Note: Descriptions are shown in the official language in which they were submitted.
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-1-
8oivent Byst~m !or Enhanaod poaotration of Pharmaa~utiaal
Compounds
Field of the Invention
This invention relates to pharmaceutical
compositions whose penetration is capable of being
i0 enhanced. This includes, but is not limited to, topical
compositions for the treatment of skin disorders wherein
the topically active pharmaceutical compound or drug is
normally a relatively insoluble (or "poorly soluble'')
weak acid or weak base, however, the drug may also be a
soluble compound whose delivery characteristics can be
altered. More specifically, this invention concerns the
solubilizing capabilities of a buffered solvent system
which makes it possible to significantly alter the dermal
penetration of pharmaceutical compounds or drugs.
2o Background of the Tnvention
Seborrheic dermatitis is a skin disorder
characterized by an abnormal increase in the
proliferation of epidenaal cells. This increase in skin
cell production causes the formation of lesions on the
surface of the skin. Though treatments vary, the use of
imidazole antifungals is of particular interest to the
present invention.
While its true cause is still a topic of debate, it
has been suggested that seborrheic dermatitis can be
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-2-
caused by a fungal infection, which is why imidazole
antifungals are so effective in its treatment. Ford et
a1. in British Journal of Dermatology vol. 107, 691-695
(1982) describe ketoconazole as fungicidal against
Pityrosporum ovale (Pityrosporum orbiculare or Malassezia
to furfur), an important etiologic factor in seborrheic
dermatitis. U.S. Pat. No. 4,942,162 discusses the use of
imidazole antifungals, specifically ketoconazole and
clotrimazole, for the treatment of psoriasis and
seborrheic dermatitis.
This treatment can come in one of two forms - oral
and topical. U.S. Pat. No. 4,491,588 describes the use
of ketoconazole and metronidazole for the treatment of
seborrheic dermatitis in a composition formulated for
oral administration. However, European Pat. Application
2o No. 396,184 states that by topically applying
ketoconazole for the treatment of dermatologic
conditions, its efficacy and safety are enhanced.
Furthermore, according to U.S. Pat. No. 4,446,145, it is
best to avoid oral therapy for the treatment of skin
diseases whenever a topical alternative is available.
Imidazoles, though potent when used as the sole
active ingredient in a composition, can be combined with
other pharmaceutical actives. World Pat. Application No.
87/04617 describes the combination of urea and imidazole
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-3-
s derivatives in a composition for the treatment of various
skin disorders, however, urea causes temporary stinging
sensation on the surface of users' skin. U.S. Pat. No.
4,446,145 describes the combination of an imidazole with
benzoyl peroxide in compositions to be used specifically
1o for the treatment of acne. Similarly, U.S. Pat. No.
5,002,938 describes a stable gel formulation for the
topical administration of imid~azoles, wherein the
imidazoles are combined with a steroid, but seborrheic
dermatitis is a chronic relapsing disease, therefore,
~5 the safety of the topical steroid preparations over a
long period of time is questionable.
Another issue in the use of imidazoles is the
delivery system. U.S. Pat. No. 5,219,877 describes a
penetration enhancing gel for ithe topical administration
20 of imidazoles, using lauryl alcohol as the penetration
enhancer. The compositions de:scribed therein, however,
specifically call for the omis:aion of propylene glycol,
whose solubilizing capabilitie:~ are well known in the
art.
25 In fact, the combination of glycols with other
solvents is a highly effective means of enhancing dermal
penetration of actives. U.K. ~?at. Application No.
2,202,743 utilizes the combination of propylene glycol
and ethanol as a dissolving intermediary for the topical
SUBSTITUTE SHEET (13ULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-4-
administration of miconazole nitrate and econazole
nitrate, but the composition described therein requires
the presence of urea to solubilize the active
ingredients. Similarly, Japanese Pat. No. 60-61518 uses
a lower alcohol-glycol system for the topical
1o administration of clotrimazole, but the composition
described therein also requires both a neutralizer and a
stabilizer.
The combination of a lower alcohol and a glycol is
well known in the art as a reliable liquid carrier
system. U.S. Pat. No. 4,994,491 uses this type of system
for the treatment of cancer with traps-retinoids. The
delivery capabilities of this combination are also
exploited in U.S. Pat. No. 4,244,948 for the topical
administration of acetylsalicylic acid, where the system
2o is described as a "onvenient vehicle."
This system is employed in many antifungal products
such as Exelderni made by Westwood-Squibb
Pharmaceuticals, Inc. (1% sulconazole nitrate), Monistat-
Derm~ available from Ortho Pharmaceutical Corporation (2%
miconazole nitrate) and Oxistat~ produced by Glaxo
Wellcome, Inc. (1% oxiconazole nitrate). Similarly, U.S.
Pat. No. 5,476,852 describes a 2% ketoconazole topical
gel formulation which includes both propylene glycol and
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
- s-
s ethanol. These products, however, require a high
concentration of imidazoles (about one to two percent) to
function properly. Another example is Nizoral~, a 2%
ketoconazole antifungal cream made by Janssen
Pharmaceutics, which contains a~ slightly different
1o solvent system. This product, while quite effective,
also requires a large percentage of ketoconazole.
It is therefore an objective of the present
invention to create a composition capable of delivering
the same therapeutic effect as current antifungal
is products at a significantly lower concentration of
antifungal active.
It is also an objective of the present invention to
create a solvent system which can be used to enhance the
delivery of relatively insohible pharmaceutical compounds
2o which are weak acids or weak bases.
It is yet another objective of the present invention
to create a solvent system which is capable of changing
the penetration characteristics of readily soluble
pharmaceutical compounds that are either acidic or basic.
2s ~umma~v of the Invention
The present invention includes a buffered solvent
system which is capable of changing the delivery
parameters of both soluble and poorly soluble topically
active pharmaceutical compounds or drugs. Surprisingly,
SUBSTITUTE SHEET (F~ULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
- 6-
the addition of this buffering component to a properly
balanced solvent system eliminates the need for excessive
amounts of the pharmaceutical compound in topical
compositions. In fact, a composition including this
system only requires a fractional amount of the
1o pharmaceutical compound necessary in products which lack
this system. This is truly important because it
addresses the problem of lack of clinical efficacy which
has plagued these topical compositions for so long.
The system comprises a volatile solvent component, a
nonvolatile solvent component and a buffer in addition to
the topically active pharmaceutical compound or drug.
Topical compositions of this nature generally contain
such optional ingredients as chelators, antioxidants,
preservatives, gelling agents and sunscreens as well as
others commonly used in the art.
Brief Description of the Drawincts
The present invention will become more readily
apparent from the information in the following figures,
which illustrate several characteristics of the preferred
embodiments.
Figure 1 is a graphical summary of the skin
permeability results from experimental Runs 1 through 4
in the formulation of ketocona~zole, propylene glycol,
ethanol and phosphate-citrate buffer.
SUBSTITUTE SHEET (RULE 26)
- CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
Figure 2 is a graphical summary of the skin
permeability results from experimental Run 6 in the
occluded formulations of ketoconazole.
Figure 3 is a graphical summary of the skin
permeability results from experimental Run 7 in the gel
formulations of ketoconazole under both occluded and
nonoccluded conditions.
Detailed Describtion of the Invention
The present invention is embodied in a topical
composition comprising:
a) a topically active pharmaceutical compound
or drug, and
b) a buffered solvent system comprising:
i) a volatile solvent component,
ii) a nonvolatile solvent component, and
2o iii) a buffer.
The topically active pharmaceutical compound or drug
used in the compositions of this invention may be chosen
from two categories: soluble and poorly soluble. Poorly
soluble compounds may be further categorized as weak
acids and weak bases.
Weak bases include such compounds as imidazoles,
triazoles, steroidal anti-inflammatory agents, other
antifungal drugs and the like.
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/LJS98/04033
_g_
The preferred imidazoles and triazoles include, but
are not limited to, ketoconazole, miconazole, econazole,
itraconazole, terconazole, saperconazole, fluconazole,
metronidazole, clotrimazole, butoconazole, oxiconazole,
sulfaconazole, sulconazole and their derivatives. The
1o most preferred pharmaceutical compound selected from this
group is ketoconazole. As elucidated in the Examples to
follow, the imidazoles and triazoles are preferably in an
amount of from about 0% (w/v) to about 1% (w/v) and more
preferably from about 0.1% (w/v) to about 0.3% (w/v).
Suitable steroidal anti-inflammatory agents may
include, although are not limited to, corticosteroids
such as hydrocortisone, dexamethasone,
hydroxyltriamcinolone, alpha-methyl dexamethasone,
dexamethasone sodium phosphate, beclomethasone
2o dipropionate, clobetasol valerate, desonide,
desoxymethasone, desoxycorticosterone acetate,
dichlorisone, diflorasone diacetate, diflucortolone
valerate, flurandrenolone, fluclorolone acetonide,
fludrocortisone, flumethasone pivalate, fluocinolone
acetonide, fluocinonide, fluocortin butyl ester,
fluocortolone, fiuprednidene (fluprednylidene) acetate,
halcinonide, hydrocortisone acetate, hydrocortisone
butyrate, methylprednisolone, triamcinolone acetonide,
cortisone, cortodoxone, flucetonide, fludrocortisone,
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-9-
difluorosone diacetate, flurandrenolone acetonide,
medrysone, amciafel, amcinafide, betamethasone and the
balance of its esters, chloroprednisone, chloroprednisone
acetate, clocortolone, clescinolone, dichlorisone,
difluprednate, flucloronide, flunisolide,
1o fluorometholone, fluperolone, fluprednisolone,
hydrocortisone valerate, hydrocortisone
cyclopentylpropionate, hydroco:rtamate, meprednisone,
paramethasone, prednisolone, p:rednisone, beclomethasone
dipropionate, betamethasone di~propionate, triamcinolone,
and mixtures thereof may be used. The preferred
steroidal anti-inflammatory agents are dexamethasone and
its derivatives, while dexamethasone sodium phosphate is
most preferred. The steroidal anti-inflammatory agents
are preferably present in an amount of from about 0%
(w/v) to about 5% (w/v).
Other antifungal drugs can be chosen from the group
consisting of morpholine and iia derivatives and
terbinafine and its derivative:a. Preferred
pharmaceutical compounds are anaorolfine and its
derivatives, while amorolfine hydrochloride is most
preferred. These antifungal drugs are preferably present
in an amount of from about 0% (w/v) to about 5% (w/v).
Weakly acidic compounds uaeful in the compositions
of this invention may be selected from the group
SUBSTITUTE SHEET (i;ULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-10-
consisting of non-steroidal anti-inflammatory agents
(NSAID's). These include, but are not limited to,
oxicams, salicylates, acetic acid derivatives, fenamates,
propionic acid derivatives, pyrazoles and mixtures
thereof. Preferred examples of weak acids suitable for
io use in the present invention are salicylic acid,
ibuprofen and indomethacin though many other appropriate
weak acids exist. These weakly acidic compounds are
preferably present in an amount of from about 0.1% (w/v)
to about 10% (w/v).
Soluble pharmaceutical compounds or drugs can be
either acidic or basic, wherein the buffered solvent
system changes the permeability parameters of these
compounds to enhance their delivery characteristics and
efficacy. Soluble pharmaceutical compounds include, for
2o example, alpha hydroxy acids. Preferred are alpha
hydroxy acids selected from the group consisting of alkyl
hydroxycarboxylic acids, aralkyl and aryl 2-
hydroxycarboxylic acids, polyhydroxy-carboxylic acids and
hydroxy-polycarboxylic acids. Most preferred are those
alpha hydroxy acids selected from the group consisting of
glycolic acid, lactic acid, malic acid, tartaric acid,
citric acid, their derivatives and mixtures thereof.
Preferably, the soluble pharmaceutical compounds are
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-11--
present in an amount of from about 4% (w/v) to about 15%
(w/v) .
The volatile solvent component of the buffered
solvent system may preferably include lower (C1-C6) alkyl
alcohols, lower alkyl glycols and lower glycol polymers.
1o More preferably, the volatile solvent is selected from
the group consisting of ethanol and isopropanol. Most
preferably, the volatile solvent is ethanol. The
volatile solvent component is 'thought to act as a
penetration enhancer, while also producing a cooling
effect on the skin as it evaporates. The amount of
volatile solvent in the system is determined by the
pharmaceutical compound being utilized, depending upon
the solubility and skin penetration of said topically
active pharmaceutical compound or drug. The criteria
2o which limit the range of the volatile solvent remain the
same, regardless of which pharmaceutical compound or drug
is used. Too little volatile :solvent in the system will
render the drug insoluble, while an excess of the
volatile solvent may cause irritation to the skin.
The nonvolatile solvent portion of the buffered
solvent system is selected from lower alkylene glycols
and lower glycol polymers. PrE:ferably, propylene glycol,
polyethylene glycol and polypropylene glycol may be used.
Most preferably, propylene glycol is used. The
SUBSTITUTE SHEET (IRULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-12-
nonvolatile solvent slows the evaporation of the volatile
solvent and reduces the vapor pressure of the buffered
solvent system. The amount of this nonvolatile solvent
component, as with the volatile solvent, is determined by
the pharmaceutical compound or drug being used. When too
io little of the nonvolatile solvent is in the sy6tem, the
pharmaceutical compound may crystallize due to
evaporation of volatile solvent, while an excess will
result in a lack of bioavailability due to poor release
of drug from solvent mixture.
The buffer component of the buffered solvent system
may be selected from any buffer commonly used in the art.
The purpose of the buffer component is to ensure that
the pharmaceutical compound or drug mostly remains in
unionized state. The choice of buffer is only limited by
2o its ability to adjust the pR of the system to be at least
about 0.5 units below the pKa of the pharmaceutical
compound when the pharmaceutical compound is a weak acid,
and at least about 0.5 units above the pKa of the
pharmaceutical compound when the pharmaceutical compound
is a weak base. Once again, the pharmaceutical compound
or drug being used dictates the type and amount of buffer
needed for the system to function properly. Some
preferable buffers include citrate, phosphate and borate
buffers and combinations thereof.
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/ITS98/04033
-13-
There are several optional ingredients which can be
added to the topical composition. These include, but are
not limited to, chelators, antioxidants, preservatives,
gelling agents, sunscreens, sunblocks, retinoids,
benzofuran derivatives, N-acetyl-L-cysteine and
1o derivatives thereof, skin protE:ctants and vitamins. The
preferred antioxidant is butylated hydroxytoluene (BHT),
though ascorbic acid and its ds:rivatives and vitamin E
and its derivatives are also among suitable agents that
may be employed as discussed in Remington~s
Pharmaceutical Sciences, Gennaro, A. R. (Editor}, 18th
edition 1990. Mack Publishing C:o., Easton, PA. pp. 1286 -
1288. which is hereby incorporated by reference.
Similarly, appropriate gelling agents can include, but
are not limited to, semisynthet:ic cellulose derivatives
2o and synthetic polymers. Preferably, the gelling agent is
hydroxypropylcellulose. The preservatives can be
selected from those common in the art as discussed in The
Theory and Practice of Industrial Pharmacy, Lachman, L.,
Lieberman, H. A., and Kanig, J. L. 3rd edition, 1986. Lea
& Febiger, Philadelphia, PA. pp. 467, 521 and 553, which
is also incorporated by reference, though the parabens,
especially methylparaben and propylparaben, are
preferred. Preferred chelators include EDTA and citric
acid, though EDTA is most preferred.
SUBSTtTUTE SHEET (E~ULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-14-
Suitable sunscreens may include, for example: p-
aminobenzoic acid {PABA), its salts and its derivatives,
anthranilates, salicylates, cinnamic acid derivatives,
dihydroxycinnamic acid derivatives, trihydroxycinnamic
acid derivatives, hydrocarbons, dibenzalacetone and
io benzalacetophenone, naphthol-sulfonates (sodium salts of
2-naphthol-3, 6-disulfonic and of 2-naphthol-6, 8-
disulfonic acids), dihydroxynaphthoic acid and its salts,
o- and p- hydroxybiphenyldisulfonates, coumarin
derivatives, quinine salts, quinoline and its
derivatives, uric and vilouric acids, tannic acid and its
derivatives, hydroquinone, benzophenones and the hydroxy-
or methoxy- substituted benzophenones, 4-
isopropyldibenzoylmethane, butylmethoxydibenzoylmethane
and etocrylene. Most preferred sunscreens useful in the
2o compositions of the present invention are 2-ethylhexyl-p-
methoxycinnamate, butylmethoxydibenzoylmethane, 2-
hydroxy-4-methoxybenzophenone, octyldimethyl-p-
aminobenzoic acid and mixtures thereof.
The key to the present invention, however, is the
ratio of volatile solvent to nonvolatile solvent to
buffer in the buffered solvent system. As evidenced by
the Examples to follow, when this system is used in
combination with ketoconazole as the topically active
pharmaceutical compound, the preferred ratio of
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-15-
ingredients is about 5% to about 15% of the nonvolatile
solvent, from about 40% to about 45% of the volatile
solvent and from about 45% to about 50% of the buffer.
The requisite concentration of ketoconazole is only about
0.3% when this system is utili.:ed, compared with values
1o seven times that much in commercial compositions which
lack this system.
The ratio of the components in the buffered solvent
system depends upon the solubility characteristics of the
pharmaceutical compound or drug under consideration. The
~s composition may take the form of a solution, gel, lotion,
cream, ointment, and the like. Following are several
examples which are meant to illustrate possible
embodiments of the present invention.
SUBSTfTUTE SHEET (MULE 26j
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-16-
EXAMPLE 1
Topical Formulation of 0.3% Retoconazole Solution and Gel
Chemically, ketoconazole is (t) cis-1-acetyl-4-[4-
[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-
dioxolan-4-yl]methoxy]phenyl]piperazine and has the
1o following structural formula:
A 0.3% ketoconazole gel was made by first preparing
a 0.1 ~ pH 6.00 phosphate-citrate buffer. Disodium EDTA
was dissolved into the buffer. Methylparaben,
2o propylparaben, BHT and ketoconazole were dissolved in
ethanol. Propylene glycol was then added to the ethanol
solution and mixed well. The buffer containing EDTA was
then added. Hydroxypropylcellulose (Klucel HF) was
slowly added to the solution while stirring. The gel was
allowed to hydrate for 24 hours and the final pH was
adjusted to 7.00 using 1M HC1.
EXAMPLE 2
0.3% Retoconazole Compositions
SUBSTITUTE SHEET (RULE 2G)
CA 02285368 1999-09-29
WO 98!43673 PCT/US98/04033
_l~_.
Thirteen solutions of 0.3% ketoconazole were
prepared in varying proportions of propylene glycol,
ethanol and buffer solution. 'the compositions are
outlined in Table 1 below.
Table 1: Solvent Compositions
Composition Propylene Ethanol (ml) Buffer (ml) pH
Glycol
(ml)
A 60 20 20 - water8.88
B 40 40 20 - water8.36
C 20 60 20 - water7.89
D 20 40 40
6.00
E 20 40 40 7.00
F 20 40 40 8.00
G 20 60 20 7.00
H 10 60 30 7.00
I 30 30 40 7.00
J 5 45 50 7.00
K 5 55 40 7.00
L O.O1M HCl ;solution 4.00
M 15 40 45 7.00
In compositions A, B and C, the aqueous phase was
water, without a buffer, while in all of the other
compositions (with the exception of composition L) the
buffer was a phosphate-citrate buffer system. In
composition L, hydrochloric acid was used as the solvent
system.
EXAMPLE 3
Permeation Studies of 0.3% Retoconazole Compositions
Permeability of ketoconazole from solutions A
2e through M as defined in Example 2 was studied across
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT1US98/04033
-18-
s human cadaver skin using Franz diffusion cells. The
Franz diffusion cell consisted of an upper donor cell and
a lower receiver cell, wherein the skin was placed
between them. The donor cell was an open cap, allowing
access to the epidermis for dosing or other purposes.
io The test material/formulation was placed on the epidermal
surface in the donor cell. The donor cell was left open
to the atmosphere under nonoccluded conditions, and
tightly sealed under occluded conditions. The donor and
receiver cells were held together with a clamp. The
15 capacity of the receiver cell was 10 ml, and the cross-
sectional area of the cells in contact with the skin was
0.6362 cm2 (0.9 cm diameter). A thermal jacket was
positioned around the receiver chamber and was heated
with an external circulating water bath. A Teflon coated
2o stirring bar was placed in the receiver chamber and an
isotonic phosphate-citrate buffer of pH 5.00 was used as
a receptor solution to fill this chamber. During the
course of an experiment, small volumes of the receptor
solution were drawn from the chamber for analysis and
25 replaced to keep the volume of the solution constant.
Three diffusion cells were used to evaluate each
solvent composition and the cells were occluded (except
where stated otherwise). At the end of a 48 hour
experimental run, the skins were separated into epidermis
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
_lg_.
and dermis, extracted with 10 ml of methanol and assayed
for ketoconazole content. The permeability results are
set forth in Table 2.
Table 2: Permeability Results for Compositions A Through
M
to (values normalized to 1% ketoconazole
strength)
Solvent CompositionpH Amount Amount Amount in
in
(PG:Ethanol:Aq Permeated Epidermi s (fig)Der~s (fig)
Phase) up to
36 hours (fig)
A (60:20:20 H2~) 8.88 11.13 8.07 t 6.60 1.83 t 1.87
B (90:90:20 H2~) 8.36 2.0:! 6.13 t 1.23 3.17 t 1.40
C (20:60:20 Hz0) 7.89 5.0:1 23.03 t 25.73 7.00 t 8.53
D (20:90:90 Buffer)6.00 22.63 15.07 t I.33 8.67 t 3.60
E (20:40:40 Buffer)7.00 29.87 22.53 t 3.87 12.10 t 3.97
F (20:40:40 Buffer)8.00 21.53 16.53 t 8.13 8.83 t 4.27
G (20:60:20 Buffer)7.00 39.27 47,67 t 40.90 25.13 t
13.87
H (10:60:30 Buffer)7.00 136.E~0 89.80 t 31.37 48.27 t
20.97
I (30:30:90 Buffer)7.00 41.9D 60.97 t 41.97 25.20 t
19.83
J (5:95:50 Buffer)7.00 133.97 219.27t 90.67*55.10 t
20.90
K (5:55:40 Buffer)7.00 193.6.0 353.93t 121.13*38.73 t 1.97
I. (O.OIM HC1) 9.00 64.7'7 339.97t 106.73*27.30 t
18.33
J Gel - Nonoccluded7.00 5.23 32.63 t 10.37 11.37 t 1.30
(5:95:50 Buffer)
M Gel - Nonoccluded7.00 2.83 24.73 t 2.00 8.30 t 1.27
(15:90:95 Buffer)
2% Nizoralm cream 7.60 0.97 15.91 t 9.85 1.98 t 1.02
Nonoccluded -
7.75
J Gel - Occluded 7.00 96.4:3 83.47 t 9.10 91.7? t
10.90
J Gel - Nonoccluded7.00 3.17 q7,87 t 17.97 5.37 t 2.07
M Gel - Occluded 7.00 9.80 53.37 t 13.60 18.90 t 9.00
M Gel - Nonoccluded7.00 2.03 29.70 t 4.13 2.83 t 1.10
* The epidermal blotting technique is not consistent with the
previous runs. The drug levels in th.e dermis seem to be reasonable.
In experimental Run 1 (compositions A, B and C),
solutions of ketoconazole were prepared in varying
proportions of propylene glycol., ethanol and water. In
experimental Run 2 (compositior,~s D,' E and F) , the final
SUBSTITUTE SHEET (i;ULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-20-
pH of the ketoconazole buffered solutions was adjusted to
6.00, 7.00 or 8.00 using 1 M HC1. In experimental Run 3
(compositions G, H and I), the pH of maximum permeability
and retention in the skin layers (pH 7.00) was selected
from Run 2, and propylene glycol, ethanol and buffer
1o compositions were varied. In experimental Run 4
(compositions J, K and L), propylene glycol composition
was fixed at 5%, and ethanol and pH 7.00 buffer
compositions were varied in compositions J and K. The
permeability of ketoconazole from compositions J and K
was compared with the permeability of ketoconazole in
hydrochloric acid (composition L) described in U.S. Pat.
No. 4,569,935. The pH of the drug solution L was 4.00.
Based upon the results from Runs 1 to 4, solvent
compositions J, H and K had maximum permeabilities and
2o retention in the skin. This is shown in Figure 1, a
graph of the cumulative amount of ketoconazole which
permeated the skin over time. After 48 hours,
compositions J, H and K had more than twice the
permeability of other compositions.
Since a high amount of alcohol in the formulation
can irritate the sensitive skin of patients with
seborrheic dermatitis, compositions J and M , which had
lesser amounts of alcohol were preferred. Other solvent
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/ilS98/04033
-21--
compositions with less ethanol were tried, but 0.3%
ketoconazole formed suspensions in those compositions.
Table 3: Compositions in which 0.3% Ketoconazole Formed
Suspensions
Composition Propylene Glycol Ethanol !ml) pH 7.00 Buffer
!ml) (ml)
I 5 40 55
II 10 30 60
III* 10 40 50
IV 15 30 55
* partially soluble
to As described in Table 3, ~0.3% ketoconazole forms a
solution only in certain proportions of solvent mixture.
To make a 0.3% ketoconazole solution, either the ethanol
content should be greater than 40% or the propylene
glycol content should be great~ar than 10%, wherein the
buffer makes up the rest of then composition. Within this
range of concentrations, the composition functions with
minimal irritation and acceptable levels of
bioavailability while being ph~rsically stable.
EXAMPLE 4
2o Preparation of Ketoconaz;ole Gel Compositions
Solvent compositions J anct M were modified with the
addition of a chelating agent, an antioxidant and
preservatives to prepare gels. They were prepared by
first dissolving HHT, methylparaben and propylparaben in
ethanol, and then adding propy7.ene glycol and phosphate-
citrate buffer containing disoclium EDTA. These solutions
were then gelled with 2% w/v of hydroxypropylcellulose
SUBSTITUTE SHEET (RULE 26)
_ CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-22-
(high viscosity grade) and adjusted to pH 7.00, the pH of
maximum skin penetration and retention, which is also the
pH of maximum chemical stability for ketoconazole.
Table 4: Solvent Compositions J and M - Modified to
Prepare Gels
Ethanol 45 ml 40 ml
0.1 ~. pH 6.00 Phosphate- 50 ml 45 ml
Citrate Buffer (with 0.05%
w/v disodium EDTA)
BHT 50 mg 50 mg
Methylparaben 200 mg 200 mg
Propvlparaben 20 ma 20 ma
l0
In experimental Run 6, ketoconazole gels of
formulations J and M were compared with the permeability
of ketoconazole from 200 mg of Nizoral~ cream under
nonoccluded conditions. In experimental Run 7,
ketoconazole gels J and M were studied for permeability
across the human cadaver skin under both occluded and
nonoccluded conditions. The data from experimental Run 5
is not analyzed as the skin samples used to test
permeability were found to be defective. As shown in
2o Figure 2, Run 5 compared occluded compositions of
Nizoral, J, K and M.
Figure 3 is a graph of Run 7 depicting the
cumulative amount of ketoconazole which permeated the
skin over time. Under occluded conditions, Gel J had
somewhat better permeation abilities than Gel M. Under
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-23~-
nonoccluded conditions, however, the two gel formulations
behaved similarly.
The unbuffered drug solutions shown in Run 1
(natural pH 7.89 to 8.88), with water as one of the
components, had lower permeabilities and lower amounts of
to drug in the skin than the compositions of Gels J and M.
The same is true for ketoconazole in the O.O1M
hydrochloric acid solution (Composition L) which was less
permeable and less retained in the dermis than from the
propylene glycol, ethanol and ;pH 7.00 buffer solvent
15 mixtures.
Permeability and retention of ketoconazole in the
skin layers increased with decreased percentage of
propylene glycol in the solvenvt. This could have been
due to poor release of ketoconazole from higher propylene
2o glycol proportions. Compositions H, J and K with 5 to
10% propylene glycol had maximum permeability and skin
retention suggesting that the buffered solvent system had
reached its maximum thermodynamic activity for
ketoconazole.
25 Permeability results from Runs 6 and 7 indicate that
the occluded cells have higher permeabilities and higher
drug levels in the skin than the nonoccluded cells. The
ketoconazole levels in receiver cells and skin layers for
J and M gels in nonoccluded ce7.ls are comparable to those
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-24-
of Nizoral~ cream even though, the gels had only 1/7 of
the ketoconazole strength of Nizoral~ cream. These
levels will be higher in seborrheic dermatitic skin which
is more permeable than normal skin.
EXAMPLE 5
to Thermal Stability Analysis of 0.3% Retoconazole
Compositions
An accelerated thermal stability analysis was
performed on gel formulations J and M at 30°C (sampling
time 16 weeks), 40°C (sampling times 8 and 16 weeks), and
50°C (sampling times 4, 8, 13 and 16 weeks). The samples
were filled into glass vials and placed at appropriate
temperatures. The data in Table 5 indicates that the
drug is highly stable in both the formulations. Less
than 5% degraded in 16 week samples stored at 50°C. A
2o slight pink color was observed in 13 and 16 week samples
studied at 50°C.
Table 5: Stability Results of 0.3% Ketoconazole Gel
Formulations at 7.00 (Percentage Remaining)
pH
Comp. Initial4 wks 8 wks 13 wks 16 wks
50C 40C 50C 50C 30C 40C 50C
J 100 97.08 98.51 9?.08 97.09 99.65 98.44 95.77
M 100 97.70 98.67 96.86 97.79 99.77 98.61 97.09
EXAMPLE 6
Solubility of Non-Steroidal Anti-Inflammatory Drugs
(NSAID ~ s)
SUBSTITUTE SHEET (RULE 26)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-25-
Salicylic acid, ibuprofen and indomethacin are all
poorly soluble in water. While their solubilities axe
better in pure ethanol [37% (w/vj, 100% (w/v) and 2.0%
(w/v) respectively], the problems of dermal irritation
described earlier become an is>>ue. When placed in two
to extreme buffered solvent systems of propylene glycol,
ethanol and 0.1 ~ phosphate-cii=rate buffer of pH 6.00,
their solubilities are as outlined in Table 6.
Table 6: Solubilities of NSAII)'s
NSAID Solubility in 10:80:10Solubility in 80:10:10
(PG:Ethanol:Buf:Eer) (PG:Ethanol:Buffer)
Salicylic acid 35$ w%v 20$ w/v
Ibuprofen 70$ w/v 20~ w/v
Indomethacin 1.5~ w/v 1.0~ w/v
15 The ibuprofen was supplied by Spectrum Chemical Mfg.
Corp., Gardena, CA. The indomethacin was supplied by
Sigma Chemical Co., St. Louis, MO and the salicylic acid
was supplied by Sigma Chemical Co., St. Louis, MO.
EXAMPLIE 7
2o Solubility of Steroidal Anti-Inflammatory Drugs
Hydrocortisone solubility is 1.27% (w/v) in
propylene glycol, 2.50% (w/v) i.n ethanol and 0.028% (w/v)
in water. Betamethasone dipropionate is sparingly
soluble in ethanol (1 gram dissolves in 30 to 100 ml),
25 and practically insoluble in water (1 gram dissolves in
more than 10,000 ml). The solubility of two steroidal
anti-inflammatory drugs was studied in two extreme
SU6STITUTE SHEET (i3U~E 26j
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
-2 6-
buffered solvent systems of propylene glycol, ethanol and
0.1 ~ phosphate-citrate buffer of pH 6.00 in the
compositions outlined in Table 7.
Table 7: Solubilities of Steroidal Anti-Inflammatory
Druas
Anti-Inflammatory Solubility in 10:80:10 Solubility in
Drug (PG:Ethanol:Buffer) 80:10:10
(PG:Ethanol:Buffer)
Hydrocortisone 2.5~ w/v 1.5~ w/v
Betamethasone 3.0$ w/v 0.75 w/v
dipropionate
Both the hydrocortisone and betamethasone
dipropionate were supplied by Spectrum Chemical Mfg.
Corp., Gardena, CA.
EXAMPLE 8
Solubility of Amorolfine
Amorolfine is a morpholine derivative applied
topically as the hydrochloride salt in the treatment of
fungal nail and skin infections. A 0.25% cream is
applied once a day to treat skin infections, including
2o various forms of tinea. For the treatment of nail
infections caused by dermatophytes, yeasts and molds, a
lacquer containing the equivalent of 5% amorolfine is
painted onto the affected nail once or sometimes twice a
week until the nail has regenerated. Amorolf ine base is
poorly soluble, though its hydrochloride salt should be
soluble to an extent of greater than 5% in water and
ethanol based upon its chemical structure.
SUBSTITUTE SHEET (RULE 2fi)
CA 02285368 1999-09-29
WO 98/43673 PCT/US98/04033
EXAMPLE 9
Solubility of Alp~~a Hydroxy Acids
Alpha hydroxy acids (AHAs) are highly soluble in
aqueous solutions throughout the pH range. Their
solubility was studied in two extreme solvent
to compositions, propylene glycol : ethanol . 0.1 ~
phosphate-citrate buffer of pH 6.00 at 10:80:10 and
80:10:10. The approximate solubilities are given in
Table 8.
Table 8: Approximate Solubilities AHA's
of
Alpha Hydroxy Solubility in Solubility in
Acid 10:80:1() 80:10:10
(PG:Ethanol:Buffer) (PG:Ethanol:Buffer)
Glycolic acid > 20% w/v 18% w/v
Lactic acid > 20% w/v >20% w/v
Malic acid 19% w/v 10% w/v
Tartaric acid 10% w/v 8% w/v
Citric acid 16% w/v-- 10% w/v
While the present invention has been illustrated by
several examples of possible embodiments, it should be
understood that these are not :limiting.
SUBSTITUTE SHEET (RULE 26)
