 x 3 weeks to
treat actinic
keratosis;
[0155] FIG. 50 shows a clinical case study of a 78 year old white male in
which a
3.75% imiquimod (IMIQ) formulation is used in a 2 cycle, 3 x 3 x 3 weeks to
treat actinic
keratosis; and
[0156] FIG. 51 shows a summary of primary and secondary efficacy endpoints in
which (a) the results of the GW01-0702 and GW01-0704 (2 x 2 x 2) studies for
each
54
CA 02649893 2009-01-15
imiquimod formulation strength, i.e., about 2.5% or about 3.75% w/w, that are
used in
the studies are combined, respectively, (b) the results of the GW01-0703 and
GW01-
0705 (3 x 3 x 3) studies for each imiquimod formulation strength, i.e., about
2.5% or
about 3.75% w/w, that are used in the studies are combined, respectively, and
(c) the
analysis is within regimen ITT populations. Complete clearance is defined as
the
absence of clinically visible or palpable AK lesions in the treatment area.
Partial
clearance is defined as at least about a 75% reduction in the number of AK
lesions in
the treatment area as compared with Baseline. P values are from Cochran-Mantel-
Haenszel test, are stratified by analysis site, within regimen, taking 2
treatment groups
at a time. The P values that are marked with ** are statistically significant
using
Hochberg modified Bonferroni procedure. LOCF = last observation carried
forward.
Confidence intervals are calculated using exact binomial statistics. In this
FIG. 51,
"2.5%" refers to a 2.5% imiquimod lower dosage strength formulation of
Examples 23-
28 and "3.75%" refers to a 3.75% imiquimod lower dosage strength formulation
of
Examples 23-28. See also FIG. 25A;
[0157] FIG. 52 shows a summary of primary and secondary efficacy endpoints
from
combined studies and an analysis across regimens for the ITT Population.
Column (1)
P values for all parameters are from the analysis of variance based on a
General Linear
Model ("GLM") including effects of dose, regimen, and analysis site within
regimen.
Column (2) P values are based on a logistic analysis of the effects of dose,
regimen,
and analysis site. In this FIG. 52, "2.5%" refers to a 2.5% imiquimod lower
dosage
strength formulation of Examples 23-28 and "3.75%" refers to a 3.75% imiquimod
lower
dosage strength formulation of Examples 23-28;
[0158] FIG. 53 shows a summary of an Investigators Global Integrated
Photodamage
("IGIP") score for the (a) GW01-0702 and GW01-0704 studies, (b) GW01-0703 and
GW01-0705 studies and (c) combined studies, i.e., GW01-0702, GW01-0703, GW01-
0704 and GW01-0705 studies, for a two-week 2-cycle treatment period (2 x 2 x 2
weeks) and a three-week 2-cycle treatment period (3 x 3 x 3 weeks) for the
Intent-To-
Treat ("ITT") population. In this FIG. 53, "2.5%" refers to a 2.5% imiquimod
lower
CA 02649893 2009-01-15
dosage strength formulation of Examples 23-28 and "3.75%" refers to a 3.75%
imiquimod lower dosage strength formulation of Examples 23-28;
[0159] FIG. 54 shows a summary of serum pharmacokinetic parameters at day 21
for
a 3.75% imiquimod formulation of Examples 23-28, PK population. The serum
analyte
is imiquimod. The calculation of accumulation ratio (RAUC, RCmax) and
effective half-
life for accumulation (T'/2 and T'/2 eff), is restricted to subjects who take
all seven doses
during the week of treatment and who take at least 80% of the prescribed doses
during
the prior two weeks. The PK parameters are not calculated for subject 001-619
and
subject 001-608. There is no concentration data for subject 001-619, and
subject 001-
608 did not take all required doses during the 21 days of treatment. AUCO_24
equals
AUCss and Cmin equals predose concentration (t = 0). In this FIG. 51,
"Imiquimod" refers
to a 3.75% imiquimod lower dosage strength formulation of Examples 23-28. See
also
Example 25;
[0160] FIG. 55 shows a calibrated graticule scale at x400 magnification; where
the 10
pm, 50 pm and 100 pm divisions are indicated;
[0161] FIG. 56 shows a schematic representation of a Franz cell;
[0162] FIG. 57 shows a summary of microscope pictures of eight 2.5% w/w
imiquimod formulations, i.e., formulations 113, 246, 247, 248, 249, 251, 252
and 253
(the formulations continued into the stability program are included for the 1
kg batches
in TABLE 18 and FIG. 64);
[0163] FIG. 58 shows a comparison of the mean cumulative amount of imiquimod
released (pg/cm2) after about 3 h for the membrane release studies (for all
the
formulations selected for Full thickness skin permeation and stability
studies) (mean
sd, where n=4);
56
CA 02649893 2009-01-15
[0164] FIG. 59 shows a comparison of the average total cumulative report
released
(pg/cm2) after 3 h for each concentration of imiquimod in the formulations
that are
tested (mean ^ sd, where n=4 for 1%, n=16 for 2.5%, n=20 for 3.75% and n=12
for
5%);
[0165] FIG. 60. shows a total amount of imiguimod that is recovered following
mass
balance for each formulation (See also Tables 35-40 for statistical analysts)
(mean
sd, refer to Table 34 for n numbers of each sample);
[0166] FIG. 61 shows a total amount of imiquimod recovered for each
formulation in
the receiver fluid, epidermis and dermis combined (mean sd, refer to Table
34 for n
numbers of each sample);
[0167] FIG. 62 shows a total amount of imiquimod recovered for the averages of
each
imiquimod concentration from each of the skin matrices.
[0168] FIGS. 63A-C show microscopic depiction of 13 imiquimod formulations,
i.e.,
3M Aldara imiquimod cream 1 kg batch, Graceway 3M Aldara imiquimod cream 1
kg
batch and formulations 110, 123, 125, 126, 182, 183, 195, 197, 250, 256 and
257 (t=0,
1, 2, 3 and 6 months) - x400 magnification;
[0169] FIG. 64 shows microscopic depiction of placebo formulations Pbol-Pbo4
(t=0,
1, 2, 3 and 6 months) - x400 magnification;
[0170] FIGS. 65A-B show microscopic depiction of 10 imiquimod formulations,
i.e.,
formulations, 116, 117, 254, 120, 235, 188, 189, 184, 255, 124, after 1 month
stability
(t=0 and 1 month) - x400 magnification;
[0171] FIG. 66 shows a comparison of the mean amount of imiquimod that is
released (pg/cm2) over a 3 hour period for the 3M Aldara imiquimod cream 1 kg
batch,
57
CA 02649893 2009-01-15
the 3M Aldara imiquimod cream sachet, the Graceway 3M Aldara imiquimod cream
1
kg batch and formulation 257, a 1 % Imiquimod formulation (mean sd, where
n=4);
[0172] FIG. 67 shows a comparison of the mean amount of imiquimod that is
released ( g/cm2) over a 3 hour period for four 2.5% imiquimod formulations,
i.e.,
formulations 110, 123, 125 and 250 (mean + sd, where n=4).
[0173] FIG. 68 shows a comparison of the mean amount of imiquimod that is
released ( g/cm2) over a 3 hour period for five 3.75% imiquimod formulations,
i.e.,
formulations 182, 183, 195, 197 and 256 (mean + sd, where n=4); and
[0174] FIG. 69 shows a comparison of the mean amount of imiguimod released
(pg/cm2) over a 3 hour period for the 2.5% (A), 3.75% (=), 3M Aldara
imiquimod
cream batch (^), Graceway Aldara imiquimod cream 1 kg batch(^) and
formulation 257
Imiquimod formulations (^) (mean sd, where n=4).
DETAILED DESCRIPTION OF THE INVENTION
[0175] By way of illustrating and providing a more complete appreciation of
the present
invention and many of the attendant advantages thereof, the following detailed
description
and examples are given concerning the novel methods and compositions.
[0176] In general, the present invention relates to a pharmaceutical
composition
comprising imiquimod and a pharmaceutically acceptable vehicle for imiquimod,
which
vehicle comprises a fatty acid. While the present invention may be embodied in
many
different forms, several specific embodiments are discussed herein with the
understanding
that the present disclosure is to be considered only as an exemplification of
the principles of
the invention, and it is not intended to limit the invention to the
embodiments described or
illustrated.
58
CA 02649893 2009-06-10
[0177] As used in the specification and claims, the phrase "substantially less-
irritating"
designates formulations that do not cause unacceptable skin irritation in
conventional
repeat skin irritation tests in albino rabbits such as that described in
Draize et al.,
"Appraisal of the Safety of Chemicals in Food, Drugs and Cosmetics", prepared
by the
Division of Pharmacology of the Food and Drug Administration, published
originally in
1959 by the Association of Food and Drug Officials of the United States,
Topeka, Kans.
(2nd printing 1965).
[0178] Unless otherwise indicated, all numbers expressing quantities, ratios,
and
numerical properties of ingredients, reaction conditions, and so forth used in
the
specification and claims are to be understood as being modified in all
instances by the
term "about".
[0179] All parts, percentages, ratios, etc. herein are by weight unless
indicated
otherwise.
[0180] As used herein, the singular forms "a" or "an" or "the" are used
interchangeably and intended to include the plural forms as well and fall
within each
meaning, unless expressly stated otherwise. Also as used herein, "at least
one" is
intended to mean "one or more" of the listed element. Singular word forms are
intended
to include plural word forms and are likewise used herein interchangeably
where
appropriate and fall within each meaning, unless expressly stated otherwise.
Except
where noted otherwise, capitalized and non-capitalized forms of all terms fall
within
each meaning.
[0181 ] By the term "bioequivalence or bioequivalent", as used herein, it
refers to lower
dosage strength formulations in which they are pharmaceutically equivalent and
their
bioavailibilities (rate and extent of absorption) after administration in the
same molar
dosage or amount are similar to such a degree that their therapeutic effects,
as to safety
and efficacy, are essentially the same. In other words, bioequivalence or
bioequivalent
means the absence of a significant difference in the rate and extent to which
imiquimod
becomes available from such formulations at the site of imiquimod action when
59
CA 02649893 2009-01-15
administered at the same molar dose under similar conditions, e.g., the rate
at which
imiquimod can leave such a formulation and the rate at which imiquimod can
either
cross the stratum corneum and/or become available at the site of action to
treat actinic
keratosis. In other words, there is a high degree of similarity in the
bioavailabilities of
two imiquimod pharmaceutical products (of the same galenic form) from the same
molar
dose, that are unlikely to produce clinically relevant differences in
therapeutic effects, or
adverse reactions, or both. The terms "bioequivalence", as well as
"pharmaceutical
equivalence" and "therapeutic equivalence" are also used herein as defined
and/or used
by (a) the FDA, (b) the Code of Federal Regulations ("C.F.R."), Title 21,
and/or (c)
Health Canada.
[0182] By the term "bioavailability or bioavailable", as used herein, it means
generally
the rate and extent of absorption of imiquimod into the systemic circulation
and, more
specifically, the rate or measurements intended to reflect the rate and extent
to which
imiquimod becomes available at the site of action or is absorbed from a drug
product
and becomes available at the site of action. In other words, and by way of
example, the
extent and rate of imiquimod absorption from a lower dosage strength
formulation of the
present invention as reflected by a time-concentration curve of imiquimod in
systemic
circulation.
[0183] By "pharmaceutical equivalence or pharmaceutically equivalent", as used
herein, it refers to lower dosage strength imiquimod formulations of the
present
invention that contain the same amount of imiquimod, in the same dosage forms,
but
not necessarily containing the same inactive ingredients, for the same route
of
administration and meeting the same or comparable compendial or other
applicable
standards of identity, strength, quality, and purity, including potency and,
where
applicable, content uniformity and /or stability.
[0184] By "therapeutic equivalence or therapeutically equivalent", it is meant
herein to
mean those lower dosage strength imiquimod formulations which (a) will produce
the
same clinical effect and safety profile when practicing the short durations of
therapy to
CA 02649893 2009-01-15
treat actinic keratosis in accordance with the present invention and (b) are
pharmaceutical equivalents, e.g., they contain imiquimod in the same dosage
form, they
have the same route of administration; and they have the same imiquimod
strength. In
other words, therapeutic equivalence means that a chemical equivalent of an
imiquimod
lower dosage strength imiquimod formulation of the present invention (i.e.,
containing
the same amount of imiquimod in the same dosage form) when administered to the
same individuals in the same dosage regimen will provide essentially the same
efficacy
and toxicity.
[0185] By "Tma,", it is meant herein to mean the time when the maximum
imiquimod
serum concentration is reached at steady state following topical application
of a lower
dosage strength imiquimod formulation of the present invention, i.e., when the
rate of
imiquimod absorption equals the rate of imiquimod elimination. In other words,
the time
that Cmax is observed for imiquimod.
[0186] By "Cmax", it is meant herein to refer to the maximum imiquimod serum
concentration that is reached at steady state following topical application of
a lower
dosage strength imiquimod formulation of the present invention, i.e., when the
rate of
imiquimod absorption equals the rate of imiquimod elimination. In other words,
it is the.
maximum serum concentration; the highest serum concentration observed during
the
imiquimod dosing or sampling interval.
[0187] By "Cm;,,", it is meant herein to refer to the minimum measurable
imiquimod
serum concentration; e.g., imiquimod serum concentration that is observed
immediately
prior to dosing on Days 7, 14, 21 and 22 (24 hours post-dose).
[0188] By "T1/Z", it is meant herein to mean the time required for half of the
quantity of
maximum imiquimod serum concentration to be eliminated once steady state is
achieved following topical application of a lower dosage strength imiquimod
formulation
of the present invention. For example, the apparent elimination half-life for
imiquimod,
that is calculated as about 0.693/XZ in accordance with Example 24.
61
CA 02649893 2009-01-15
[0189] By "AUCO-24", it is meant herein to mean the area under the serum
imiquimod
concentration versus a 24 hour time curve following topical application of a
lower
dosage strength imiquimod formulation of the present invention, i.e., a
measure of
imiquimod exposure over a 24 hour period. For example, the area under the
imiquimod
serum concentration versus time curve, from 0 to 24 hours, that is calculated
using the
linear trapezoid rule or extrapolated to 24 hours in cases where reportable
values are
not obtainable up to that time point.
[0190] By "AUCo-t", it is meant herein to mean the area under the imiquimod
serum
concentration versus time curve, from 0 to the time of the last non-zero
concentration on
Day 1; that is calculated using the linear trapezoid rule.
[0191] By "RAUC", it is meant herein to mean the accumulation ratio; that are
calculated as the AUCo_24 value during multiple-imiquimod dose administration
divided
by the AUCo-24 value following the first dose (i.e., Day 21/Day 1); or the
accumulation
ratios that are calculated for an imiquimod metabolite only if sufficient non-
zero time
points are available to reasonably estimate AUCo-24.
[0192] By "AUCo-iõf", it is meant herein to mean the area under the imiquimod
serum
concentration versus time curve, from 0 to infinity; AUCo-;nf that is
calculated on Day 1 as
AUC(o-;,,fl = AUC(o-t) + Ct/Ke, (where Ct = the fitted last non-zero
concentration,
AUCo_t = the AUC from time zero to the time of the last non-zero concentration
and Kei
= the elimination rate constant).
[0193] By "Rcmax", it is meant herein to mean the accumulation ratio;
calculated as
the Cmax value during multiple-dose administration divided by the Cmax value
following
the first dose (i.e., Day 21/Day 1)
[0194] By "kz EFF", it is meant herein to mean the effective elimination rate
constant,
calculated as -In(1-1 /RAUC)/tau.
62
CA 02649893 2009-01-15
[0195] By "T% EFF", it is meant herein to mean the effective half-life for
accumulation;
calculated as 0.693/a,z EFF'
[0196] By "Az", it is meant to refer to an elimination rate constant, i.e.,
the rate at
which imiquimod disappears from the site of measurement once steady state is
achieved following topical application of a lower dosage strength imiquimod
formulation
of the present invention. In other words, the apparent elimination rate
constant; that is
calculated using linear regression on the terminal portion of the In
concentration versus
time profile.
[0197] By "geometric mean", it refers a statistical average of a set of
transformed
numbers often used to represent a central tendency in highly variable data. It
is
calculated from data transformed using powers or logarithms and then
transformed
back to original scale after averaging.
[0198] By "geometric mean ratio", it refers to a ratio of two geometric means,
where
the "geometric LS mean test" is the numerator of the geometric mean ratio, and
the
"geometric LS mean reference" is the denominator of the geometric mean ratio.
[0199] By "RH", it refers herein to relative humidity.
[0200] By "cPs, it refers herein to centipoise.
[0201] By "h", it refers herein to hours.
[0202] By "ITT", it refers to an intent-to-treat population.
[0203] By "Pbo, it refers to placebo.
[0204] By "EOS", it refers to End of Study.
63
CA 02649893 2009-01-15
[0205] By "V", it refers to vehicle.
[0206] Studies GW01-0702 and GW01-0704 are duplicative studies that
investigate 2-
week treatment cycles, wherein the 2-week treatment cycles are separated by a
two
week rest period (no treatment) (2 x 2 x 2), and studies GW01-0703 and GW01-
0705
are duplicative studies that investigate 3-week treatment cycles, wherein the
3-week
treatment cycles are separated by a three week rest period (no treatment) (3 x
3 x 3).
See flow diagrams depicted in Table 64 herein below.
[0207] By "L2", it refers to a 2.5% lower dosage strength imiquimod
formulation that is
described in Examples 23-28 and the FIGS. and that is used in connection with
studies
GW01-0702 and GW01-0704.
[0208] By "L3", it refers to a 3.75% lower dosage strength imiquimod
formulation that
is described in Examples 23-28 and the FIGS. and that is used in connection
with
studies GW01-0702 and GW01-0704.
[0209] By "H2", it refers to a 2.5% lower dosage strength imiquimod
formulation that is
described in Examples 23-28 and the FIGS. and that is used in connection with
studies
GW01-0703 and GW01-0705.
[0210] By "H3", it refers to a 3.75% lower dosage strength imiquimod
formulation that
is described in Examples 23-28 and the FIGS. and that is used in connection
with
studies GW01-0703 and GW01-0705.
[0211] By "AE", it refers herein to adverse events.
[0212] By "2 x 2 x 2", as used herein, it refers to a two-week, 2-cycle AK
treatment
regimen, wherein (1) during the first 2 weeks (the first cycle of treatment),
a lower
dosage strength imiquimod formulation of the present invention is applied once
daily
64
CA 02649893 2009-06-10
each day to an AK treatment area, (2) during the second 2 weeks, there is a
rest period
in which no treatment occurs, and (3) during the third 2 weeks (the second
cycle of
treatment), the same formulation is again applied once daily each day to the
same AK
treatment area, In other words, during the first 2 weeks, treatment is on,
during the
second 2 weeks, treatment is off, and during the third 2 weeks, treatment is
on again,
[0213] By "3 x 3 x 3", as used herein, it refers to a three-week, 2-cycle AK
treatment
regimen, wherein (1) during the first 3 weeks (the first cycle of treatment),
a lower
dosage strength imiquimod formulation of the present invention is applied once
daily
each day to an AK treatment area, (2) during the second 3 weeks, there is a
rest period
in which no treatment occurs, and (3) during the third 3 weeks (the second
cycle of
treatment), the same formulation is again applied once daily each day to the
same AK
treatment area, In other words, during the first 3 weeks, treatment is on,
during the
second 3 weeks, treatment is off, and during the third 3 weeks, treatment is
on again,
[0214] The present invention provides pharmaceutical formulations such as
creams,
ointments, foams, gels, lotions and adhesive coatings that contain imiquimod
and a fatty
acid such as isostearic, linoleic, unrefined oleic acid, refined oleic acid,
such as Super
Refined oleic acid NF (e.g., a highly purified oleic acid, i.e., an oleic
acid which has low
polar impurities, such as peroxides, a low peroxide value and is marketed by
CRODA;
see e.g., www.crodausa.com) and mixtures thereof. The formulations of the
invention
provide desirable skin penetrability of the imiquimod.
[0215] The compound imiquimod is a known antiviral agent that is also known to
induce
interferon biosynthesis. It can be prepared using the method disclosed in U.S.
Pat. No.
4,689,338. The compound can be used to treat actinic keratosis. The amount of
imiquimod present in a formulation of the present invention will be an
effective amount
to treat actinic keratosis to achieve total AK lesion clearance or partial AK
lesion
reduction or clearance, to prevent the recurrence of such a disease and/or to
promote immunity against such a disease with an acceptable safety profile. An
example of an effective amount of imiquimod in a formulation of the present
CA 02649893 2009-06-10
invention is between about 1.0 percent and about 4.25 percent by weight based
on
the total weight of a formulation, more preferably between about 1.5%, 1.75%,
2.0%,
2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%, 4.0% and 4.25%, even more
preferably between about 2.0%, 2.25%, 2.5%, 2.75%, 3.0%, 3.25%, 3.5%, 3.75%
and
4.0%, and still even more preferably between about 2.5%, 2.75%, 3.0%, 3.25%,
3.5%
and 3.75%. Imiquimod formulations of the present invention that contain about
2.5%
imiquimod or about 3.75% imiquimod by weight based on the total weight of the
formulation are most preferred.
[0216] Likewise, a shortened period or duration, as contemplated by the
present
invention, will be for reduced periods of time effective to treat actinic
keratosis as
discussed herein above, e.g., up to six weeks, again depending upon the lower
dosage strength imiquimod formulation of the present invention that is
selected for
daily application, and preferably up to four weeks. By way of example, short
periods
of treatment with lower dosage strength imiquimod formulations for treating
actinic
keratosis, include:
(a) applying an effective amount of imiquimod, such as via the lower dosage
strength imiquimod formulations of the present invention to the area affected
with
actinic keratosis, as follows: applying an effective amount once per day for
fourteen
(14) consecutive days, followed by a rest period of for fourteen (14) days (no
treatment), followed by again applying an effective amount once per day for
fourteen
(14) days for a total of twenty-eight (28) doses or four weeks to treat
actinic keratosis
(2-cycle therapy); or
(b) applying an effective amount of imiquimod, such as via the lower dosage
strength imiquimod formulations of the present invention to the area affected
with
actinic keratosis, as follows: applying an effective amount once per day for
twenty one
(21) days, followed by a rest period of twenty one (21) days (no treatment,
followed by
again applying an effective amount once per day for twenty one (21)
consecutive days
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CA 02649893 2009-01-15
for a total of forty-two (42) doses or six weeks to treat actinic keratosis (2-
cycle
therapy); or
(c) applying an effective amount of imiquimod, such as via a suitable lower
dosage strength imiquimod formulation of the present invention to the area
affected
with actinic keratosis, once per day for up to about forty-two (42) days or
less and,
preferably, for up to about twenty-eight days (28) or less (1-cycle therapy).
[0217] A fatty acid such as isostearic acid, paimitic acid, stearic acid,
linoleic acid,
refined oleic acid, such as Super Refined oleic acid NF (e.g., a highly
purified oleic
acid, i.e., an oleic acid which has low polar impurities, such as peroxides, a
low peroxide
value and is marketed by CRODA; see e.g., www.crodausa.com), an unrefined
oleic acid
blended with effective amounts of antioxidants or mixtures thereof are
incorporated into
formulations of the present invention. The total amount of fatty acid present
in a
formulation is preferably between about 3 percent and about 45 percent by
weight
based on the total weight of a formulation. It should be understood that when
oleic
acid is selected as a fatty acid, that stability may present issue. Thus,
stabilizers, such as
anti-oxidants and the like, may be required to preserve pharmaceutical
elegance and
stability over the life of the oleic acid formulation.
[0218] A pharmaceutical formulation of the invention can be in a form such as
a
cream, an ointment, a foam, a gel, a lotion, a pressure-sensitive adhesive
composition,
or other forms known to those skilled in the art, each particular form
containing imiquimod
and fatty acid in particular amounts, and optionally containing various
additional
elements. The preferred amounts of drug and fatty acid, and the amounts and
types of
optional elements used in formulations of the invention are discussed below
with
particular reference to creams, ointments and adhesive compositions.
[0219] A cream according to the invention contains 1-isobutyl-lH-imidazo[4,5-
c]quinolin-4-amine and fatty acid.
67
CA 02649893 2009-01-15
[0220] The amount of 1 -iso butyl- 1 H-i mid azo [4,5-c]-quinol in-4-a mine
present in a
cream is preferably about 0.5 percent to about 9 percent by weight, and more
preferably
about 1 percent to about 5 percent by weight, based on the total weight of the
cream.
[0221] The total amount of fatty acid present in a cream of the invention is
preferably
about 3 percent to about 45 percent by weight, and more preferably about 5
percent to
about 25 percent by weight, based on the total weight of the cream.
[0222] Optionally, a cream of the present invention can contain emollients,
emulsifiers,
thickeners, and/or preservatives.
[0223] Emollients such as long chain alcohols, e.g., cetyl alcohol, stearyl
alcohol and
cetearyl alcohol; hydrocarbons such as petrolatum and light mineral oil; or
acetylated
lanolin can be included in a cream of the invention. A cream can contain one
or more of
these emollients. The total amount of emollient in a cream of the invention is
preferably
about 5 percent to about 30 percent, and more preferably about 5 percent to
about 10
percent by weight based on the total weight of the cream.
[0224] Emulsifiers such as nonionic surface active agents, e.g., polysorbate
60
(available from ICI Americas), sorbitan monostearate, polyglyceryl-4 oleate,
and
polyoxyethylene(4)lauryl ether or trivalent cationic a cream of the invention.
A cream
can contain one or more emulsifiers. Generally the total amount of emulsifier
is
preferably about 2 percent to about 14 percent, and more preferably about 2
percent to
about 6 percent by weight based on the total weight of the cream.
[0225] Pharmaceutically acceptable thickeners, such as Xanthum gum, Guar gum,
Veegum gumTMK (available from R. T. Vanderbilt Company, Inc.), and long chain
alcohols (i.e. cetyl alcohol, stearyl alcohol or cetearyl alcohol) can be
used. A cream
can contain one or more thickeners. The total amount of thickener present is
preferably
about 3 percent to about 12 percent by weight based on the total weight of the
cream.
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CA 02649893 2009-01-15
[0226] Preservatives such as methylparaben, propylparaben and benzyl alcohol
can be
present in a cream of the invention. The appropriate amount of such
preservative(s) is
known to those skilled in the art.
[0227] Optionally, an additional solubilizing agent such as benzyl alcohol,
lactic acid,
acetic acid, stearic acid, salicylic acid, any alpha-hydroxy acid such as
glycolic acid, or
hydrochloric acid can be included in a cream of the invention.
[0228] If an additional solubilizing agent is used, the amount present is
preferably
about 1 percent to about 12 percent by weight based on the total weight of the
cream.
[0229] Optionally, a cream of the invention can contain a humectant such as
glycerin,
skin penetration enhancers such as butyl stearate, and additional solubilizing
agents.
[0230] Generally, a cream consists of an oil phase and a water phase mixed
together to
form an emulsion. Preferably, the amount of water present in a cream of the
invention is
about 45 percent to about 85 percent by weight based on the total weight of
the cream.
The oil phase of a cream of the invention can be prepared by first combining
the 1-
isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine or 1-(2-methylpropyl)-1 H-
imidazo[4,5-
c]quinolin-4-amine and the fatty acid (if the cream contains benzyl alcohol it
can also be
added at this point) and heating with occasional stirring to a temperature of
about 50 C. to
85 C. When the 1-isobutyl-lH-imidazo[4,5-c]quinolin-4- amine or 1-(2-
methylpropyl)-1H-
imidazo[4,5-c]quinolin-4-amine appears to be completely dissolved, the
remaining oil
phase ingredients are added and heating is continued until dissolution appears
to be
complete.
[0231] The water phase can be prepared by combining all other ingredients and
heating with stirring until dissolution appears to be complete.
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CA 02649893 2009-01-15
[0232] The creams of the invention are generally prepared by adding the water
phase
to the oil phase with both phases at a temperature of about 65 C to 75 C. The
resulting
emulsion is mixed with a suitable mixer apparatus to give the desired cream.
[0233] An ointment of the invention contains an ointment base in addition to 1-
isobutyl-
1 H-itnidazo[4,5-c]quinolin-4-amine and fatty acid.
[0234] The amount of I-isobutyl-1 H-imidazo[4,5-c]-quinolin-4-amine present in
an
ointment of the invention is preferably about 0.5 percent to about 9 percent,
and more
preferably about 0.5 percent to about 5 percent by weight based on the total
weight of the
ointment.
[0235] The total amount of fatty acid present in an ointment of the invention
is
preferably about 3 percent to about 45 percent, and more preferably about 3
percent to
about 25 percent based on the total weight of the ointment.
[0236] A pharmaceutically acceptable ointment base such as petrolatum or
polyethylene glycol 400 (available from Union Carbide) in combination with
polyethylene
glycol 3350 (available from Union Carbide) can be used. The amount of ointment
base
present in an ointment of the invention is preferably about 60 percent to
about 95
percent by weight based on the total weight of ointment.
[0237] Optionally, an ointment of the invention can also contain emollients,
emulsifiers
and thickeners. The emollients, emulsifiers, and thickeners and the preferred
amounts
thereof described above in connection with creams are also generally suitable
for use in
an ointment of the invention.
[0238] An ointment according to the invention can be prepared by combining 1-
isobutyl- 1 H-imidazo[4,5-c]quinolin-4-amine with fatty acid and heating with
occasional
stirring to a temperature of about 65 C. When the 1 -isobutyl-1 H-imidazo[4,5-
c]-quinolin-4-
amine or 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine appears to be
CA 02649893 2009-01-15
completely dissolved, the remaining ingredients are added and heated to about
65. C.
The resulting mixture is mixed with a suitable mixer while being allowed to
cool to room
temperature.
[0239] A pressure-sensitive adhesive composition of the invention contains 1-
isobutyl-
1 H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1 H-imidazo[4,5-
c]quinolin-4-
amine, fatty acid, and a pressure sensitive adhesive polymer.
[0240] The amount of 1-isobutyl-lH-imidazo[4,5-c]-quinolin-4-amine or 1-(2-
methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine present in a pressure
sensitive
adhesive composition of the invention is preferably about 0.5 percent to about
9 percent
by weight, and more preferably about 3 percent to about 7 percent by weight
based on the
total weight of the adhesive composition. The amount of fatty acid present is
preferably
about 10 percent to about 40 percent by weight, more preferably about 15
percent to
about 30 percent by weight, and most preferably about 20 percent to about 30
percent by
weight, based on the total weight of the adhesive composition.
[0241] Preferably, the adhesive polymer utilized in a pressure sensitive
adhesive
composition of the invention is substantially chemically inert to 1-isobutyl-
lH-
imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1 H-imidazo[4,5-
c]quinolin-4-
amine. The adhesive polymer is preferably present in an amount of about 55
percent
to about 85 percent by weight based on the total weight of the composition.
Suitable
adhesive polymers include acrylic adhesives that contain, as a major
constituent
(i.e., at least about 80 percent by weight of all monomers in the polymer), a
hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol,
the alkyl
alcohol containing 4 to 10 carbon atoms. Examples of suitable monomers are
those
discussed below in connection with the "A Monomer". These adhesive polymers
can
further contain minor amounts of other monomers such as the "B Monomers"
listed
below.
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CA 02649893 2009-01-15
[0242] Preferred adhesives include acrylic pressure-sensitive adhesive
copolymers containing A and B Monomers as follows: Monomer A is a hydrophobic
monomeric acrylic or methacrylic acid ester of an alkyl alcohol, the alkyl
alcohol
containing 4 to 10 carbon atoms, preferably 6 to 10 carbon atoms, more
preferably 6 to
8 carbon atoms, and most preferably 8 carbon atoms. Examples of suitable A
Monomers are n-butyl, n-pentyl, n-hexyl, isoheptyl, n-nonyl, n-decyl,
isohexyl, 2-
ethyloctyl, isooctyl and 2-ethylhexyl acrylates. The most preferred A Monomer
is
isooctyl acrylate.
[0243] Monomer B is a reinforcing monomer selected from the group consisting
of
acrylic acid; methacrylic acid; alkyl acrylates and methacrylates containing 1
to 3
carbon atoms in the alkyl group; acrylamide; methacrylamide; lower alkyl-
substituted
acrylamides (i.e., the alkyl group containing 1 to 4 carbon atoms) such as
tertiary-butyl
acrylamide; diacetone acrylamide; n-vinyl-2-pyrrolidone; vinyl ethers such as
vinyl
tertiary-butyl ether; substituted ethylenes such as derivatives of maleic
anhydride,
dimethyl itaconate and monoethyl formate and vinyl perfluoro-n-butyrate. The
preferred B Monomers are acrylic acid, methacrylic acid, the above-described
alkyl
acrylates and methacrylates, acrylamide, methacrylamide, and the above-
described
lower alkyl substituted acrylamides. The most preferred- B Monomer is
acrylamide.
[0244] In one embodiment of a pressure-sensitive adhesive composition of the
invention, the pressure-sensitive adhesive copolymer containing A and B
Monomers
as set forth above preferably contains the A Monomer in an amount by weight of
about
80 percent to about 98 percent of the total weight of all monomers in the
copolymer.
The A Monomer is more preferably present in an amount by weight of about 88
percent to about 98 percent, and is most preferably present in an amount by
weight
of about 91 percent to about 98 percent. The B Monomer in such a copolymer is
preferably present in the pressure-sensitive adhesive copolymer in an amount
by
weight of about 2 percent to about 20 percent, more preferably about 2 percent
to
about 12 percent, and most preferably 2 to 9 percent of the total weight of
the
monomers in the copolymer.
72
CA 02649893 2009-06-10
[0245] In another embodiment of a pressure-sensitive adhesive composition of
the invention, the adhesive copolymer comprises about 60 to about 80 percent
by
weight (and preferably about 70 to about 80 percent by weight) of the above-
mentioned
hydrophobic monomeric acrylic or methacrylic acid ester of an alkyl alcohol
(i.e.,
Monomer A described above) based on the total weight of all monomers in the
copolymer; about 4 to about 9 percent by weight based on the total weight of
all
monomers in the copolymer of a reinforcing monomer selected from the group
consisting of acrylic acid, methacrylic acid, an alkyl acrylate or
methacrylate containing
1 to 3 carbon atoms in the alkyl group, acrylamide, methacrylamide, a lower
alkyl-
substituted acrylamide, diacetone acrylamide and N-vinyl-2-pyrrolidone; and
about 15
to about 35 percent by weight (and preferably about 15 to about 25 percent by
weight)
of vinyl acetate based on the total weight of all monomers in the copolymer.
In this
embodiment the preferred acrylic or methacrylic acid ester is isooctyl
acrylate and the
preferred reinforcing monomer is acrylamide.
[0246] The above described adhesive copolymers are known, and methods of
preparation therefore are well known to those skilled in the art, having been
described
for example, in U.S. Pat. No. 24,906 (Ulrich). The polymerization reaction can
be carried
out using a free radical initiator such as an organic peroxide (e.g.,
benzoyiperoxide)
or an organic azo compound (e.g., 2,2'- azobis(2,4-dimethylpentanenitrile),
available
under the trade designation "Vazo 52" from DuPont).
[0247] Since pressure-sensitive adhesives such as those described above are
inherently rubbery and tacky and are suitably heat and light stable, there is
no need to
add tackifiers or stabilizers. However, such can be added if desired.
[0248] Optionally, a pressure sensitive adhesive composition of the invention
can also
contain one or more skin penetration enhancers such as glyceryl monolaurate,
ethyl
oleate, isopropyl myristate, diisopropyl adipate and N,N-dimethyldodecylamine-
N-oxide,
73
CA 02649893 2009-01-15
either as a single ingredient or as a combination of two or more ingredients.
The skin
penetration enhancer(s) preferably form a substantially homogeneous mixture
with the
pressure sensitive adhesive polymer or copolymer. The total amount of skin
penetration
enhancer(s) present in a pressure sensitive adhesive composition of the
invention is
preferably about 3 percent to about 25 percent by weight, more preferably
about 3
percent to about 10 percent by weight based on the total weight of the
adhesive
composition.
[0249] When the skin penetration enhancer is a single ingredient, it is
preferably a
skin penetration enhancer such as isopropyl myristate, diisopropyl adipate,
ethyl oleate,
or glyceryl monolaurate.
[0250] When a combination skin penetration enhancer is used, it is preferably
a
combination such as: ethyl oleate with glyceryl monolaurate; ethyl oleate with
N,N-
dimethyidodecylamine-N-oxide; glyceryl monolaurate with N,N-
dimethyldodecylamine-
N-oxide; and ethyl oleate with both glyceryl monolaurate and N,N-
dimethyldodecylamine-N-oxide.
[0251] A pressure-sensitive adhesive composition of the invention can be
prepared by
combining dry adhesive, 1-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine, fatty
acid, and
skin penetration enhancer(s) with an organic solvent. The preferred organic
solvents are
methanol and ethyl acetate. The total solids content of the adhesive coating
is
preferably in the range of about 15 percent to about 40 percent, and more
preferably in
the range of about 20 to about 35 percent based on the total weight of the
adhesive
coating. The resulting mixture is shaken or mixed for a period of about 20 to
72
hours. When this method is used it is preferred that the 1-isobutyl-1H-
imidazo[4,5-c]-
quinolin-4-amine be in micronized form (i.e., particle size of 1-2 microns in
diameter).
Optionally, the mixture can be heated during shaking.
[0252] In a preferred method, the 1-isobutyl-lH-imidazo[4,5-c]-quinolin-4-
amine or 1-
(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine is combined with the fatty
acid and
74
CA 02649893 2009-01-15
shaken at 40 C. until there appears to be complete dissolution. The remaining
ingredients are added and the mixture is shaken for a period of about 20 to 72
hours.
[0253] The pressure-sensitive adhesive compositions described above are
preferably coated onto one surface of a suitable backing of sheet material,
such as a
film, to form a pressure-sensitive adhesive coated sheet material. A pressure-
sensitive adhesive coated sheet material of the invention can be prepared by
knife
coating a suitable release liner to a predetermined uniform thickness with a
wet
adhesive formulation. This adhesive coated release liner is then dried and
laminated
onto a backing using conventional methods. Suitable release liners include
conventional release liners comprising a known sheet material, such as a
polyester
web, a polyethylene web, or a polystyrene web, or polyethylene-coated paper,
coated with a suitable silicone-type coating such as that available under the
trade
designation Daubert 164Z, from Daubert Co. The backing can be occlusive, non-
occlusive or a breathable film as desired. The backing can be any of the
conventional
materials for pressure-sensitive adhesive tapes, such as polyethylene,
particularly low
density polyethylene, linear low density polyethylene, high density
polyethylene,
randomly-oriented nylon fibers, polypropylene, ethylene-vinylacetate
copolymer,
polyurethane, rayon and the like. Backings that are layered, such as
polyethylene-
aluminum-polyethylene composites are also suitable. The backing should be
substantially non-reactive with the ingredients of the adhesive coating. The
presently
preferred backing is low density polyethylene.
[0254] The pressure-sensitive adhesive coated sheet material of the invention
can
be made in the form of an article such as a tape, a patch, a sheet, a dressing
or any
other form known to those skilled in the art.
[0255] Preferably, an article in the form of a patch is made from an adhesive
coated
sheet material of the invention and applied to the skin of a mammal. The patch
is
replaced as necessary with a fresh patch to maintain the particular desired
therapeutic
effect of the 1- isobuty1-1 H-imidazo[4,5-c]quinolin-4-amine.
CA 02649893 2009-06-10
[0256] The inherent viscosity values reported in the Examples below were
obtained by the conventional method used by those skilled in the art. The
measurement of the viscosity of dilute solutions of the adhesive, when
compared to
controls run under the same conditions, clearly demonstrates the relative
molecular weights. It is the comparative values that are significant; absolute
figures
are not required. In the examples, the inherent viscosity values were obtained
using a
Cannon-Fenske #50 viscometer to measure the flow time of 10 ml of a polymer
solution (0.2 g polymer/deciliter tetrahydrofuran, in a water bath controlled
at 25 C.).
The examples and the controls were run under identical conditions. The test
procedure
followed and the apparatus used are explained in detail in the Textbook of
Polymer
Science, F. W. Billmeyer, Wiley-Interscience, 2nd Edition, 1971 under: Polymer
chains
and their characterization, D. Solution Viscosity and Molecular Size, pp 84-
85.
[0257] As indicated herein above, and in accordance with the present
invention, the
present invention contemplates bioequivalent or interchangeable lower dosage
strength imiquimod formulations. By way of an example, bioequivalent or
interchangeable 3.75% lower dosage strength imiquimod topical formulations, as
contemplated by the present invention, include those 3.75% imiquimod
formulations
that have comparable in-vivo serum profiles, i.e., wherein the following in-
vivo
parameters are either the same or may vary up to about 25% or more (See also
FIG.
54), when such 3.75% formulations are topically administered daily to the same
individuals in the same dosage regimen in accordance with the short durations
of
therapy, such as the two-cycle therapies, of the present invention:
(a) a Day 21 Tmax of from about 4 hours to about 16 hours and preferably a
mean TmaX of about 7.4 hours with a standard deviation ("SD") of about 3.5, a
median
TmaX of about 9 hours and a geometric mean TmaX of about 6.6 hours and a
coefficient of
variation ("CV") of about 48%;
76
CA 02649893 2009-01-15
(b) a Day 21 Cmax of from about 0.07 to about 0.6 ng/ml and preferably a
mean Cmax of about 0.3 ng/ml with a standard deviation of about 0.16, a median
Cmax of
about 0.35 and a geometric mean Cmax of about 0.27 ng/ml and a coefficient of
variation
of about 49%;
(c) a Day 21 TI/2 of from about 9.7 to about 84 hours and preferably a mean
T1/2 of about 29.3 hours with a standard deviation of about 17, a median T1/2
of about
25.6 hours and a geometric mean T1/2 of about 26 hours and a coefficient of
variation of
about 58%;
(d) a Day 21 AUCO-24 of from about 1.1 to about 12 ng-hr/ml and preferably a
mean AUCO-24 of about 6 ng-hr/ml with a standard deviation of about 3, a
median AUCo_
Z4 of about 7 ng*hr/ml and a geometric mean AUCO-24 of about 5 ng-hr/ml and a
coefficient of variation of about 52%;
(e) a Day 21 Az of from about 0.008 hr' to about 0.07 hr' and preferably a
mean Az of about 0.03 hr' with a standard deviation of about 0.01, a median Az
of about
25.6 hr' and a geometric mean Az of about 0.03 hr' and a coefficient of
variation of
about 49%;
(f) a Day 21 Cmin of from about 0.06 to about 0.4 and preferably a mean Cmin
of about 0.20 with an SD of about 0.11, a median Cmin of about 0.19 and a
geometric
mean Cmin of about 0.17 and a coefficient of variation of about 55%;
(g) at Day 14/7 (a ratio of the trough concentration at Day 14 over the trough
concentration at Day 7), a trough concentration geometric mean ratio of about
1.09 with
a 90% confidence interval ("CI") within a range of between about 0.8 and about
1.5;
(h) at Day 21/14 (a ratio of the trough concentration at Day 21 over the
trough
concentration at Day 14), a trough concentration geometric mean ratio of about
1.33
with a 90% confidence interval ("Cl") within a range of between about 0.9 and
about 1.9;
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CA 02649893 2009-01-15
(i) at Day 22/21 (a ratio of the trough concentration at Day 22 over the
trough
concentration at Day 21) a trough concentration geometric mean ratio of about
0.93 with
a 90% confidence interval ("Cl") within a range of between about 0.6 and about
1.3;
(j) a mean peak imiquimod serum concentration of about 0.323 ng/ml at Day
21;
(k) a Day 21 RAUC of from about 1 to about 7 and preferably a mean RAUC
of about 4 with a standard deviation of about 2, a median RAUC of about 3.5
and a
geometric mean RAUC of about 3.3 and a coefficient of variation of about 56%;
(I) a Day 21 RCmax of from about 0.5 to about 5 and preferably a mean RCmax
of about 3 with a standard deviation of about 1.5, a median RCmax of about 2.7
and a
geometric mean RCmax of about 2.4 and a coefficient of variation of about 54%;
(m) a Day 21 L,\zeff of from about 0.006 hr' to about 0.08 hr' and preferably
a
mean LAzeff of about 0.02 hr' with a standard deviation of about 0.02, a
median L,\zeff
of about 0.01 hr' and a geometric mean LAzeff of about 0.16 hr' and a
coefficient of
variation of about 97%; and
(n) a Day 21 T'~Zeff of from about 8 hr to about 110 hr and preferably a mean
T'Zeff of about 55 hr with a standard deviation of about 36, a median T'2eff
of about 50 hr
and a geometric mean T'2eff of about 42 hr' and a coefficient of variation of
about 66%.
[0258] While the lower dosage strength imiquimod pharmaceutical formulations
of
the present invention can be formulated into any form known to the art, such
as a
cream, an ointment, a foam, a gel, a lotion or a pressure-sensitive adhesive
composition or patch, it should be understood that the creams, ointments,
foams, gels
and lotions may be packaged into any suitable container, such as unit-dose
sachets or
packets or multi-dose tubes or containers. A packaged amount of an imiquimod
78
CA 02649893 2009-06-10
pharmaceutical formulation contemplated by the present invention includes any
suitable
amount, such as about 250 mg to about 500 mg or more, and preferably about 250
mg,
about 300 mg, about 350 mg, about 400 mg, about 450 mg or about 500 mg unit-
dose
sachets or packets.
[0259] Examples of various embodiments of the present invention will now be
further
illustrated with reference to the following examples. Thus, the following
examples are
provided to illustrate the invention, but are not intended to be limiting
thereof. Parts
and percentages are by weight unless otherwise specified. Examples of creams,
ointments and pressure sensitive adhesive compositions contemplated by the
present
invention are described in U.S. Patent No. 4,689,338 and U.S. Patent No.
5,238,944.
Percent modifications for, e.g., imiquimod and vehicle, to generate imiquimod
formulations as described herein are likewise contemplated by the present
invention. In
addition, the formulations described and disclosed in U.S. Patent Publication
No.
2007/0123558, Serial No. 11/276,324, U.S. Patent Publication No. 2007/0264317,
Serial No. 433,471, and US2007/0900550, Publication No. W02008098232 (Al), are
also contemplated by the present invention.
PREPARATIVE METHOD 1
Laboratory Scale Preparation of Isooctylacrylate/Acrylamide Copolymer
[0260] To a 114 gram narrow-mouth glass bottle were added: 18.6 g isooctyl
acrylate, 1.4 g acrylamide, 0.04 g benzoyl peroxide, 27.0 g ethyl acetate and
3.0 g
methanol. The solution was purged for thirty five seconds with nitrogen at a
flow rate of
one liter per minute. The bottle was sealed and placed in a rotating water
bath at 55 C
for twenty-four hours to effect essentially complete polymerization. The
polymer was
diluted with ethyl acetate/methanol (90/10) to 23.2 percent solids and had a
measured
inherent viscosity of 1.26 dl/g in ethyl acetate.
79
CA 02649893 2009-01-15
PREPARATIVE METHOD 2
Pilot Plant Scale Preparation of Isooctylacrylate/Acrylamide Copolymer
[0261] 155 kg isooctylacrylate, 11.6 kg acrylamide, 209.1 kg ethyl acetate and
23.2 kg
methanol were charged to a clean, dry reactor. Medium agitation was applied.
The
batch was deoxygenated with nitrogen while heating to an induction temperature
of
55 C. 114 g LucidolT"^ 70 initiator (available from Pennwalt Corp.) mixed with
2.3 kg
ethyl acetate was charged to the reactor. The temperature was maintained at 55
C.
throughout the reaction. After 5.5 hours reaction time, 114 g LucidolT"" 70
mixed with
2.3 kg ethyl acetate were charged to the reactor. After 9.0 hours reaction
time, an
additional 114 g LucidolT"' 70 initiator mixed with 2.3 kg ethyl acetate were
charged to the
reactor. The reaction was continued until the percent conversion was greater
than 98
percent as measured by gas chromatographic evaluation of residual monomer
concentration. The resulting polymer solution was diluted to 25-28 percent
solids with
ethyl acetate/methanol (90/10) and had a measured Brookfield viscosity of
17,000-
21,000 centipoises using spindle #4 at 12 rpm. The polymer had a measured
inherent
viscosity of 1.3-1.4 dllg in ethyl acetate.
[0262] The above-mentioned procedure was found to provide a pressure-sensitive
adhesive that is equivalent in the practice of the present invention to a
pressure-
sensitive adhesive prepared according to Preparative Method 1.
[0263] A 25-30 percent solids solution of the isooctyl acrylate:acrylamide
(93:7)
adhesive copolymer in ethyl acetate/methanol (90:10) was coated onto a two-
sided
release liner using a knife-coater and coating at 0.5 mm in thickness. The
adhesive-
coated laminate was dried first at 82 C for 3 minutes and then at 116 C for 3
minutes. The dried adhesive coating was then stripped off the release liner
and placed
in a glass bottle. The foregoing procedure results in a reduction of the
amount of any
residual monomer in the adhesive copolymer.
CA 02649893 2009-01-15
PREPARATIVE METHOD 3
Preparation of Isooctyl Acrylate: Acrylamide: Vinyl Acetate (75:5:20)
Copolymer
[0264] The procedure of Preparative Method 1 above acrylate, 8.0 g acrylamide,
32.0 g vinyl acetate, 0.32 g benzoyl peroxide, 216.0 g ethyl acetate and 24.0
g methyl
alcohol. The resulting polymer was diluted with the ethyl acetate/methyl
alcohol
mixture to 21.52% solids. The adhesive polymer had a measured inherent
viscosity of
1.40 dl/g in ethyl acetate at a concentration of 0.15 g/dI. Its Brookfield
viscosity was
2,300 centipoise.
PREPARATIVE METHOD 4
Preparation of Isooctyl Acrylate Acrylamide: Vinyl Acetate (75:5:20) Copolymer
[0265] A master batch was prepared by combining 621.0 g of isooctyl acrylate,
41.4
g of acrylamide, 165.6 g of vinyl acetate, 1.656 g of 2,2'-azobis(2,4-
dimethylpentanenitrile) (available from the DuPont Company as Vazo.TM.52),
884.52
g of ethyl acetate and 87.48 g of methanol. A 400 g portion of the resulting
solution
was placed in an amber quart bottle. The bottle was purged for two minutes
with
nitrogen at a flow rate of one liter per minute. The bottle was sealed and
placed in a
rotating water bath at 45 C for twenty-four hours to effect essentially
complete
polymerization. The copolymer was diluted with 250 g of ethyl acetate/methanol
(90/10) to 26.05% solids and had a measured inherent viscosity of 1.27 dl/g in
ethyl
acetate at a concentration of 0.15 g/dl. Its Brookfield viscosity was 5580
centipoise.
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EXAMPLE 1
[0266] A cream according to the present invention is prepared from the
following
ingredients:
% by Weight Amount
Oil Phase
1-isobutyl-1H-imidazo[4,5-c]-quinolin-4- 1.0 40.0 g
amine
lsostearic acid 10.0 400.0 g
Benzyl alcohol 2.0 80.0 g
Cetyl alcohol 2.2 88.0 g
Stearyl alcohol 3.1 124.0 g
Polysorbate 60 2.55 102.0 g
Sorbitan monostearate 0.45 18.0 g
Aqueous Phase Glycerin 2.0 80.0 g
Methylparaben 0.2 8.0 g
Propylparaben 0.02 0.8 g
Purified water 76.48 3059.2 g
[0267] The materials listed above were combined according to the following
procedure:
The glycerin, methylparaben, propylparaben and water were weighed into a 4
liter glass beaker then heated on a hot plate with stirring until the parabens
isostearic
acid and 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine were weighed into an 8
liter
stainless steel beaker and heated on a hot plate until the amine was in
solution (the
temperature reached 69 C.). The benzyl alcohol, cetyl alcohol, stearyl
alcohol,
polysorbate 60 and sorbitan monostearate were added to the isostearic acid
solution
and heated on a hot plate until all material was dissolved (the temperature
reached
75 C.). With both phases at approximately the same temperature (65 -75 C.),
the
water phase was added to the oil phase. The mixture was mixed with a
homogenizer
for 13 minutes then put into a cool water bath and mixed with a 3 inch
propeller for 40
minutes (the temperature was 29 C.). The resulting cream was placed in glass
jars.
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EXAMPLES 2-9
[0268] Using the general method of Example 1, the cream formulations shown in
Tables 1 and 2 are prepared.
Table 1
% by Weight
Example Example Example Example 5
2 3 4
Oil Phase
1-isobutyl-1 H-imidazo-[4,5- 1.0 1.0 1.0 1.0
c]quinolin-4-amine
Isostearic acid 10.0 10.0 5.0 5.0
Benzyl alcohol 2.0
Cetyl alcohol 1.7
Stearyl alcohol 2.3
Cetearyl alcohol 6.0 6.0 6.0
Polysorbate 60 2.55 2.55 2.55 2.55
Sorbitan monostearate 0.45 0.45 0.45 0.45
BrijTM 30a 10.0
Aqueous Phase
Glycerin 2.0 2.0 2.0 2.0
Methylparaben 0.2 0.2 0.2 0.2
Propylparaben 0.02 - 0.02 0.02 0.02
Purified water 77.78 77.78 82.78 72.78
a BrijTM 30 (polyoxyethylene(4) lauryl ether) is available from ICI Americas,
Inc.
Table 2
% by Weight
Example Example Example Example
6 7 8 9
Oil Phase
1-isobutyl-1 H-imidazo-[4,5- 1.0 1.0 1.0 1.0
c]quinolin-4- amine
Isostearic acid 10.0 25.0 10.0 6.0
Benzyl alcohol 2.0 2.0
Cetyl alcohol 2.2 1.7
Stearyl alcohol 3.1 2.3
Cetearyl alcohol 6.0 6.0
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Polysorbate 60 2.55 3.4 2.55 2.55
Sorbitan monostearate 0.45 0.6 0.45 0.45
BrijTM 30a 10.0
Aqueous Phase
Glycerin 2.0 2.0 2.0 2.0
Methylparaben 0.2 0.2 0.2 0.2
Propylparaben 0.02 0.02 0.02 0.02
Purified water 67.78 60.48 79.78 79.78
a BrijTM 30 (polyoxyethylene(4) lauryl ether) is available from ICI Americas,
Inc.
EXAMPLE 10
[0269] A cream according to the present invention is prepared from the
following
ingredients in the following Table 3:
Table 3
% by Weight Amount
Oil Phase
1-isobutyl-1H-imidazo[4,5- 1.0 3.00 g
c]quinolin-4-amine
Isostearic acid 5.0 15.0 g
White petrolatum 15.0 45.0 g
Light mineral oil 12.8 38.4 g
1 Aluminum stearate 8.0 24.0 g
Cetyl alcohol 4.0 12.0 g
WitconolT"" 14a 3.0 9.00 g
Acetylated lanolin 1.0 3.0 g
Propylparaben 0.063 0.19 g
Aqueous Phase
VeegumTM K' 1.0 3.0 g
Methylparaben 0.12 0.36 g
Purified water 49.017 147.05 g
a WitconolTM 14 (polyglyceryl4 oleate) is available from Witco Chemical Corp.
Organics
Division
b VeegumTM K (colloidal magnesium aluminum silicate) is available from R. T.
Vanderbilt Company Inc.
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[0270] The materials listed above were combined according to the following
procedure:
The 1-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine and the isostearic acid were
weighed into a glass jar and heated with occasional stirring until the amine
was dissolved
(the temperature reached 68 C.). To this solution was added, the petrolatum,
mineral oil,
aluminum stearate, cetyl alcohol, WitconolT"" 14, acetylated lanoline and
propylparaben. The mixture was heated to 75 C. In a separate beaker, the
methylparaben and water were combined and heated until the paraben dissolved
(the
temperature reached 61 C.). The VeegumTM K was added to the aqueous solution
and heated at 75 C. for 30 minutes while mixing with a homogenizer. With both
phases
at 75 C., the aqueous phase was slowly added to the oil phase while mixing
with a
homogenizer. Mixing was continued for 30 minutes while maintaining a
temperature to
about 80 C. The jar was then capped and the formulation was allowed to cool.
EXAMPLE 11
[0271] An ointment according to the present invention is prepared from the
ingredients in
the following Table 4:
Table 4
% by Weight Amount
1 -isobutyl-1 H-imidazo[4,5-c]quinolin-4- 1.0 0.20 g
amine
Isostearic acid 5.0 1.00 g
Mineral oil 12.8 2.56 g
White petrolatum 65.2 13.04 g
Cetyl alcohol 4.0 0.80 g
Acetylated lanolin 1.0 0.20 g
WitconolTM 143.0 0.60 g
Aluminum stearate 8.0 1.60 g
CA 02649893 2009-01-15
[0272] The materials listed above are combined according to the following
procedure:
The 1-isobutyl-lH-imidazo[4,5-c]quinolin-4-amine and the isostearic acid were
placed in a glass jar and heated with stirring until the amine was dissolved.
The
remaining ingredients were added and the resulting mixture was heated to 65 C.
and
then mixed while being allowed to cool to room temperature.
EXAMPLE 12
[0273] Using the general procedure of Example 11 an ointment containing the
ingredients in the following Table 5 is prepared.
Table 5
% by Weight Amount
1-Tsobuty1-1f-/-imidazo[4,5-c]quinolin-4- 1.0 0.20 g
amine
Isostearic acid 6.0 1.20 g
Polyethylene Glycol 400 55.8 11.16 g
Polyethylene Glycol 3350 32.6 6.52 g
Stearyl alcohol 4.6 0.92 g
EXAMPLES 13-15
[0274] Creams of the present invention are prepared using the ingredients
shown in
Table 6. The Example I except that benzyl alcohol was used with the isostearic
acid to
dissolve the 1-isobuty1-1H-imidazo [4,5-c] quinolin-4- amine.
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TABLE 6
Example 13 Example 14 Example 15
Amount % by Amount % by Amount % by
Oil Phase Weight Weight Weight
1 -isobutyl-1 H-imidazo[4,5-c]quinolin- 50 5.0 4.85
4-amine
Isostearic acid 25.0 25.0 24.3
Benzyl alcohol 2.0 2.0 1.94
Cetyl alcohol 2.2 2.2 1.16
Stearyl alcohol 3.1 3.1 1.75
Petrolatum 3.0 2.91
Polysorbate 60 3.4 3.4 4.13
Sorbitan monostearate 0.6 0.6 0.73
Stearic acid 9.71
Aqueous Phase
Glycerin 2.0 2.0 1.94
Methylparaben 0.2 " 0.2 0.19
Propylparaben 0.02 0.02 0.02
EXAMPLE 16
[0275] A cream according to the present invention is prepared from the
ingredients in
the following Table 7:
Table 7
% by Weight % by Weight Amount
Oil Phase Amount
1 -isobutyl-1 H-imidazo[4,5-c]quinolin-4- 4.0 0.80 g
amine
Isostearic acid 20.0 4.00 g
Benzyl alcohol 2.0 0.40 g
Cetyl alcohol 2.2 0.49 g
Stearyl alcohol 3.1 0.62 g
Polysorbate 60 3.4 0.68 g
Sorbitan monostearate 0.6 0.12 g
Aqueous Phase
1-isobutyl-lH-imidazo [4,5-c]quinolin-4- 1.0 0.2 g
amine
Glycerin 2.0 0.4 g
85% Lactic acid 1.0 0.22 g
Methylparaben 0.2 0.04 g
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Propylparaben 0.02 0.004 g
Purified water 60.48 12.0 g
[0276] The materials listed above are combined according to the following
procedure:
The isostearic acid and 0.8 g of 1-isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine
or
1-(2-methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine were combined in a glass
jar and
heated with stirring until the amine had dissolved. The remaining oil phase
ingredients
were added to this solution and the mixture was heated to about 70 C. The
aqueous
phase ingredients were weighed into a separate beaker and heated with stirring
until the
amine and the parabens had dissolved. With both phases at about 70 C., the
water
phase was added to the oil phase and mixed with a propeller until the mixture
cooled to
room temperature.
EXAMPLE 17
[0277] A mixture of 5.9415 g of the 93:7 isooctyl acrylate:acrylamide adhesive
copolymer prepared in PREPARATIVE METHOD 2 above, 1.5126 g isostearic acid,
2.0075 g ethyl oleate, 0.3021 g glyceryl monolaurate, 0.2936 1-isobutyl-lH-
imidazo[4,5-
c]quinolin-4-amine- (micronized) and 23.7 g of 90:10 ethyl acetate: methanol
was
placed in a small glass jar. The jar was placed on a horizontal shaker and
shaken at
room temperature for about 13 hours. The formulation was coated at a thickness
of 20
mils onto a 5 mil Daubert 164Z liner. The laminate was oven dried for 3
minutes at
105 F., for 2 minutes at 185 F., and for 2 minutes at 210 F. The resulting
adhesive
coating contained 59.1 percent 93:7 isooctyl acrylate:acylamide adhesive
copolymer, 15.0
percent isostearic acid, 20.0 percent ethyl oleate, 3.0 percent glyceryl
monolaurate and
2.9 percent 1-isobuty1-lH-imidazo[4,5-c]quinolin-4-amine. The material was
then
laminated with 3 mil low density polyethylene backing and die cut into 2.056
cm2
patches.
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EXAMPLES 18-20
Pressure-Sensitive Adhesive Coated Sheet Materials Prepared Using Unmicronized
1-
isobutyl-1 H-imidazo[4,5-c]quinolin-4-amine
[0278] Using the general method of Example 17 the formulations shown below are
prepared. 1-Isobutyl-IH-imidazo[4,5-c]quinolin-4-amine or 1-(2-methylpropyl)-1
H-
imidazo[4,5-c]quinolin-4-amine that had been ground with a mortar and pestle
was
used. The adhesive was the 93:7 isooctyl acrylate:acrylamide copolymer
prepared in
Preparative Method 1 above. The solvent was 90:10 ethyl acetate:methanol. All
formulations in the following Table 8 were mixed at room temperature.
Table 8
Example 18 Example 19 Example 20
1 -isobutyl-1 H-imidazo[4,5-c]quinolin- 5.0 3.0 3.0
4-amine
Ethyl oleate 5.1 5.0 8.0
Isostearic acid 10.0 10.0 6.0
Oleic acid 20.0 20.0 13.0
Glyceryl monolaurate 1.5 1.5 1.5
N,N-dimethyldodecylamine- 1.0 1.1 3.0
N-oxide Adhesive 57.4 59.3 65.4
EXAMPLE 21
[0279] A formulation with the same components in the same proportions as
Example
18 is prepared using a different method. The 1-isobutyl-lH-imidazo[4,5-c]-
quinolin-4-
amine or 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine was combined
with the
oleic and isostearic acids and shaken at 40 C. until there was complete
dissolution of
the 1 -isobutyl-1 H-imidazo-[4,5-c]quinolin-4-amine or 1-(2-methylpropyl)-1H-
imidazo[4,5-
c]quinolin-4-amine. The remaining ingredients were added and shaken a 40 C.
for 72
hours. Patches measuring 2.056 cm2 were prepared by the general method of
Example 17.
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EXAMPLE 22
[0280] A mixture of 2.4734 g 1-isobutyl-lH-imidazo[4,5-c]-quinolin-4-amine or
1-(2-
methylpropyl)-1 H-imidazo[4,5-c]quinolin-4-amine, 3.3315 g isostearic acid and
6.6763 g
oleic acid is prepared. To 1.8738 g of the above mixture was added 2.8750 g of
the
93:7 isooctyl acrylate:acryamide adhesive copolymer prepared in Preparative
Method 2
above, 0.2548 g of ethyl oleate, 0.0510 g N,N-dimethyldodecylamine-N-oxide,
0.0820
g glyceryl monolaurate (from Lauricidin, Inc.) and 14.0457 g of 90:10 ethyl
acetate/methanol. The above was shaken for 30 hours at room temperature on a
horizontal shaker. Transdermal patches were then prepared generally according
to the
procedures of Example 17.
EXAMPLE 23
Topical Imiquimod Pharmaceutical Cream Formulations
[0281] Creams are prepared in accordance with the present invention using the
ingredients shown in this Example 23.
[0282] The materials listed below in this Example 23 are combined according to
the
following procedure to make cream formulations in the following Table 9 of
this
Example 23:
CA 02649893 2009-01-15
Table 9. Lower Dosage Strength Imiquimod Formulations
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 1 2 3 4 5 6
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 68.98 66.98 64.98 61.98 60.73 60.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 7 8 9 10 11 12
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 66.98 60.98 60.98 57.08 58.98 55.78
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 13 14 15 16 17 18
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 56.48 67.08 59.98 5&.98 56.98 61.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.00 1.00 1.00 1.00 1.00 1.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 19 20 21 22 23 24
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 68.73 66.73 64.73 61.73 60.48 60.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w /aw/w %w/w %w/w %w/w
Formulation 25 26 27 28 29 30
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 66.73 60.73 60.73 56.83 58.73 55.53
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 31 32 33 34 35 36
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 56.23 66.83 59.73 58.73 56.73 61.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.25 1.25 1.25 1.25 1.25 1.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 37 38 39 40 41 42
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 68.48 66.48 64.48 61.48 60.23 60.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 43 44 45 46 47 48
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 66.48 60.48 60.48 56.58 58.48 55.28
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 49 50 51 52 53 54
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 55.98 66.58 59.48 58.48 56.48 61.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.50 1.50 1.50 1.50 1.50 1.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 55 56 57 58 59 60
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 68.23 66.23 64.23 61.23 59.98 59.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75
Total 100.00 100.00 100.00 100.00 100.00 100.00
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 61 62 63 64 65 66
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
-Purified water 66.23 60.23 60.23 56.33 58.23 55.03
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 67 68 69 70 71 72
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 55.73 66.33 59.23 58.23 56.23 61.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 1.75 1.75 1.75 1.75 1.75 1.75
Total 100.00 100.00 100'.00 100.00 100.00 100.00
96
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 73 74 75 76 77 78
Fatty acid* 10.00 12.50 25.00 10.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.70 4.00 4.00 2.20
Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.10
White petrolatum 5.00 5.00 3.00 3.40 2.80 3.00
Polysorbate 60 3.40 3.40 3.40 3.80 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 1.00 1.00 1.00
Glycerin 5.00 5.00 2.00 1.00 3.00 3.00
Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.75
Purified water 65.98 63.48 54.78 70.28 64.28 59.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 79 80 81 82 83 84
Fatty acid* 10.00 12.50 25.00 10.00 15.00 25.00
Cetyl alcohol 2.20 2.20 2.70 4.00 4.00 2.70
Stearyl alcohol 3.10 3.10 3.80 2.00 2.00 3.80
White petrolatum 5.00 5.00 3.00 3.40 2.80 3.00
F'olysorbate 60 3.40 3.40 3.40 3.80 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 0.60 1.00 1.00 0.60
Glycerin 5.00 5.00 2.00 1.00 3.00 2.00
Xanthan gum 0.50 0.50 0.50 0.30 0.70 0.50
Purified water 65.98 63.48 54.78 70.28 64.28 54.78
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02,
Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00
1ota1 100.00 100.00 100.00 100.00 100.00 100.00
97
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 85 86 87 88 89 90
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 55.48 66.08 58.98 57.98 -55.98 60.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.00 2.00 2.00 2.00 2.00 2.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 91 92 93 94 95 96
Fatty acid* 15.00 12.50 25.00 15.00 10.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.00 2.00 2.20
Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.10
White petrolatum 6.00 5.00 3.00 3.40 2.80 3.00
Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.00
Sorbitan
Monostearate 1.00 1.00 0.60 0.20 1.00 1.00
Glycerin 5.00 5.00 2.00 3.00 3.00 3.00
Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.75
Purified water 60.23 63.23 55.23 66.83 70.23 59.48
Benzyl alcohol 1.00 2.00 2.00 1.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
98
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 97 98 99 100 101 102
Fatty acid* 15.00 12.50 25.00 15.00 10.00 25.00
Cetyl alcohol 2.20 2.20 2.20 2.00 2.00 2.70
Stearyl alcohol 3.10 3.10 3.10 2.00 2.40 3.80
White petrolatum 6.00 5.00 3.00 3.40 2.80 3.00
Polysorbate 60 3.00 3.00 3.40 3.80 3.80 3.40
Sorbitan
Monostearate 1.00 1.00 0.60 0.20 1.00 0.60
Glycerin 5.00 5.00 2.00 3.00 3.00 2.00
Xanthan gum 1.00 0.50 1.00 0.30 0.30 0.50
Purified water 60.23 63.23 55.23 66.83 70.23 54.53
Benzyl alcohol 1.00 2.00 2.00 1.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 103 104 105 106 107 108
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 55.23 65.83 58.73 57.73 55.73 60.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.25 2.25 2.25 2.25 2.25 2.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
99
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 109 110 111 112 113 114
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 2.50 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 65.98 65.48 63.48 60.48 59.23 59.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 115 116 117 118 119 120
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 65.48 59.48 59.48 55.58 57.48 54.28
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
100
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 121 122 123 124 125 126
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 54.98 65.58 58.48 57.48 55.48 60.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 2.50 2.50 2.50 2.50 2.50 2.50
L_Total 100.00 100.00 100.00 100.00 100.00 100.00
~- Excipients %w/w %w/w %w/w aw/w %w/w %w/w
F
Formulation 127 128 129 130 131 132
Fatty acid* 15.00 18.00 15.00 20.00 12.50 20.00
Cetyl alcohol 2.00 2.00 2.00 2.00 2.20 2.20
Stearyl alcohol 2.00 2.00 2.40 2.40 3.10 3.10
, White petrolatum 3.40 2.80 3.40 2.80 5.00 3.00
_Polysorbate 60 3.00 3.80 3.00 3.00 3.40 3.00
Sorbitan
Monostearate 1.00 1.00 0.20 0.20 0.60 1.00
Glycerin 3.00 2.00 1.00 3.00 6.00 3.00
Xanthan gum 0.30 0.70 0.70 0.30 0.50 0.75
r Purified water 65.08 62.48 67.08 61.08 61.48 58.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3-.00 3.00 3.00 3.00 3.00 3.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
101
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 133 134 135 136 137 138
Fatty acid* 15.00 18.00 15.00 20.00 12.50 25.00
Cetyl alcohol 2.00 2.00 2.00 2.00 2.20 2.70
Stearyl alcohol 2.00 2.00 2.40 2.40 3.10 3.80
White petrolatum 3.40 2.80 3.40 2.80 5.00 3.00
Polysorbate 60 3.00 3.80 3.00 3.00 3.40 3.40
Sorbitan
Monostearate 1.00 1.00 0.20 0.20 0.60 0.60
Glycerin 3.00 2.00 1.00 3.00 6.00 2.00
Xanthan gum 0.30 0.70 0.70 0.30 0.50 0.50
Purified water 65.08 62.48 67.08 61.08 61.48 53.78
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
lmiquimod 3.00 3.00 3.00 3.00 3.00 3.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 139 140 141 142 143 144
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 54.48 65.08 57.98 56.98 54.98 59.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.00 3.00 3.00 3.00 3.00 3.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
102
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 145 146 147 148 149 150
Fatty acid* 15.00 20.00 15.00 20.00 10.00 20.00
Cetyl alcohol 2.00 2.00 4.00 4.00 2.20 2.20
Stearyl alcohol 2.00 2.40 2.40 2.40 3.10 3.10
White petrolatum 3.40 2.80 2.50 3.40 5.00 3.00
Polysorbate 60 3.00 3.00 3.00 3.80 3.40 3.00
Sorbitan
Monostearate 1.00 0.20 1.00 1.00 0.60 1.00
Glycerin 3.00 3.00 1.00 3.00 5.00 3.00
Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.75
Purified water 64.83 60.83 - 65.33 57.23 64.73 58.48
Benzyl alcohol 2.00 2.00 2.00 1.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 151 152 153 154 155 156
Fatty acid* 15.00 20.00 15.00 20.00 10.00 25.00
Cetyl alcohol 2.00 2.00 4.00 4.00 2.20 2.70
Stearyl alcohol 2.00 2.40 2.40 2.40 3.10 3.80
White petrolatum 3.40 2.80 2.50 3.40 5.00 3.00
Polysorbate 60 3.00 3.00 3.00 3.80 3.40 3.40
Sorbitan
Monostearate 1.00 0.20 1.00 1.00 0.60 0.60
Glycerin 3.00 3.00 1.00 3.00 5.00 2.00
Xanthan gum 0.30 0.30 0.30 0.70 0.50 0.50
Purified water 64.83 60.83 65.33 57.23 64.73 53.53
Benzyl alcohol 2.00 2.00 2.00 1.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
103
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 157 158 159 160 161 162
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 54.23 64.83 59.98 56.7-3 54.73 59.73
Benzyl alcohol 2.00 2.00 2.00 2.00. 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.25 3.25 3.25 3.25 3.25 3.25
1_Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 163 164 165 166 167 168
Fatty acid* 15.00 10.00 12.50 19.00 20.00 20.00
Cetyl alcohol 2.00 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10
White petrolatum 3.40 5.00 5.00 3.00 3.00 3.00
Polysorbate 60 3.00 3.40 4.00 3.40 3.40 3.00
Sorbitan
Monostearate 0.20 0.60 0.60 0.60 0.60 1.00
Glycerin 1.00 4.00 5.00 2.00 6.00 3.00
Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.75
Purified water 66.58 65.48 61.38 60.48 56.48 58.23
Benzyl alcohol 2.00 2.00 2.00 2.00 1.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
104
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 169 170 171 172 173 174
Fatty acid* 15.00 10.00 12.50 19.00 20.00 25.00
Cetyl alcohol 2.00 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.40 5.00 5.00 3.00 3.00 3.00
Polysorbate 60 3.00 3.40 4.00 3.40 3.40 3.40
Sorbitan
Monostearate 0.20 0.60 0.60 0.60 0.60 0.60
Glycerin 1.00 4.00 5.00 2.00 6.00 2.00
Xanthan gum 0.70 0.50 0.50 0.50 0.50 0.50
Purified water 66.58 65.48 61.38 60.48 56.48 53.28
Benzyl alcohol 2.00 2.00 2.00 2.00 1.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 175 176 177 178 179 180
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petroiatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 53.98 64.58 57.48 56.48 54.48 59.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.50 3.50 3.50 3.50 3.50 3.50
Total 100.00 100.00 100.00 100.00 100.00 100.00
105
CA 02649893 2009-01-15
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 181 182 183 184 185 186
Fatty acid* 20.00 20.00 25.00 18.75 20.00 21.25
Cetyl alcohol 4.00 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 2.40 3.10 3.10 3.10 3.10 3.10
White petrolatum 2.80 3.00 3.00 5.00 5.00 3.75
Polysorbate 60 3.00 3.40 3.40 3.00 3.40 3.40
Sorbitan
Monostearate 1.00 0.60 0.60 1.00 0.60 0.60
Glycerin 1.00 2.00 2.00 5.00 5.00 5.00
Xanthan gum 0.30 0.50 0.50 0.50 0.50 0.50
Purified water 64.53 59.23 54.23 55.48 54.23 54.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 187 188 189 190 191 192
Fatty acid* 20.00 20.00 20.00 25.00 18.75 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 59.23 53.23 53.23 54.33 55.48 53.03
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 193 194 195 196 197 198
Fatty acid* 25.00 20.00 20.00 20.00 20.00 21.00
Cetyl alcohol 2.20 4.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.40 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 5.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan 0.60 1.00 0.60 0.60 0.60 0.60
Monostearate
Glycerin 2.00 3.00 2.00 5.00 5.00 5.00
Xanthan gum 1.00 0.70 0.50 0.50 0.50 0.50
Purified water 53.73 55.73 57.23 56.23 54.23 53.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.75 3.75 3.75 3.75 3.75 3.75
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 199 200 201 202 203 204
Fatty acid* 20.00 25.00 22.50 20.00 20.00 22.50
Cetyl alcohol 2.20 2.70 2.20 4.00 2.20 2.20
Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10
White petrolatum 6.00 3.00 3.00 3.40 5.00 4.00
Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40
Sorbitan
Monostearate 1.00 0.60 0.60 1.00 0.60 0.60
Glycerin 5.00 2.00 2.00 3.00 2.00 2.00
Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50
Purified water 52.98 52.78 55.98 55.48 56.98 55.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 205 206 207 208 209 210
Fatty acid* 20.00 25.00 22.50 20.00 20.00 22.50
Cetyl alcohol 2.20 2.70 2.20 4.00 2.20 2.20
Stearyl alcohol 3.10 3.80 3.10 2.40 3.10 3.10
White petrolatum 6.00 3.00 3.00 3.40 5.00 4.00
Polysorbate 60 3.00 3.40 3.40 3.80 3.40 3.40
Sorbitan
Monostearate 1.00 0.60 0.60 1.00 0.60 0.60
Glycerin 5.00 2.00 2.00 3.00 2.00 2.00
Xanthan gum 0.50 0.50 1.00 0.70 0.50 0.50
Purified water 52.98 52.78 55.98 55.48 56.98 55.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 211 212 213 214 215 216
Fatty acid* 25.00 15.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.2 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 53.48 64.08 56.98 55.98 53.98 58.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.00 4.00 4.00 4.00 4.00 4.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
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- Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 217 218 219 220 221 222
Fatty acid* 15.00 15.00 15.00 20.00 15.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.10
White petrolatum 1.00 3.00 2.00 3.00 6.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.00 3.00
Sorbitan
Monostearate 0.60 0.60 0.60 0.60 1.00 1.00
Glycerin 2.00 2.00 5.00 2.00 5.00 3.00
Xanthan gum 0.50 0.50 0.50 0.50 0.75 0.75
Purified water 65.73 63.73 61.73 58.73 57.48 57.48
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 223 224 225 226 227 228
Fatty acid* 15.00 15.00 15.00 25.00 18.0 25.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 3.80
White petrolatum 3.00 6.00 6.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40
Sorbitan
Monostearate 0.60 0.60 1.00 0.50 1.00 0.60
Glycerin 2.00 5.00 5.00 2.00 5.00 2.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 0.50
Purified water 63.73 57.73 57.73 53.83 55.73 52.53
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
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Excipients %w/w %w/w %w/w %w/w %w/w %w/w
Formulation 229 230 231 232 233 234
Fatty acid* 25.00 15.00 20.00 20.00 20.0 20.00
Cetyl alcohol 2.20 2.00 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 2.00 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.40 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.80 3.40 3.40 3.40 3.40
Sorbitan
Monostearate 0.60 0.20 0.60 0.60 0.60 0.60
Glycerin 2.00 3.00 2.00 5.00 5.00 2.00
Xanthan gum 1.00 0.30 0.50 0.50 0.50 0.50
Purified water 53.23 63.83 56.73 55.73 53.73 58.73
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 . 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 4.25 4.25 4.25 4.25 4.25 4.25
Total 100.00 100.00 100.00 100.00 100.00 100.00
*The Fatty acid referenced in thisTable 9 can be, for example, linoleic acid
(la), stearic acid (sa),
palmitic acid (pa), isostearic acid (isa), unrefined oleic acid, (uoa),
refined oleic acid, such as
super refined oleic acid (roa), or mixtures thereof.
[0283] The work area, all vessels and equipment is initially cleaned prior to
commencing manufacture. A 2 L glass container and paddle stirrer blade are
placed
onto a balance and the weight is recorded. The paddle is then removed from the
vessel. The isostearic acid and benzyl alcohol are weighed directly into the 2
L glass
container. The imiquimod is then weighed into the 2 L glass container and a
spatula
is used to ensure the imiquimod is wetted with the isostearic acid and benzyl
alcohol
mixture. The 2 L container is then heated in a water bath to about 55 5 C
while
stirring with a Heidolph mixer (Note: aluminum foil is placed around the top
of the
vessel and the paddle for the mixer, to limit evaporation). The solution is
visually
inspected to confirm the imiquimod has fully dissolved prior to mixing with
cetyl alcohol,
stearyl alcohol, white petrolatum, polysorbate 60 and sorbitan monostearate.
Cetyl
alcohol, stearyl alcohol, white petrolatum, polysorbate 60 and sorbitan
monostearate
are then weighed directly into the 2 L container and mixing is continued at
about 55 5
C until the oil phase is completely in solution. Separately, about 2 L of
water are
placed into a beaker and heated to 55 5 C while stirring with a magnetic
follower.
Briefly, about 500 ml of the- heated water is transferred into a 1 L beaker
and placed
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into the water bath maintained at about 55 5 C. Half of the amount of
glycerin
required for the final formulation is then weighed into the beaker along with
the total
amount of methylparaben and propylparaben to the water (where both methyl and
propyl paraben are weighed into weighing boats first, a pipette is used to
remove a
portion of the heated water to wash out the weighing boats to ensure total
transfer of
both the propyl- and methylparaben into the aqueous phase). The mixture is
continuously stirred at about 55 5 C (this is the aqueous phase). The
remaining
glycerin is then added to a 28 ml vial and the xanthan gum is added and mixed
using a
small overhead mixer (IKAO-Werke Lab Egg) with paddle attachment for about 10
min.
The glycerin and xanthan mixture are then added slowly into the vortex of the
aqueous
phase, and a further aliquot of about 20 ml of heated water is used to rinse
the vessel
out into the water phase to ensure complete transfer. The water phase is then
heated
and mixed at about 55 5 C until the xanthan gum mixture is fully and evenly
dispersed
into the aqueous phase. The temperatures of both the water phase and oil phase
are
both maintained at about 55 5 C. The aqueous phase is then transferred into
the oil
phase and the speed of the Heidolph mixer is increased during addition. The
mixture is
then homogenized on high speed for about 3 min and transferred immediately
back to
the Heidolph mixture; however, the contents of the homogenized sample, about 2
L,
are mixed at about room temperature and allowed to cool to about 35 C. The
container
and contents and the paddle from the overhead mixer are then re-weighed and
the
weight of the paddle and 2 L beaker, as determined above, are subtracted to
determine the total weight of the formulation remaining. The total weight
(about 1 kg) of
the cream is then made up to weight with heated water (Note: water evaporated
during
heating, which needs to be corrected at this point). The mixture is then
transferred
back onto the Heidolph mixer at about room temperature and mixed until the
temperature of the formulation is below about 28 C. The lid of the container
is then
placed onto the vessel and stored at room temperature.
[0284] The lower dosage strength formulations of this Example 23 are believed
to be
stable and consistent with the specifications for the commercially available
Aldara 5%
imiquimod cream. More preferably, low dosage formulations of this Example 23,
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especially as to those lower dosage strength formulations wherein the vehicle
comprises
an isostearic acid as the fatty acid, are believed to have the following:
(1) Stability. The imiquimod formulations of the present invention, when they
are measured on HPLC at 25 C/60%RH, 30 C/65%RH and 40 C/75%RH over, one,
two, three and six months, demonstrate stability consistent with the Aldara
5%
imiquimod cream;
(2) Degradation Products. No degradation products are detected in the
formulations of the present invention, at its current recommended storage
temperatures
of about 4-25 C. In addition, there are no degradation products detected at
any of the
temperatures or time points mentioned under "Stability" above, when analyzed
at about
318 nm
(3) Homogeneity. The amount of imiquimod that is recovered from the
formulations at any of the above-mentioned temperatures and time points is
between
about 90 to about 110% w/w thereby demonstrating good homogeneity;
(4) Benzyl Alcohol Content. The formulations of the present invention are also
within specifications for the Aldara 5% imiquimod cream, i.e., between 1.0
%w/w and
2.1 %w/w, at any of the above-mentioned temperatures and time points as to
benzyl
alcohol content.
(5) Microscopic Stability. There is no change in the particle size and no
crystals are detected in the formulations of the present invention when they
are stored at
25 C/60%RH and analyzed over a six month period;
(6) Macroscopic Stability. There are no obvious physical changes in the
formulations of the present invention when they are stored at 25 C/60%RH and
analyzed over a six month period;
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(7) Viscosity. The formulations of the present invention are within the range
of
the specifications for the Aldara 5% imiquimod cream, i.e., between 2000 cPs
and
35,000 cPs, when they are stored at 25 C/60%RH and analyzed over a six month
period; pH Stability. The formulations of the present invention are within the
range of the
specifications for the Aldara 5% imiquimod cream, i.e., between pH 4.0 and pH
5.5)
when they are stored at 25 C/60%RH and analyzed over a six month period;
(8) Preservative Efficacy Test ("PET"). The formulations of the present
invention demonstrate sufficient reductions in colony forming unit counts for
each of the
organisms with which the formulations are inoculated, i.e., S. aureus, E.
coli, Ps.
Aeruginosa, C. albicans, and A. niger, at 2-8 C and 40 C over a 28 day test
period and
meet the requirements specified in both the USP and EP.
(9) Imiquimod In vitro Release. The Aldara 5% imiquimod cream releases
statistically significant (p<0.05) higher amounts of imiquimod over a 3 hour
time period
in comparison to the lower dosage strength formulations of the present
invention
through a synthetic membrane, e.g., Microporous polyethylene film 3M No. 9711
CoTranTM. There is no statistical difference (p<0.05) in the total cumulative
amount of
imiquimod that is released from any of the 3.75% w/w imiquimod formulations.
There is
no statistical difference (p<0.05) in the total cumulative amount of imiquimod
that is
released from any of the 2.5% w/w imiquimod formulations. The Aldara 5%
imiquimod
cream also statistically significantly (p<0.05) releases imiquimod at a faster
rate over a 3
hour time period in comparison to the lower dosage strength formulations of
the present
invention through a synthetic membrane, e.g., Microporous polyethylene film 3M
No.
9711 CoTranTM. There is no statistical difference (p<0.05) between the
imiquimod
release rates for any of the 3.75% w/w imiquimod formulations. There is no
statistical
difference (p<0.05) between the imiquimod release rates for any of the 2.5%
w/w
imiquimod formulations. Thus, the greater the amount of imiquimod in a
formulation, the
faster and greater the total amount of imiquimod that is released from such
formulation
that the amount and rate of release of imiquimod are concentration dependant
and that
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CA 02649893 2009-01-15
the rates and amounts of release of imiquimod from the formulations of the
present
invention are linear and dose proportionate to the Aldara 5% imiquimod cream;
(10) Imiquimod In vitro Skin Permeation (Franz Cell Study). With respect to
statistical analyses, there is no statistical difference between the lower
dosage strength
formulations of the present invention and the Aldara 5% imiquimod cream as to
the
amount of imiquimod recovered from the receiver fluid, epidermis and dermis
combined.
Nonetheless, there is a statistically significant (p<0.05) dose proportionate
difference
between the amount of imiquimod recovered from each of the matrices with
respect to
the concentration of imiquimod in the lower dosage strength formulations of
the present
invention and the Aldara 5% imiquimod cream for both un-absorbed and stratum
corneum. Thus there is a linear dose release between the amount of imiquimod
that is
applied and recovered in each of the matrices, i.e., receiver fluid,
unabsorbed dose,
stratum corneum, epidermis and dermis.
[0285] ANOVA statistical analysis at 95% confidence level is used to analyze
the
stability data generated, including the data generated for the membrane and
skin
permeation experiments.
[0286] It is also believed that the formulations of the present invention,
including the
formulations identified in this Example 23, have Hydrophilic-lipophilic
balance (HLB) values
between about 12 and 15, and more preferably between about 12.4 and about
13.4.
1. Physical Characterization and Testing
[0287] The following is conducted for physical characterization of lower
dosage
strength imiquimod formulations, e.g., formulations identified in Table 12 and
Table 18,
and for testing lower dosage strength imiquimod formulations, e.g., imiquimod
formulations identified in Tables 13-17.
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CA 02649893 2009-01-15
(A) Analytical method - HPLC Assay
[0288] A summary of an HPLC method is provided in Table 10.
Table 10. Summary of HPLC Methodology
HPLC 9. Waters 265 (Alliance Separations module), Water
HPLC System 996 (Photodiode array detector), CPU (Compaq), Software -
Microsoft Windows NT Version 4.00.1381 and Analysis
software -Millenium32 Version 4.00.00.00
Column Supelcosil LC-8-DB (5mm, 15 x 0.46 cm)
Guard Column Supelguard LC-8-DB 2cm
Detection UV at 258 nm
Sample Temperature 25 C
Column Temperature 25 C
Flow Rate 2 mI/min
Mobile Phase 72:28 aqueous:ACN (1 % TEA solution, 0.2% Octyl Sodium
Sulfate, adjusted to pH 2.0 with H3PO4
Injection Volume 20 ial
~ ..__._
Run Time 12 min
i--
Needle Wash 10:90 0.1 N HCI:water
(B) Preparation of HPLC Reagents
(1) Mobile Phase:
[0289] About 2.0 g octyl sodium sulfate (OSS) is weighed into a large beaker
and is
mixed with about 990 ml Milli-Q ultrapure water and about 10.0 ml of
triethylamine
(TEA). The mixture is sonicated and stirred for about 5 min to dissolve the
solids. A pH
meter is then placed in the mixture and the pH of the OSS/TEA solution is
adjusted to
about 2.0 with concentrated H3PO4, stirring continuously during the adjusting
procedure.
The entire mixture is then filtered through a 0.2 pm filter. The filtrate is
mixed with
acetonitrile (HPLC grade) in the ratio of about 72:28 aqueous: acetonitrile by
volume.
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CA 02649893 2009-01-15
(2) Sample Diluent
[0290] About 250 ml acetonitrile (HPLC grade), about 740 ml purified water and
about
ml of concentrated HCI are mixed together in a 1 L volumetric flask.
(3) Receiver Fluid
[0291] About 100 ml of a commercially available standardized 1 N HCI solution
is
diluted to about 1000 ml with Milli-Q ultra pure water.
(4) Standards
[0292] Imiquimod standards are prepared, as described under Sample Diluent and
Receiver Fluid, for stability test and receiver for membrane release tests.
Initially, a
stock solution of imiquimod is prepared by dissolving about 25 mg of imiquimod
into
about 50 ml of solvent (either Sample Diluent or Receiver Fluid) to give a
concentration
of about 500 pg/ml in Sample Diluent or Receiver Fluid.
[0293] A calibration range as shown in Table 11 is prepared for each HPLC run.
Table 11. Preparation of Calibration Standards
Volume of stock Final concentration of Test
solution Volume of diluent Item (iag/m1)
(ml)
10 0 500
5 5 250
4 6 200
2 8 100
1 9 50
0.5 9.5 25
0.2 9.8 10
116
CA 02649893 2009-01-15
Volume of stock Final concentration of Test
solution Volume of diluent Item (pg/m1)
(ml)
0.1 9.9 5
(5) Combination Standard
[0294] The following combination standard solution is also prepared; whereby,
about
500 mg of methylparaben and about 50 mg propylparaben are weighed into a
single
250 ml volumetric flask and is diluted to volume with sample diluent above, to
form the
parabens solution. In addition, about 500 mg of imiquimod and about 200 mg
benzyl
alcohol are also weighed into a single 100 ml volumetric flask and about 10 ml
of the
parabens solution is then transferred into the imiquimod/benzyl alcohol
volumetric which
is made up to volume with diluent and is sonicated to dissolve fully.
(6) Impurity standards
[0295] Impurity standards are prepared separately at a concentration of about
50
p.g/ml in Sample Diluent and are analyzed in each HPLC run. The impurity
standards
that are included in each HPLC run are as follows:
= N-propyl imiquimod
= N-methyl imiquimod
= 4-hydroxyimiquimod
= 4-chloro imiquimod
117
CA 02649893 2009-01-15
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U)
U)
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cn
p
o r ~ m E
_
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0 -
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CA 02649893 2009-01-15
3 o a c o
3 o v
N 3 u . O R O
N 3 ~ O
3 O
N 3 ~ OoW O O N`~ O rv NO o O
O O O
N 3 ~ N O
t7 N ~
N o O
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0 0 0 0 0 0
n N o a O
N o N
N
3 ~ a
N 3 0~n o o u ~ o
N 3
o O O O o O O u i a O N N N O O
3
0 o e
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o
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3 0 ~ o o o
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~ g 3 s ` n o ~ a _ & ~ >
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CA 02649893 2009-01-15
Table 15
3.75% Imiquimod 182 188 189 183 184 255 193 245 195 256 197
Formula8ons %wlw %w!w %wlw %w/w %w/w %w/w %w/w %wlw %wlw
Fxcipients
Isostearic acid 20.00 20.00 20.00 25.00 18.75 25.00 25.00 20 2000 20.00 20.00
Cetyl alcohol 2.20 2.20 2.20 2.20 2.20 2.70 2.20 4 2.20 2.20 2.20
Stearyl alcohol 3.10 3.10 3.10 3.10 3.10 380 3.10 2.4 3.10 3.10 3.10
VJhite petrolatum 3.00 6.00 15,00 3.00 5.00 3.00 3.00 3 4 5.00 3.00 5.00
Polysorbate 60 3.40 3.40 3.00 3.40 3.00 3.40 3.40 3.8 3 40 3.40 3.40
Sorbitan Monostearate 0.60 0.60 1.00 0.60 1.00 0.60 0.60 1 0.60 0.60 0.60
Glycerine 2.00 5.00 5.00 2.00 5.00 2.00 2.00 3 2.00 5.00 5.00
Xanthan gum 0.50 0.50 0.50 0.50 0.50 1.00 1.00 0.7 0.50 0.50 0.50
Purified water 59.23 53.23 53.23 54.23 55.48 53.73 53.73 55.73 57.23 58.23
54.23
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00 2.00 2 2.00 2.00 2,00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20 0.20 0.2 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 3.75 3.75 3.75 3.75 3.75 335 3.75 175 3.75 3.75 3.75
0.00 - 100.00 0.00
Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 10 10
HLB Values 13.4 114 12.4 13.4 12 4 13.4 13.4 12.8 13 4 13.4 13.4
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CA 02649893 2009-01-15
[0297] In Table 16, compositions for Aldara 5% imiquimod cream and 1%
imiquimod cream formulations are shown. Also shown in the Table 16, are four
placebo
formulations Pbol, Pbo2, Pbo3 and formulation Pbo4,
Table 16
3M 257 Placebos
Formulations Aldara (1 %)
(5% Pbol Pbo2 Pbo3 Pbo4
Bulk)
%w/w %w/w %w/w %w/w %w/w %w/w
Excipients -
Isostearic acid 25.00 25.00 20.00 20.00 20.00 20.00
Cetyl alcohol 2.20 2.40 2.20 2.20 2.20 2.20
Stearyl alcohol 3.10 3.40 3.10 3.10 3.10 3.10
White petrolatum 3.00 3.00 5.00 3.00 5.00 3.00
Polysorbate 60 3.40 3.40 3.40 3.40 3.40 3.40
Sorbitan 0.60 0.60 0.60 0.60 0.60 0.60
Monostearate
Glycerin 2.00 2.00 2.00 5.00 5.00 2.00
Xanthan gum 0.50 0.50 0.60 0.60 0.50 0.50
Purified water 52.98 58.48 80.98 59.98 57.98 62.98
Benzyl alcohol 2.00 2.00 2.00 2.00 2.00 2.00
Methylparaben 0.20 0.20 0.20 0.20 0.20 0.20
Propylparaben 0.02 0.02 0.02 0.02 0.02 0.02
Imiquimod 5.00 1.00 0.00 0.00 0.00 0.00
Total 100.00 100.00 100.00 100.00 100.00 100.00
HLP Values 13.37 13.37 13.37 13.37 13.37 13.37
(C) Uniformity/homogeneity
[0298] Following a 1 kg batch manufacturing process as described in this
Example
23, 3 x 150 mg samples (top, middle and bottom) are removed from each 1 kg
bulk
batch using a positive displacement pipette and are extracted and are analyzed
as
described in Section, entitled "Imiquimod Content" described hereinafter.
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CA 02649893 2009-01-15
(D) Preparation of Stability Samples
[0299] Each of the 1 kg batches are sub-aliquoted individually into 21 x 60 ml
glass
powder jars, where:
= 5 x 50 g(25 C/60%RH t= 0 h, 1 month, 2 months, 3 months, 6 months)
= 5 x 50 g(30 /65%RH - t= 0 h, 1 month, 2 months, 3 months, 6 months)
= 5 x 50 g(40 C/75% RH - t= 0 h, 1 month, 2 months, 3 months, 6 months)
= 1 x 60 g (PET sample, placed at 2-8 C)
= 1 x 20 g (placed at 2-8 C)
= 1 x 20 g (placed at -20 C)
= The remaining formulation, is divided into 3 additional aliquots and each is
piaced
at 25 C/60%RH, 30 /65%RH and 40 C/75% RH.
[0300] All batches are characterised based on the protocols that are shown in
Section
entitled Protocol for the Assessment of Formulations. Once each aliquot is
removed
from the relevant stability conditions at each time point; the remaining
aliquot from each
sample is placed in a fridge at 2-8 C for future reference if required.
[0301] Following the 1 month stability time point, the benzyl alcohol content
of the
formulations are monitored; for all subsequent time points, the placebo
formulations are
analyzed by HPLC. Thus, there are no t=0 measurements for benzyl alcohol
content for
placebo formulations Pbol, Pbo2 and Pbo3.
(E) Protocol for the assessment of formulations
[0302] The protocols that are used for the assessment of the formulations are
as
follows:
(1) Macroscopic Appearance
[0303] Macroscopic appearance is determined by visual examination of the
physical
characteristics which include appearance and texture of each cream.
Macroscopic
appearance is performed at each time point (t = 0, 1, 2, 3 and 6 months) for
the 25 C
stability samples, as follows:
123
CA 02649893 2009-01-15
= Using a medium Granton pallet knife, a small aliquot of sample
(approximately
1 to 2 g) is removed from its container and is placed on the surface of a
large
Granton pallet knife.
= The medium Granton pallet knife is then used to smooth the cream over the
surface of the large Grantonn pallet knife, by using a backward and forward
motion of the spatula until a visually uniform layer of cream is obtained on
the
large Granton pallet knife.
= Visual observations of the cream are recorded which are based on, the
presence
of lumps, graduals or ease of spread over the surface of the spatula.
(2) Microscopic Appearance
[0304] Formulations are viewed under a light microscope (Leica DME FD198536
Light Microscope), to determine particle size, uniformity and the absence of
particulates.
Digital images of each formulation are taken at each time point (t = 0, 1, 2,
3 and 6
months) for the 25 C stability samples, as follows:
= The microscope is set up so that the camera (Nikkon Cool Pix 4500 digital
camera) is attached to the relay lens of the microscope and the 40x objective
lens is set into place to view the sample. Camera settings: Image size:1280 x
960 pixels, Image quality: Fine.
= A small droplet of the formulation to be viewed is placed onto a microscope
slide
(Fisher-brand microscope slides, Cat No. 7101) using a micro-spatula. The
microscope slide is then covered using a cover glass (Fisher-brand cover
glass,
width: 22 - 32 mm, thickness: 0.13-0.17 mm).
= The microscope slide with the formulation is then placed under the 40x
objective.
Using the fine adjustment knob of the light microscope, the slide is brought
into
sharper-focus to get a clear view.
= Once a clear distinct view is obtained, pictures are taken (x400
magnification).
= The particle sizes of formulations prepared are determined using a graticule
(Olympus, Objective Micrometer, 0.01 mm). Overall uniformity and particle size
are measured using the scale on the calibrated graticule shown in FIG. 55.
Five
random locations on each slide for each formulation are chosen to assess
uniformity and particle size.
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CA 02649893 2009-01-15
(3) Imiquimod Content
[0305] The imiquimod content of the formulations is measured at each time
point (t =
0, 1, 2, 3 and 6 months) for the 25 C and 40 C stability samples. The 30 C
stability
samples are removed from the stability cabinet at each time point and placed
at about
2-8 C for future reference, as follows:
= About 150 mg of the formulation is removed from each sample and is
transferred
into a 50 ml volumetric flask.
= About 30 - 40 ml of diluent (about 250 ml acetonitrile (HPLC grade), about
740
ml purified water and about 10 ml of concentrated HCI are mixed together in a
1
L volumetric flask) is then added to the volumetric flask containing the
aliquot of
the formulation.
= The sample is then vortex mixed for approximately 1 min or until the
formulation
has visibly completely dispersed into the diluent.
= The sample is then sonicated for about 5 min and then is left to cool to
room
temperature.
= The sample is then filled to volume with diluent and is mixed by inverting
the
volumetric flask.
= This step is followed by filtration through a 0.45 mm filter directly into a
2 ml
HPLC vial and the cap crimped.
= The sample is then analysed on the HPLC using the method described in
Section
entitled Analytical Method - HPLC Assay described above, with the standard
solutions as described above in Sections entitled Standards Combination
Standard and Impurity Standard. This method also allows for the detection and
measurement of benzyl alcohol.
(4) Related Substances/ Degradation Products
[0306] Following the extraction and analysis, as described above under
Imiquimod
Content, the chromatograms for each formulation are compared to those
generated for
the impurity standards, as described above under Impurity Standards, to
identify if there
are any degradation peaks present. As the preservatives have similar retention
times
as the degradation products, the chromatograms are viewed at an absorbance of
318
125
CA 02649893 2009-01-15
nm wavelength at which the preservatives do not absorb to confirm the absence
of
degradation products.
(5) pH measurements
[0307] The pH of the formulations are measured at each time point (t = 0, 1,
2, 3 and
6 months). The pH measurement protocol is as follows:
= A small sample of the formulation is applied on to the surface of a strip of
pH
paper (Fisher-brand pH paper: FB33045, Range pH 0.5-5.5) and is spread
evenly over the surface using a spatula.
= The pH paper with the formulation on it is then left for 10 min to ensure
that the
paper does absorb the cream (which is confirmed by a color change).
= The pH of the formulation is then determined by comparing the color on the
strip
of pH paper with a range of colors (color chart) that are provided with the
Fisher-
brand pH paper.
(6) Viscosity from Flow Curve (Rheology Bohlin CVO
measurements)
[0308] The rheology of the formulations are measured at each time point (t =
0, 1, 2, 3
and 6 months) for the 25 C stability samples.
(7) Rheology Oscillation Methodology (Bohlin CVO)
[0309] The Crossover and G' values of the ICH stability samples are measured
for all
the t=0 samples. See e.g., Tables 18 and 26. The 'crossover' point is an
indication of
the elastic structure of the formulation and a high cross over point indicates
that more
force is required to breakdown the formulation thus providing an indication
for longer
term stability of the cream formulations. The G' value is a measurement of the
elastic
part of the formulation, whereby a high G' value indicates a more rigid
formulation which
'recovers' more easily from applied shear stress.
(8) Viscosity (Brookfield) Measurements
126
CA 02649893 2009-01-15
[0310] The viscosity of the formulations is measured at each time point (t =
0, 1, 2, 3
and 6 months) for the 25 C stability samples.
(9) Preservative Efficacy Test Protocol
[0311] The preservative efficacy test is performed on formulations 110, 126,
Pbo4
and 182 which are stored at about 2 - 8 C and about 40 C for about 3 months.
Preservative efficacy testing is carried out according to the procedure
described in line
with the methodology described in the USP 2007 and EP 2007. The time points,
at
which the inoculated samples are tested are: Oh, 24h, 48h, 7 days, 14 days, 21
days
and 28 days.
[0312] Method validation is performed using Staphylococcus aureus cultures to
confirm the neutralizing effect'of D/E broth, for this purpose 110 and 182 are
used to
confirm neutralization of the preservatives.
II. Test Item Release Studies through Synthetic
Membranes
(A) In vitro screening of release profiles through synthetic membranes
[0313] The release of imiquimod from 13 formulations (n=4 for each) are
compared
using methodology based on the principles of the FDA, SUPAC-SS guidelines. The
formulations that are tested included: 3M's Aldara 5% imiquimod cream 1 kg
bulk
sample, Aldara 5% imiquimod cream sachet (commercial product), Graceway's
Aldara 5% imiquimod cream 1 kg batch, and formulations 257 (1%), 123, 250,
125,
110, 182, 195, 256, 197 and 183. The protocol for the investigation is as
follows:
[0314] A synthetic membrane (Microporous polyethylene film 3M No. 9711
CoTranTM)
is mounted in a small Franz cell (refer to FIG. 56) with a receiver fluid (0.1
N HCI) to
ensure sink conditions (is equilibrated for a minimum of 30 min prior to
dosing). An
infinite dose of formulation (230 to 250 NI is dispensed using a calibrated
positive
displacement pipette) is applied to the membrane (using the pipette tip to
gently spread
over the surface) and the diffusion of imiquimod that is measured over time
(n=4 per
127
CA 02649893 2009-01-15
formulation). Briefly 200 pl of the receiver fluid is removed using a 250 pl
Hamilton
syringe at each time point (0, 15, 30, 60, 120 and 240 min) and is analysed on
the
HPLC using the method, as described under Analytical Method - HPLC Assay. The
sample of receiver fluid is removed at each time point and is replaced with
fresh pre-
warmed (32 C) receiver fluid.
III. In vitro Skin Permeation Study
(A) Analytical Methods
(1) Liquid Scintillation Method Details
[0315] Samples are added to a scintillation vial and about 4 ml of
scintillation cocktail
(Hionic-fluor) is added. The vial is capped and is shaken using a vortex mixer
until the
sample is mixed with the scintillation cocktail. The scintillation vials are
then loaded into
racks before analysing on the scintillation counter, using the settings listed
as follows.
= Model of scintillation counter: Beckman LS 5000 CE
= Isotope setting: C14
= Counting time: 5 min
= Calculation mode: SL DPM
= Count samples: 1 times
= Replicates: 1
= Quench monitor: Yes
(B) Radioactive purity of Imiquimod14C
1. Preparation of Stock
[0316] The radio-labelled material is as follows:
Imiquimod stock (c14): Specific activity of about 57 mCl/mmol with a
radiochemical purity of about 99.2% is supplied as a powder in a borosilicate
multi-dose
vial with additional screw cap.
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CA 02649893 2009-01-15
[0317] Working stock solutions are prepared by addition of 1 ml isostearic
acid to the
imiquimod powder using a needle and syringe inserted through the septum of the
vial.
The screw cap is then replaced securely and the vial shaken on a vortex mixer
until all
the imiquimod dissolves in the isostearic acid. The homogeneity is also
confirmed.
This results in a stock solution containing about 1000 Ci/mI.
(C) Preparation of Formulations
[0318] The method for the preparation of about a 100g radioactive batch is as
follows:
= The glass container and mixer paddle attachment are placed onto a balance
and
the weight is recorded before the container and paddle are removed.
= The amount of imiquimod required for the formulation is added by weight and
the
remaining isostearic acid (minus 1.38 g) and benzyl alcohol are added to the
container.
= The entire mixture is heated in a water bath at about 55 5 C while
stirring with
a small over head mixer (IKAO-Werke Lab Egg) and paddle attachment.
= Cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60 and
sorbitan
monostearate are added into the beaker and mixed at about 55 5 C until the
oil
phase is completely in solution.
= Separately, about 200 ml of water is heated in a beaker to about 55 5 C
while
stirring with a magnetic follower.
= About 50 ml of the heated water is transferred into a beaker and is placed
in a
water bath maintained at about 55 5 C and half the glycerine, methyl
hydroxyparabens and propyl hydroxyparabens are added (where both methyl
and propyl parabens are weighed into weighing boats first) to the water and is
stirred at about 55 5 C (this is the aqueous phase).
= The remaining glycerine is added to a 28 ml vial with the xanthan gum and is
mixed using a small over head mixer (IKAO-Werke Lab Egg) with paddle
attachment for about 10 min.
= The glycerine and xanthan mixture are then added into the vortex of the
aqueous
phase, using about a 5 ml aliquot of heated water to rinse the vessel out into
the
water phase.
129
CA 02649893 2009-01-15
= Mixing of the water phase is continued for at least about 5 min.
= The aqueous phase is transferred into the oil phase, increasing the stirring
speed
during addition.
= The mixture is stirred on high speed maintaining the temperature at about 55
C for 30 min.
= The vessel is removed from the mixer and is homogenised using the 1 cm head
for about 3 min.
= Mixing is continued while cooling to about 35 C and the total weight of the
cream
is made up to weight with heated water. The mixture is transferred to the
overhead stirrer and cooling and stirring is continued to about 25 C.
= The formulations are then aliquoted in to screw top vials and are sealed
with
Parafilm placed around the screw top lid.
= About 9.862 g of the formulation is weighed into a vial and is placed in a
water
bath at about 5 C. About 138 mg of radio-labelled working stock solution is
then
added to the formulation and the formulation is thoroughly mixed using a
spatula
while cooling.
(D) Homogeneity Control
[0319] Following manufacturing of the formulations, the following test is
performed:
[0320] For each of the formulations, three aliquots (top, middle and bottom of
batch)
of approximately 5 mg is exactly weighed directly into a scintillation vial,
where about 4
ml of scintillation cocktail is added. All of the samples are then directly
quantified on the
Liquid Scintillation Counter ("LSC") to confirm homogeneity within 10%.
(E) Franz cell study
[0321] The method involves the use of full thickness human skin that is
mounted in a
Franz cell with about a 0.01 N hydrochloric acid as receiver fluid to ensure
sink
conditions. A dose of formulation equivalent to about 10 mg/cm2 is applied to
the
membrane and the diffusion of imiquimod is measured over time. Human skin from
cosmetic reduction surgery is used. Subcutaneous fat is removed mechanically
prior to
preparation of the skin section for the study. The formulations (64) are
applied to the
surface of the membrane using a positive displacement pipette. The
investigation is
130
CA 02649893 2009-01-15
performed in several experiments. Two skin donors are used randomly and are
assigned across all experiments so that each formulation is tested on both
skin donors.
Each experiment consists of two randomly assigned formulations (n=6 cells per
formulation) and two comparator formulations (n=6 cells per comparator). The
receptor
compartment of the Franz cells is then filled with the receiver fluid and the
cells are fixed
in a water bath maintained at about 37 C. The receptor compartment contents
are
continuously agitated by small magnetic followers. At t=1, 8 and 24 h, samples
of
receiver fluid are taken from the receptor compartment, and are replaced with
fresh
receiver fluid and are assayed by scintillation counting.
(F) Mass balance
[0322] At the end of the experiment, a mass balance experiment is carried out,
where
the amount of 14C imiquimod remaining in the donor compartment, surface
residue,
Stratum corneum (SC), remaining epidermis, dermis and receiver compartment is
quantified. This method involves removal of the SC by tape stripping and
processing of
the remaining epidermal layer and dermis using standard procedures. The
protocol for
the mass balance is as follows:
[0323] Unabsorbed dose: The surface of each Franz cell donor chamber is wiped
gently with a cotton bud using 5 clockwise and anti-clockwise movements. This
procedure is repeated on 4 occasions using alternate wet (receiver fluid) and
dry cotton
buds. The cotton buds are added to scintillation cocktail before analysis. Two
tape
strips are removed from the skin and these are regarded as unabsorbed
formulation
and included in the total surface activity. The Stratum corneum) (SC) is
removed by
carefully tape stripping the membrane ten times using Scotch adhesive tape.
Collectively, each tape is placed into a scintillation vial to which 4 ml of
scintillation
cocktail are added before analysis. Epidermal layer: The remaining section of
the
epidermis (following tape stripping) is carefully removed from the dermis with
a scalpel.
The epidermis is placed into a glass vial containing 2 ml of Soluene 350 and
is
incubated at about 50 C for about 72 h before analysis by LSC. The remaining
dermal
131
CA 02649893 2009-01-15
layer is placed in to a glass vial containing about 2 ml of Soluene 350 and is
incubated
at about 50 C for about 72 h before analysis by LSC.
(G) Analysis of Data
[0324] ANOVA statistical analysis at a 95% confidence level is used to analyse
the
data generated for the membrane release and skin permeation experiments.
[0325] An example of the ANOVA statistical analysis is as follows:
Individual 95% Cls For Mean Base on
Pooled StDev
Level N Mean StDev +------------+------------+------------+------------
Formulation X 4 4605.5 626.9 (-- *---)
Formulation Y 4 1862.8 185.9 (---*----)
Formulation Z 4 1845.6 206.4 (---*---)
+------------+------------+------------+------------
0 1500 3000 4500
Whereby, no significance (p>0.05) is shown by two overlapping histograms (e.g.
Y and
Z), whereas a significant difference (P<0.05) can be identified by two
histograms which
don't overlap (e.g. X and Y and X and Z). The width of the each histogram is a
reflection of the pooled standard deviation from all data sets.
IV. Results and Discussion
(A) Degradation Product Analysis
[0326] It is discovered that the preservatives (benzyl alcohol, methylparaben
and
propylparaben) at about 318 in the imiquimod formulations can not be detected.
Thus,
by analysing the imiquimod formulations at this wavelength, it permits the
detection of
degradation products, if any, in the presence of preservatives. However, no
degradation products are identified at about 318 nm for any of the imiquimod
formulations tested up to and including the 6 month stability time point at
about 25 C
and about 40 C.
[0327] In Table 17 and FIG.57, they show a summary of the findings, whereby
simple
microscopic analysis of the imiquimod formulations identify formulations with
132
CA 02649893 2009-01-15
inconsistent particle size and large aggregation of material. Summary and
composition
of lower dosage strength imiquimod formulations are listed in Table 13 and
Table 14.
133
CA 02649893 2009-01-15
3 E 5 n 9
=- o _ E o ~ n rv
E
N 3 L ~ O O
E E w
L n N
N 3
E N N
3 E
N 3 n n
a N
o t y (O
N ~ t m 1 N a
3 L N a
0 3 o
N o ~ E w ~}
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= ~
N 3 L N V a
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N 3
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CA 02649893 2009-01-15
~O g E c g E
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1~ y g E ~ 3 g
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=ny 4 =
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}M a
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m8
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CA 02649893 2009-01-15
(B) Scale-up and ICH stability
1. Homogeneity
[0328] In Table 19, formulations 245, 121 and 193 show signs of phase
separation.
All the other formulations in Table 19 show good homogeneity, and are
subsequently
sub-aliquoted and placed on stability as described above under Preparation of
Stability
Samples.
Table 19. Homogeneity Results from 1 kg batches, where Samples are Removed
from Top Middle and the Bottom of the Batch for Comparison of Homogeneity.
Formulation % Recovery %CV
3M Aldara 5% Batch 102.69 2.29 2.23
257 (1 %) 100.29 0.68 0.68
197 96.81 2.15 2.22
183 97.56 0.48 0.50
245 91.08 12.80 14.06
182 97.68 0.73 0.75
189 98.32 0.92 0.94
184 98.37 1.61 1.63
193 97.21 0.22 0.23
188 98.95 2.48 2.51
195 99.66 0.70 0.70
255 99.46 0.49 0.49
256 98.80 0.75 0.76
Graceway Aldara 5% 102.74 1.26 1.23
Imiquimod
110 101.43 0.63 0.62
116 100.39 0.18 0.18
117 100.49 0.64 0.64
250 99.98 0.37 0.37
254 98.70 0.21 0.21
120 100.02 0.34 0.34
121 106.22 0.09 0.09
235 101.04 0.21 0.21
123 101.75 0.28 0.28
136
CA 02649893 2009-01-15
Formulation % Recovery %CV
124 95.00 0.32 0.34
125 101.12 0.12 0.12
126 102.37 0.58 0.57
Pbol N/A N/A
Pbo2 N/A N/A
Pbo3 N/A N/A
Pbo4 N/A N/A
(C) Stability
1. Stability of Imiquimod in Formulations
[0329] In Table 20, imiquimod in the formulations is stable at both about 25 C
and
about 40 C over an about six month period, although the results for three and
six
months at both about 25 C and about 40 C look consistently higher than
previous time
points. This could be attributed to a small amount of water evaporation from
the
containers. In addition, all samples are consistent with the commercially
supplied
Aldara 5% imiquimod cream sample. There are no degradation products detected
in
any of the samples in Table 20 at any of the temperatures and time points when
analyzed at about 318 nm. With reference to formulation specification, the
specification
amount of imiquimod that is recovered from the samples in Table 20 is between
about
90%-110% w/w, thereby confirming that the samples fall within their target
specification.
In other words, and by way of example, the specification amount of imiquimod
that is
recovered from preferred 2.5% imiquimod formulations of the present invention
will fall
within between about 2.25% and about 2.75% w/w and the amount of imiquimod
that is
recovered from preferred 3.7.5% imiquimod formulations of the present
invention will fall
within between about 3.38% and about 4.12% w/w. Thus, in accordance with the
present invention, the amount of imiquimod recovery from preferred
formulations will fall
within about the 100% 10% w/w specification of their target concentrations.
137
CA 02649893 2009-01-15
~ ~
s
3 H U +1 +1 +1 +i -.i +1 +l +1 + +1
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M ~ Z
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i[ = ' m - - ~ " -_E - Y' $ m
r~i L~ E Ã e U u~
CA 02649893 2009-01-15
2. Stability of Benzyl Alcohol in Formulations
[0330] In Table 21, Benzyl alcohol content is found to fall over the duration
of the
stability tests. The greatest loss observed is in the placebo's; Pbo4 (1.08
0.02% w/w),
Pbol (1.01 0.03%w/w), Pbo2 (1.04 0.08% w/w) and Pbo3 (1.11 0.00% w/w)
and
the active formulation 257 (1 %) (1.37 0.01% w/w) which shows a loss in
benzyl
alcohol at about 40 C for about 6 months down from 2.0% w/w. The specified
range for
benzyl alcohol in the Aldara 5% imiquimod cream formulations (1.0 to 2.1 %
w/w), are
within specification for Aldara 5% imiquimod cream. The decrease in benzyl
alcohol
content from the formulations is possibly the result of the formation of an
ester (benzyl
isostearate), whereby there is a reaction betwe.en the excipients of benzyl
alcohol and
isostearic acid.
139
CA 02649893 2009-01-15
O 2 8 s
~ Z
4) +1 +I +1 +1 --i +I +~ + H +I +I +1 +1 +1 +1
~ L E
cn s
C t_)
2 t o s s s s = e s
I +~ +1 +i +i +I +1 +1 +~ +1 +i
E
r-
~ Q - -
.~ ~ ~Bos~g
~ E + +i +i +i
3"r
y v ~- - - -
c'a
O c
- - - 8 8 S 8 ^ 8
1 ~ ~ +i +i + F~ +i +i +i +i +i +i
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O q~ a :f 3 m a 8 m S; s '
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s~ N~ooB - - ao
+1 +1 ++1 +1 ++1 +
os N
o
:E M
y= Z o a s o s o s= o
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L (C
(1) 3
a
cc S~ o o s s s s o o s s
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+1 +1 +1 +I +1 +I +1 1 11 +1 +1 +1 +1 +I +1 J +I +I +I +1 +I +1 +1 +1 +1
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d d d a~ ffi m
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CA 02649893 2009-01-15
(D) Microscopic stability of the formulations
[0331] In Table 22, there is no change in the particle size in any of the
formulations
tested at about 25 C over about a 6 month period. In addition, and with
reference to the
microscopic photographs presented in FIGS. 63A-C and 64; no crystals are
detected.
For completeness and reference, the pictures of the formulations rejected
after one
month stability are shown in FIGS. 65A-B.
Table 22. Results of Particle Size of the Formulations when viewed under a
Microscope at 25 C over a 6 Month Period.
Particle size (pM)
Formulation T= 0 t=1 Month t=2 Months t=3 Months t=6 Months
3M Aldara 5% <10 <10 <10 <10 <10
GRACEWAY
Aldara 5% <10 <10 <10 <10 <10
257 (1 %) <10 <10 <10 <10 <10
110 <10 <10 <10 <10 <10
250 <10 <10 <10 <10 <10
182 <10 <10 <10 <10 <10
195 10 10 10 10 10
123 10 10 10 10 10
125 10 10 10 10 10
256 10 10 10 10 10
197 10 10 10 10 10
183 10 10 10 10 10
126 <10 <10 <10 <10 <10
Pbol <10 <10 <10 <10 <10
Pbo2 <10 <10 <10 <10 <10
Pbo3 <10 <10 <10 <10 <10
Pbo4 <10 <10 <10 <10 <10
141
CA 02649893 2009-01-15
(E) Macroscopic stability of the formulations
[0332] In Table 23, there are no obvious physical changes in the formulations
that are
tested over the six month stability program, with the exception of the
placebos, which
become notably less viscous. See also Tables 24-26.
Table 23. Macroscopic Appearance when lmiquimod Formulations are stored at
about 25 C over about a 6 Month Period.
AG- sPalula Tesl (25'G semple oMy) Visual Vixosily (25 G samqe oNy)
Imigwmoa
. Fommlauoe
t= 0 t--1 moruM1 12 moruhs t"~i moraM t'~ moMM1S t~ t--1 morxh t--2 mamhs J
morahs moMhs
3M Altlara0t 5% GIossy, very Glossy, very Glossy, very Glossy, very Glosry,
very
Imiqumad smoolM1 smooM smooM smooth smoolh High MediVm-Hlgh Medium Metlium-
HigM1 Medium
Graceway
Ndam 5% GIOSSy, very Glossy, very Glossy, very Glossy, very GIOSSy, very
Imigwmod smoaM smooM smooM smooM smooM HigM1 High Medium-High HigM1 Medium
Glgmsy and GIoTy and Gl ssnsy, very Glomy. very Gl grry, very lu
It 257 (1%) ooM ooM ooM ooth ooM Medium Medium-High Medium-HigM1 Medium-High
L. v osiy
Glossy, vlery Glosry, ~tery Glo,s%, slightly Glossy, slghtly GIO1e , slighdy
110 slighlly lexured slightly tewetl eNred tured tured HigM1 High High High
Medium
Glossy and
h , some Glossy and Glossy, Very Glossy, Very GIossy, Very
smoo
25g aemtion teamred slightly tertured slightly texturetl sligM1lly teatured
Medium Medium-High Medium-Higlh MeAium-HigM1 Medium
Very smlmsy antl Very smlossy and Very s~lossy and Very lossy and Very smlossy
and
182 ooM ooM ooM ooM ooM Hiyh Medium-High Medium-HigA Medium-HigM1 High Glossy,
slightly Glossy, shgM1lly Glossy, very Glossy, slighlfy Glossy, slightly
195 textured texNred slightly tertured tenured IexMed HigM1 High Medium-High
Medium-High Hlgh
~._.
Glosry, slightly Glassy, slighAy
xlured, d. Glossy, slightly
Glossy and Glosry, slighlly exlure
123 smaoM texlured smooMed oul smooMetl oul tezlured Medium-HigM1 Medium-HigM1
Medium-HigM1 High Medium
a Glossy wi
and M1 slight Glossy, slighAy
I~-Glossy ~ nd ~ Glo aeanog oM s tee
12A ooM oolh Glossy, mootlM1 Mietl Medium Medium Medium Medium-High Low
Glossy, slgM1Py Glossy, slighlly Glossy, slghtly Glossy, slghlly Glossy,
sllghtly
)56 texlured texlured lextured IexNred texlured Medium-HigM1 Medium-High
Medium-High Medium-HigM1 High
l.-_.
Glossy, sllghtly Glossy, very Glosry an Glos ntl Glosry and
19l texNred sliyhMy le:lured lerturetl sligM1dyAlexmred slightly textured
Medium Medium-High High High High
Glossy, smoo Glosry and Glossy and Glossy and Glossy end
183 s1igM11 anaM1On smooM smooM smooM smooM High Medium-High Medium-High
Medium-HigM1 Low
Glossy, ve Smoah, slghtly Glossy and Slightly Iexlured,
126 slightly lexl ed texNred, glossy smooM sheen Glossy Mcdium Medium Medium
Medium Law viscusiry
Glosry and Very glossy and Very glossy and Very glossy and GIossy and
Pbnl smooM smooth smooM smooN smooM Low Medium-Low Medium-Low Low Low
I-_ -
Glossry and Glossy and Glossy and Glossy, very Glosry and
Pho2 smooM smooM smooM sligM1tty lexlured smooM Medium-Low Medium MediurmLvn
Medium-Low Low
Glossy, very Glossy, very
Glossy and Gtossy and sligM1tly tex ured slighlty lexlured Glossy and
PhoJ smooM smooM hut smoothed out hut smaotM1ed oul smooM Low Medium-Low
Medium-LOw Medium-LOw Medium
Glossy and Giossy and Glossy and Glossy antl Smooth cTeam
Pho4 smnoth smooM smooM smooM high sheen Medium-Lo Medium Medium-Low Low Low
142
CA 02649893 2009-01-15
Table 24. Stability Data for 10 Formulations, i.e., Formulations 116, 117,
120, 124,
188, 184, 189, 235, 254 and 255, rejected after 1 Month Stability, with
respect to
the Spatula Test, Visual Viscosity and Particle Size (as determined by
microscopy).
Formulation Spatula Test Visual Viscosity Majority of particle
size (pM)
T= 0 T=1 T= 0 T=1 T= 0 T=1 Month
Month Month
116 Glossy, Glossy, Medium Medium- 10 10
textured textured High
117 Glossy, Glossy, Medium- Medium- <10 <10
slightly slightly High High
textured textured
254 Smooth with Smooth, High Medium- <10 <10
matt matt High
appearance
120 Smooth, Smooth, Very High Very High <10 <10
matt maft
appearance,
some
aeration
235 Glossy, Glossy, Medium- Medium <50 <50
textured but very Low
does slightly
smooth out textured
but does
smooth
out
188 Glossy and Glossy Medium- High <10 <10
textured and Low
textured
189 Glossy, very Glossy, High Very High <10 <10
slightly slightly
textured textured
184 Glossy, Glossy, High High <10 <10
slightly slightly
143
CA 02649893 2009-01-15
textured textured
255 Glossy and Glossy High High 10 <10
smooth and
smooth
124 Glossy, very Glossy, Medium- Medium- <10 <10
slightly very High High
textured slightly
textured
Table 25. pH Stability Data for 10 Imiquimod Formulations, i.e., Formulations
116, 117, 120, 124, 188, 184, 189, 235, 254 and 255, Rejected after 1 Month
Stability.
---
Formulatio pH
n T= 0 T= 1 Month
Identity
116 5.0 4.7
117 4.5 4.5
254 4.7 4.7
120 4.5 4.5
235 4.5 4.5
188 4.7 4.7
189 4.7 4.7
184 4.7 4.7
255 4.5 4.5
124 4.5 4.5
Table 26. Viscosity Stability Data for 10 Imiquimod Formulations, i.e.,
Formulations 116, 117, 120, 124, 188, 184, 189, 235, 254 and 255, Rejected
after 1
Month Stability
Formulation Crossove G' Brookfield (cps) Bohlin Viscosity (cps)
144
CA 02649893 2009-01-15
T= 0 T= 0 T= 0 Month T= 0 T=1 Month
116 9.0 478 601867 63500 15350 13300
117 14.0 1151 1216667 1281000 17250 15600
254 10.3 1399 1476667 1423000 19050 19000
120 15.3 884 1416667 1393000 20250 20900
235 6.0 134 245333 313000 6350 5700
188 14.0 708 1141333 1254000 20350 20750
189 34.8 1037 1344333 1463000 18700 18550
184 23.0 1054 1475667 1350000 20200 21600
255 16.0 1488 2483333 1334000 21150 25150
124 7.0 561 849000 663000 14400 14250
(F) Brookfield Viscosity Stability Results of Formulations
[0333] In Table 27, Brookfield viscosity measurements are notoriously variable
and,
as such, there are fluctuations in the measurements of the formulations over
about a 6
month period when stored at about 25 C. Variations in results are further
observed if
the spindle or the speed of the spindle rotation is altered. Although the
majority of the
formulations are measured using the same settings and spindle; the placebo
formulations (Pbol, Pbo2, Pbo3 and Pbo4) result in torque measurements below
the
threshold required for accurate measurements and subsequently readings are
inaccurate. Attempts are made to change the settings and spindles; however,
results
are vastly different and thus unreliable. See also Tables 24-26.
Table 27. Viscosity and Rheology Measurements of Imiquimod Formulations
stored at 25 C over a 6 Month Period.
FwmWaoon G(Pa) Cro wa (o) 6ronkfieW (cPs) BoM14n Vscosiry (cPo) (~ on 3M
melM1Od)
Idm4N t= 0 1= 0 1=1 Manth 1=2 Monlhs r3 MomM1S 1=6 MnMhs = 0 t=I Monlh 1=2
Months t=3 Monlhs 1=6 Momhs
3M FICxaCI 5% 507 112.5 660333 623000 337000 428813 166233 15)00 17300 17620
13296 12833
Imipimotl
Grxeay 2440r08 5% 716 105 1108667 1109000 587667 768566 252033 18250 20250
19900 18697 15100
miQUimod
257 (1%) 352 10 52 642667 600000 220333 351566 13600 15050 11500 6075 3139
145
CA 02649893 2009-01-15
110 783 11.5 87100 119000 782330 619300 36606] 16250 16400 18000 16.359 14016
250 320 9 695333 816000 551333 394166 141400 13700 16400 14950 10587 5890
182 702 85 693067 100000 903667 523033 273233 18050 17850 18550 16820 13691
195 692 15 1141333 1293000 719333 618133 381700 17600 11600 16500 16208 14696
123 510 10.8 804000 113000 386333 701500 199933 15800 16250 15200 13095 9581
125 485 8 5 603000 707000 429667 412133 127061 14900 17650 15300 13069 8301
256 667 ] 3 1126000 955000 691661 751523 249500 19400 18300 18750 15453 12379
197 646 14 1082667 131000 613667 607366 274400 17750 17950 17600 15861 13524
183 719 10.3 E93333 839000 596000 332900 188000 18700 19100 18600 15906 12120
126 AP 430100 235066 228104 212500 105220 16]83 00 1 12]39 14749 10856.5 8]89
5
PBOi 306 11 85000 ' = ' ' 1214450 7500 7969 2508.3
P802 263 13 79500 14200 13950 9100 6452.5 2611.6
P1303 305 11 5 11]G00 12200 13850 9000 8395 3256.5
P804 22]800 10350 7953 5511 3550 2247
= resuRs un-reliable and not presented as the torque was out of range (due to
low viscosity) for the Brookfield viscometer using the settings and spindle
used for all the other
samples. Altemative spindles and settings were investigated, however, the
results were vastly different than previous readings.
" no recorded measuremeots, as test was only required for initial formulations
choice and development.
146
CA 02649893 2009-01-15
(G) Bohlin viscosity Results
[0334] Also as shown in Table 27, the Bohlin viscosity results are in contrast
to the
results of the Brookfield viscosity and appear to be more consistent for all
formulations.
A fall in the viscosity is observed for 257 (1%) and placebo formulations,
Pbol-4, over
the 6 month stability study, whereby the viscosity falls by approximately 50%.
All
formulations are within the range of the specifications for the Aldara 5%
imiquimod
cream formulation (2000 to 35,000 cps). See also Tables 24-26.
(H) pH Stability of Formulations
[0335] In Table 28, it reports that the specification for all formulations
that are tested,
fall within the Aldara 5% imiquimod cream specifications (pH 4.0 to 5.5). A
slight
variation in pH is observed over the 6 month period for all of the
formulations. See also
Tables 24-26.
Table 28. ph for Imiquimod Formulations when Stored at about 25 C and about
40 C over a 6 Month Period. Grey Areas Indicate No Test Is Performed.
pH
Formulation t= 0 t=1 month 1=2 montAs t=3 months t=6 months
25 C 25 C 40 C 25 C 40 C 25 C 40 C 25 C 40 C
3M Aldara 5% 4.5 4.5 4.5 4.5 4.5 4.7 43 4.1
Imiquimod Graceway Aldara 5% 4.5 4.5 4.5 4.5 4.5 4.5 43 4.5
Imiquimod
257 (1%) 4.2 4.5 4.5 4.5 4.5 41 4.1 3.9
110 5 4.7 4.7 4.7 4.7 4.4 45 4.3'
250 4.2 42 42 4.5 4.2 4 4.2 4_1
182 4.5 4.5 4.5 4.5 4.5 4.6 43 4.3
195 4.7 4.5 4.5 4.5 4.5 4.7 4.5 4.5
123 4.5 4.7 4.7 4.7 4.7 4.3 4.1 4.3
125 4.5 4.5 4.5 45 4.5 42 4.1 41
256 4.7 43 4.7 4.7 43 4.4 4.3 4.3
197 4.5 4.7 4.7 4.7 4.7 4.6 4.5 43
147
CA 02649893 2009-01-15
183 4.5 4.5 4.5 4.5 4.5 4.2 4.5 41
126 4.2 4.3 4 4.3 4.3 4.3 4.3 41 41
Pbol 4.5 4.5 4.5 4.5 4.2 4.5 4.0 4.0
Pbo2 4.5 4.5 4.2 4.2 4.2 4.2 4.1 4.1
Pbo3 4.5 4.5 4.5 4,2 4.2 4.2 4.2 4.2
Pbo4 4.5 4.2 4.5 4.2 4.2 4.1 4.1 4.0 40
* 30 C sample analyzed as the 40 C sample had phase separated
(1) Preservative efficacy test
[0336] Table 29 reports final viable counts of organism inoculations that are
added to
the formulations.
Table 29. Total Viable Counts that are obtained for the Organism Inoculates
into
the Imiquimod Formulations
Organism Mimi for 182 and Cfu/ml for 126 and
110 Pbo4
Staphylococcus aureus 2.4E+08 3.1 E+08
Escherichia coli 1.7E+08 2.1 E+08
Pseudomonas aeruginosa 9.OE+07 1.1 E+08
Candida albicans 1.OE+08 1.1 E+08
Aspergillus niger 1.7E+07 1.6E+08
[0337] Table 30 shows colony forming unit count (cfu) for Staphylococcus
aureus
after PET validation is performed on two formulations stored at about 2 - 8 C.
Table 30. Viable counts that are obtained for Staphylococcus aureus that are
Inoculated Formulations after PET Validation
148
CA 02649893 2009-01-15
Imiquimod Suspension Dilution Viable count (cfu/ml)
Formulation fluid
1 ml in 9 ml 2.20E+08
D/E broth
0.1 ml in 0.9 mi 2.80E+08
110
Ringer's 1 mi in 9 ml 1.00E+03
solution 0.1 ml in 0.9 ml 1.50E+03
- 1 ml in 9 mi 2.30E+08
D/E broth
0.1 ml in 0.9 ml 2.60E+08
182
Ringer's 1 ml in 9 ml 1.00E+03
solution 0.1 ml in 0.9 ml 1.40E+03
[0338] The preservative efficacy test ("PET") is a procedure used to
demonstrate
antimicrobial activity of a formulation with respect to the preservative
system used. In
Table 31, cell counts that are recovered from the inoculated formulations at
various time
points are reported. The data shows that sufficient log reductions are present
in the
formulations at about 2-8 C and about 40 C and meet the requirements that are
specified in both the USP and EP.
149
CA 02649893 2009-01-15
0
~ m a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a a ¾
u a a a a a a a u a a a a a a a a a n u a a a a a a a n d
~
(D
8 8
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~
0
~
N $ S
~
a)
Q
s
~
w
L
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U
a
L. S S
LO
O T
U
4)
L
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s
r.+
r.y+
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U
=
~
E y c y N `, N m õ o o c .
4 4 4 4 a R 4
L 0
O cp
LL lV
A L
O ~
O
Y _ .. U .. U .. a .. U
U N^ < <
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o N O ^ o~
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CA 02649893 2009-01-15
< a < a <
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CA 02649893 2009-01-15
(J) Test Item Release Studies through Synthetic Membranes
[0339] In FIG. 58, it indicates that there is a trend between the
concentrations of
imiquimod present in the formulation as compared to the amount that is
released. This
is supported by the results presented in FIG. 59 and the corresponding
statistical
analysis, where it can be seen that that the higher the imiquimod
concentration in the
formulation, the greater the release of imiquimod. However, formulation 183
(3.75%
w/w imiquimod) gives a statistically (at a 95% confidence level) greater
cumulative
release of imiquimod when it is compared to the 2.5% w/w formulations. All of
the 5%
w/w formulations, i.e., Aldara 5% imiquimod cream batch, Aldara 5% imiquimod
cream Graceway batch, and Aldara 5% imiquimod cream Sachet), result in
significantly (p<0.05) higher amounts of imiquimod released over a 3 h time
period in
comparison to 1%, 2.5% and 3.75% w/w imiquimod formulations. There is no
statistical
difference (p>0.05) in the total cumulative amount of imiquimod that is
released from
any of the 3.75% w/w imiquimod formulations; likewise there is also no
statistical
difference (p>0.05) from the 2.5% w/w imiquimod formulations.
[0340] ANOVA statistical analysis (95% confidence level): mean total
cumulative
amount that is released (pg/cm2) after 3 h (from results that are presented in
FIG. 58):
Source DF SS MS F P
Formulation 12 86439222 7203268 19.40 0.000
Error 39 14484370 371394
Total 51 100923592
S = 609.4 R-Sq = 85.65% R-Sq (adj) = 81.23%
Individual 95% Cls For Mean Based on
Pooled StDev
Level N Mean St. Dev +----------------+---------------+--------------+---------
-
Aldara 3M 5% 4 5332.8 734.2 ( * )
Aldara sachet 4 4605.5 626.9 (---*-- )
110 4 1862.8 185.9 ( * )
250 4 1845.6 206.4 ( * )
182 4 3161.3 774.9 ( * )
195 4 3046.2 988.2 ( * )
123 4 2094.9 674.6 ( * )
125 4 2134.1 369.0 ( * )
256 4 2918.7 59.5 ( * )
197 4 2766.0 929.1 ( * )
183 4 3453.2 564.4 ( * )
MedPharm Aldara 4 4813.3 660.7 (-- * )
257% 4 586.9 170.2 (---*---)
152
CA 02649893 2009-01-15
+---------------+--------------+--------------+------------
0 1500 3000 4500
Pooled StDev = 609.4
[0341] ANOVA statistical analysis (95% confidence level): mean total
cumulative
amount that is released (pg/cm2) after 3 h for each concentration of imiquimod
in the
formulations that are tested (from results that are presented in FIG. 59):
Source DF SS MS F P
Formulation 3 83957708 27985903 79.18 0.000
Error 48 16965878 353456
Total 51 100923586
S = 594.5 R-Sq = 83.19% R-Sq (adj) = 82.14%
Individual 95% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev +----------------+---------------+--------------+---------
-
1% 4 586.9 170.2 ( * )
2.50% 16 1984.4 389.9 ( * )
3.75% 20 3069.1 702.3 (* )
5.00% 12 4917.2 689.4 ( * )
+---------------+--------------+--------------+------------
0 1500 3000 4500
Pooled StDev = 594.5
[0342] The result for the rate of release presented in Table 32, indicate that
the
higher the amount of imiquimod in the formulation, the faster the rate of
release of
imiquimod. Similar to the results of the cumulative amount permeated, there is
no
statistical difference (p>0.05) between the results for the 2.5% w/w imiquimod
formulations (Table 32 and FIG. 67) and likewise for the 3.75% w/w imiquimod
formulations (Table 32 and FIG. 68). See also FIGS. 66 and 69.
Table 32. Comparison of Mean Flux of Imiquimod (pg/Cm2) over a 3 H Period for
Membrane Release Tests (Mean Sd, Where N=4) that are Presented as a
Function of 4Time from 15 Min To 3 H.
Flux Aime
Formulations Mean sd
Graceway Aldara 5% 3720.65 569.38
Imiquimod
3M Aldara 5% Imiquimod 3873.38 479.64
Cream Bulk
153
CA 02649893 2009-01-15
Flux Ame
Formulations Mean sd
3M Aldara 5% Imiquimod 3319.56 494.32
Cream sachet
257 (1 %) 504.40 148.43
123(2.5%) 1539.39 482.36
250(2.5%) 1396.68 173.65
125 (2.5%) 1592.98 324.51
110(2.5%) 1518.29 151.17
182 (3.75%) 2410.03 599.08
195 (3.75%) 2310.06 597.59
256 (3.75%) 2424.87 28.09
197 (3.75%) 2116.53 723.60
183 (3.75%) 2516.84 357.41
[0343] ANOVA statistical analysis (95% confidence level): mean amount of
imiquimod
released (pg/cm2) over a 3 hour period for the membrane release studies (mean
sd,
where n=4) presented as a function of 4time from 15 min to 3 h (from results
presented
in Table 32):
Source DF SS MS F P
Formulation 12 45353042 3779420 19.05 0.000
lirror 39 7739267 198443
1'otal 51 53092309
S-- 445.5 R-Sq = 85.42% R-Sq (adj) = 80.94%
Individua195% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev +----------------+---------------+--------------+---------
-
3M Aldara~' 5% 4 3873.4 479.6 (* )
Imiquimod Cream
Bulk
3M Aldara"' 5% 4 3319.6 494.3 ( *)
Imiquimod Cream
Sachet
110 4 1518.3 151.2 ( --*- )
250 4 1396.7 173.6 ( * )
182 4 2410.0 599.1 ( * )
195 4 2310.1 597.6 ( * )
123 4 1539.4 482.4 ( * )
125 4 1593.0 324.5 ( * )
256 4 2424.9 28.1 ( * )
154
CA 02649893 2009-01-15
197 4 2116.5 723.6 ( * )
183 4 2516.8 357.4 (---*---)
Graceway "' 5% 4 3720.6 569.4 ( * )
Imiquimod Cream
257 1% 4 504.4 148.4 ( * )
+---------------+--------------+--------------+------------
0 1200 2400 3600
Pooled StDev =445.5
[0344] ANOVA statistical analysis (95% confidence level): Comparison of the
mean
amount of imiguimod released (Ng/cm2) over a 3 hour period for the 3M Aldara
5%
imiquimod cream 1 kg - batch, the 3M Aldara 5% imiquimod cream sachet, the
Graceway Aldara 5% imiquimod cream 1 kg batch and 257, 1 % Imiquimod
formulation
(mean sd, where n=4) - refer to FIG. 66:
Source DF SS MS F P
Formulation 3 57378855 19126285 54.74 0.000
Error 12 4192460 349372
Total 15 61571315
S = 591.1 R-Sq = 93.19% R-Sq (adj) = 91.49%
Individual 95% CIs For Mean Based on Pooled
StDev
Level N Mean St.Dev +----------------+---------------+--------------+----------
Aldara 3M 5% 4 5332.8 734.2 (*-)
Aldara sachet 4 4605.5 626.9 (---*---)
MedPharm Aldara 4 4813.3 660.7 (---*---)
U2F 1% 4 586.9 170.2 (*)
+---------------+--------------+--------------+------------
0 1600 3200 4800
Pooled StDev = 591.1
[0345] ANOVA statistical analysis (95% confidence level): Comparison of the
mean
amount of imiquimod released (Ng/cm2) over a 3 hour period for 2.5% imiquimod
formulations 123, 250, 125 and 110 (mean sd, where n=4) - refer to FIG.67:
Source DF SS MS F P
Formulation 3 274778 91593 0.55 0.659
Error 12 2004990 167083
Total 15 2279769
S = 408.8 R-Sq = 12.05% R-Sq (adj) = 0.00%
Individual 95% CIs For Mean Based on Pooled
155
CA 02649893 2009-01-15
StDev
Level N Mean St.Dev ---+---------+---------+---------+------
GW002 4 1862.8 185.9 (--------------- *---------------
GW008 4 1845.6 206.4 (--------------- *---------------
GW037 4 2094.9 674.6 (--------------- *---------------
GW039 4 2134.1 369.0 (--------------- *---------------)
---+---------+---------+---------+------
1500 1800 2100 2400
Pooled StDev = 408.8
[0346] ANOVA statistical analysis (95% confidence level): Comparison of the
mean
amount of imiquimod released (pg/cm2) over a 3 hour period for 3.75% imiquimod
formulations 182, 195, 256, 197 and 183 (mean sd, where n=4) - refer to FIG.
68:
Source DF SS MS F P
Formulation 4 1084063 271016 0.49 0.743
Error 15 8286917 552461
Total 19 9370981
S= 743.3 R-Sq = 11.57% R-Sq (adj) = 0.00%
Individual 95% CIs For Mean Based on Pooled
StDev
Level N Mean St. Dev -------+---------+---------+---------+--
GW030 4 3161.3 774.9 (-------------*------------)
GW033 4 3046.2 988.2 (------------- *------------
GW040 4 2918.7 59.5 (------------- *------------
GW041 4 2766.0 929.1 (------------- *------------ )
GW042 4 3453.2 564.4 -------+---------+---------+---------+--
2400 3000 3600 4200
Pooled StDev = 743.3
[0347] As discussed under FIG. 69 in the Brief Description of the Drawings,
FIG. 69
shows a comparison of the mean amount of imiguimod released (pg/cm2) over a 3
hour
period for the 2.5% (A), 3.75% (=), 3M Aldara imiquimod cream batch (^),
Graceway
Aldara imiquimod cream 1 kg batch(^) and formulation 257 Imiquimod
formulations (^)
(mean sd, where n=4).
[0348] Based on the results; it appears that the greater the amount of
imiquimod in
the formulation, the faster and greater the total amount of imiquimod that is
released,
156
CA 02649893 2009-01-15
suggesting that the amount and rate of release are concentration dependant.(K)
In
vitro Skin Permeation Study
(1) Homogeneity
[0349] Manufacture of the formulations (about 100g batches) is first
performed, which
batches are then mixed with the radioactive labelled material. The batches are
prepared by omitting about 1.38g of isostearic acid which is added with the
radio-
labelled imiquimod. The homogeneity of the test formulations, see Table 33, is
measured as described in under Homogeneity Control above and all compositions
are
confirmed to meet the criterion (<10% CV).
Table 33. Homogeneity of Radioactivity for Imiquimod Formulations
Formulation % CV
Graceway Aldara 5% lmiquimod Cream 0.93
3M AldaraR 5% Imiquimod Cream 1.50
182 0.80
195 2.39
256 1.17
197 0.07
183 1.54
110 0.71
250 2.53
123 1.89
125 1.53
126 2.55
257 (1 %) 2.30
(2) Franz cell study
[0350] The data that is shown in Table 34 is the actual amount of imiquimod
that is
recovered for each formulation from the various matrices, which is also
represented
graphically in FIG. 60. FIG. 61 represents the total amount of imiquimod that
is
recovered for each formulation in the epidermis, dermis and receiver fluid
combined.
157
CA 02649893 2009-01-15
a
o d a
il N
E
d.+
VI w o o c
, N
N N
C +i E
R e
0
-
m E
U) N E 0
o -a
a~
L e
O S
I.L
N o 0 0 0 o
. _ o 0 0 0 0 0 0 0
.~ -
~
0
O o a o
~
cr o 0
=~ ¾
~
0
~ E e
E a E
(h o a_ E v ~ oe eap N a o
_
~ a ~ E
E m~ U Q E o 0
CA 02649893 2009-01-15
[0351] The only data rejected from that presented in Table 34, FIG 60 and FIG.
61
are obvious outliers that are observed on the basis of cell failure.
[0352] The average data for the 5%, 1%, 3.75% and 2.5% w/w formulations
showing
the amount of imiquimod that is recovered from the unabsorbed fraction, in the
Stratum
corneum and in the epidermis, dermis and receiver fluid combined are shown in
FIG.
62. This data shows that there is a linear dose release between the amount of
imiquimod applied and recovery in each of the matrices. See also Table 35 for
stability
of calibration standards in spent receiver fluid and Tables 36-40-for
statistical analysis.
Table 35. Stability of Calibration Standards in Spent Receiver Fluid (Stored
In
HPLC Crimp Top Vials at Each Temperature (Where Recovery was Compared To
T=0)
48h % recovered in Spent
receiver fluid
Standard
(tig/ml) Spent receiver fluid: Fridge RT 37 C
105.5 88.242 88.546 91.704
84.4 84.561 84.421 85.629
52.75 91.776 92.027 93.779
42.2 Full thickness + placebo 83.976 84.144 86.439
21.1 84.584 85.162 88.000
10.55 88.307 86 897 90398
5.275 90.260 87.973 86.134
105.5 90.545 92.275 92.278
844 98.841 99.790 101.010
52.75 92.317 92.152 95.282
42.2 Full thickness 95.103 95.805 95.939
21.1 91.876 91.968 93.847
10.55 94.989 93.522 97.826
5.275 94.586 95.232 90.611
105.5 83.833 84515 84 903
84.4 95.620 96033 98.178
52.75 85.635 88.169 86.906
42.2 Epidermal sheet + placebo 93077 92.904 95.095
211 101.831 105.389 105.213
10.55 84.046 85 095 89.945
5.275 88.881 86.540 86.828
105.5 90.465 92.089 91.501
84.4 81.350 82.276 82694
52.75 87.669 89.096 90.943
422 Epidermal sheet 85.716 86.340 89.641
21.1 95.828 97098 97470
~ -- 10.55 93.180 94.971 97.099
5.275 88.938 91447 85995
159
CA 02649893 2009-01-15
Tables 36-40. Statistical Analysis for Amount of Imiquimod that is Recovered
following Mass Balance Test
[0353] ANOVA statistical analysis (95% confidence level): Amount of imiquimod
that
is recovered following mass balance test from receiver fluid (from results
that are
presented in FIG. 60) is shown in Table 36:
Table 36
Source DF SS MS F P
Cl 14 0.12075 0.01006 1.84 0.066
F..rror 52 0.28455 0.00547
Total 64 0.40530
S = 0.07397 R-Sq = 29.79% R-Sq (adj) = 13.59%
Individual 95% CIs For Mean Based on Pooled
StDev
Level N Mean St. Dev ---------+---------+---------+---------+
3M Aldara 5% 4 0.05250 0.05909 (---------*---------)
Imiquimod Cream
110 2.5% 6 0.00000 0.00000 (------- *-------)
250 2.5% 5 0.00400 0.00894 (------- *-------)
182 3.75% 6 0.07833 0.14400 (---------*---------)
195 3.75% 4 0.08250 0.14500 (----------*----------)
123 2.5% 5 0.01200 0.01095 (-------- *-------)
125 2.5% 6 0.02333 0.02503 (-------*------)
256 3.75% 5 0.15600 0.14064 (------- *--------)
197 3.75% 5 0.05800 0.06611 (------- *--------)
183 3.75% 4 0.01750 0.01708 (--------*--------)
126 5 0.00600 0.00894 (---------*---------)
(Jraceway Aldara 6 0.02833 0.03312 (---------*---------)
5% Imiquimod
Cream
25? (1 %) 4 0.00500 0.00577 (--------- *---------)
---------+----------+-----------+---------+
0.000 0.080 0.160 0.240
Pooled StDev = 0.07397
[0354] ANOVA statistical analysis (95% confidence level): Amount of imiquimod
that
is recovered following mass balance test from un-absorbed dose (from results
that are
presented in FIG. 60) is shown in Table 37:
Table 37
Source DF SS MS F P
Cl 12 50777 4231 16.83 0.000
Frror 52 13071 251
l otal 64 63848
160
CA 02649893 2009-01-15
S = 15.85 R-Sq = 79.53% R-Sq (adj) = 74.80%
Individual 95% CIs For Mean Based on Pooled
StDev
Level N Mean St. Dev ------------+---------------+--------------+----------+---
3M Aldara' 5% 4 132.75 35.25 (--*---)
Imiquimod Cream
1102.5% 6 52.93 9.69 ( * )
250 2.5% 5 82.46 6.57 ( * )
182 3.75% 6 85.75 9.63 (* )
195 3.75 /a 4 74.19 13.80 ( *---)
123 2.5% 5 68.33 7.10 ( * )
125 2.5% 6 72.82 9.61 ( * )
256 3.75% 5 71.73 16.15 ( * )
197 3.75% 5 110.54 13.91 ( * )
183 3.75 /a 4 113.85 23.27 ( * )
126 5 63.98 11.78 ( * )
Graceway Aldara"' 6 127.06 23.46 (* )
5% Imiquimod
Cream
'257 (1%) 4 28.88 9.20 ( * )
--------------+---------------+-----------+---------+---
35 70 105 140
Pooled StDev = 15.85
[0355] ANOVA statistical analysis (95% confidence level): Amount of imiquimod
that
is recovered following mass balance test from Stratum corneum (from results
that are
presented in FIG. 60) is shown in Table 38:
Table 38
Source DF SS MS F P
(11 12 21479 1790 6.72 0.000
i rror 52 13848 266
1 utal 64 35327
ti- 16.32 R-Sq = 60.80% R-Sq (adj) = 51.75%
Individual 95% Cls For Mean Based on Pooled
StDev
Level N Mean St. Dev --+---------+----------+----------+------
IM Aldara"' 5% 4 74.38 21.17 (------*-----)
liniquimod Cream
110 2.5% 6 33.96 8.41 ( * )
250 2.5% 5 28.30 8.21 (------* )
l82 3.75% 6 46.85 13.50 (------*-----)
195 3.75% 4 57.41 22.92 (------*-----)
123 2.5% 5 35.93 23.25 (------* )
125 2.5% 6 28.88 10.80 (------ *-----)
256 3.75% 5 33.41 10.67 (------*-----)
197 3.75% 5 41.61 14.62 (------*-----)
183 3.75% 4 41.00 13.97 (------*-----)
126 5 29.59 11.11 (------* ---)
161
CA 02649893 2009-01-15
Graceway Aldara 6 80.78 28.60 (------*-----)
5% Imiquimod
Cream
257 (1 %) 4 12.49 7.49 (------*-----)
--+---------+----------+----------+-----
0 25 50 75
Pooled StDev = 16.32
[0356] ANOVA statistical analysis (95% confidence level): Amount of imiquimod
that
is recovered following mass balance test from epidermis (from results that are
presented in FIG. 60) is shown in Table 39:
Table 39
Source DF SS MS F P
Cl 12 187.78 15.65 3.26 0.002
Error 52 249.79 4.80
Total 64 437.57
S = 2.192 R-Sq = 42.91% R-Sq (adj) = 29.74%
Individua195% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev ------+---------+---------+---------+---
3M Aldara`k' 5% 4 6.600 3.823 (------* --)
Imiquimod Cream
110 2.5% 6 3.248 1.717 (------*-----)
250 2.5% 5 2.350 1.514 (------ *-----)
182 3.75% 6 3.643 2.083 (------* )
195 3.75% 4 7.055 4.580 (------*-----)
123 2.5% 5 4.196 3.782 (------*-----)
125 2.5% 6 1.123 1.039 (------ *----- )
256 3.75% 5 1.990 1.588 (------ *----- )
197 3.75% 5 2.208 0.797 (------ *-----)
183 3.75% 4 3.260 1.053 (------*-----)
126 5 2.360 0.903 (------* -)
Graceway Aldara"" 6 2.895 1.752 (------*-----)
5% Imiquimod
Cream
257 (1%) 4 0.415 0.273 (------*-----)
--------------+---------------+-----------+---------+---
0.0 3.0 6.0 9.0
Pooled StDev = 2.192
[0357] ANOVA statistical analysis (95% confidence level): Amount of imiquimod
that
is recovered following mass balance test from dermis (from results that are
presented in
FIG. 60) is shown in Table 40:
Table 40
162
CA 02649893 2009-01-15
Source DF SS MS F P
CI 12 340.72 28.39 3.29 0.001
Error 52 448.34 8.62
Total 64 789.06
S = 2.936 R-Sq = 43.18% R-Sq (adj) = 30.07%
Individual 95% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev ------+---------+---------+---------+---
3M Aldara' 5% 4 3.960 0.825 (-------- *-------)
Imiquimod Cream
1102.5% 6 2.323 1.068 (------ *------)
250 2.5% 5 1.164 0.663 (------ *------ )
182 3.75% 6 6.937 5.445 (------ *------)
195 3.75% 4 2.473 1.733 (------- *-------)
123 2.5% 5 1.796 0.715 (------- *-------)
125 2.5% 6 1.518 1.020 (------- *------- )
256 3.75% 5 9.030 5.305 (------ *------)
197 3.75% 5 2.532 2.036 (------- *------- )
183 3.75% 4 5.110 4.638 (-------- *------)
126 5 4.436 3.626 (------ *------)
------
Graceway Aldara"" 6 2.758 1.721 (------ *------
5% Imiquimod
Cream
257 (1%) 4 1.533 2.099 (------ *------)
------+---------------+-----------+---------+-----
0.0 3.5 7.0 10.5
Pooled StDev = 2.936
[0358] The results that are presented in FIG. 61, indicate that the delivery
of the
imiquimod into the receiver fluid, epidermis and dermis combined from
formulations
182, 195 and 256 are similar to the Aldara 5% imiquimod cream formulation
when
comparing averages. With respect to the statistical analysis, there is no
statistical
difference (p>0.05) between 110 (2.5%), 126 (2.5%), 123 (2.5%), 182, (3.75%),
195
(3.75%), 256 (3.75%), 197 (3.75%) and 183 (3.75%) when compared to Aldara 5%
imiquimod cream formulation in the amount of imiquimod that is recovered from
the
receiver fluid, epidermis and dermis combined.
163
CA 02649893 2009-01-15
[0359] In Table 41, ANOVA statistical analysis (95% confidence level) are
presented:
Total amount of imiquimod that is recovered for each formulation in the
receiver fluid,
epidermis and dermis combined (from the results that are presented in FIG. 61:
Table 41
Source DF SS MS F P
Cl 12 573.2 47.8 3.28 0.001
Error 52 758.2 14.6
Total 64 1331.4
S = 3.819 R-Sq = 43.05% R-Sq (adj) = 29.91%
Individual 95% CIs For Mean Based on Pooled
StDev
Level N Mean St.Dev ----+---------+---------+---------+-----
257 (1%) 4 1.958 2.357 (-------*-------)
110 2.5% 6 5.572 2.706 (------- *-------)
250 2.5% 5 3.524 1.445 (-------*-------)
123 2.5% 5 6.010 4.296 (--------*-------)
125 2.5% 6 2.663 0.837 (------- *------ )
126 2.5% 5 6.804 3.538 (-------- *--------
182 3.75% 6 10.662 6.441 (------- *--------)
195 3.75% 4 9.608 5.392 (------- *-------- )
256 3.75% 5 11.180 5.770 (-------- *--------)
197 3.75% 5 4.800 1.749 (-------- *-------- )
183 3.75% 4 8.388 3.666 (--------- *---------)
Graceway Aldara 6 5.682 2.671 (---------*---------)
5% Imiquimod
Cream
3M Aldara 5% 4 10.613 4.211 (--------- *---------)
Imiquimod Cream
----+---------+---------+---------+-----
0.0 5.0 10.0 15.0
Pooled StDev = 3.819
[0360] The results that are presented in FIG. 62 and statistical analysis in
Tables 42-
46 indicate that there is a distinct dose proportionate trend between the
amount of
imiquimod that is recovered from each of the matrices with respect to the
concentration
of imiquimod in the formulation for both un-absorbed and Stratum comeum. The
trend
in this data, is also observed for the epidermis (with respect to average
values in the
statistical analysis).
164
CA 02649893 2009-01-15
[0361] In Tables 42-46, statistical analysis for the total amount of imiquimod
recovered from each of the matrices (1 %, 2.5%, 3.75% and 5% w/w formulations)
[0362] ANOVA statistical analysis (95% confidence level): Total amount of
imiquimod
that is recovered for imiquimod concentration combined from each of the
matrices from
un-absorbed dose (from results presented in FIG. 62) in Table 42:
Table 42
Source DF SS MS F P
Cl 3 44198 14733 35.53 0.000
Frror 61 25293 415
Total 64 69491
S = 20.36 R-Sq = 63.60% R-Sq (adj) = 61.81%
Individua195% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev --------------+---------------+-----------+---------+-
1% 4 28.88 9.20 ( * )
2.5% 27 64.08 16.24 ( * )
3.75% 24 90.75 22.48 ( * )
5% 10 129.33 26.99 ( * )
--------------+---------------+-----------+---------+-
35 70 105 140
Pooled StDev = 20.36
[0363] ANOVA statistical analysis (95% confidence level): Total amount of
imiquimod
that is recovered for imiquimod concentration combined from each of the
matrices from
Strateum corneum (from results presented in FIG. 62) in Table 43:
Table 43
Source DF SS MS F P
cI 3 19744 6581 25.76 0.000
l=.rror 61 15583 255
Total 64 35327
S = 15.98 R-Sq = 55.89% R-Sq (adj) = 53.72%
Individual 95% Cls For Mean Based on
Pooled StDev
Level N Mean St. Dev -+---------+---------+---------+---------
1 % 4 12.49 7.49 (-----"-----
Z 51/,. 27 31.34 12.57 (")
3.75% 24 43.74 15.85 ( ' )
5%. 10 78.22 24.79 ( ' )
-+---------+---------+---------+---------
165
CA 02649893 2009-01-15
0 25 50 75
Pooled StDev = 15.98
[0364] ANOVA statistical analysis (95% confidence level): Total amount of
imiquimod
that is recovered for imiquimod concentration combined from each of the
matrices from
epidermis (from results presented in FIG. 62) in Table 44:
166
CA 02649893 2009-01-15
Table 44
Source DF SS MS F P
Cl 3 55.25 18.42 2.94 0.040
Error 61 382.32 6.27
Total 64 437.57
S = 2.504 R-Sq = 12.63% R-Sq (adj) = 8.33%
Individua195% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev --------+--------+--------+--------+-
1% 4 0.415 0.273 (--------- *---------)
2 5% 27 2.621 2.137 ( * )
3.75% 24 3.505 2.729 ( * )
5% 10 4.377 3.200 (------*-----)
--------+--------+--------+--------+-
0.0 2.5 5.0 7.5
Pooled StDev = 2.504
[0365] ANOVA statistical analysis (95% confidence level): Total amount of
imiquimod
that is recovered for imiquimod concentration combined from each of the
matrices from
dermis (from results presented in FIG. 62) in Table 45:
Table 45
Source DF SS MS F P
(1 3 147.4 49.1 4.67 0.005
l:rror 61 641.7 10.5
Total 64 789.1
S- 1243 R-Sq = 18.68% R-Sq (adj) = 14.68%
Individual 95% CIs For Mean Based on
Pooled StDev
i,evel N Mean St. Dev -------+---------+---------+---------+--
(''a 4 1.533 2.099 (--------------- *---------------)
27 2.223 1.974 ( * )
i.75% 24 5.407 4.694 ( * )
ro 10 3.239 1.502 (-------- *--------)
-------+---------+---------+---------+--
0.0 2.5 5.0 7.5
Pooled StDev = 3.243
[0366] ANOVA statistical analysis (95% confidence level): Total amount of
imiquimod
that is recovered for imiquimod concentration combined from each of the
matrices from
receiver fluid (from results presented in FIG. 62) in Table 46:
167
CA 02649893 2009-01-15
Table 46
Source DF SS MS F P
Cl 3 0.07047 0.02349 4.28 0.008
Error 61 0.33483 0.00549
Total 64 0.40530
S = 0.07409 R-Sq = 17.39% R-Sq (adj) = 13.32%
Individua195% CIs For Mean Based on
Pooled StDev
Level N Mean St. Dev ----+---------+---------+---------+-----
1% 4 0.00500 0.00577 (---------------- *----------------)
2.5% 27 0.00926 0.01542 (-----*------)
3.75% 24 0.08083 0.11632 (----- *------) _
5% 10 0.03800 0.04392 (--------- *---------- )
----+---------+---------+---------+-----
-0.050 0.000 0.050 0.100
Pooled StDev = 0.07409
[0367] The following Tables 47-59 summarize results for formulations 126, 182
and
Pbo4.
Table 47. Stability of Imiquimod in the Formulations. Percentage of imiquimod
that is recovered from each formulation compared to theoretical when stored at
25 C and 40 C over a 6 month period.
t = 1 month t = 2 months t= 3 manhs t= 6 momhs
Formulations t= 0 h 25 C 40 C 25 C 40 C 25 C 40 C 25C 40 C
182 96.16 ! 0 25 10201 ! 001 9846 t 0.15 9900 t 0.12 9907 ! 0.10 101.48 ! 0.27
104.39 t 1.55 10291 ! 1.16 99.12 045
P1304 0 o a 0 0 o o 0 0
126 102.3] t 0.59 10284 t 045 104.11 t 0.04 10002 f 0.95 101.32 t 040 9928 t
325 9843 1 0.55 101.95 0 37 103.02 t 189
Table 48. Stability of Imiquimod in the Formulations. Identification of
Imiquimod
when the formulations are stored at 25 C and 40 C over a 6 month period
(confirmed by HPLC).
T T 2 months I s T= 6 momhs
Furmulauons T = 0
25'C 40 C 25 C 25 C 40 C 40 C 25'C 40 C
182 Complies Complies Complies Complies Compiles Complies Complies Compiles
Complies
126 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
GW030P Complies Complies Complies Complies Complies Complies Complies Complies
Complies
168
CA 02649893 2009-01-15
Table 49. Stability of Benzyl Alcohol in the Formulations. Amount of benzyl
alcohol that is recovered from each of the formulations when the formulations
are
stored at 25 C and 40 C over a 6 month period.
I t= 2 mw101s t= 3 momhs t= 6 manths
FormWations t = 0 h
25 C 40'C 25'C 40 C 25'C 40 C 25'C 40'C
182 21] ! 0.00 2.17 x 000 1.95 a 0.01 2.11 i 0.91 197 3 000 194 t 0.01 182 f
0.04 1&5 a 0.03 148 t 005
PBO4 193 002 183; 006 190 i 003 191 , 0.01 151 ! 000 181 x 0.01 1.39 S 0.01
171 i 001 108 x 0.02
121 2.00 3 0.02 2.02 ! 0.01 1 89 ! 0.01 1.86 ! 0 02 1 65 : 0 02 2.00 ! 0.00
110 f 0 04 2 01 0.03 1.55 s 0.02
Table 50. Stability of Benzyl Alcohol in the Formulations. Identification of
Benzyl
alcohol when the formulations are stored at 25 C and 40 C over a 6 month
period
(confirmed by HPLC).
T 1 montll T T T 6 months
Formulalions T = 0
25'C 40'C 25 C 25 C 40'C 40 C 25'C 40 C
182 Complies Complies Complies Complies Compiles Complies Complies Compiles
Complies
126 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
PBO4 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
Table 51. Stability of Methylparabens in the Formulations. Amount of
Methylparabens that are recovered from each of the formulations when the
formulations are stored at 25 C and 40 C over a 6 month period.
t= 1 month t= 2 months t= 3 months t= 6 months
Formulations
t= 0 h 25'C 40 C 25 C 40'C 25 C 40'C 25 C 40 C
182 0.18 2 0001 0.18 ~ 0.000 0.19 3 0.001 020 t 0.001 020 3 0.000 0.19 t 0.000
0.20 ! 1 .aoa 0.19 t 0852 019 f 0.001
P804 Olg 000 0.19 x 0.003 0.18 ~ 0.002 020 t 0001 020 ! 0.000 020 S 0001 020
! 0.001 0.20 ! 0001 0.20 - 0.002
126 020 t 0 002 0.20 ! 0001 0.19 t 0 000 0.19 t 0.001 0 21 t 0.00 0.21 t e001
0 20 0.001 0.20 x 0.001 0.20 f 0 001
Table 52. Stability of Methylparabens in the Formulations. Identification of
Methylparabens when the formulations are stored at 25 C and 40 C over a 6
month period (confirmed by HPLC).
T = 1 month T = 2 months T = 3 months T = 6 months
FormulaBuns T = 0
25'C 40'10 25 C 25'C 40'C 40'C 25'C 40'C
182 Complies Complies Complies Complies Compiles Complies Complies Compiles
Complies
126 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
PB 4 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
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Table 53. Stability of Propylparabens in the Formulations. Amount of
Propylparabens that are recovered from each of the formulations when the
formulations are stored at 25 C and 40 C over a 6 month period.
Formulations t= 1 month t= 2 momhs t = 3 months t = 6 momhs
c= 0 h 25C 4o=C 25=C 4o=C 25=C 40 C 25=C 40 C
182 0019 x 0000 0 020 0o01 0018 0000 0018 t 0000 0018 t 0 000 0021 t 0.002
0022 t 0001 0019 ! 0.000 0019 t 00010
p804 0018 } 0001 0.018 0.001 0.18 1 0001 0.19 f 0.000 3o20 t 0000 0020 S
0.002 0.020 S 0.002 0018 0000 0.020 0.001
126 0.018 0.000 0.019 ! 0001 0.021 0.001 0.018 t 0.000 0.119 S 0001 0020 t
0.001 0010 S 0001 0020 ! 0.000 0.020 t 0.001
Table 54. Stability of Propylparabens in the Formulations. Identification of
Propylparabens when the formulations are stored at 25 C and 40 C over a 6
month period (confirmed by HPLC).
T = 1 murMl T T 3 manths T Famuladons T = 0
25=C 40 C 25=C 25=C 40=C 40 C 25 C 40=C
182 Complies Complies Complies Complies Compiles Complies Complies Compiles
Complies
126 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
PB04 Complies Complies Complies Complies Complies Complies Complies Complies
Complies
Table 55. Microscopic Stability of the Formulations. The results of the
particle
size for each formulation which is determined by optical microscopy at 25 C
over
a 6 month period.
Particle size (pM)
Formulation
t= 0 t=1 Month t=2 Months t=3 Months t=6 Months
182 <10 <10 <10 <10 <10
PBO4 <10 <10 <10 <10 <10
126 <10 <10 <10 <10 <10
Table 56. pH stability of the Formulations. The results of the pH test for
each of
the formulations when the formulations are stored at 25 C and 40 C over a 6
month period. Grey area indicate no test was performed.
Formulation pH
t=0 t=1 month t=2 months t=3 months t=6 months
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CA 02649893 2009-01-15
25 C 25 C 40`C 25 C 40`C 25 C 40 C 25 C 40"C
182 4.5 4.5 4.5 4.5 4.5 4.6 4.3 4.3
PBO4 4.5 4.2 4.5 4.2 4.2 4.1 4.1 4.0 4.0
126 4.2 4.3 4.3 4.3 4.3 4.3 4.3 4.1 4.1
Table 57. Macroscopic stability of the Formulations. The results of the
macroscopic appearance test when the formulations are stored at 25 C over a 6
month period.
Appearance spatula Test (25=C sample onty) Ysual vscasity (25'C sample onry)
Forrnula0on
t=0 t=1 month t=2 months t=3 months t=6 months t=O t=1 month t=2 months t=3
months t=6 months
182 Very glossy Very glossy Very glossy and Very glossy Very glossy aM Hlgh
Medium-High Medium-High Medium-High High
and smooth ana smooth smooth arW smooth mooth
Glossy, very Smooth, slightly Giassy and Slightly
te sllghtly sm Glossy Medlum Medium Me]lum Metlium Low viscosity
126
PB04 xtured textured, glossy ooth textured, sheen
Glossy ard Glossy and Glossy and Glossy and Smooth cream MediumLow Metlium
MediumLOw Low Low
smooth mooth smooth smooth high sheen
Table 58. Brookfield and Bohlin Viscosity. The results of the viscosity and
rheology measurements for the formulations that are stored at 25 C over a 6
month period.
G'(Pa) Crossover (o) Brook6eld (cPs) Bohlin Ytscosiry (cPs) (based an 3M
me9hod)
Fonnulabon Ident'ity
t=2 t=3 t~ t=1 t=2 t=3 t=6
t=0 I=0 t=0 t=1 Month Months Months Months t_0 Month Months Months Months
182 702 8.5 693067 1097000 904667 523033 273233 18050 17850 18550 16820 13691
126 " 430100 235066 228104 212500 105720 16783 12739 14749 10856.5 8789.5
~--
PBO4 227800 10350 7953 5511 3550 2247
* Results not presented as the torque is out of range (due to low viscosity)
for the
Brookfields viscometer based on the setting and spindle that are used for all
the other
samples. Alternative spindles and settings are investigated; however, the
results are
vastly different compared to previous readings.
** no recorded measurements.
Table 59. Identification of 4-hydroxy Imiquimod when the formulations are
stored
at 25 C and 40 C over a 6 month period (confirmed by HPLC at 318 nm).
Formulations t=0 t=1 month t=2 months 1=3 months t=6 months
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CA 02649893 2009-06-10
25'C 25 C 40 C 25 C 40 C 25 C 40'C 25'C 40'C
182 NMT 01% w!w NMT 0.1% w/w NMT 0_1% w!w NMT 0_1% w/w NMT 0_1% Wfw NMT 01%
wAV NMT 0.1% WAM NMT 01% w/w NMT 01% wlw
PBO4 NMT 0.1% wrW NMT 01% w/w NMT 01% w/w NMT 01% w/w NMT 01% w/w NMT 01% w/w
NMT 0.1% w/w NMT 01% wAV NMT 0.1% w/w
Q8 NMT 0.1% w/w NMT 0.1% w/w NMT 01% w/w NMT 01% w/w NMT 0.1% wAv NMT 0_1% w/w
NMT 01% W/w NMT 0.1% wlw NMT 01% w/w
Example 24
Four Phase 3 Randomized, Double-Blinded, Multicenter, Placebo-Controlled
Clinical Studies
[0368] In this Example 24, four Phase 3 randomized, double-blinded,
multicenter,
placebo-controlled clinical studies comparing the efficacy and safety of a
3.75%
imiquimod cream of Example 23 and a 2.5% imiquimod cream of Example 23 to
placebo
in the treatment of typical visible or palpable actinic keratoses of the face
or balding
scalp. Subjects, who are determined to be eligible during the screening phase,
are
randomized in a 1:1:1 ratio to receive either 2.5% imiquimod cream, 3.75%
imiquimod
cream or placebo cream once daily during the treatment cycles. Studies GW01-
0702
and GW01-0704 are duplicative studies that investigate 2-week treatment
cycles,
wherein the 2-week treatment cycles are separated by a two week rest period
(no
treatment), and studies GW01-0703 and GW01-0705 are duplicative studies that
investigate 3-week treatment cycles, wherein the 3-week treatment cycles are
separated
by a three week rest period (no treatment). See flow diagrams depicted in
Table 60
herein below. The study entry criteria and endpoints are identical for all
four studies.
Each study has the same length of a post treatment follow-up period in which
the
primary endpoint in all four studies is at 8 weeks following the last
treatment application.
Thus, four Phase 3 clinical studies with two formulations (2.5% and 3.75%
imiquimod
creams) and one pharmacokinetic study (Example 25) with one formulation of
3.75%
imiquimod cream are conducted for the treatment of actinic keratosis diagnosed
on the
face or balding scalp. See also the FINAL LABEL and the PRODUCT MONOGRAPH,
which are filed contemporaneously. See also the following studies: (1)
Sponsored and
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CA 02649893 2009-06-10
information provided by: Graceway Pharmaceuticals, LLC, Study entitled "Safety
and
Effectiveness Study of Imiquimod Creams for Treatment of Actinic Keratoses
[Aks]", and
ClinicalTrials.gov Identifier No.: NCT00605176; (2) Sponsored and information
provided
by: Graceway Pharmaceuticals, LLC, Study entitled "Safety and Effectiveness
Study of
Imiquimod Creams for Treatment of Actinic Keratoses [Aks]", and
ClinicalTrials.gov
Identifier No.: NCT00603798; and (3) Sponsored and information provided by:
Graceway Pharmaceuticals, LLC, Study entitled "Follow-up Study to Evaluate
Sustained
Clearance Rates of Actinic Keratoses up to One Year", and ClinicalTrials.gov
Identifier
No.: NCT00668733. The four Phase 3 clinical studies with two formulations
(2.5% and
3.75% imiquimod creams) and the one pharmacokinetic study (Example 25) are
summarized as follows:
[0369] In Example 25, a pharmacokinetic study conducted under maximal use
conditions (Study GW01-0706) is described as indicated above.
[0370] Four randomized, double-blinded, placebo-controlled Phase 3 clinical
studies
(differing only in the duration of treatment and interval cycles) are
characterized as
follows:
1. Studies GW01-0702 & GW01-0704 (2-week treatment cycle regimen): two
identical studies evaluating 2.5% imiquimod cream, 3.75% imiquimod cream or
placebo
cream which is applied daily for two 2-week treatment cycles. The first
treatment cycle
consists of two weeks of daily treatment followed by two weeks of no
treatment, and the
second treatment cycle consists of an additional two weeks of daily treatment
followed
by eight weeks of post treatment follow-up period (total study duration 14
weeks); and
2. Studies GW01-0703 & GW01-0705 (3-week treatment cycle regimen): two
identical studies evaluating 2.5% imiquimod cream, 3.75% imiquimod cream or
placebo
cream which is applied daily for two 3-week treatment cycles. The first
treatment cycle
consists of three weeks of daily treatment followed by three weeks of no-
treatment, and
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CA 02649893 2009-01-15
the second treatment cycle consists of an additional three weeks of daily
treatment
followed by eight weeks of post treatment follow-up period (total study
duration 17
weeks).
[0371] The clinical studies are displayed in Table 61 below. All 4 Phase 3
studies are
conducted at separate study sites to provide independent confirmatory evidence
of
safety and efficacy. The results from these studies are evaluated and based on
the
safety and efficacy results from all four studies. -
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CA 02649893 2009-01-15
Table 61. Summary of Studies of lmiquimod for the Actinic Keratosis.
Study Number Treatments Brief Study
Number/ of Description/Comments
Status Subjects
GW01-0706 19 = Two 250 mg packets of = Pharmacokinetic study is
3.75% imiquimod is applied conducted under maximal
to the entire face or balding use conditions in AK
scalp every day for 3 weeks subjects. Study designed to
demonstrate steady-state
conditions.
GWOI-0702 242 = Up to two 250 mg packets = Phase 3 study of the 2-week
are applied to the entire face treatment cycle regimen
or balding scalp (2 weeks on treatment, 2
weeks of no treatment,
= 2.5% imiquimod cream every followed by 2 weeks on
day for two 2-week treatment treatment).
cycles
3.75% imiquimod cream Primary endpoint of complete
= every day for two 2-week clearance at 8 weeks after
treatment cycles treatment (Week 14; End Of
Study - EOS)
= Placebo every day for two
2-week treatment cycles
GWOI-0704 237 = Same treatments as Study = Duplicate of study 02 is
02 conducted at independent
study centers.
GW01-0703 240 = Up to two 250 mg packets = Phase 3 study of the 3-week
are applied to the entire face treatment cycle regimen
or balding scalp (3 weeks on treatment, 3
= 2.5% imiquimod every day weeks of no treatment,
for two 3-week treatment followed by 3 weeks on
cycles treatment).
= 3.75% imiquimod every day Primary endpoint of complete
for two 3-week treatment clearance at 8 weeks after
cycles treatment (Week 17; EOS)
= Placebo every day for two
3-week treatment cycles
GW01-0705 250 = Same treatments as Study = Duplicate of Phase 3 study
03 03 is conducted at
independent study centers.
[0372] All four Phase 3 studies are randomized, double-blinded, multicenter,
placebo-
controlled studies comparing the efficacy and safety of 3.75% imiquimod cream
and
2.5% imiquimod cream to placebo in the treatment of typical visible or
palpable actinic
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CA 02649893 2009-01-15
keratoses of the face or balding scalp. Subjects determined to be eligible
during the
screening phase are randomized in a 1:1:1 ratio to receive either 3.75%
imiquimod
cream, 2.5% imiquimod cream or placebo cream once daily during the treatment
cycles.
Studies GW01-0702 and GW01-0704 investigate two 2-week treatment cycles that
are
separated by a two weeks of no treatment, and studies GW01-0703 and GW01-0705
investigate two 3-week treatment cycles that are separated by three weeks of
no
treatment.
[0373] Studies GW01-0702 and GW01-0704 are conducted concurrently according to
identical protocols. A total of approximately 479 subjects are randomized in a
1:1:1 ratio
(approximately 240 to each treatment arm) to achieve approximately 450
subjects
completing the study. The treatment arms are:
= 2.5% imiquimod cream
= 3.75% imiquimod cream
= placebo cream
[0374] Eligible subjects for the study are at least 18 years of age, with
about 5 to 20
typical visible or palpable actinic keratosis lesions (AKs) in an area that
exceeded 25
cm2 on either the face or the balding scalp. The treatment area could be
either the
entire face, excluding the ears, or the balding scalp, but not both. Apart
from the
primary diagnosis, the subjects are to be in good general health, and free of
conditions
which might put them at undue risk during study procedures. They must not use
imiquimod cream on the face or scalp within 1 year of study entrance, nor use
other
potentially interfering medications within pre-specified washout intervals
prior to study
entrance.
[0375] The randomized, blinded study product is used in 2 treatment cycles
each of 2
weeks duration, separated by a 2-week period without treatment. Once a day
during the
treatment cycles, subjects apply the study cream in a thin layer to the entire
treatment
area. A maximum of 2 packets (i.e., up to 500 mg) could be applied for a given
dose.
The study cream is applied prior to normal sleeping hours and is removed
approximately
8 hours later with mild soap and water.
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[0376] During the 2 treatment cycles of 2 weeks, subjects are scheduled for a
total of
9 study visits:
= Visit 1, Screening
= Visit 2, Baseline, Cycle 1 Treatment Initiation
= Visit 3, Week 1
= Visit 4, Week 2, End of Cycle 1
= Visit 5, Week 4, Cycle 2 Treatment Initiation
= Visit 6, Week 5
= Visit 7, Week 6, End of Cycle 2 (End of Treatment)
= Visit 8, Week 10, Follow-up
= Visit 9, Week 14, End of Study, Primary Efficacy Endpoint
[0377] The objective of the studies is to compare the safety and efficacy of
2.5%
imiquimod cream and 3.75% imiquimod cream vs. placebo in the treatment of
actinic
keratosis when the cream is applied once daily for two 2-week treatment cycles
separated by a 2-week no-treatment period.
[0378] The two additional Phase 3 studies, GW01-0703 and GW01-0705, are
conducted concurrently according to identical protocols. These studies are
also
randomized, double-blind, multicenter, placebo-controlled trials identical to
the pivotal
studies in all respects except for the duration of the treatment regimens and
corresponding differences in visit schedules. The planned number of subjects,
randomization methodology, entrance criteria, and study drug formulations are
the same
as in the two Phase 3 GW01-0702 and GW01-0704 studies trials.
[0379] As in the GW01-0702 and GW01-0704 studies, the randomized, blinded
study
products are used in two 2-week treatment cycles, but in GW01-0703 and GW01-
0705,
the treatment cycles are of three weeks duration, separated by a 3-week period
without
treatment.
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CA 02649893 2009-01-15
[0380] During the two treatment cycles of three weeks, subjects are scheduled
for a
total of 11 study visits:
= Visit 1, Screening
= Visit 2, Baseline, Cycle 1 Treatment Initiation
= Visit 3, Week 1
= Visit 4, Week 2
= Visit 5, Week 3, End of Cycle 1
= Visit 6, Week 6, Cycle 2 Treatment Initiation
= Visit 7, Week 7
= Visit 8, Week 8
= Visit 9, Week 9, End of Cycle 2 (End of Treatment)
= Visit 10, Week 13, Follow-up
= Visit 11, Week 17, End of Study, Primary Efficacy Endpoint
[0381] Thus, two pairs of 2 identical Phase 3 studies (four Studies) regarding
efficacy
and safety of four and six weeks of treatment with imiquimod formulations for
actinic
keratosis are conducted. See Table 62. Each pair evaluates a different
treatment
regimen and each individual study contains two imiquimod concentrations, i.e.,
2.5%
and 3.75% imiquimod formulations with comparisons to placebo (double-blinded).
Table 62 - Four Clinical Trials
2x2x2 wks = GW01-0702
92.5% (N=81) L2
=3.75% (N=81) H2
=Vehicle (N=80) V
2x2x2 wks = GW01-0704
=2.5% (N=79) L2
93.75% (N=79) H2
=Vehicle (N=79) V
3x3x3 wks = GW01-0703
=2.5% (N=82) L3
93.75% (N=80) H3
=Vehicle (N=78) V
3x3x3 wks = GW01-0705
=2.5% (N=82) L3
=3.75% (N=82) H3
=Vehicle (N=82) V
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CA 02649893 2009-01-15
[0382] The study design is as summarized in Table 63 - Study Designs below.
Table 63 - Study Designs
2 Cycles + 8 wks Follow-up
Cycle I Cycle?
No TX
Daily TX No TX Daily TX - Follow up
Rest Period
8 wks - Endpoint is
determined at end
of week 14 for the
2x2x2 study or
week 17 for the
2 or 3 wks 2 or 3 wks 2 or 3 wks 3x3x3 study
[0383] In contrast, the FDA approved treatment regimen for treating actinic
keratosis
with Aldara 5% imiquimod cream is two times per week for 16 weeks and end
point is
determined at end of week 24.
[0384] The key entry criteria for these four studies are: (1) 18 years of age
or greater;
(2) 5-20 AKs in treatment area; (3) the treatment area exceeds 25 cm2; and (4)
the
treatment area is either full face or balding scalp, but not both. As a
historical reference,
the FDA approved treatment area for Aldara 5% imiquimod cream is 25 cm2 and
the
number of AK lesions treated in the treatment area is generally between 4 and
8.
[0385] Key efficacy measures for these four studies are a reduction of AK
lesions from
Baseline to End of Study (Week 14 or 17):
= Primary: complete clearance (yes/no)*
= Secondary: at least 75% reduction in number of AK lesions (partial
clearance yes/no)*
= Secondary: percent reduction in number of AK lesions analyzed as
a continuous variable
179
CA 02649893 2009-01-15
* All AK lesions that are cleared including newly arising sub-clinical lesions
[0386] The protocol for the two pairs of identical phase three studies (4
Studies)
includes: (1) voluntary rest periods of any length during treatment cycles are
permitted;
(2) the subjects keep to original study schedule irrespective of rest periods
or missed
doses; and (3) the subjects apply the imiquimod formulation in Cycle 2
irrespective of
clearance in Cycle 1.
[0387] The key safety measures for the study are: (1) adverse events; (2)
local skin
reactions (LSRs), including (a) area under the curve (AUCsum) and (b) erythema
(includes severe); (3) rest periods; and (4) study discontinuations.
[0388] Study flow diagrams are depicted in Table 64 below:
Table 64 - Study Flow Diagrams
Studies GW01-0702 and GW01-0704
Daily
2.5 ~ Daily 2.5%
Screening 3.75% Daily 3.75 / Daily
Placebo Daily Placebo Daily
Studies GW01-0703 and GW01-0705
2.5 / Daily 2.5 / Daily
Screening 3.75 / Daily 3.75 / Daily
Placebo Daily Placebo Daily
BL 2 4 6 9 14 17
Week
Endpoint No Treatment
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CA 02649893 2009-01-15
[0389] The LSR AUC sum is defined as follows:
(1) LSRs (0-3 scale)
- Erythema
- Edema
- Weeping/exudate
- Scabbing/crusting
- Flaking/scaling/dryness
- Erosion/ulceration*
(2) AUCsUm
- Sum of individual LSR Scores
- Over study duration (14 or 17 weeks; includes 4 or 6
weeks on treatment)
*0-2 scale
[0390] The population of the study is summarized in the Table 65 - Population
below
and as follows:
(1) 969 AK subjects enrolled to 4 studies;
(2) 646 subjects are randomized to active imiquimod cream:
= 160 to 2.5% imiquimod cream, 2-week cycles
= 160 to 3.75% imiquimod cream, 2-week cycles
= 164 to 2.5% imiquimod cream, 3-week cycles
= 162 to 3.75% imiquimod cream, 3-week cycles; and
(3) The subjects are enrolled at 51 sites geographically
distributed in the USA, wherein:
= Median number of subjects enrolled per site: 18
= Range: 2 to 34.
Table 65 - Population
L2 H2 L3 H V
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2.5% 2W 3.75% 2W 2.5% 3W 3.75% 3W Vehicle
(N=160) (N=160) (N=164) (N=162) (N=323)
Age, 64 (39-90) 64 (36-89) 66 (33-87) 64 (40-90) 64 (37-89)
Mean (Range)
Sex, 79 83 78 76 82
% male
Race 100 100 100 99 99
% white
Treatment Area, 73/27 76/2 70/30 71/2 75/25
% Face/Scalp
Skin Type, 84 87 88 90 86
% I, II, and III
Baseline Count, 10.9/10.0 11.0110.0 10.6/10.0 11.1/9.0 10.8/10.0
Mean/Median
[0391] A summary of drug exposure and compliance is set forth in the Table 66
Drug
Exposure/Compliance below.
Table 66 - Drug Exposure/Compliance
L2 H2 L3 H V
2.5% 3.75% 2.5% 3Week 3.75% Vehicle
2Week 2Week (N=164) 3Week (N=323)
(N=160) (N=160) (N=162)
Average Number of
Packets Used Per 1.71 1.62 1.68 1.67 1.70
Application
Number (%) 2(1.3) 9(5.6) 69(3.7) 9(5.6) 14(4.4)
Subjects
Noncompliant*
[0392] The following efficacy and safety results are observed and reported in
FIGS. 1-
24 and 51-52:
(1) all active treatment groups show statistically significant differences
from
vehicle in all efficacy measures; and
(2) there are no consistent statistically significant differences between the
2.5% and 3.75% treatment groups (*) within each of the studies;
*Partial clearance is significantly different between L2 and H2 in the GW01-
0704 study, but not in the GW01-0702 study;
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*Percent reduction between L2 and H2 in PP GW01-0704 study and PP
GW01-0702 study, not in ITT population.
*Percent reduction between L3 and H3 in PP GW01-0705 study, not in ITT
population and
not in GW01-07023 study.
[0393] Primary analysis populations are defined prospectively for the
analysis. The
primary population to be analyzed for efficacy and safety is the Intent-To-
Treat ("ITT")
population, including all randomized subjects. The Per Protocol ("PP")
population
includes subjects who complete the study without any protocol violations.
Subjects are
excluded from the PP population if any of the following criteria are met.
= Failure to meet Inclusion/Exclusion criteria
= Took restricted medications/treatments
= Nonadherence to the visit schedule
= Noncompliance with study treatment
[0394] The investigators determine the treatment area for the studies at
baseline
(either the entire face or the balding scalp, but not both). Subjects are
instructed to
apply a thin layer of study medication to the treatment area, up to two
packets (up to 500
mg) of product, avoiding the periocular areas, lips and nares. Subjects return
for clinic
visits over the course of the study for efficacy and safety measurements.
[0395] Actinic keratosis lesions arise on a background of UV-damaged skin, and
therefore, usually occur over an extensive area or field of sun-exposed skin.
The
creams are applied to the entire face or balding scalp, and not just the 5-20
individual
lesions required for study entry. Application to the full face of balding
scalp provides
clear direction to subjects regarding the area to be treated without reference
to the exact
location of lesions; additionally application to the full face or balding
scalp has the
potential to treat sub-clinical or incipient lesions. Two concentrations of
imiquimod
cream (2.5% and 3.75%) are used and compared to placebo for each study
regimen,
allowing a direct comparison of the concentrations for study outcomes.
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[0396] As indicated above, treatment cycles of two or three weeks are chosen
for
these Phase three studies. It is observed that sizable numbers of subjects
receiving the
5% imiquimod cream two or three times a week take rest periods typically at
the 4-6
week point in therapy. The need for rest periods is usually preceded by an
increase at
-2-3 weeks in signs and symptoms of local skin reactions. Cycle treatment (two
cycles
of three times a week for four consecutive weeks) appears to reduce but not
eradicate
the need for rest periods among subjects. The current Phase three studies
investigate
daily dosing (for two or three weeks) followed by an interval of two or three
weeks of no
treatment before repeating another two- or three-week treatment cycle. This
`no
treatment period' is expected to occur after the initial onset of signs and
symptoms
which herald the onset of pharmacodynamic effects of imiquimod treatment.
[0397] Subjects were instructed to apply the cream for a second treatment
cycle
irrespective of the degree of lesion clearance with the initial treatment
cycle. This is
consistent with the current Aldara package insert, which mandates a full 16
weeks of
treatment irrespective of interim treatment response. The use of two treatment
cycles
allows for a uniform assessment point for all subjects at 8 weeks following
the
termination of the second treatment cycle, irrespective of initial treatment
response. The
two-cycle treatment course is anticipated to have a beneficial effect on `sub-
clinical'
lesions. Previous studies suggest that these lesions may become visible
approximately
two weeks into a treatment course. A second treatment cycle has the potential
to treat
both residual clinically evident AK lesions as well as any sub-clinical
lesions.
[0398] AK lesions are counted at study visits to derive the one primary
(Complete
Clearance) and two secondary (Partial Clearance, Percent AK reduction)
efficacy
endpoints. To meet the Complete Clearance primary efficacy endpoint, subjects
needed
to be clear of all lesions in the treatment area, irrespective of whether
those lesions were
identified at baseline or later.
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[0399] The primary efficacy variable is subject status with respect to
complete
clearance of AK lesions at the end of study (EOS; 8 weeks following the last
scheduled
dose). The EOS visits occurred at Week 14 for the GW01-0702/GW01-0704 studies,
and at Week 17 for the GW01-0703/GW01-0705 studies. Complete clearance was
defined as the absence of clinically visible or palpable AK lesions in the
treatment area.
[0400] The secondary efficacy variables are:
= Subject status with respect to partial clearance of AK lesions at EOS,
defined as
at least about a 75% reduction in the number of AK lesions in the treatment
area
compared with Baseline;
= Percent change (reductions) from Baseline to EOS in investigator counts of
AK
lesions.
[0401] The statistical methods for efficacy analyses are the same in all four
Phase 3
studies.
[0402] Efficacy analyses are conducted on the ITT population and on the PP
population. For the primary efficacy variable, imputations are made for
missing data
points using last observation carried forward (LOCF, primary analysis), taking
all missed
observations as failure (sensitivity analysis), and using observed cases only
(supportive
analysis). The PP population analysis uses only cases that are observed. For
analysis
of secondary efficacy variables, only the LOCF method is used for the ITT
population,
and only cases that are observed for the PP population. All data from interim
visits
(before EOS/Early Termination) are analyzed at their nominal time points.
[0403] The allowed visit window at EOS, is any time more than 42 days after
the date
of last dose (or last rest). Subjects with no EOS visit are excluded from the
PP
population. In the ITT population, subjects without an in-window EOS visit are
analyzed
using the LOCF.
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[0404] All pairwise comparisons of active treatment versus placebo are made
using
Hochberg's modified Bonferroni procedure. If either test is significant at a
0.025 level of
significance, then that test is considered significant. Otherwise, if both
tests are
significant at 0.05, then both tests are considered significant. The 3.75% and
2.5%
imiquimod treatment groups are compared to each other at the 0.05 level of
significance
if at least one of these treatment groups is found to be different than the
placebo using
the Hochberg's test.
[0405] In this way, complete clearance rates, partial clearance rates, change
from
Baseline AK lesion counts, and percent change from baseline AK lesion counts
are
analyzed using Cochran-Mantel-Haenszel (CMH) statistics, stratifying on
center.
[0406] If at least one of the active arms is found to be superior to placebo
in the
primary efficacy variable of complete clearance, the secondary efficacy
variable of
partial clearance is compared between each of the active arms and placebo
using
Hochberg's modified Bonferroni procedure. If the secondary efficacy variable
of partial
clearance is found to be superior to placebo in either of the active treatment
groups,
then the secondary efficacy variable of percent reduction is tested. Tertiary
efficacy
variables- are tested without adjustment for multiplicity at the nominal 5%
level.
[0407] In order to obtain at least 6 subjects per center per treatment group,
investigational centers yielding fewer than 18 subjects are combined together
in order of
geographical proximity. The exact composition of these "analysis centers" is
determined
and documented prior to breaking the study blind. The stratification for CMH
analyses is
based on the analysis centers, not on the actual investigational centers.
[0408] In the primary analysis of complete clearance rate, the Breslow-Day
statistic is
tested at the 10% level for heterogeneity of the odds ratios across analysis
centers. A
finding of statistical significance in this test is followed by exploratory
analyses to
characterize the source of the heterogeneity.
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[0409] The primary efficacy variable is summarized without statistical testing
by
success frequency by investigator center, by analysis center, by gender, by
age
subgroup, by skin type subgroup, by baseline lesion count subgroup, and by
treatment
area (face or balding scalp).
[0410] Subjects who show a greater number of AK lesions at any time post-
baseline
compared to the baseline lesion count are of particular interest since the new
lesions
may represent sub-clinical lesions which are present but unobserved at the
baseline
visit. The proportion of subjects who show new lesions while on treatment are
presented by treatment group, and the primary efficacy variable is summarized
in this
subject subgroup.
[0411] All safety measures are analyzed using the ITT data set. Safety is
assessed
by collection of adverse events which are fully characterized as to intensity,
seriousness
and relationship to study drug. Additionally, local skin reactions (LSRs) are
anticipated
adverse events related to the pharmacodynamic activity of the drug; therefore,
LSRs are
assessed by the investigator at each study visit. Six LSRs (erythema, edema,
weeping/exudate, flaking/ scaling/dryness, scabbing/crusting, and
erosion/ulceration)
are rated by the investigator at each study visit on a 0-3 scale (save
erosion/ulceration
rated 0-2). Data relating to rest periods are collected. Vital signs and
laboratory data
are collected prestudy or baseline and at end of study.
[0412] Adverse events (AEs) are coded using Medical Dictionary for Regulatory
Activities (MedDRA) terminology. Treatment-emergent AEs are summarized for
each
treatment group by the overall incidence of at least one event, incidence by
system
organ class, and incidence by system organ class and preferred term. Treatment-
emergent AEs are also summarized by severity, and by relationship to study
product.
The AE incidence is summarized by gender, by age subgroup, by skin type
subgroup,
by baseline lesion count subgroup, and by location of treatment area (face or
balding
scalp). Serious AEs and discontinuations due to AEs are listed by subject.
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[0413] The intensity of each local skin reaction (LSR) type (erythema, edema,
weeping/exudate, flaking/ scaling/dryness, scabbing/crusting, and
erosion/ulceration)
and the most intense reaction (post-baseline) for each type are summarized by
frequency counts and mean scores by treatment group and study visit. An LSR
sum
score is computed at each study visit, and 3 areas under the curve (AUC, in
days) are
calculated; from Baseline to beginning of Treatment Cycle 2, from beginning of
Treatment Cycle 2 to End of Study (EOS), and from Baseline to EOS. These
values are
compared pairwise between treatment groups using Fisher's least significant
differences
in the 1-way analysis of variance (treatment group).
[0414] The number and percentage by treatment group of subjects who require a
rest
period (1 or more, by treatment cycle and overall) are analyzed using CMH
statistics. A
similar analysis summarized the number and percentage of subjects by treatment
group
(1) who require a rest period in both treatment cycles, (2) who require a rest
period in
Cycle 1 only, and (3) who require a rest period in Cycle 2 only. The number of
dosing
days missed due to rest periods and the number of dosing days prior to the
beginning of
the first rest period are analyzed using nonparametric CMH methods for each
treatment
cycle and overall.
[0415] Clinical laboratory values are listed, and frequency counts in alert
status shifts
are tabulated.
[0416] The preliminary results from each of the Phase 3 clinical studies are
summarized in the sections below, with the results of paired identical studies
(GW01-0702/GW01-0704 and GW01-0703/ GW01-0705 presented side by side).
Overall, a total of 969 subjects are enrolled into the four Phase 3 studies.
Fifty-one
independent sites in the United States enrolled subjects in the Phase 3
studies. The
number of subjects that are included in the ITT Data sets are tabulated in
Table 67.
Table 67: Number of Subjects Included in the ITT Data Sets
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Study 3.75% IMIQ 2.5% IMIQ Placebo Overall
GWOI-0702 81 81 80 242
GWOI-0704 79 79 79 237
Combined 2-Week Treatment 160 160 159 479
Cycle Regimen Studies
Study 3.75% IMIQ7 2.5% IMIQ Placebo Overall
GW01-0703 80 82 78 240
GWOI-0705 82 82 86 250
Combined 3-Week Treatment 162 164 164 490
L Cycle Regimen Studies
Studies of Two-Week Treatment Cycles
[0417] Preliminary data from the Two-week Treatment Cycle Studies (GW01-0702
and
GW01-0704) are presented below.
[0418] Subject Disposition for studies GW01-0702 and GW01-0704 is tabulated in
Table 68.
Table 68: Subject GW01-0702 GW01-0704
Disposition; Two-
Week Treatment Cycle
Regimen Studies
2.5% 3.75% Placebo 2.5% 3.75% Placebo
IMIQ IMIQ IMIQ IMIQ
Total no. of subjects, n (%)
Randomized 81 81 80 79 79 79
Completed Studya 78 74 (91.4) 75 (93.8) 76 (96.2) 75 (94.9) 75 (94.9)
(96.3)
Discontinued Study 3(3.7) 7(8.6) 5(6.3) 3(3.8) 4(5.1) 4(5.1)
Reasons for discontinuation
from the study, n (%b)
Safety reasons (AEs) 1(1.2) 1(1.2) 2(2.5) 0 1(1.3) 1(1.3)
Investigator's request 0 0 0 0 0 0
Subject's request (not AE) 1 (1.2) 3(3.7) 2(2.5) 1 (1.3) 1 (1.3) 2(2.5)
Noncompliance 0 0 0 0 1(1.3) 0
Use of concomitant 0 1(1.2) 0 0 0 1(1.3)
therapy
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Lost to follow-up 1 (1.2) 2(2.5) 1 (1.3) 1 (1.3) 0 0(0.0)
Other (not AE) 0 0 0 1(1.3) 1(1.3) 0
AE = adverse event; IMIQ= Imiquimod
a: Includes subjects who complete both the treatment periods and the post-
treatment follow-up
period.
b: Percentage of randomized population.
[0419] Subject demographics for each study are tabulated in Table 69, and the
number of baseline AK lesions for each study are tabulated in Table 70.
Table 69: Demographic Summary - Two-Week Treatment Cycle Regimen
Studies; ITT Population
GW01-0702 GW01-0704
2.5% 3.75% 2.5% IMIQ 3.75%
IMIQ IMIQ Placebo (N=79) IMIQ Placebo
(N=81) (N=81) (N=80) (N=79) (N=79)
Age in years
Mean SD 63.7 63.8 63.6 65.0 65.3 65.0 9.5
10.7 11.1 8.3 10.3 10.0
Median 63.3 63.9 63.4 64.4 65.3 63.7
Minimum, Maximum 43.8, 88.7 36.5, 89.8 42.7, 39.6, 90.0 36.3, 86.4 46.4, 89.1
83.1
Sex, n (%)
Male 59 (72.8) 69 (85.2) 70 (87.5) 68 (86.1) 63 (79.7) 60 (75.9)
Female 22 (27.2) 12 (14.8) 10 (12.5) 11 (13.9) 16 (20.3) 19 (24.1)
Race, n (%)
White 81 (100) 81(100) 80 (100) 79 (100) 79 (100) 78 (98.7)
Non-White 0 0 0 0 0 1(1.3)
Ethnicity, n (%)
Hispanic 4(4.9) 5(6.2) 5(6.3) 0 1 (1.3) 0
Non-Hispanic 77 (95.1) 76 (93.8) 75 (93.8) 79(100) 78 (98.7) 79 (100)
Fitzpatrick skin type, n
(%)
1 9(11.1) 5(6.2) 6(7.5) 20 (25.3) 17 (21.5) 13 (16.5)
II 35 (43.2) 43 (53.1) 25 (31.3) 27 (34.2) 31 (39.2) 33 (41.8)
III 23 (28.4) 17 (21.0) 37 (46.3) 20 (25.3) 26 (32.9) 26 (32.9)
IV 11 (13.6) 15 (18.5) 11 (13.8) 11 (13.9) 5(6.3) 5(6.3)
V 3(3.7) 1(1.2) 1(1.3) 1(1.3) 0 2(2.5)
Location of Treatment Area, n(%)
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GWOI-0702 GWOI-0704
2.5% 3.75% 2.5% IMIQ 3.75%
IMIQ IMIQ Placebo (N=79) IMIQ Placebo
(N=81) (N=81) (N=80) (N=79) (N=79)
Face 61 (75.3) 66 (81.5) 60 (75.0) 56 (70.9) 55 (69.9) 59 (74.7)
Balding Scalp 20 (24.7) 15 (18.5) 20 (25.0) 23 (29.1) 24 (30.4) 20 (25.3)
SD = standard deviation; IMIQ = Imiquimod
Fitzpatrick skin type: I=burns easily, never tans; ll=burns easily, tans
minimally with difficulty; lll=burns
moderately, tans moderately and uniformly; IV=burns minimally, tans moderately
and evenly; V=rarely
burns, tans profusely; Vl=never burns, tans profusely.
Table 70: Actinic Keratosis Lesions at Baseline - Two-Week Treatment Cycle
Regimen Studies; ITT Population
GW01-0702 GW01-0704
2.5% 3.75% 2.5% 3.75%
Baseline values IMIQ IMIQ Placebo IMIQ IMIQ Placebo
(N=81) (N=81) (N=80) (N=79) (N=79) (N=79)
Mean (SD) 11.11 (4.42) 10.89 11.74 (4.77) 10.77 (4.44) 11.16 10.82 (4.64)
(4.90) (4.81)
Median 10 9 10 10 11 10
Minimum, 5, 20 5, 20 5, 20 5, 20 5,29 5, 20
Maximum
P value vs 0.376 0.256 NA 0.864 0.542 NA
Placeboa
P value vs 3.75% 0.818 NA NA 0.688 NA NA
imiquimod
creama
SD = Standard deviation
a P values are from Cochran-Mantel-Haenszel test, are stratified by
investigator center, taking 2 treatment groups at
a time.
[0420] Subjects in studies GW01-0702 and GW01-0704 are compliant with the
administration of study medication; greater than 91 % of the subjects are
compliant with
the dosing regimen. Compliance is defined as applying more than 75% of the
prescribed doses; `rest' days are considered as application days.
[0421] Primary and secondary efficacy results for the GW01-0702 and GW01-0704
studies are presented in Table 71, Table 72 and Table 73. The primary efficacy
variable is the rate of complete clearance at EOS (Week 14). The secondary
efficacy
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variables are the rate of partial clearance (at least 75% reduction in AKs
from baseline)
at EOS, and the percent change from Baseline to EOS in investigator counts of
AK
lesions. Both active treatment arms demonstrate greater efficacy than placebo,
which is
statistically significant for all primary and secondary endpoints.
Table 71: ITT (LOCF) Complete Clearance Rates at EOS for Individual Two-
Week Treatment Cycle Regimen Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GWOI-0702 25.9% (21/81) 23.5% (19/81) 2.5% (2/80)
GW01-0704 45.6% (36/79) 38.0% (30/79) 10.1% (8/79)
Combined 35.6% (57/160) 30.6% (49/160) 6.3% (10/159)
Table 72: ITT (LOCF) Partial Clearance Rates at EOS for Individual Two-Week
Treatment Cycle Regimen Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GW01-0702 45.7% (37/81) 42.0% (34/81) 18.8% (15/80)
GWOI-0704 73.4% (58/79) 54.4 % (43/79) 26.6% (21/79)
Combined 59.4% (95/160) 48.1 % (77/160) 22.6% (36/159)
Table 73: ITT (LOCF) Median Percent Change from Baseline in AK Lesion
Count at EOS for Individual Two-Week Treatment Cycle Regimen
Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GW01-0702 -72.7% -60.0% -21.1%
GWOI-0704 -90.9% -76.5% -30.0%
Combined -81.8% -71.8% -25.0%
[0422] The incidence rates for selected safety parameters for the combined Two-
Week Treatment Cycle Regimen studies are displayed in Table 74.
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Table 74: Summary of Incidence Rates for Selected Safety Parameters
(Combined Two-Week Treatment Cycle Regimen Studies)
3.75% IMIQ 2.5% IMIQ Placebo
(N=160) (N=160) (N=159)
Discontinued study 2(1.3%) 1(0.6%) 3(1.9%)
prematurely due to safety
reasons, n (%)
Treatment-related AEs, n (%) 31 (19.4%) 19(11.9%) 4(2.5%)
Rest periods, n (%) 17(10.6%) 11(6.9%) 0(0%)
[0423] The most common treatment-related adverse events are displayed in Table
75
below.
Table 75: Incidence of Most Common* Treatment-Related Adverse Events
(Combined Two-Week Treatment Cycle Regimen Studies)
3.75% IMIQ 2.5% IMIQ Placebo
MedDRA Term (N=160) (N=160) (N=159)
Application site pruritus 7(4.4%) 6(3.8%) 1(0.6%)
Application site pain 5(3.1%) 2(1.3%) 0%
Application site irritation 5(3.1%) 4(2.5%) 0%
Fatigue 4 (2.5%) 0% 0%
Headache 4(2.5%) ? (0.6%) 2 (1.3%)
Dizziness 3(1.9%) 0% 0%
Lymphadenopathy 3(1.9%) 3(1.9%) 0%
Nausea 3(1.9%) 1 (0.6%) 0%
Pyrexia 2(1.3%) 0% 0%
Application site swelling 2(1.3%) 0% 0%
Arthraigia 2(1.3%) 0% 0%
*> 1% in the 3.75% imiquimod treatment group
[0424] For each of the two-week treatment cycle regimen studies, LSRs appear
to be
dose-dependent. The combined AUC of LSRsum Scores are 272, 242 and 140 for the
3.75% imiquimod, 2.5% imiquimod, and placebo treatment groups, respectively.
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Erythema is the most intense LSR during the treatment cycles, and on average
all LSRs
return to baseline at the first observation post-treatment cycle (within
either two or four
weeks, following cycles 1 and 2, respectively). The combined incidence of
severe
erythema is 26.3%, 14.4%, and 0% for the 3.75% imiquimod, 2.5% imiquimod, and
placebo treatment groups, respectively.
[0425] There were 12 subjects with 15 serious adverse events reported in the
two-
week treatment cycle regimen studies, of which one of the serious adverse
events for
one of the subjects is considered related to treatment (diarrhea with
secondary nausea /
fatigue reported in the 3.75% treatment group).
[0426] In the two-week treatment cycle regimen studies, both 2.5% and 3.75%
imiquimod creams demonstrate substantial efficacy for the treatment of AKs
that is
consistently significantly greater than that of placebo cream, with a trend
toward greater
efficacy in the 3.75% group. Both products are well-tolerated as evidence by
measures
of adverse events, ability of subjects to remain in the study, incidence of
rest periods,
and compliance with study regimen. Both active products result in increases in
local
skin reactions versus the placebo cream. For both active creams, the LSRs
rapidly
reduces with the completion of each treatment cycle and these LSRs are
associated
with relatively few reported application site reactions.
Studies of Three-Week Treatment Cycles
[0427] Preliminary data from the Three-Week Treatment Cycle Regimen Studies
(GW01-0703 and GW01-0705) are presented as follows.
[0428] Subject Disposition for Studies GW01-0703 and GW01-0705 is tabulated in
Table 76.
Table 76: Subject Disposition; Three-Week Treatment Cycle Regimen Studies
GW01-0703 G01-0705
2.5% 3.75% [2.5~/o 3.75%
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IMIQ IMIQ Placebo IMIQ IMIQ Placebo
Total no. of subjects, n(%)
Randomized 82 80 78 82 82 86
Completed Study a 77 (93.9) 76 (95.0) 73 (93.6) 80 76 (92.7) 81 (94.2)
(97.6)
Discontinued Study 5(6.1) 4(5.0) 5(6.4) 2(2.4) 6(7.3) 5(5.8)
Reasons for discontinuation
from the study, n (%b)
Safety reasons (AEs) 1 (1.2) 2(2.5) 0 1 (1.2) 2(2.4) 1 (1.2)
Investigator's request 0 0 0 0 0 0
Subject's request (not AE) 3(3.7) 2(2.5) 4(5.1) 0 2(2.4) 0
Noncompliance 1 (1.2) 0(0.0) 0(0.0) 0 0 0
Use of concomitant 0 0 0 0 0 0
therapy
Lost to follow-up 0 0 0 0(0.0) 1 (1.2) 1 (1.2)
Other (not AE) 0(0.0) 0(0.0) 1 (1.3) 1 (1.2) 1 (1.2) 3(3.5)
AE. = adverse event; IMIQ= Imiquimod
a: Includes subjects who complete both the treatment periods and the post-
treatment follow-up period.
b: Percentage of randomized population.
[0429] Subject demographics for each study are tabulated in Table 77, and the
number of baseline AK lesions for each study are tabulated in Table 78.
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Table 77: Demographic Summary - Three-Week Treatment Cycle Regimen
Studies; ITT Population
GWOI-0703 GWOI-0705
2.5% 3.75% 2.5% IMIQ 3.75%
IMIQ IMIQ Placebo (N=82) IMIQ Placebo
(N=82) (N=80) (N=78) (N=82) (N=86)
Age in years
Mean SD 65.7 64.5 63.0 66.4 64.1 64.4
10.4 10.8 10.1 10.0 9.7 11.5
Median 66.7 64.0 63.6 65.9 63.7 65.8
Minimum, Maximum 33.3, 84.2 40.3, 85.5 39.8, 83.8 45.4, 87.3 41.6, 37.9, 87.0
90.9
Sex, n (%)
Male 62 (75.6) 63 (78.8) 63 (80.8) 66 (80.5) 60 (73.2) 72 (83.7)
Female 20 (24.4) 17 (21.3) 15 (19.2) 16 (19.5) 22 (26.8) 14 (16.3)
Race, n (%)
White . 82(100) 78 (97.5) 77 (98.7) 82 (100.0) 82 86 (100.0)
(100.0)
Non-White 0 2(2.5) 1 (1.3) 0 0 0
Ethnicity, n (%)
Hispanic 2(2.4) 1 (1.3) 0(0.0) 6(7.3) 6(7.3) 6(7.0)
Non-Hispanic 80 (97.6) 79 (98.8) 78(100) 76 (92.7) 76 (92.7) 80 (93.0)
Fitzpatrick skin type, n
(%)
1 8(9.8) 11 (13.8) 11 (14.1) 12 (14.6) 11 (13.4) 12 (14.0)
II 35 (42.7) 31 (38.8) 28 (35.9) 28 (34.1) 47 (57.3) 39 (45.3)
III 28 (34.1) 24 (30.0) 26 (33.3) 33 (40.2) 21 (25.6) 23 (26.7)
IV 9(11.0) 13 (16.3) 10 (12.8) 8(9.8) 3(3.7) 9(10.5)
V 2(2.4) 1( 1.3) 3(3.8) 1(1.2) 0 3(3.5)
Location of Treatment Area, n (%)
Face 63 (76.8) 54 (67.5) 60 (76.9) 52 (63.4) 61 (74.4) 62 (72.1)
Balding Scalp 19 (23.2) 26 (32.5) 18 (23.1) 30 (36.6) 21 (25.6) 24 (27.9)
SD = standard deviation; IMIQ = Imiquimod
Fitzpatrick skin type: 1=burns easily, never tans; ll=burns easily, tans
minimally with difficulty; lll=burns moderately,
tans moderately and uniformly; IV=burns minimally, tans moderately and evenly;
V=rarely burns, tans profusely;
Vl=never bums, tans profusely.
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Table 78: Actinic Keratosis Lesions at Baseline - Three-Week Treatment Cycle
Regimen Studies; ITT Population
GWOI-0703 GW01-0705
2.5% 3.75% 2.5% 3.75%
Baseline values IMIQ IMIQ Placebo IMIQ IMIQ Placebo
(N=82) (N=80) (N=78) (N=82) (N=82) (N=86)
Mean (SD) 10.74 ( 4.45) 11.99 11.24 (4.70) 10.43 10.26 (4.12) 9.49(3.67)
(5.47) (4.05)
Median 10 11 10 9 9 8
Minimum, 5, 20 5, 23 5, 20 5, 20 5, 20 5, 20
Maximum
P value vs 0.408 0.359 NA 0.094 0.197 NA
Placeboa
P value vs 3.75% 0.113 NA NA 0.776 NA NA
imiquimod
creama
SD=Standard deviation
a P values are from Cochran-Mantel-Haenszel test, stratified by investigator
center, taking 2 treatment groups at a
time.
[0430] Subjects in studies GW01-0703 and GW01-0705 are compliant with the
administration of study medication; greater than 92% of the subjects are
compliant with
the dosing regimen. Compliance is defined as applying more than 75% of the
prescribed doses; 'rest' days are considered as application days.
[0431] Primary and secondary efficacy results for the GW01-0703 and GW01-0705
studies are presented in Table 79, Table 80, and Table 81. The primary
efficacy
variable is the rate of complete clearance at EOS (Week 17). The secondary
efficacy
variables are the rate of partial clearance (at least 75% reduction in AKs
from baseline)
at EOS, and the percent change from Baseline to EOS in investigator counts of
AK
lesions. Both active treatment arms demonstrate greater efficacy than placebo,
which is
statistically significant for all primary and secondary endpoints.
Table 79: ITT (LOCF) Complete Clearance Rates at EOS for Individual
Three-Week Treatment Cycle Regimen Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GW01-0703 32.5% (26/80) 23.2% (19/82) 5.1% (4/78)
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[GwO1-07o5 35.4% (29/82) 26.8% (22/82) 5.8% (5/86)
Combined 34.0% (55/162) 25% (41/164) 5.5% (9/164)
Table 80: ITT (LOCF) Partial Clearance Rates at EOS for Individual Three-Week
Treatment Cycle Regimen Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GWOI-0703 56.3% (45/80) 46.3% (38/82) 11.5% (9/78)
GWOI-0705 51.2% (42/82) 39.0% (32/82) 14.0% (12/86)
Combined 53.7% (87/162) 42.7% (70/164) 12.8% (21/164)
Table 81: ITT (LOCF) Median Percent Change from Baseline in AK Lesion
Count at EOS for Individual Three-Week Treatment Cycle Regimen
Studies
Study 3.75% IMIQ 2.5% IMIQ Placebo
GWOI-0703 -82.3% -66.7% -23.6%
GW01-0705 -78.9% -66.7% -22.5%
I Combined -80.0% -66.7% -23.6%
[0432] The incidence rates for selected safety parameters for the combined
three-
week treatment cycle regimen studies are displayed in Table 82.
Table 82: Summary of Incidence Rates for Selected Safety Parameters
(Combined Three-Week Treatment Cycle Regimen Studies)
3.75% IMIQ 2.5% IMIQ Placebo
(N=162) (N=164) (N=164)
Discontinued study 4(2.5%) 2(1.2%) 1(0.6%)
prematurely due to safety
reasons, n (%)
Treatment-related AEs, n (%) 60 (37.0%) 44 (26.8%) 4(2.4%)
Rest periods, n (%) 44(27.2%) 28 (17.1%) 0(0%)
[0433] The most common treatment-related adverse events are displayed in
Table 83..
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Table 83: Incidence of Most Common* Treatment-Related Adverse Events
(Combined Three-Week Treatment Cycle Regimen Studies)
MedDRA Term 3.75% IMIQ 2.5% IMIQ Placebo
(N=162) (N= 164) (N= 164)
Application site pain 15(9.3%) 11(6.7%) 0%
Application site pruritus 14 (8.6%) 12 (7.3%) 1(0.6%)
Influenza like illness 12 (7.4%) 6(3.7%) 0%
Application site irritation 9(5.6%) 6(3.7%) 1(0.6%)
Fatigue 7 (4.3 /o) 5 (3.0%) 0%
Application site bleeding 5(3.1%) 2(1.2%) 0%
Lymphadenopathy 5 (3.1 %) 4(2.4%) 0%
Pyrexia 5 (3.1 %) 0% 0%
Headache 4 (2.5%) 4 (2.4%) 0%
Cheilitis 3(1.9%) 1 (0.6%) 1 (0.6%)
Myalgia 3(1.9%) 0% 0%
Application site discomfort 2(1.2%) 0% 0%
Application site erythema 2(1.2%) 0% 0%
Chills 2(1.2%) 1 (0.6%) 0%
Dysphonia 2(1.2%) 0% 0%
Herpes simplex 2(1.2%) 2(1.2%) 0%
Herpes zoster 2(1.2%) 0% 0%
Lethargy 2(1.2%) 0% 0%
Nausea 2 (1.2%) 1 (0.6%) 0%
*> 1% in the 3.75% imiquimod treatment group
[0434] For each of the three-week treatment cycle regimen studies, LSRs appear
to
be dose-dependent. The combined AUC of LSRsõm Scores are 413, 372 and 189 for
the
3.75% imiquimod, 2.5% imiquimod, and placebo treatment groups, respectively.
Erythema is the most intense LSR during the treatment cycles, and on average
all LSRs
return to baseline at the first observation post-treatment cycle . The
combined incidence
of severe erythema is 44.7%, 28.2%, and 0% for the 3.75% imiquimod, 2.5%
imiquimod,
and placebo treatment groups, respectively.
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[0435] There are 13 subjects who report 18 serious adverse events in the Three-
Week
Treatment Cycle Regimen studies; one of these serious adverse events is
considered
related to treatment (pancytopenia reported in the 3.75% treatment group; note
that this
subject had a previous history of pancytopenia).
[0436] In the Three-Week Treatment Cycle Regimen studies, both 2.5% and 3.75%
imiquimod creams demonstrate substantial efficacy for the treatment of AKs
that is
consistently significantly greater than that of placebo cream, with a trend
toward greater
efficacy with the higher concentration cream. Discontinuation rates for any
cause, as
well as for safety reasons are low in all treatment groups, and as such, both
imiquimod
creams can be considered `well-tolerated'. However, a larger number of
subjects that
are treated with either the 2.5% or 3.75% imiquimod creams require rest
periods from
the intended two 3-week treatment cycles. Rest periods and other measures of
treatment tolerability (related adverse events, application site reactions,
LSRs)
demonstrate a dose dependent effect, with the highest incidences in the 3.75%
3-week
cycle treatment group.
[0437] Selection of the optimal dose/regimen for submission for marketing
approval
requires the comparisons of both the benefits and risks for each of each
dose/regimen
combinations that are studied. Studies GW01-0702 and GW01-0704 are duplicate
studies investigating two 2-week treatment cycles (aka two-week treatment
cycle
regimen studies); and studies GW01-0703 and GW01-0705 are duplicate studies
investigating two 3-week treatment cycles (aka three-week treatment cycle
regimen
studies). Data from the four Phase 3 studies are combined as identical pairs
(GW01-
0702/GW01-0704 and GW01-0703/ GW01-0705).
[0438] Identical pairs of studies, each including 3 treatment groups, are
considered in
the analysis of dose/regimen selection:
= Two-Week Treatment Cycle Regimen (Studies GW01-0702 and GW01-0704)
o 3.75% imiquimod
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o 2.5% imiquimod
o Placebo
= Three-Week Treatment Cycle Regimen (Studies GW01-0703 and GW01-0705)
0 3.75% imiquimod
0 2.5% imiquimod
o Placebo
[0439] To examine the impact of drug concentrations on efficacy, the four
imiquimod
treatment groups (2.5% and 3.75%, 2-week and 3-week regimens) can be combined
by
concentration, irrespective of treatment regimen. Data for 2.5% imiquimod
(both 2 and
3-Week Treatment Cycle GroLips) versus that of 3.75% imiquimod (both 2 and 3-
Week
Treatment Cycle Groups) are evaluated for efficacy effects of concentration
(refer to
Table 84 below). Preliminary evaluation suggests an effect of drug
concentration in
-favor of the 3.75% concentration for all three efficacy endpoints: Complete
Clearance,
Partial Clearance, and Percent Reduction from Baseline of AK lesions.
Preliminary
evaluation suggests that the two regimens (2-week and 3-week treatment cycles)
are
comparable in terms of the efficacy endpoints. In addition, all four dosing
regimens that
are used show statistically and clinically significant effectiveness in the
reduction of AK
lesions in the target population.
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Table 84: Analysis of Primary and Secondary Efficacy Endpoints (Combined
Studies)
2-Week Cycle Regimen 3-Week Cycle Regimen
Parameter 3.75% 2.5% Placebo 3.75% 2.5% Placebo
Complete Clearance at EOS
n/N, (%) 57/160 49/160 10/159 55/162 41/164 9/164
(35.6) (30.6) (6.3) (34.0) (25.0) (5.5)
95% 28.2, 43.6 23.6, 38.4 3.1, 11.3 26.7, 18.6, 2.5, 10.2
confidence 41.8 - 32.3
interval
Partial Clearance at EOS
n/N, (%) 95/160 77/160 36/159 87/162 70/164 21/164
(59.4) (48.1) (22.6) (53.7) (42.7) (12.8)
95% 51.3, 67.1 .40.2, 56.2 16.4, 45.7, 35.0, 8.1, 18.9
confidence 29.9 61.6 50.6
interval
Percent Change in Number of AK Lesions from Baseline to EOS
N 160 160 159 162 164 164
Median -81.8 -71.8 -25.0 -80.0 -66.7 -23.6
Mean (SD) -68.7 -59.2 -27.6 -64.3 -57.0 -24.5
(43.4) (41.6) (52.1) (43.0) (45.4) (47.0)
95% -75.4, - -65.7, - -35.7, - -71.0, - -64.0, -31.7, -
confidence 61.9 52.7 19.4 57.7 -50.0 17.2
interval
[0440] As indicated herein, the efficacy results for the two 2-cycle treatment
regimens,
i.e., the 2 x 2 x 2 weeks and 3 x 3 x 3 weeks treatment cycles, suggest that
the
additional doses provided in the 3-week treatment cycle regimen results in no
additional
efficacy over that shown for the 2-week treatment cycle regimen. This finding
is
consistent with the rank order performance of the 3.75% product for all
efficacy
endpoints in all four individual Phase 3 studies. Therefore, from an efficacy
standpoint,
the 3.75% imiquimod cream, when applied daily in two 2-week treatment cycles,
is
believed to be the preferred dose and regimen combination to treat actinic
keratosis.
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[0441] Safety for all four dose regimens is also considered. Since the longer
3-week
treatment regimen (with its greater drug exposure) shows no additional
efficacy, it is
believed that a choice of a 3-week regimen should be based on an improved
safety
profile.
[0442] As with efficacy, safety data are examined from the pooled identical
studies
(GW01-0702/GW01-0704 and GW01-0703/GW01-0705).
Key safety outcomes are presented above and included:
= Incidence of Discontinuation from Study
= Incidence of Discontinuation from Study due to Safety Reasons (AEs)
= Incidence of Rest Periods
= Incidence of Treatment-Related AEs
= AUC of LSRsum scores
[0443] With the exception of LSRs (which are investigator assessed 'signs'),
these
measures address symptoms that are experienced by the subject or investigator
actions
that are related to subject safety (i.e., discontinuations, rest periods,
adverse events
including LSRs requiring medical intervention).
[0444] As can be seen in Table 85 below, discontinuation rates from the four
Phase 3
studies for all causes (including safety) are low across all treatment groups,
thus
supporting the overall tolerability of all dose regimens. Inspection of the
incidence rates
for Rest Periods and Treatment-Related AEs suggests that the 3-week Treatment
Cycle
Regimens are relatively less well-tolerated than both 2-week Treatment Cycle
Regimens.
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Table 85: Selected Safety Parameters (Combined Studies)
Combined Two-Week Treatment Combined Three-Week
Cycle Regimen Studies Treatment Cycle Regimen
Studies
3.75% 2.5% IMIQ Placebo 3.75% 2.5% Placebo
IMIQ (N=160) (N=159) IMIQ IMIQ (N=164)
(N=160) (N=162) (N=164)
Discontinued 11(6.9%) 6(3.8%) 9(5.7%) 10(6.2%) 7(4.3%) 10
study prematurely (6.1%)
(any reason)
Discontinued 2(1.3%) 1(0.6%) 3(1.9%) 4(2.5%) 2(1.2%) 1(0.6%)
study prematurely
due to safety
reasons, n (%)
Treatment-related 31 19 4(2.5%) 60 44 4(2.4%)
AEs, n (%) (19.4%) (11.9%) (37.0%) (26.8%)
Rest periods, n (%) 17 11(6.9%) 0(0%) 44 28 0(0%)
(10.6%) (27.2%) (17.1%)
[0445] For the 2-week treatment cycle regimen, the 2.5% and 3.75% imiquimod
creams show similar tolerability. Although the overall incidences of treatment-
related
adverse events for the 2-week Treatment Cycle Regimens show a dose-related
trend
(see above 85), the most common. treatment-related AEs are application site
reactions
(see Tables 75 and 83). Inspection of the individual treatment-related AEs
reveals low
rates for all the individual terms, irrespective of dose group. AEs that may
reflect
systemic pharmacologic effects of imiquimod's activation of cytokines (e.g.,
fatigue) are
reported; however, systemic AEs occur at a low rate.
[0446] Additional to the adverse event data above, the physical signs of
anticipated
local skin reactions (LSRs) are rated by the investigators via six assessments
scores at
each study visit. The assessments scores are summated and then integrated
across
the study duration as AUC of LSRs,,m scores. The AUC of LSRSõm scores for all
four
treatment groups are presented in Table 86.
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Table 86: Summary of AUC of LSRsum Scores (Combined Across Studies)
3.75% IMIQ 2.5% IMIQ Placebo
Combined Two-Week Treatment 272 242 140
Cycle Regimen Studies
Combined Three-Week Treatment 413 372 189
Cycle Regimen Studies
[0447] The difference in AUC of LSRS,,R, scores by treatment regimen is
remarkable.
Note that the scores for the 3-week cycle treatment cycle regimens (including
placebo)
reflect the longer dosing and study duration associated with those study
designs.
Nonetheless, the data shows pronounced increases in AUC of LSRs,m scores for
both
doses in the 3-week cycle treatment groups. Scores for both of the 2-week
cycle
treatment groups are lower than the 3-week treatment cycle regimens, with a
relatively
small increase in the 3.75% AUC of LSRsõm score compared to the 2.5% imiquimod
treatment group for the 2-week treatment cycle regimen studies.
[0448] Looking across the safety parameters, it appears that the short 2-week
Treatment Cycle Regimen is relatively better tolerated than the 3-week
Treatment Cycle
Regimen. Within the 2-week cycle Treatment Cycle Regimen both doses are well-
tolerated, although safety incidence rates and scores appear to slightly favor
the 2.5%
concentration.
[0449] As discussed, the 3-week Treatment Cycle Regimens, irrespective of
product
concentration, demonstrates a less favorable safety profile versus the 2-week
Treatment
Cycle Regimens with no offsetting efficacy benefit. Within the 2-week
Treatment Cycle
Regimen studies, the 2.5% imiquimod formulation appear to have a slightly
improved
safety profile to the 3.75% product, though both products are well-tolerated.
However,
the 3.75% product shows a consistent incremental efficacy benefit to the 2.5%
product.
[0450] In the primary ITT efficacy analysis, missing observations due to early
discontinuation are imputed using the last observation carried forward (LOCF).
Baseline
data are carried forward if no post-Baseline data existed for the subject. The
sensitivity
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of the primary outcome to imputation methods is explored in each of the
separate
clinical study reports, and the results are found to be robust with respect to
changes in
imputation methodology. The results of the PP analysis are also found to be
entirely
consistent with those of the ITT analysis.
[0451] Wherever the investigator reported AK lesion count as "indeterminate,"
the
subject is considered not cleared (and not partially cleared), but the
numerical lesion
count is taken as a missing value.
[0452] The demographic and background characteristics of the efficacy study
populations by treatment group in all 4 Phase 3 studies are combined by
identical study
design in pairs (i.e., GW01-0702 and GW01-0704 will be combined in one pair
and
GW01-0703 and GW01-0705 will be combined in a second pair). The number and
percentage by treatment group and overall are presented for subjects
randomized,
subjects included in the ITT population, subjects completing the study, and
subjects
discontinuing the study, overall and by reason for discontinuation.
[0453] Subject age, height, weight, and Baseline lesion count is summarized by
mean,
standard deviation, median, and range by treatment group. Sex, race,
ethnicity,
Fitzpatrick skin type, location of treatment area (face or balding scalp), and
prior AK
treatment history is characterized by frequency distribution by treatment
group.
[0454] Descriptive statistics (mean, standard deviation, median, and range) is
used to
summarize product usage and exposure for the ITT populations by treatment
group.
Measures of study medication exposure, for each treatment cycle and overall,
includes
the total duration of treatment (date of last dose minus date of first dose
plus 1,
excluding the no-treatment period), the total number of applications, the
total number of
packets used, the total amount of active drug applied, and the average number
of
packets used per application. The number and percentage of subjects by
treatment
group who make fewer than 75% of the required applications (fewer than 21
applications
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and/or rest days in the 2-week treatment cycle regimen, and fewer than 32
applications
and/or rest days in the 3-week treatment cycle regimen) is reported.
[0455] The primary efficacy variable prospectively defined for all studies is
subject
status with respect to complete clearance of AK lesions at End of Study. This
is defined
as the absence of clinically visible or palpable AK lesions in the treatment
area.
[0456] Secondary efficacy variables are:
= Subject status with respect to partial clearance of AK lesions at End of
Study,
defined as at least a 75% reduction in the number of AK lesions in the
treatment
area compared with Baseline.
= Percent change from Baseline to End of Study in investigator counts of AK
lesions.
[0457] The comparative and integrated analysis of efficacy focuses on the
primary and
two secondary efficacy variables. Integrated and comparative summaries is
presented
at the primary time point of End of Study. The studies are reviewed separately
as well
as with the identical studies combined in pairs: GW01-0702 and GW01-0704 for
the 2-
week treatment cycle regimen, and GW01-0703 and GW01-0705 for the 3-week
treatment cycle regimen.
[0458] In the planned statistical analyses defined prospectively and
presented, all
pairwise comparisons of active treatment versus placebo are made using
Hochberg's
modified Bonferroni procedure. If either test is significant at a 0.025 level
of
significance, then that test is considered significant. Otherwise, if both
tests are
significant at 0.05, then both tests are considered significant. The 3.75% and
2.5%
treatment groups are compared to each other at the 0.05 level of significance
if at least
one of these treatment groups is found to be different than the placebo using
the
Hochberg test.
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[0459] In this way, complete clearance rates, partial clearance rates, change
from
Baseline AK lesion counts, and percent change from Baseline AK lesion counts
are
analyzed using Cochran-Mantel-Haenszel (CMH) statistics, stratifying on site.
[0460] In the primary analysis of complete clearance rate, the Breslow-Day
statistic is
tested at the 10% level for heterogeneity of the odds ratios across analysis
sites. There
are no findings of statistical significance in these tests for any of the
studies.
[0461] In order to characterize and explore the efficacy of the proposed drug
product
in subpopulations of interest, the data from the two pivotal studies is
combined and
analyzed by age, sex, Fitzpatrick skin type, treatment area, and baseline
lesion count.
In each case, the ITT population is divided into two subpopulations based on
the specific
covariate of interest. For age, the subpopulations are selected as less than,
or greater
than or equal to, 65 years old. For skin type and baseline lesion count, the
subpopulations are selected as above or below the approximate median value of
the
covariate (combining I with II, and combining III, IV, V, and VI) for skin
type; taking less
than or equal to 10 vs greater than 10 for baseline lesion count). P values
for complete
clearance and partial clearance are computed using a generalized linear model
(PROC
GENMOD) assuming a multinomial distribution (DIST=MULT) and a cumulative login
link function (LINK=CLOGIT) including effects of treatment, subpopulation, and
interaction. P values for percent reduction are derived from the analysis of
variance
(PROC GLM) including effects of treatment, subpopulation, and interaction. A
similar
analysis is presented for the subpopulation of subjects who showed increased
AK lesion
count at any time after baseline. This subpopulation is characterized in
current Aldara
labeling as having had "sub-clinical lesions". In these four studies, it is
seen that the
great majority of subjects are included in this subpopulation.
[0462] The LSR intensities are summarized in each study by frequency counts
and
mean score by treatment group and study visit for each LSR type:
= Erythema (O=None, 1=Faint to mild redness, 2=Moderate redness, 3=lntense
redness),
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= Edema (O=None, 1=Mild visible or barely palpable swelling/ induration,
2=Easily
palpable swelling/induration, 3=Gross swelling/induration),
= Weeping/Exudate (O=None, 1=Minimal exudate, 2=Moderate exudate, 3=Heavy
exudate),
= Flaking/Scaling/Dryness (O=None, 1 =Mild dryness/flaking, 2=Moderate
dryness/flaking, 3=Severe dryness/flaking),
= Scabbing/Crusting (O=None, 1=Crusting, 2=Serous scab, 3=Eschar),
= Erosion/Ulceration (O=None, 1 =Erosion, 2=Ulceration).
[0463] The most intense reaction (post-baseline) for each type is also
presented by
frequency distribution and mean score by treatment group.
[0464] An LSR sum score is computed at each study visit (addition of six
scores).
Three areas under the curve (AUC, in days, using the trapezoidal
approximation) are
calculated for each subject: from Baseline to beginning of Treatment Cycle 2,
from
beginning of Treatment Cycle 2 to End of Study, and from Baseline to End of
Study.
These values are compared pair wise between treatment groups using Fisher's
least
significant differences in the one-way analysis of variance (treatment group).
Discontinued subjects are included in this analysis using LOCF. Details of the
calculation of AUC are provided in the clinical study reports.
[0465] A pooled analysis of is also provided, with P values derived from the
analysis of
variance (PROC GLM) including effects of concentration, regimen, and
interaction.
When calculating the AUC over the course of the study period, it is noted that
studies
GW01-0702 and GW01-0704 are 14 weeks in duration, while GW01-0703 and GW01-
0705 are 17 weeks in duration. The additional three weeks in the AUC for the
GW01-
0703 and GW01-0705 studies correspond to two additional weeks of treatment and
one
additional week in the no-treatment period between treatment cycles.
Nonetheless,
subjects in all four studies are followed through eight weeks after the last
treatment
application in order to allow complete healing of local skin reactions. Thus,
the
comparison of AUC LSR between the 14-week studies and the 17-week studies,
without
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adjustment, allows an evaluation of the relative duration, as well as the
severity of local
skin reactions resulting from each of the four dosing regimens.
[0466] The number and percentage of subjects by treatment group combining GW01-
0702 with GW01-0704 and GW01-0703 with GW01-0705 is presented for each of the
following safety indicators.
= Requiring Rest Period
= Discontinuing the Study Prematurely for Any Reason
= Discontinuing the Study Prematurely for Safety Reasons
= Any Adverse Event
= Any Treatment-Related Event
= Any Application Site Reaction
= Any Serious Adverse Event
= Any Severe Adverse Event
[0467] The incidence of subjects requiring rest periods is calculated for each
treatment
group by Cycle 1, Cycle 2 and Overall.
[0468] Adverse events (AEs) is coded using MedDRA (Version 11) terminology.
Treatment-emergent AEs is summarized for each treatment group (with the four
Phase
3 studies combined in pairs) by:
= n (%) of Subjects in Decreasing Order of Incidence in the 3.75% 2-Week
Treatment Cycle Group, Adverse Events with Incidence > 1% in the 3.75% 2-
Week Treatment Cycle Group;
= n (%) of Subjects in Decreasing Order of Incidence in the 3.75% 2-Week
Treatment Cycle Group, Adverse Events Considered Treatment-related by the
Investigator;
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= n (%) of Subjects in Decreasing Order of Incidence in the 3.75% 2-Week
Treatment Cycle Group, Adverse Events Rated Severe;
= n (%) of Subjects in Decreasing Order of Incidence in the 3.75% 2-Week
Treatment Cycle Group, All Application Site Reactions.
[0469] The incidence of adverse events is summarized by gender, by age
subgroup,
by skin type, by baseline lesion count, and by location of treatment area
(face or balding
scalp). For age, the subpopulations is selected as less than or greater than
or equal to,
65 years old. For skin type and baseline lesion count, the subpopulations is
selected as
above or below the approximate median value of the covariate (combining I with
II, and
combining III, IV, V, and VI for skin type; taking less than or equal to 10 vs
greater than
for baseline lesion count).
[0470] Serious AEs and AEs which led to the discontinuation of the subject
from the
study is listed by subject.
[0471] The frequency counts of shifts in alert status (normal to high, low to
normal,
etc) from Screening to End of Study is tabulated by treatment group for each
laboratory
parameter combining the four Phase 3 studies in pairs.
Example 25
An Open Label, Single Center, Non-Randomized Pharmacokinetic (PK) Study
[0472] An open label, single center, non-randomized pharmacokinetic (PK) study
in
adult subjects diagnosed with actinic keratosis ("AK") is conducted. This PK
study is
designed to quantify the pharmacokinetic profile of imiquimod and its
metabolites
following 3 weeks (21 days) of daily applications of a 3.75% imiquimod
formulation of
Example in adult subjects diagnosed with actinic keratosis (AK). The study is
conducted
under maximal use conditions (dose, duration, disease severity, and
application areas)
in a population that had at least 10 AK lesions in the application area. The
application
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area is the entire face (exclusive of nares, vermilion, periocular areas and
ears) and/or
th6 entire balding scalp; areas estimated as approximately 200 cm2. If the
area of the
entire balding scalp is less than 200 cm2, the forehead area is included in
order for the
entire treatment area to be approximately 200 cm2. The daily dose is 2 packets
of
3.75% imiquimod cream for three continuous weeks.
[0473] Thus, this PK study is conducted under maximal use conditions: (1) at
least 10
clinically typical visible or palpable AK lesions within the treatment area
(balding scalp or
face); (2) application of 2 full packets (250mg of formulation per packet) of
3.75%
imiquimod formulation once daily for 21 days (maximal dosing regimen); and (3)
a skin
area of approximately 200 cm2 of the entire face or balding scalp (maximal
treatment
area).
[0474] Subjects stay at the study center overnight at treatment initiation
(Day 1, 1 st
dose), and end of treatment (Day 21, last dose) visits for collection of a 24-
hour serum
PK profile. During the domicile periods of initiation (Day 1), and end of
treatment (Day
20-21) visits, serum PK samples are collected predose and at planned time
points
through 24 hours post dose. At the end of treatment (Day 21), additional PK
samples
are taken at approximately 48 and 72 hours post application. Single serum
samples for
PK analyses of trough concentrations are obtained at Day 7 and Day 14 (in the
morning
prior to dosing).
[0475] Adverse events, study medication accountability, and dosing compliance
are
reviewed at each visit. Routine clinical laboratory assessments (serum
chemistry,
hematology and urinalysis) are performed at Screening, Day 1(predose), and the
end of
study visits.
[0476] Nineteen subjects (14 males/5 females) are enrolled into the study and
18
completed. One female subject discontinues the study prematurely due to
concurrent
adverse events (moderate body aches and moderate fatigue), and therefore does
not
have a PK profile at Day 21 (steady-state). For the 19 enrolled subjects, 15
subjects
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apply the study medication to the entire face, and the remainder apply the
study
medication to the balding scalp (which may include the upper face if < 200
cm2).
[0477] A total of 19 subjects have pharmacokinetic profiles (sampling over 24
hours)
following the first dose, and 18 subjects have pharmacokinetic profiles
(sampling over
72 hours) on Day 21. One subject misses a dose on Day 20, and therefore is
excluded
from the Day 21 analysis (17 subjects have adequate data for Day 21 analyses
of
AUCO-24, Cmax and Tmax). Trough serum concentrations are obtained on Days 7,
14,
21, and 22. The trough concentrations on Days 7 and 14 are obtained during
outpatient
treatment while the trough concentrations on Days 21 and 22 are obtained while
the
subjects are dosed in the clinical research facility. Trough imiquimod
concentrations are
summarized in Table 87.
Table 87 Summary of Imiquimod Trough Concentrations (ng/mL); Subjects
with Paired, Non-zero Data
Geometric Geometric Geometric 90%
LS Mean LS Mean Mean Confidence
N Test Reference Ratio Interval
1.0888 (0.7933 -
Day 14/7 15 0.1391 0.1277 1.4946)
1.3328 (0.9193 -
Day 21/14 16 0.1791 0.1344 1.9325)
0.9331 (0.6612 -
Day 22/21 16 0.1671 0.1791 1.3169)
[0478] Serum concentrations of imiquimod are relatively low in subjects
treated with
daily applications of an imiquimod 3.75% cream of Example 23 for up to 21
days.
While serum concentrations of two imiquimod metabolites (S 26704 and S 27700
combined) are measured throughout the study, very few samples had
concentrations
above the lower limit of quantitation (LLOQ). Therefore, these data are too
sparse to
assess.
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[0479] The ratio of trough concentrations is examined to determine whether
steady-
state conditions are achieved during 21 days of topical treatment with 3.75%
imiquimod
cream. Under steady-state treatment conditions, the trough concentrations,
aside from
variability, demonstrate a stable plateau value (i.e., not significantly
increasing over
time, as indicated by a ratio significantly > 1). Considering the variability
in imiquimod
trough concentrations (observed CV% ranged from 47.6-58.0%), a ratio < 1.43
(following log transformation) is pre-selected to indicate the achievement of
steady
state; all three ratios meet that criterion. This analysis of trough ratios
(i.e., using only
those subjects with paired, non-zero data) is also confirmed by an analysis
which
includes all subjects with paired data by replacing the zero (BQL) values with
0.025
ng/mL (1/2 of the LLOQ).
[0480] The single-dose and steady-state pharmacokinetic parameters for daily
application of 3.75% imiquimod cream are summarized in Table 88 and Table 89.
Table 88 Preliminary Steady-State (Day 21)
Imiquimod Pharmacokinetic Variables
AUCO_24 Cmax Tmax xz T1/2
(ng.hr/mL) (ng/mL) (hr) (hr') (hr)
N 17 17 17 15 15
Geometric
Mean 5.029 0.274 6.623 0.027 26.11
Mean 5.974 0.323 7.356 0.029 29.26
SD 3.088 0.159 3.500 0.014 16.98
CV% 51.7% 49.2% 47.6% 48.5% 58.0%
Median 7.019 0.350 9 0.0271 25.56
Min 1.139 0.069 4 0.0082 9.72
Max 11.800 0.588 16 0.0713 84.06
Table 89 Single-dose and Steady-state Pharmacokinetics of 3.75% Imiquimod
Cream of Example 23 (Study GW01-0706)
Mean (SD)
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CA 02649893 2009-01-15
Parameter N` Day 1 N d Day 21
Cmax (ng/mL) 17 0.136 (0.059) 17 0.323 (0.159)
Cmin (ng/mL)a - NA 17 0.199 (0.109)
Tmax (hr)b 17 9.0 (4.0-24.03) 17 9.0 (4.0-16.0)
AUC0_24 (ng=hr/mL) 17 1.831 (0.889) 17 5.974 (3.088)
AUCo_t (ng=hr/mL) 17 1.679 (1.056) - NA
AUCo_;nf (ng=hr/mL) 11 4.443 (1.309) - NA
AZ (1/hr) 11 0.0450 (0.0219) 15 0.0294 (0.0142)
Ty, (hr) 10 19.818 (10.125) 15 29.260 (16.979)
RAUC - NA 15 3.873 (2.153)
Rcmax - NA 15 2.810 (1.514)
AZEFF (hr') - NA 15 0.0235 (0.0229)
T'/,EFF (hr) - NA 15 55.339 (36.380)
NA=Not applicable
a Pre-dose concentration (t=0)
b Median (minimum-maximum)
Subjects 001-601 and 001-618 were BLQ, therefore unable to calculate PK
parameters
d Subject 001-619 did not have concentration data on Day 21; Subject 001-608
excluded due to
missed dose on Day 20
[0481] Peak exposure (Cmax) and total exposure (AUCo 24) for imiquimod are
higher on
Day 21 than Day 1 when analyzing all subjects in the pharmacokinetic
population. The
mean accumulation ratios, RCmax and RAUC, for all subjects in the
pharmacokinetic
population are about 2.810 and about 3.873, respectively. The serum
concentration
profile on Day 21 is relatively flat across the dosage interval, and mean Cmax
(0.323 0.159 ng/mL) is less than twice the level of mean Cmi, (0.199 0.109
ng/mL).
The mean effective half life for accumulation is about 55.3 hours and the mean
observed elimination half life is about 29.3 hours on Day 21. Analysis of
trough
concentrations over time indicate that steady state conditions are achieved
between
Day 7 and Day 14, which is consistent with the time to steady state that is
predicted
from observed elimination half life (approximately 6 days) and the effective
half life for
accumulation (approximately 12 days).
[0482] In a comparison of female and male subjects who apply an imiquimod
3.75%
cream of Example 23 to the face, serum pharmacokinetics for imiquimod are very
similar for both groups on Day 21. In a comparison of scalp and face
applications in
male subjects, imiquimod Cmax and AUCo 24 are lower on Day 21 in subjects who
apply
215
CA 02649893 2009-01-15
study medication to balding scalp rather than to the face. Analyses of the
subgroups
are limited by wide variability in the data, small overall numbers, and a
large disparity in
group sizes (female/male comparison of 4 versus 10 subjects, and scalp/face
comparison of 3 versus 10 subjects).
[0483] Under maximal use conditions following daily administration at steady-
state,
the mean (SD) peak imiquimod serum concentrations are about 0.323 (0.159)
ng/mL,
and the median time to peak concentration is about 9 hours. Comparison of the
mean
Cmax concentrations and the mean trough concentrations indicates a relatively
flat
concentration-time profile throughout the dosing interval. The observed
elimination half-
life averaged about 29.26 hours (range 9.72-84.06 hours).
[0484] Steady state is believed to be achieved in this study by day 14 or the
second
week of daily dosing. Subjects in this study apply 2 packets (500 mg of cream -
250
mg/packet; 18.75 mg of imiquimod) daily for 3 weeks to the entire face or
balding scalp,
and the mean peak serum imiquimod concentration (Cmax) is about 0.323 ng/mL.
In a
previous study of the 5% imiquimod cream, subjects who receive 2 packets (500
mg of
cream; 25 mg of imiquimod) 3 times per week for 16 weeks to the scalp, the
mean peak
serum imiquimod concentration (Cmax) is 0.2 ng/mL: Subjects who receive six
packets
(1500 mg cream; 75 mg of imiquimod) 3 times per week for 16 weeks to the hand
and
forearms) have a Cmax of 3.5 ng/ml. These results are shown below in Table 90.
Table 90. Mean Peak Serum Imiquimod Concentration in Adults
Following Administration of the Last Topical Dose of
Aldara 5% Imiquimod Cream During Week 16 (Actinic
Keratosis)
Amount of Aldara 5% Mean peak serum imiquimod
Imiquimod Cream applied concentration [Cmad
12.5 mg (1 packet) 0.1 ng/mL
25 mg (2 packets) 0.2 ng/mL
75 mg (6 packets) 3.5 ng/mL
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CA 02649893 2009-01-15
Source: Current Aldara Package Insert: Section 12.3 Pharmacokinetics: Table
10
[0485] Pharmacokinetic data are available from three studies of patients with
AK, one
using the 3.75% imiquimod formulation of Example 23 (Study GW01-0706), and two
studies using the marketed Aldara 5% imiquimod cream formulation (Study 1520-
IMIQ
and Study 1402-IMIQ). The dosage, treatment duration, application site and
application
area in these studies is summarized in Table 91.
Table 91. Summary of Dosage, Application Site, and Treated Surface Area for
Studies GW01-0706, 1520-IMIQ, and 1402-IMIQ
Weekly
Study Dose Duration N a Site Area
Dosage (imiquimod)
Study GW01-0706
(3.75% imiquimod cream)
2 packets (18.75 mg) daily 131.25 mg 21 days 17 Face or Scalp 200 cm2
Study 1520-IMIQ
(5% imiquimod cream)
6 packets (75 mg) 2 x weekly 150 mg 16 wks d 13 NS > 25% of
BSA
Study 1402-IMIQ
~ (5% imiquimod cream)
1 packet (12.5 mg) 3 x weekly 37.5 mg 16 wks 23 Face 25 cm2
2 packets (25 mg) 3 x weekly 75 mg 16 wks 11 Scalp >25 cm2
6 packets (75 mg) 3 x weekly 225 mg 16 wks 24 Hands/Arms b NS c
NS = not specified; BSA= Body surface area
a Number of subjects in PK population at steady-state
b Applied to dorsal surface of forearms and hands, 3 packets applied to each
side
c Not specified; estimated in the range of 300-400 cm2 based on the protocol
description
d Data from one 16-week treatment cycle, subjects could receive up to 3 cycles
of treatment over 18 months.
[0486] While studies 1402-IMIQ and GW01-0706 are primarily pharmacokinetic
studies, the data from Study 1520-IMIQ is a large long-term safety trial (551
subjects
enrolled), and the pharmacokinetic data comes from subset of subjects
representing a
cohort receiving maximal exposure to imiquimod (6 packets of 5% cream applied
twice
weekly to >25% of their body surface area). Subjects in this study could
participate in
217
CA 02649893 2009-01-15
up to three 16-week treatment cycles during the 18-month study. In Study 1520-
IMIQ,
71.9% of subjects (396 of 551) in the safety population have completed the
trial.
Subjects in the safety population average 466.9 days in the study and apply an
estimated average of 214.6 packets of study drug (2682.5 mg of imiquimod). At
study
initiation, the median prescribed dose is about 3.3 packets twice weekly, and
380 of 551
subjects (69%) have received a dose of 3 or more packets twice weekly, and 182
subjects have received the maximal exposure of 6 packets twice weekly.
[0487] Based on the total amount of drug administered during one week of
treatment,
the weekly dose of the an 3.75% imiquimod lower dosage strength formulation of
Example 23 and the novel two week 2-cycle dosage regimen (2 packets daily or
131.25
mg imiquimod weekly) is similar to the weekly dose that was used in the 1520-
IMIQ
study, and falls between the two higher doses used in Study 1402-IMIQ. In
addition, the
novel two week 2-cycle dosage regimen treats a larger surface area (about 200
cm)
than the previously approved regimens for AK on the face and balding scalp (25
cm2).
Systemic exposure at steady-state is summarized in Table 92.
218
CA 02649893 2009-01-15
Table 92. Summary of Systemic Exposure at Steady-State Following
Administration of 3.75% or 5% Imiquimod Cream [Mean(SD) Serum
Imiquimod Cmax and AUCss]
Cmax (ng/mL) AUC (ng-hr/mL)
Mean (SD) Ratio a Mean Ratio a
(SD)
Study GWOI-0706
2 pkts (18.75 mg) daily to face/scalp 0.323 (0.159) 5.974
(3.088)
Study 1520-IMIQ b _
6 pkts (75 mg) 2 x weekly to > 25% BSA 0.958 (1.18) 2.96 24.3 (26.9) 4.07
Study 1402-IMIQ
1 pkts (12.5 mg) 3x/week to face 0.120 (0.0629) 0.37 2.06 (1.70) 0.34
2 pkts (25 mg) 3x/week to scalp 0.214 (0.0968) 0.66 4.89 (4.41) 0.82
6 pkts (75 mg) 3x/week to hand/forearms` 1.35 (0.841) 4.18 29.1 (17.1) 4.87
6 pkts (75 mg) 3x/week to hand/forearms d 3.53 (6.52) 10.92 55.4 (76.0) 9.27
Pkts = packets; BSA= Body surface area
a 5% imiquimod regimen/3.75% imiquimod regimen
b Month 4 data
c Data from Harrison et al, 20041 (rejecting outliers that were >5X the SD of
their respective means)
d Data from the 1402-IMIQ2 report that includes outliers
[0488] The mean Cmax and AUC in Study GW01-0706 at steady state are
substantially
lower than those that are observed following administration of the high dose
used in the
large safety trial (6 packets, 75 mg, twice weekly, Study 1520-IMIQ). Based on
these
results, it is believed that the novel treatment regimen, i.e., an 3.75%
imiquimod lower
dosage strength formulation of Example 23 applied daily in a two week 2-cycle
dosage
regimen (2 packets daily or 131.25 mg imiquimod weekly) has about an 3- to 4-
fold
safety margin for systemic exposure relative to the high-dose exposure in
Study 1520-
IMIQ. Thus, these results indicate that the intended dose of an 3.75%
imiquimod cream
product of Example 23 has less systemic exposure than what is observed in the
high
dose group for the 5% imiquimod cream product in the long-term safety Study
1520-IMIQ.
[0489] Pharmacokinetic profiles were obtained following single-dose and repeat-
dose
administration of 3.75% imiquimod cream in Study GW01-0706 (see Table 89
above).
219
CA 02649893 2009-01-15
The mean (SD) accumulation ratios that are calculated from Cmax and AUCO_24
are about
2.810 (1.514) and about 3.873 (2.153), respectively. The mean effective half-
life for
accumulation is about 55.3 hours and the mean observed elimination half-life
is about
29.3 hours on Day 21. Analysis of trough concentrations over time indicate
that
steady-state conditions are achieved between Day 7 and Day 14,.
[0490] In summary, the amount of imiquimod that is absorbed into systemic
circulation
after topical application of an imiquimod 3.75% cream of Example 23 to the
face and/or
scalp once daily for up to 21 days is low; peak and total serum imiquimod
concentrations
are increased by about 3 to 4 fold between Day 1 and Day 21. Steady state is
achieved
by Day 14. Cmax and AUCo 24 on Day 21 appear to be similar in female and male
subjects and lower in male subjects who apply an imiquimod 3.75% cream of
Example
23 to balding scalp rather the face.
[0491] Thus, the mean peak serum imiquimod concentration that is observed with
the
daily application of the 3.75% imiquimod product (about 0.323 ng/mL) is within
the mean
peak serum imiquimod concentrations previously observed with Aidara 5%
imiquimod
cream.
Example 26
Meta-Analysis - Efficacy, Adverse Events, Local Skin Reactions and Rest
Periods
[0492] A meta analysis is conducted across the four clinical studies described
in
Example 24. Data for Aldara 5% imiquimod cream is displayed for comparative
purposes. See, e.g., FIGS. 25-30 Of course, the Aldara data concerned much
smaller
size treatment areas and a smaller number of AK lesions per treatment than the
clinical
studies that are described in Example 24.
[0493] Turning now to FIGS. 25 and 25A, they show the pooled actinic keratosis
lesion clearance rates, i.e., complete and partial clearance rates for the
2.5% and 3.75%
imiquimod formulations of Example 23 that are used in the short duration
therapies (2 x
220
CA 02649893 2009-01-15
2 x 2 weeks and 3 x 3 x 3 weeks), are about as equally effective as the Aldara
5%
imiquimod cream treatment, even though Aldara was applied twice a week for 16
weeks on treatment areas no greater than about 25 cm2 and to no more than
between
about 4 and 8 AK lesions.
[0494] In FIG. 26, it shows the complete clearance rates for the 2.5% and
3.75%
imiquimod formulations of Example 23, that are used in the short duration
therapies,
i.e., 2 x 2 x 2 weeks and 3 x 3 x 3 weeks, are about as equally effective as
the Aldara
5% imiquimod cream treatment, even though Aldara was applied twice a week for
16
weeks on treatment areas no greater than about 25 cm2 and to no more than
between
about 4 and 8 AK lesions.
[0495] In FIG. 27, it shows the partial clearance rates for the 2.5% and
3.75%'
imiquimod formulations of Example 23, that are used in the short duration
therapies,
i.e., 2 x 2 x 2 weeks and 3 x 3 x 3 weeks, are about as equally effective as
the Aldara
5% imiquimod cream treatment even though Aldara was applied twice a week for
16
weeks on treatment areas no greater than about 25 cm2 and to no more than
between
about 4 and 8 AK lesions.
[0496] In FIGS. 28 and 28A-B, an adverse events comparison is shown between
the
2.5% and 3.75% imiquimod formulations of Example 23 that are used in the short
duration therapies, i.e., 2 x 2 x 2 and 3 x 3 x 3 weeks, and the Aldara 5%
imiquimod
cream treatment that are used twice a week for 16 weeks on treatment areas no
greater
than about 25 cm2 and no more than between about 4 and 8 AK lesions, to treat
actinic
keratosis. As depicted in FIGS. 28 and 28A-B, there is a higher percentage of
application site reactions and upper respiratory infections with the Aldara
5% imiquimod
cream treatment than with the low dosage strength 2.5% and 3.75% imiquimod
formulations that are used in the short duration therapies, i.e., 2 x 2 x 2
and 3 x 3 x 3
weeks, even though the 2.5% and 3.75% imiquimod formulations of Example 23 are
applied daily on treatment areas much greater than 25cm2.
221
CA 02649893 2009-01-15
[0497] In FIG. 29, it shows the incidence of severe local skin reactions
erythema for
the 2.5% and 3.75% imiquimod formulations of Example 23 that are used in the 2
x 2 x
2 week short duration therapy are comparable to the Aldara 5% imiquimod cream
treatment, but higher for the 3 x 3 x 3 week therapy.
[0498] In FIG. 30, it shows the incidence of rest periods for the 2.5% and
3.75%
imiquimod formulations of Example 23 that are used in the 2 x 2 x 2 week short
duration
therapy are lower than the Aldara 5% imiquimod cream treatment, but higher
for the 3 x
3 x 3 week therapy.
Example 27
A com~arison between the Four Clinical Studies Described in Example 24 and
AldaraR
[0499] A comparative analysis is conducted across the four clinical studies
described
in Example 24 and Aldara . See, e.g., FIGS. 28, 28A-B and 36-42. As previously
indicated, treatment with Aldara concerns much smaller size treatment areas
and a
smaller number of AK lesions per treatment than the clinical studies that are
described
in Example 24.
[0500] As to FIGS. 28 and 28A-B, see Example 27.
[0501] Turning now to FIGS. 36 and 36A, the pooled percent of complete
clearance
rates for the 2.5% and 3.75% imiquimod formulations of Example 23, that are
used in
the 2 x 2 x 2 weeks studies, and the 3 x 3 x 3 weeks studies of Example 24,
are
displayed. Results across treatment regimens (2 week or 3 week treatment
cycles) are
comparable. A dose response between 2.5% and 3.75% imiquimod formulations of
Example 23 is evident irrespective of regimen (2 week or 3 week treatment
cycles).
[0502] Turning now to FIGS. 37 and 37A, the pooled percent of partial complete
clearance rates for the 2.5% and 3.75% imiquimod formulations of Example 23,
that are
222
CA 02649893 2009-01-15
used in the 2 x 2 x 2 weeks studies, and the 3 x 3 x 3 weeks studies of
Example 24,
are displayed. Results across treatment regimens (2 week or 3 week treatment
cycles)
are comparable. A dose response between 2.5% and 3.75% imiquimod formulations
of
Example 23 is evident irrespective of regimen (2 week or 3 week treatment
cycles).
[0503] Turning now to FIGS. 38 and 38A, the pooled percent of AK lesion median
%
reduction for the 2.5% and 3.75% imiquimod formulations of Example 23, that
are used
in the 2 x 2 x 2 weeks studies, and the 3 x 3 x 3 weeks studies of Example 24,
are
displayed. Results across treatment regimens (2 week or 3 week treatment
cycles) are
comparable. A dose response between 2.5% and 3.75% imiquimod formulations of
Example 23 is evident irrespective of regimen (2 week or 3 week treatment
cycles).
[0504] Turning now to FIG. 39, they show that the percent of subjects who took
at
least one rest period during treatment for the 2.5% and 3.75% imiquimod
formulations of
Example 23, that are used in the 2 x 2 x 2 weeks studies of Example 24, are
less than
those taken with Aldara 5% imiquimod cream.
[0505] Turning now to FIG. 39A, the selected safety parameters for the
combined 2 x
2 x 2 or 3 x 3 x 3 studies show that the safety events are less favorable in
the 3 x 3 x 3
studies than the 2 x 2 x 2 studies.
[0506] Turning now to FIG. 40, it shows the percent of local skin reactions
(LSRs) of
subjects with severe LSRs for the 2.5% and 3.75% imiquimod formulations of
Example
23, that is used in the 2 x 2 x 2 week studies of Example 24. Overall, the
incidence
rates for severe LSRs are relatively low, and as for Aldara 5% imiquimod
cream, the
most common severe LSR is erythema.
[0507] Turning now to FIG. 41, it shows the incidence of adverse events of
subjects
for the 2.5% and 3.75% imiquimod formulations of Example 23, that is used in
the 2 x 2
x 2 week studies of Example 24. The most common adverse event is application
site
reactions which occurs at a lower rate than Aldara 5% imiquimod cream.
223
CA 02649893 2009-01-15
[0508] Turning now to FIG. 41A, it shows the incidence of treatment-related
adverse
events of subjects for the combined 2 x 2 x 2 or 3 x 3 x 3 studies. This shows
that the
incidence of adverse events are less favorable in the 3 x 3 x 3 studies than
the 2 x 2 x 2
studies.
[0509] Turning now to FIG. 42, it shows the benefit/risk analysis for both (1)
the 2.5%
and 3.75% imiquimod formulations of Example 23, that are used in the 2 x 2 x 2
week
studies of Example 24, and (2) the Aidara 5% imiquimod cream, to treat
actinic
keratosis. As is shown, the 3.75% imiquimod formulation provides incremental
efficacy
benefit to the 2.5% imiquimod formulation as defined by results for complete
clearance,
partial clearance and median percent reductions. The 3.75% imiquimod
formulation
provides comparable efficacy to Aldara 5% imiquimod cream as defined by
partial
clearance and median percent reductions not withstanding the differences in
treatment
area size and baseline numbers of AK lesions in the studies of the 3.75% and
5%
imiquimod formulations. As to risk, the incidences of severe erythema and the
incidences of rest periods among the 2.5%, 3.75% and 5% (Aldara ) imiquimod
formulations are generally similar (that is within approximately 10% of each
other). As
noted with the assessment of benefits, these results are not withstanding the
differences
in treatment area size and baseline numbers of AK lesions in the studies of
the 2.5%,
3.75% and 5% imiquimod formulations. The third measure of risk, that is
incidence of
application site reactions, shows low incidence rates for both the 2.5% and
3.75%
imiquimod formulations and a minimum 3-fold higher incidence rate with the
Aldara 5%
imiquimod cream formulation.
Example 28
Eight Individual Clinical Cases - Four Individual Two Week, 2-Cycle Clinical
Cases
and Four Individual Three Week, 2-Cycle Clinical Cases
[0510] This Example 28 is directed to eight clinical cases wherein subjects
diagnosed
with actinic keratosis are treated with either 2.5% or 3.75% low dosage
strength
224
CA 02649893 2009-01-15
imiquimod formulations of Example 23 in accordance with either a two-cycle, 2
week on
x 2 week off x 2 week on treatment regimen or a two-cycle, 3 week on x 3 week
off x 3
week on treatment regimen, as described herein. See, e.g., FIGS. 43-50 for a
summary
of results.
[0511] According to the clinical case summarized in FIG. 43, a 39 year old
white male
has an AK lesion count of 11 on his balding scalp at treatment initiation.
Consistent with
the present invention, the full balding scalp is treated daily with a single
dose of a 2.5%
imiquimod formulation of Example 23. The 2.5% imiquimod formulation is
packaged in
individual packets in an amount of 250 mg/packet. The number of average
packets that
are used by this 39 year old white male for each individual daily dose is 1.25
packets.
During the two-cycle, 2 x 2 x 2 weeks, treatment period, this 39 year old
white male
neither misses a dose nor takes a rest period.
[0512] Referring now to FIG. 43, the 39 year old white male is treated as
follows:
during the first cycle of treatment, one dose (1.25 packets on average) of the
2.5%
imiquimod formulation is applied to his full balding scalp once per day for 14
days;
during the next 14 days, treatment is suspended; during the second cycle of
treatment,
treatment is carried out identical to the treatment that is used during the
first cycle. At
the end of the second cycle, the 39 year old white male is monitored for an
additional 8
weeks. During the entire 14 weeks, the 39 year old white male is monitored for
total or
partial clearance, local skin reactions, including erythema, and adverse
events at (a)
baseline, (b) week 2, (c) week 6, (d) week 10, and (e) week 14.
[0513] In still referring to FIG. 43, at baseline before therapy, there is an
AK lesion
count of 11 and a local skin reaction (erythema) score of 0. At week 2, the AK
lesion
count is IND, but there is a local skin reaction erythema score of 2. At week
6, the AK
lesion count remains IND, but the local skin reaction erythema score is
reduced to 1. At
week 14, the AK lesion count remains 0 (total clearance) and the local skin
reaction
erythema score returns to normal or baseline score. Lymphadenopathy is
reported as a
related adverse event.
225
CA 02649893 2009-01-15
[0514] Thus, this clinical case as summarized in FIG. 43, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that total or complete clearance is achieved with a 2.5%
imiquimod
formulation of Example 23 when applied to the full balding scalp of a subject
diagnosed
with actinic keratosis following a 2 cycle, 2 x 2 x 2 weeks, treatment period.
This
Example 28, as described in FIG. 43, also demonstrates the unique bimodal or
camelback pattern as to the local skin reaction score for erythema during the
2 cycle, 2 x
2 x 2 weeks, treatment regimen, which is generated when following the short
durations
of therapy in accordance with the present invention.
[0515] According to the clinical case summarized in FIG. 44, a 74 year old
white male
with Fitzpatrick skin type III has an AK lesion count of 8 on his balding
scalp at treatment
initiation. Consistent with the present invention, the entire balding scalp is
treated daily
with a single dose of a 2.5% imiquimod formulation of Example 23. The 2.5%
imiquimod formulation is packaged in individual packets in an amount of 250
mg/packet.
The number of average packets that are used by this 74 year old white male for
each
individual daily dose is 2.0 packets. During the two-cycle, 2 x 2 x 2 weeks,
treatment
period,.this 74 year old white male neither misses a dose nor takes a rest
period.
[0516] Referring now to FIG. 44, the 74 year old white male, is treated as
follows:
during the first cycle of treatment, one dose (2.0 packets on average) of the
2.5%
imiquimod formulation is applied to his full balding scalp once per day for 14
days;
during the next 14 days, treatment is suspended; during the second cycle of
treatment,
treatment is carried out identical to the treatment that is used during the
first cycle. At
the end of the second cycle, the 74 year old white male is monitored for an
additional 8
weeks. During the entire 14 weeks, the 74 year old white male is monitored for
total or
partial clearance, local skin reactions, including erythema, and adverse
events at (a)
baseline, (b) week 2, (c) week 4, (d) week 6, (e) week 10, and (f) week 14.
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[0517] In still referring to FIG. 44, at baseline before therapy, there is an
AK lesion
count of 8 and a local skin reaction (erythema) score of 0, a baseline score
of 0. At
week 2, the AK lesion count is 19, but there is a local skin reaction erythema
score of 2.
At week 4, the AK lesion count is reduced to 12, and the local skin reaction
erythema
score is reduced to 1. At week 6, the AK lesion count is increased to 33 and
the local
skin reaction erythema score is increased to 3. At week 10, the AK lesion
count is
reduced to 1 and the local skin reaction erythema score is now 0. At week 14,
the AK
lesion count is up to 2 (partial clearance) and the local skin reaction
erythema score
remains 0 or the same as the baseline score. No adverse events are reported.
[0518] Thus, this clinical case as summarized in FIG. 44, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that a reduction in AK lesions (partial clearance) of about 75%
from
baseline is achieved with a 2.5% imiquimod formulation of Example 23 when
applied to
the full balding scalp of a subject diagnosed with actinic keratosis following
a 2 cycle, 2 x
2 x 2 weeks, treatment period. This Example 28, as described in FIG. 44, is
another
example of the unique bimodal or camelback pattern as to the local skin
reaction score
for erythema during the 2 cycle, 2 x 2 x 2 week, treatment regimen, that is
generated
when following the short durations of therapy in accordance with the present
invention.
[0519] According to the clinical case summarized in FIG. 45, a 66 year old
white
female with Fitzpatrick skin type II has an AK lesion count of 9 on her face
at treatment
initiation. Consistent with the present invention, the full face is treated
daily with a single
dose of a 3.75% imiquimod formulation of Example 23. The 3.75% imiquimod
formulation is packaged in individual packets in an amount of 250 mg/packet.
The
number of average packets that are used by this 66 year old white female for
each
individual daily dose is 1.26 packets. During the two-cycle, 2 x 2 x 2 weeks,
treatment
period, this 66 year old white female neither missed a dose on day 29 and took
rest
periods on days 11, 12, 13 and 14.
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[0520] Referring now to FIG. 45, the 66 year old white female is treated as
follows:
during the first cycle of treatment, one dose (1.26 packets on average) of the
3.75%
imiquimod formulation is applied to her full face once per day for 14 days;
during the
next 14 days, treatment is suspended; during the second cycle of treatment,
treatment is
carried out identical to the treatment that is used during the first cycle. At
the end of the
second cycle, the 66 year old white female is monitored for an additional 8
weeks.
During the entire 14 weeks, the 66 year old white female is monitored for
total or partial
clearance, local skin reactions, including erythema, and adverse events at (a)
baseline,
(b) week 2, (c) week 6 and (d) week 14.
[0521] In still referring to FIG. 45, at baseline before therapy, there is an
AK lesion
count of 9 and a local skin reaction (erythema) score of 0. At week 2, the AK
lesion
count is IND, but there is a local skin reaction erythema score of 2. At week
6, the AK
lesion count remains IND, but the local skin reaction erythema score is
reduced to 1. At
week 14, the AK lesion count is 0 (total clearance) and the local skin
reaction erythema
score remains at 1. Dizziness, facial stinging, sunburn (mild) are reported as
related
adverse events.
[0522] Thus, this clinical case as summarized in FIG. 45, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that total clearance is achieved with a 3.75% imiquimod
formulation of
Example 23 when applied to the full face of a subject diagnosed with actinic
keratosis
following a 2 cycle, 2 x 2 x 2 weeks, treatment period. This Example 28, as
described
in FIG. 45, also demonstrates the unique bimodal or camelback pattern as to
the local
skin reaction score for erythema during the 2 cycle, 2 x 2 x 2 weeks,
treatment regimen,
which is generated when following the short durations of therapy in accordance
with the
present invention.
[0523] According to the clinical case summarized in FIG. 46, a 73 year old
white male
with Fitzpatrick skin type II has an AK lesion count of 9 on his face at
treatment initiation.
Consistent with the present invention, the full face is treated daily with a
single dose of a
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3.75% imiquimod formulation of Example 23. The 3.75% imiquimod formulation is
packaged in individual packets in an amount of 250 mg/packet. The number of
average
packets that are used by this 73 year old white male for each individual daily
dose is
1.18 packets. During the two-cycle, 2 x 2 x 2 weeks, treatment period, this 73
year old
white male neither misses a dose nor takes a rest period.
[0524] Referring now to FIG. 46, the 73 year old white male, is treated as
follows:
during the first cycle of treatment, one dose (1.18 packets on average) of the
3.75%
imiquimod formulation is applied to his full face once per day for 14 days;
during the next
14 days, treatment is suspended; during the second cycle of treatment,
treatment is
carried out identical to the treatment that is used during the first cycle. At
the end of the
second cycle, the 73 year old white male is monitored for an additional 8
weeks. During
the entire 14 weeks, the 73 year old white male is monitored for total or
partial
clearance, local skin reactions, including erythema, and adverse events at (a)
baseline,
(b) week 2, (c) week 4, (d) week 6, (e) week 10, and (f) week 14.
[0525] In still referring to FIG. 46, at baseline before therapy, there is an
AK lesion
count of 9 and a local skin reaction (erythema) score of 0. At week 2, the AK
lesion
count is 22, but there is a local skin reaction erythema score of 3. At week
4, the AK
lesion count is reduced to 3, and the local skin reaction erythema score is
reduced to 0.
At week 6, the AK lesion count is increased to 5 and the local skin reaction
erythema
score is increased to 2. At week 10, the AK lesion count is reduced to 2 and
the local
skin reaction erythema score is now 0. At week 14, the AK lesion count remains
at 2
(partial clearance) and the local skin reaction erythema score remains at 0 or
the same
as the baseline score. No adverse events are reported.
[0526] Thus, this clinical case as summarized in FIG. 46, further demonstrates
efficacy without treatment limiting local skin reactions or adverse events and
further
demonstrates that a reduction in AK lesions (partial clearance) of greater
than about
75% from baseline is achieved with a 3.75% imiquimod formulation of Example 23
when applied to the full face of a subject diagnosed with actinic keratosis
following a 2
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cycle, 2 x 2 x 2 weeks, treatment regimen. This Example 28, as described in
FIG. 46, is
another example of the unique bimodal or camelback pattern as to the local
skin
reaction score for erythema during the 2 cycle, 2 x 2 x 2 weeks, treatment
regimen,
which is generated when following the short durations of therapy in accordance
with the
present invention.
[0527] According to the clinical case summarized in FIG. 47, a 70 year old
white male
has an AK lesion count of 10 on his face at treatment initiation. Consistent
with the
present invention, the full face is treated daily with a single dose of a 2.5%
imiquimod
formulation of Example 23. The 2.5% imiquimod formulation is packaged in
individual
packets in an amount of 250 mg/packet. The number of average packets that are
used
by this 70 year old white male for each individual daily dose is 2.0 packets.
During the
two-cycle, 3 x 3 x 3 weeks, treatment period, this 70 year old white male
neither misses
a dose nor takes a rest period.
[0528] Referring now to FIG. 47, the 70 year old white male is treated as
follows:
during the first cycle of treatment, one dose (2.0 packets on average) of the
2.5%
imiquimod formulation is applied to his full face once per day for 21 days;
during the next
21 days, treatment is suspended; during the second cycle of treatment,
treatment is
carried out identical to the treatment that is used during the first cycle. At
the end of the
second cycle, the 70 year old white male is monitored for an additional 8
weeks. During
the entire 17 weeks, the 70 year old white male is monitored for total or
partial
clearance, local skin reactions, including erythema, and adverse events at (a)
baseline,
(b) week 3, (c) week 9, and (d) week 17.
[0529] In still referring to FIG. 47, at baseline before therapy, there is an
AK lesion
count of 10 and a local skin reaction (erythema) score of 1. At week 3, the AK
lesion
count is IND, but there is a local skin reaction erythema score of 3. At week
9, the AK
lesion count increases to 13, but the local skin reaction erythema score
remains at 3. At
week 17, the AK lesion count is reduced to 5 (partial clearance) and the local
skin
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reaction erythema score returns to 1, i.e., normal or baseline score. No
adverse events
are recorded.
[0530] Thus, this clinical case as summarized in FIG. 47, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that partial clearance is achieved with a 2.5% imiquimod
formulation of
Example 23 when applied to the full face of a subject diagnosed with actinic
keratosis
following a 2 cycle, 3 x 3 x 3 week, treatment regimen. This Example 28, as
described
in FIG. 47, also demonstrates the unique bimodal or camelback pattern as to
the local
skin reaction score for erythema during the 2 cycle, 3 x 3 x 3 weeks,
treatment regimen,
which is generated when following the short durations of therapy in accordance
with the
present invention.
[0531] According to the clinical case summarized in FIG. 48, a 65 year old
white
female has an AK lesion count of 7 on her face at treatment initiation.
Consistent with
the present invention, the full face is treated daily with a single dose of a
2.5%
imiquimod formulation of Example 23. The 2.5% imiquimod formulation is
packaged in
individual packets in an amount of 250 mg/packet. The number of average
packets that
are used by this 65 year old white female for each individual daily dose is
1.69 packets.
During the two-cycle, 3 x 3 x 3 weeks, treatment period, this 65 year old
white female
neither misses a dose nor takes a rest period.
[0532] Referring now to FIG. 48, the 65 year old white female is treated as
follows:
during the first cycle of treatment, one dose (1.69 packets on average) of the
2.5%
imiquimod formulation is applied to her full face once per day for 21 days;
during the
next 21 days, treatment is suspended; during the second cycle of treatment,
treatment is
carried out identical to the treatment that is used during the first cycle. At
the end of the
second cycle, the 65 year old white female is monitored for an additional 8
weeks.
During the entire 17 weeks, the 65 year old white female is monitored for
total or partial
clearance, local skin reactions, including erythema, and adverse events at (a)
baseline,
(b) week 3, (c) week 9, and (d) week 17.
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[0533] In still referring to FIG. 48, at baseline before therapy, there is an
AK lesion
count of 7 and a local skin reaction (erythema) score of 1. At week 3, the AK
lesion
count is 1, but the local skin reaction erythema score remains at 1. At week
9, both the
AK lesion count and the local skin reaction erythema score are reduced to 0.
At week
17, the AK lesion count remains at 0 (complete clearance) and the local skin
reaction
erythema score remains at 0, i.e., below normal or baseline score. All adverse
events
that are recorded are unrelated.
[0534] Thus, this clinical case as summarized in FIG. 48, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that complete clearance is achieved with a 2.5% imiquimod
formulation of
Example 23 when applied to the full face of a subject diagnosed with actinic
keratosis
following a 2 cycle, 3 x 3 x 3 weeks, treatment regimen. This Example 28, as
described
in FIG. 48, also demonstrates the unique bimodal or camelback pattern as to
the local
skin reaction score for erythema during the 2 cycle, 3 x 3 x 3 week, treatment
regimen,
which is generated when following the short durations of therapy in accordance
with the
present invention.
[0535] According to the clinical case summarized in FIG. 49, a 79 year old
white male
has an AK lesion count of 14 on his face at treatment initiation. Consistent
with the
present invention, the full face is treated daily with a single dose of a
3.75% imiquimod
formulation of Example 23. The 3.75% imiquimod formulation is packaged in
individual
packets in an amount of 250 mg/packet. The number of average packets that are
used
by this 79 year old white male for each individual daily dose is 1.14 packets.
During the
two-cycle, 3 x 3 x 3 week, treatment period, this 79 year old white male
neither misses a
dose nor takes a rest period.
[0536] Referring now to FIG. 49, the 79 year old white male is treated as
follows:
during the first cycle of treatment, one dose (1.14 packets on average) of the
3.75%
imiquimod formulation is applied to his full face once per day for 21 days;
during the next
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21 days, treatment is suspended; during the second cycle of treatment,
treatment is
carried out identical to the treatment that is used during the first cycle. At
the end of the
second cycle, the 79 year old white male is monitored for an additional 8
weeks. During
the entire 17 weeks, the 79 year old white male is monitored for total or
partial
clearance, local skin reactions, including erythema, and adverse events at (a)
baseline,
(b) week 3, (c) week 9 and (d] week 17.
[0537] In still referring to FIG. 49, at baseline before therapy, there is an
AK lesion
count of 14 and a local skin reaction (erythema) score of 1. At week 3, the AK
lesion
count is up to 16, and the local skin reaction erythema score is increased to
3. At week
9, however, the AK lesion count falls to 6 and local skin reaction erythema
score is
reduced to 2. At week 17, the AK lesion count is 0 (total or complete
clearance) and the
local skin reaction erythema score falls to 0, below normal or baseline. No
adverse
events are reported.
[0538] Thus, this clinical case as summarized in FIG. 49, demonstrates
efficacy
without treatment limiting local skin reactions or adverse events and further
demonstrates that total or complete clearance is achieved with a 3.75%
imiquimod
formulation of Example 23 when applied to the full face of a subject diagnosed
with
actinic keratosis following a 2 cycle, 3 x 3 x 3 week, treatment regimen. This
Example
28, as described in FIG. 49, also demonstrates the unique bimodal or camelback
pattern
as to the local skin reaction score for erythema during the 2 cycle, 3 x 3 x 3
weeks,
treatment regimen, which is generated when following the short durations of
therapy in
accordance with the present invention.
[0539] According to the clinical case summarized in FIG. 50, a 78 year old
white male
has an AK lesion count of 8 on his balding scalp at treatment initiation.
Consistent with
the present invention, the entire balding scalp is treated daily with a single
dose of a
3.75% imiquimod formulation of Example 23. The 3.75% imiquimod formulation is
packaged in individual packets in an amount of 250 mg/packet. The number of
average
packets that are used by this 78 year old white male for each individual daily
dose is 2.0
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packets. During the two-cycle, 3 x 3 x 3 weeks, treatment period, this 78 year
old white
male neither misses a dose nor takes a rest period.
[0540] Referring now to FIG. 50, the 78 year old white male, is treated as
follows:
during the first cycle of treatment, one dose (2.0 packets on average) of the
3.75%
imiquimod formulation is applied to his full balding scalp once per day for 21
days;
during the next 21 days, treatment is suspended; during the second cycle of
treatment,
treatment is carried out identical to the treatment that is used during the
first cycle. At
the end of the second cycle, the 78 year old white male is monitored for an
additional 8
weeks. During the entire 17 weeks, the 78 year old white male is monitored for
total or
partial clearance, local skin reactions, including erythema, and adverse
events at (a)
baseline, (b) week 3, (c) week 9, and (d) week 17.
[0541] In still referring to FIG. 50, at baseline before therapy, there is an
AK lesion
count of 8 and a local skin reaction (erythema) score of 1. At week 3, the AK
lesion
count is IND, but there is a local skin reaction erythema score of 3. At week
9, the AK
lesion count is up to 2, but the local skin reaction erythema score is reduced
to 1. At
week 17, both the AK lesion count and the local skin reaction erythema score
are at 0.
All adverse events that incur are recorded as unrelated to treatment.
[0542] Thus, this clinical case as summarized in FIG. 50, further demonstrates
efficacy without treatment limiting local skin reactions or adverse events and
further
demonstrates that complete clearance is achieved with a 3.75% imiquimod
formulation
of Example 23 when applied to the full balding scalp of a subject diagnosed
with actinic
keratosis following a 2 cycle, 3 x 3 x 3 weeks, treatment regimen. This
Example 28, as
described in FIG. 50, is another example of the unique bimodal or camelback
pattern as
to the local skin reaction score for erythema during the 2 cycle, 3 x 3 x 3,
treatment
regimen, which is generated when following the short durations of therapy in
accordance
with the present invention. In Example 23 herein above, formulations 126 and
182,
wherein the fatty acid is isa, are the formulations that are used in Examples
24-28 and
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in FIGS. 1-54 discussed and described herein above. In addition, isa
formulations 126
and 182 pass the PET tests when stored at about 40 C for about 3 months.
[0543] In case of conflict, the present specification, including definitions,
shall control.
Various modifications and alterations to this invention will become apparent
to those
skilled in the art without departing from the scope and spirit of this
invention. Illustrative
embodiments and examples are provided as examples only and are not intended to
limit
the scope of the present invention. The scope of the invention is limited only
by the
claims set forth as follows.
235
