Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS AND METHODS FOR TREATING
DERMATOLOGICAL CONDITIONS
FIELD OF THE INVENTION
The present invention relates generally to systems and methods for
treating various dermatological conditions. More particularly, the present
invention .relates to solidifying adhesive formulations having a viscosity
suitable
for application to skin areas afflicted with a dermatological condition, and
which
form a sustained drug-delivering solidified adhesive layer on the skin.
BACKGROUND OF THE INVENTION
Skin or dermatological conditions affect millions of people across the
world. Such conditions include infections from fungal, bacterial, and viral
sources, alopecia, photo or sun damaged skin, dermatitis, and psoriasis.
Treatments are generally available for each of these treatments, but current
treatments have some pronounced drawbacks. For example, one type of viral
infection is a herpes infection. Herpes infections often occur on lips, e.g.
cold
-
sores, and on the genitals. there are two common dosage forms available for
treating cold sores and genital herpes, namely topical and oral. Both delivery
forms have certain drawbacks. For example, 'oral delivery of acyclovir, an
anti-
viral drug, can cause undesirable side effects such as upset stomach, loss of
appetite, nausea, vomiting, diarrhea, headache,..dizziness, or Weakness. One
drawback of current topical anti-cold sore formulations, in the form of
ointments
and creams such as Zovirax ointment and cream, is that they are often
inadvertently wiped off from the treatment site when the subject eats, drinks,
or
licks his/her lips, etc. This is believed to be a reason why topical cold sore
formulations often need to be applied many times a day, which is very
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inconvenient and frequently results in poor patient compliance: When a topical
.
. anti-herpes formulation is applied on the genitals, the drug is often
subject to
inadvertent removal by underwear and adjacent healthy skin/mucosal surface
'
contact. In addition, some topical=formulations usually contain volatile =
solvent(s), such as water and ethanol, which tend to evaporate shortly after
application. The complete evaporation of such solvents can cause a significant
decrease or even termination of dermal drug delivery, thereby prematurely =
ending treatment. Additionally, semisolid formulations.are often "rubbedinto"
the skin, which does not necessarily mean the drug formulation is actually =
delivered into the skin. Instead,-this phrase often means that a very thin
layer of
the drug formulation is applied onto the surface of the skin. Such thin layers
of
traditional topical semisolid formulations may not contain sufficient quantity
of
active drug to achieve sustained delivery over long periods of time.
Another example is photo damaged skin. It is believed that topical
application of immune activators.such as imiquimod can be used to treat photo
damages and.premature aging of the skin, which are characterized by fine
lines,
wrinkles, roughness, dryness, laxity, and/or irregular pigmentation. For
example, treatment of visible signs of photo aging with an imiquimod over
several weeks can improve the morphology and appearance of photo damaged
skin. However, the only commercially available dosage form of imiquimod,
Aldata Cream from 3M, was not designed or approved for treating photo .
damaged skin, i.e. it was approved for treating genital warts and basal cell=
= carcinoma: After the cream is applied on and rubbed "into" the skin, most
of the
drug does not really get into the skin. Instead, most of the drug stays on the
=
surface of the skin for a long duration during which it is subject to
unintentional
removal. For example, the cream applied on a subject's face and forehead
before bedtime can be removed by the pillow or blanket during the night.
Similar drawbacks can be found with many Of the available treatments for .
the other above mentioned dermatological conditions.
In view of the shortcomings of current dermal formulations for treating
dermatological disorders, it would be desirable to provide Systems,
formulations,
and/or methods that i) provide more sustained drug delivery over long periods
of
=
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3
=
time, ii) are not vulnerable to unintentional removal by contact with
clothing, iii)
provide a protective physical barrier that is beneficial in certain disease
treatment, and/or iv) are easily removed after application and use.
S SUMMARY OF THE INVENTION
It has been recognized that it would be advantageous to provide
'formulations and related methods for treating dermatological conditions which
are capable of providing sustained release of drug and do not suffer from the
drawback of unintentional removal. In accordance with this, the present
invention is drawn generally to a formulation for treating dermatolological
conditions, comprising a drug that is effective for treating a dermatological
condition, a.solvent vehicle, and a solidifying agent. The solvent vehicle can
comprise a volatile solvent system including at least one volatile solvent,
and a
non-volatile solvent system including at least one non-volatile solvent,
wherein
the non-volatile solvent system is capable of facilitating delivery of the
drug at
therapeutically effective rates over a sustained period of time. The
formulation
can have.a viscosity suitable for application and adhesion. to a skin surface
prior
to evaporation of the volatile solvent system. The formulation applied to the
skin
surface can form a soft, coherent; solidified layer after.at.least partial
evaporation of the volatile solvent system. Further, the drud.can continue to
be
delivered after the volatile solvent system is at least substantially
evaporated. ==
The dermatological conditions which can be treated include a bacterial
infection,
= a virus infection, a filingal infection, alopecia, dermatitis, psoriasis,
photo
=
damaged skin, and combinations thereof
In another embodiment, a method of treating dermatological conditions
can comprise applying a solidifying adhesive formulation to an infected skin
surface: The formulation can be a formulation as described in the previous
embodiment. Additional steps include solidifying the formulation to form a
soft,
coherent, solidified layer on the infected skin surface by at least partial
evaporation of the volatile solvent system, and dermally delivering .the drug
from
=
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4
the solidified layer to the infected skin site at therapeutically effective
rates over a sustained
period of time.
In another embodiment, the invention relates to a soft, coherent, solidified
layer for
treating dermatological conditions an infection can comprise a drug that is
effective for
treating the dermatological condition; a non-volatile solvent system including
at least one
non-volatile solvent, wherein the non-volatile solvent system facilitates the
delivery of the
drug at therapeutically effective rates over a sustained period of time; and a
solidifying
agent. The solidified layer can preferably be stretchable by 5% (or even 10%)
in one
direction without cracking, breaking, and/or separating from a skin surface to
which the layer
is applied.
According to one aspect, the invention relates to an adhesive solidifying
formulation
for treating a dermatological condition, comprising: a) a drug for treating a
dermatological
condition; b) a solvent vehicle, comprising: i) a volatile solvent system
including at least one
volatile solvent, and ii) a non-volatile solvent system including at least one
non-volatile
solvent, wherein the non-volatile solvent system is capable of facilitating
delivery of the drug
at a therapeutically effective rate over a sustained period of time; and c) a
solidifying agent.
In the above formulation, the weight ratio of the non-volatile solvent system
to the
solidifying agent is from about 0.5:1 to about 2:1, and the formulation has a
viscosity
suitable for application and adhesion to a skin surface prior to evaporation
of the volatile
solvent system. The formulation when applied to the skin surface forms a
solidified layer
after at least partial evaporation of the volatile solvent system, and the
drug continues to be
dermally delivered after the volatile solvent system is at least substantially
evaporated.
In the above formulation, water and liquids more volatile than water are is
considered to be volatile solvents.
According to another aspect, the invention relates to a use of an adhesive
solidifying
formulation as described herein for treating a dermatological condition.
Preferably, the use
is by (a) applying said formulation to a skin surface; (b) solidifying the
formulation to form a
soft, coherent, solidified, layer on the skin surface by at least partial
evaporation of the
volatile solvent system; and (c) dermally delivering the drug from the
solidified layer to the
infected skin site over a sustained period of time.
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4a
According to a further aspect, the invention relates to a soft, coherent
solidified layer
for treating a dermatological condition, comprising: a) a drug that is for
treating a
dermatological condition; b) a non-volatile solvent system including at least
one non-volatile
solvent, wherein the non-volatile solvent system facilitates the delivery of
the drug at a
therapeutically effective rate over a sustained period of time; and c) a
solidifying agent.
In the above product, the solidified layer is capable of adhering to a skin
surface to
which the layer is applied and wherein the weight ratio of the non-volatile
solvent system to
the solidifying agent is from about 0.5:1 to about 2:1.
Additional features and advantages of the invention will be apparent from the
following detailed description and figure which illustrate, by way of example,
features of the
invention.
BRIEF DESCRIPTION OF THE DRAWING
FIG. us a graphical representation of the cumulative amount of acyclovir
delivered
transdermally over time from two separate formulations in accordance with
embodiments of
the present invention compared to the marketed product Zovirax cream.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT(S)
Before particular embodiments of the present invention are disclosed and
described,
it is to be understood that this invention is not limited to the particular
process and materials
disclosed herein as such may vary to some degree. It is also to be understood
that the
terminology used herein is used for the purpose of describing particular
embodiments only
and is not intended to be limiting, as the scope of the present invention will
be defined only
by the appended claims and equivalents thereof.
In describing and claiming the present invention, the following terminology
will be
used.
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= 5
=
The singular forms "a," "an," and "the" include plural referents unless the
context clearly dictates otherwise. Thus, for example, reference to "a drug"
-
includes reference to one or more of such compositions.
"Skin" is defined to include human skin (intact, diseased, ulcerous, or =
broken), finger and toe nail surfaces, and mucosal surfaces that are usually
at
least partially exposed to air such as lips, genital and anal mucosa, and
nasal
and oral mucosa. =
The phrase "dermatological condition" refers to any Skin condition, or
= combination of skin conditions, including bacterial infection, viral
infection,
fungal infection, alopecia, psoriasis, dermatitis, or photo damaged skin.
When referring to skin that is "photo damaged," both acute photo
damage and chronic photo damage is included herein. Acute photo damage
can be manifest as a sunburn, and chronic photo damage can be seen as
gradual changes in the skin caused by an accumulation of sun exposure
throughout a period of months, but more typically years. Thus, photo damage
includes human skin having experienced photo damage of some type, which
can be manifest as premature aging, fine lines, wrinkles, roughness, dryness,
laxity, irregular pigmentation, pre-cancerous lesions and/or skin cancers.
Similarly, "skin damage" can be defined to include photo damage, premature
aging, fine lines, wrinkles, roughness, dryness, laxity, and/or irregular
pigmentation of the skin.
The term "drug(s)" refers to any bioactive agent or agents which can be
used to effectively treat dermatological conditions. For example when the
dermatological condition is a fungal infection antifungal drugs Can be used.
Examples of antifungal drugs which can be used in the present invention
Include, but are not limited.to, amorolfine, butenafine, naftifine,
terbinafine,
fluconazole, itraconazole, ketocOnazole, posaconazole, ravuconazole,
= voriconazole, clotrimazole, butoconazole , econazole, miconazole,
oxiconazole,
sulConazole, terconazole, tioconazole, caspofungin, micafungin, anidulafingin,
amphotericin B, AmB., nystatin, pimaricin, griseofulvin, ciclopirox olamine,
haloprogin, tolnaftate, and undecylenate, or combinations thereof.
=
=
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When the dermatological condition is a viral infection anti-viral drugs
including, but not limited to, acyclovir, penciclovir, fainciclovir,
valacyclovir,
behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox,
podophyllotoxin,ribavirin, abacavir, delavirdine, didanosine, efavirenz,
lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenavir,
indinavir,
nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir,
ribavirin, -
rimantadine,.zanamivir, or combinations thereof can be used.
When the dermatological condition is a bacterial infection, antibacterial
drugs Can be used include, but are not limited to,. erythromycin, clindamycin,
tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as
ciproflaxin, or combinations thereof: The active drug in the formulations and
methods of the present invention for treating skin infections can also include
=
immune modulating agents, including but is not limited to imiquimod
When the dermatological condition is photo damaged skin, drugs which
can be used include, but are not limited to immune modulating agents or
immune activators which are capable of increasing immunity of the human skin
mucosa. Non-limiting examples of such drugs include imiquimod, rOsiqUimod,
== or combinations thereof.
When the dermatological. condition is alopecia, generally any drug which
is capable of stimulating hair growth when dermally delivered can be. used.
This
. . includes compositions that are traditionally identified as drugs, as
well other
bioactive agents that are not always considered to be "drugs" in the classic
sense. Examples of drugs which can be used in the present invention include
corticosteroidS such as betamethasone dipropionate, halobetasol propionate,
diflorasone diacetate, triamcinolone acetonide, desoximethasone, fluoainonide,
halcinonide, mometasone furoate, betamethasone Valerate, fluocinonide,
fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide,
flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate,
alclometasone dipropionate, flu methasone pivolate, hydrocortisone, .
hydrocortisone acetate, and combinations thereof. Other drugs can also be
used. Other examples include drugs which can irritate the skin to stimulate
hair
growth such as minoxidil, spironolactone, finasteride, anthralin, tretinoin
topical
=
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immunotherapeutic agents such as dinitrochlorobenzene, squaric acid dibutyl
ester, diphenylcyclopropenone, other hair growth stimulants, or combinations
thereof.
When the dermatological condition is psoriasis or dermatitis, drugs which
can be used include, but are not limited to, agents selected from the drug
classes of corticosteroids, immune modulators, vitamin D3 and its analogs,
retinoic acids and their pharmaceutically active derivatives, or combinations
.
thereof. Specific non-limiting examples of such drugs include betamethasone
dipropidnate, clobetasol propionate, halobetasol propionate, diflorasone.
_ diacetate, amcinonide, desoximethasone, fluocinonide, halcinonide, -
mometasone furoate, betamethasone valerate, fluocinonide, fluticasone
propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide,
=
desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone
dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate,
' tacrolimus, pigrolimus, tazarotene, isotretinoin,.cyclosporin, anthralin,
vitamin
D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, or
combinations thereof.
= When referring generally to a "drug," it is understood that there are
various forms of a given drug, and those various forms are expressly included.
In accordance with this, variOus drug forms include polymorphs, salts,
hydrates, = .
" solvates, and cocrystals. This includes compositions that are traditionally
identified as drugs, as well other bioactive agents that are not always
considered to be "drugs" in the classic sense, but which can provide a
.
therapeutic effect for certain conditions. In one embodiment, a single agent
can
be effective in treating multiple dermatological conditions: In another -
embodiment, multiple drugs for treating a single dermatological condition can
be
concurrently present and delivered from the same solidified formulation. In
another embodiment, multiple. drugs targeting separate dermatological
conditions can be delivered from the same solidified formulation. =
. The term "emollient," "moisturizing agent," "moisturizer," and "humectant"
can be used interchangeably and refer to a substance capable of softening,
soothing, or enhancing a skin's ability to retain moisture in or on the
surface
=
=
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thereof. Non-limiting examples of such compounds include glycerol, propylene
glycol, dipropylenen glycol, butylene glycol, sorbitol, honey and honey
derivatives such as honeyquat, urea and urea derivatives such as hydroxyethyl
urea, ammonium lactate, sodium lactate, potassium lactate, pyroglutamic acid
and its salts, sodium malates, polydextrose, triacetin, mannitol, oxidised
polyethylene, isomalt, maltitol and maltitol syrup, lactitol, xylitol,
erythrit, and
combinations thereof.
. The phrases "topical delivery" or "topical delivery of drugs" shall mean
the delivery of a drug to a skin tissue, and subsequent absorption into the
skin
that may occur. .
The phrases "dermal drug delivery" or "dermal delivery of drug(s)" shall
include both transdermal and topical drug delivery, and includes the delivery
of
=
drug(s) to, through, or into the skin. "Transdermal delivery" of drug can be
targeted to skin tissues just under the skin, regional tissues or organs under
the
skin, systemic circulation, and/or. the central nervous system.
The term "flux" such as in the context of "dermal flux" or "transdermal
flux," respectively, refers to the quantity of the drug permeated into or
across
skin per unit area per unit time. A typical unit of flux is microgram per
Square
centimeter per hour. One way to measure flux is to place the formulation on a
.
known skin area of a human volunteer and measure how much drug can
permeate into or across skin.within certain time constraints. Various methods
(in vivo methods) might be used for the measurements as well. The method
described in Example 1 or other similar method (in vitro methods) can also be
=
used to measure flux. Although an in vitro method uses human epidermal
membrane obtained from a cadaver, or freshly separated skin tissue from
hairless Mice rather than measure drug flux across the skin using human
volunteers, it is generally accepted by those skilled in the art that results
from a
properly designed and executed in vitro test can be used to estimate or
predict
the results of an in vivo test with reasonable reliability. Therefore, "flux"
values
. referenced ih this patent application can mean that measured by either in
vivo or
in vitro methods. ==
=
=
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The term "flux-enabling" with respect to the non-volatile solvent system
(or solidified layer including the same) refers to a non-volatile solvent
system
(including one or more non-volatile solvents) selected or formulated
specifically
to be able to provide therapeutically effective flux for a particular drug(s).
For
topically or regionally delivered drugs, a flux enabling non-volatile solvent
system is defined as a non-volatile solvent system which, alone without the
help
of any other ingredients, is capable of delivering therapeutic effective
levels of
the drug across, onto or into the subject's skin when the non-volatile solvent
system is satUrated with the drug. For systemically targeted drugs, a flux
enabling non-volatile solvent system is a non-volatile solvent system that can
' provide therapeutically effective daily doses over 24 hours when the non-
volatile
solvent system is saturated with the, drug and is in full contact with the
subject's
= skin with no more than 500 cm2 contact area. In one embodiment, the
contact
area for the non-volatile solvent system is no more than 100 cm2. Testing
using
this saturated drug-in-solvent state can be used to measure the maximum flux-
generating ability of a non-volatile solvent system.' To determine flux, the
drug. .
. solvent mixture needs to be kept on the skin for a clinically
sufficient amount of
time. In reality, it may be difficult to keep a liquid solvent on the skin of
a human
volunteer for an extended period of time. Therefore, an alternative method to
determine whether a solvent system is "flux-enabling" is to measure the in
vitro
drug permeation across the hairless mouse skin or human cadaver skin using .
= the apparatus and method described in Example 1, This and similar methods
=
are commonly used by those'skilled in the art to evaluate permeability and =
feasibility of formulations. Alternatively, whether a non-volatile solvent
system is
flux-enabling can be tested on the skin of a live human subject with means to
. maintain the non-volatile solvent system with saturated drug on the skin,
and
such means may not be practical for a product. For example, the non-volatile
solvent System With saturated drug can 'be soaked into an absorbent fabric
material which is then applied on the skin and covered with a protective
membrane. Such a system is not practical as a pharmaceutical product, but is
appropriate for testing whether a non-volatile Solvent system. has the
intrinsic
. = ability to provide sufficient drug flux, or whether it is flux-
enabling.
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It is also noted that once the formulation forms a solidified layer, the
solidified layer can also be "flux enabling" for the drug while some of the
non-
volatile solvents remain in the solidified layer, even after the volatile
solvents
(including water) have been substantially evaporated.
5 The phrase "effective amount," "therapeutically effective amount,"
"therapeutically effective rate(s)," or the like, as it relates to a drug,
refers to
sufficient amounts or delivery rates of a drug which achieves any appreciable
level of therapeutic results in treating a condition for which the drug is
being
delivered. It is understood that "appreciable level of therapeutic results"
may or
10 may not meet any government agencies' efficacy standards for approving
the
commercialization of a product. It is understood that various biological
factors
may affect the ability of a substance to perform its intended task. Therefore,
an
"effective amount," "therapeutically effective amount," or "therapeutically
effective rate(s)" may be. dependent in some instances on such biological
factors to some degree. However, for each drug, there is usually a consensus
among those skilled in the art on the range of doses or fluxes that are
sufficient
in most subjects. Further, while the achievement of therapeutic effects may be
measured by a physician or other qualified medical personnel using evaluations
known in the art, it is recognized that individual variation and response to
= treatment may make the achievement of therapeutic effects a subjective -
decision. The determination of a therapeutically effective amount or delivery
rate IS well within the ordinary skill in the art of pharmaceutical sciences
and
medicine.
= "Therapeutically effective flux" is defined as the permeation flux of the
selected drug that delivers sufficient amount of. drug into or across the skin
to be
clinically beneficial. It does not necessarily mean that most of the subject
population can obtain some degree of benefit or'the benefit is high enough to
be
= deemed "effective" by relevant government agencies or the medical
profession. =
More specifically, for drugs that target skin or regional tissues or organs
close to =
the skin surface (such as joints,.certain muscles, or tissues/organs that are
at
least partially within 5 cm of the skin surface), "therapeutically effective
flux"
refers to the drug flux that can deliver a sufficient amount of the drug into
the
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11
target tissues within a clinically reasonable amount of time. For drugs that
target the systemic circulation, "therapeutically effective flux" refers to
drug flux
that, via clinically reasonable skin contact area, can deliver sufficient
amounts of
the selected drug to generate clinically beneficial plasma or blood drug
concentrations within a clinically reasonable time. Clinically reasonable skin
contact area is defined as a size of skin application area that most subjects
would accept. Typically, a skin contact area of 400 cm2 or. less is considered
reasonable. Therefore, in order to deliver 4000 mcg of a drug to the systemic
circulation via a 400 cm2 skin contact area over 10 hours, the flux needs to
be at ,
least 4000 mcg/400cm2/10 hour, which equals 1 mcg/cm2/hr. By this definition,
different drugs have=different "therapeutically effective flux."
Therapeutically
effective flux" may be different in different subjects and or at different
times for
even the same subject. However, for each drug, there is usually a consensus
among the skilled in the art on the range of doses or fluxes that are
sufficient in
most subjects at most times. =
The following are estimates of flux for some drugs that are therapeutically
effective or more than sufficient:
= =
=
Table A - In vitro steady state flux values of various drugs
Estimated
= Therapeutically
Drug Indication =effectiVe flux*
(mcgicm2/h)
. =
Ropivacaine** Neuropathic pain . 5
=
Lidocaine Neuropathic pain = . 30* =
= ACyclovir Herpes simplex
virus ' 3
Ketoprofen Musculoskeletal pain = = 16
=
Diclofenac Musculoskeletal pain 1
. = Clobetasol Dermatitis, psoriasis, =
0.05
= = eczema
= Betamethason6
Dermatitis, psoriasis, = =
0.01
eczema
Testosterone Hypogonadal men, 0.8
=
Testosterone Hormone treatment for =
0.25 .
postmenopausal women
lmiquimod = Warts; basal cell 0.92
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carcinoma =
* Flux determined using an in vitro method described in Example 1.
** Estimated flux based on known potency relative to lidocaine.
The therapeutically effective flux values in Table A (with the exception of
ropivacaine) represent the steady state flux values of marketed products
through hairless mouse or human epidermal membrane in an in vitro system
described in Example 1. These values are meant only to be estimates and to
provide a basis of comparison for formulation development and optimization.
The therapeutically effective flux for a selected drug could be very different
for
different diseases to be treated for, different stages of diseases, and
different
individual subjects. It should be noted that the flux listed may be more than
therapeutically effective. =
The following examples listed in Table B illustrate screening of non-
volatile solvent's flux enabling ability for some of the drugs specifically
studied.
Experiments were carried out as described in Example 1 below and the results
are further discussed in the subsequent Examples 2-9.
= Table B - in vitro steady state flux values of various drugs from non-
volatile
solvent systems
Drug Non-Volatile Solvent
Average Flux* =
(mcg/cm2/hr)
Betamethasone Oleic acid 0.009
0.003 =
Diprppionate Sorbitan Monolaurate 0.03
0.02
, Clobetasol Propionate Propylene Glycol (PG) 0.0038
0.0004
= Light
Mineral Oil 0.031 0.003
=
== Isostearic acid (ISA) 0.019
0.003
Ropivacaine , Glycerol = 1:2 0.7=
=
Mineral Oil = 8.9 0.6
= Ketoprofen Polyethylene
glycol 400 5 2 - .
= Span 20 15
3
Acyclovir = Polyethylene glycol 400 . 0
lsostearic acid.4- 10%
=2.7 0.6
= trolamine
* Each value represents the mean and st. dev of three determinations. .
=
=
=
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The in vitro steady state flux values in Table B from non-volatile solvents
show surprising flux-enabling and non flux-enabling solvents. This information
can be used to guide formulation development.
The term "plasticizing" in relation to flux-enabling non-volatile solvent(s)
is defined as a flux-enabling non-volatile solvent that acts as a plasticizer
for the
solidifying agent. = A "plasticizer" is an agent which is capable of
increasing the
percentage elongation of the formulation after the volatile solvent system has
at
least substantially evaporated. Plasticizers also have the capability to
reduce
the brittleness of solidified formulation by making it more flexible and/or
elastic.
For example, propylene glycol is a "flux-enabling, plasticizing non-volatile
solvent" for the drug ketoprofen with polyvinyl alcohol as the selected
solidifying
agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-
97 or Avalure UR 405 as solidifying agents does not provide the same
plasticizing effect. The combination of propylene glycol and Gantrez S-97 or
Avalure UR 405 is less compatible and results in less desirable formulation
for
topical applications. = Therefore, whether a given non-volatile solvent is
"plasticizing" depends on which solidifying agent(s) is selected.
Different drugs often have different matching flux-enabling non-volatile
solvent systems which provide particularly good results. Examples of such are
noted in Table C. Experiments were carried out as described in Example 1
below and the results are further discussed in the subsequent Examples 2-9. -
=
=
Table C - In vitro steady state flux values of various drugs from particularly
high
flux-enabling non-volatile solvent systems
High flux-enabling non- = Avg. Flux*
Drug volatile solvent (mcg/cm2/h)
Ropivacaine ISA 11 .2
=
Span 20 = 26 8 =
Ketoprofen Propylene glycol (PG) = 90 50 .
Acycolvir ISA + 30% trolamine 7 2
= Betamethasone Propylene Glycol 0.20 0.07
Dipropionate
Clobetasol PG+ISA (Ratio of PG:ISA
= 0.8 0.2
Propionate ranging from 200:1 to 1:1)
?` Each value represents the mean and St. dev of three determinations.
=
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14
It should be noted that "flux-enabling non-volatile solvent," "flux-enabling,
plasticizing non-volatile solvent," or "high flux-enabling non-volatile
solvent" can
be a single chemical substance or a mixture of two or more chemical
substances.. For example, the steady state flux value for clobetasol
propionate
in Table C is a 9:1 for propylene glycol : isostearic acid mixture that
generated
much higher clobetasol flux than propylene glycol or ISio alone (see Table B).
Therefore; the 9:1 propylene glycol:isostearic acid mixture is a "high flux-
enabling non-volatile solvent" but propylene glycol or isostearic acid alone
is
not.
The term "adhesion" or "adhesive" when referring to a solidified layer
herein refers to sufficient adhesion between the solidified layer and the skin
so
that the layer does not fall off the skin during intended use on most
subjects.
Thus, "adhesive" or the like when used to describe the solidified layer means.
the solidified layer is adhesive to the body surface to which the initial
formulation
layer was originally applied (before the evaporation of the volatile
solvent(s)).. In
one embodiment, it does not mean the solidified layer is adhesive on the
opposing side. In addition, it should be noted that whether a solidified layer
can
adhere to.a skin surface for the desired extended period of time partially
depends on the condition of the body surface. For example, excessively
sweating or oily skin, or oily substances on the skin surface may make the
solidified layer less adhesive to the skin. Therefore, the adhesive solidified
layer
of the current invention may not be able to maintain perfect Contact with the
=
body surface and deliver the drug over a sustained period of time for every
subject under any conditions on the body surface. A standard is that it
maintains
good contact with most of the body surface, e.g. 706/0 of the total area, over
the
specified period of time for most subjects under normal conditions of the body
surface, and external environment.
The terms "flexible," "elastic," "elasticity," or the like, as used herein
refer
to sufficient elasticity of the solidified layer so that it is not broken if
it is
stretched in at least one direction by up to about 5%, and often to about 10%
or
even.greater. For example, a solidified layer that exhibits acceptably
elasticity
=
=
CA 02633489 2011-11-17
=
=
and adhesion to skin can be attached to human skin over a flexible skin =
location, e.g., elbow, finger, wrist, neck, lower back, lips, knee, etc., and
will
remain substantially intact on the skin upon stretching of the skin. It should
be
noted that the solidified layers of the present invention do not necessarily
have
5 to have any elasticity in some embodiments.
The term "peelable," when used to describe the solidified layer, means
the solidified layer can be lifted from the skin surface in one large piece or
few to
several large pieces, as Opposed to many small pieces or crumbs.
The term "sustained" relates to therapeutically effective rates of dermal drug
10 delivery
for a continuous period of time of at least 30 minutes, and in some =
embodiments, periods of time of at least about 2 hours, 4 hours, 8 hours, 12
hours, 24 hours, or longer.
"Volatile solvent syste.m" can be a single solvent or a mixture of solvents
that are volatile, including water and solvents that are more volatile than
water.
= =
15 Non-limiting examples of volatile solvents that can be used in the
present
invention include denatured alcohol, methanol, ethanol, isopropyl
= alcohol, water, propanol, C4-C6 hydrocarbons, butane, isobutene,
pentane, hexane, acetone, ethyl acetate, fluoro-chloro-
hydrocarbons, methyl ethyl ketone, methyl ether,
hydrofluorocarbons, ethyl ether, 1,1,1,2 tetrafiuorethane,
= 1,-1,1,2,3,3,3-heptafiuoropropane,.1,1,1,3,3,3 hexafluoropropane, or
combinations thereof. . .
"Non-volatile solvent system" can be a single solvent or mixture of
solvents that are less volatile than water. It can also contain substances
that
=
are solid or liquid at room temperatures, such as pH or ion-pairing agents.
After
evaporation of the volatile-solvent system, most of the non-volatile solvent
system should remain in the solidified layer for an amount of time sufficient
to
derrnally deliverya given drug to, into, or through the skin of a subject at a
sufficient flux for a period of time to provide a therapeutic effect. In some
.
embodiments, in order to obtain desired permeability for an active drug and/or
compatibility with solidifying agents or other ingredients of the formulation,
a
mixture of two or more non-volatile solvents can be used to form the non-
volatile
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solvent system. In one embodiment, the combination of two or more non-
volatile solvents to form a solvent system provides a higher transdermal flux
for
a drug than the flux provided for the drug by each.of the non-volatile
solvents
individually. The non-volatile solvent system may also serve as a plasticizer
of
the solidified layer, so that the solidified.layer is elastic and flexible.
The term "solvent vehicle" describes compositions that incidde both a
volatile solvent system and non-volatile solvent system. The volatile solvent
"
system is chosen so as to evaporate from the adhesive formulation quickly to
form, a solidified layer, and the non-volatile solvent system is formulated or
chosen to substantially remain as part of the solidified layer after volatile
solvent
system evaporation so as to provide continued delivery of the drug. Typically,
the drug can be partially or completely dissolved in the solvent vehicle or
formulation as a whole. Likewise, the drug can also be partially or completely
solubilizable in the non-volatile solvent system once the volatile solvent
system
=
is evaporated. Formulations in which the drug is only partially dissolved in
the
non-volatile sOlvent system after the evaporation of the volatile solvent
system
have the potential to maintain longer duration of sustained delivery, as the
undissolved drug can dissolve into the non-volatile solvent system as the
dissolved drug is being depleted from the solidified* layer during drug
delivery..,
"Adhesive solidifying formulation" or "solidifying formulation" refers to a
composition that has a viscosity suitable for application to a skin
surface.prior to
evaporation of its volatile solvent(s), and which can become a solidified
layer
after evaporation of at least a portion of the volatile solvent(s). The
solidified
layer, once formed, can be very durable. In one embodiment, once solidified on
25, a skin surface, the formulation can form a peel. The peel can be a
soft,
= . .
coherent solid that can be removed by peeling large pieces from, the skin
relative to the size of the applied formulation, and often, can be peeled from
the
skin as a single piece. The application viscosity is typically more viscous
than a
water-like liquid, but less viscous than a soft solid. Examples of preferred
viscosities include materials that have consistencies similar to pastes, gels,
ointments, and the like, e.g., viscous liquids that flow but are not subject
to
spilling. Thus, when a composition is said to have a viscosity "suitable for
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17 =
=
application" to a skin surface, this means the composition has a viscosity
that is
high enough so that the composition does not substantially run off the skin
after
being applied to skin, but also has a low enough viscosity so that it can be
easily spread onto the skin. A viscosity range that meets this definition can
be
. from about 100 cP to about 3,000,000 cP (centipoises), and more preferably
from about 1,000 cP to about 1,000,000 cP.
in some embodiments of the present invention, it may be desirable to add
an additional agent or substance to the formulation so as to provide enhanced
or increased adhesive characteristiCs. The additional adhesive agent or
substance can be an additional non-volatile Solent or an additional
solidifying
agent. Non-limiting examples of substances which might be used as additional
adhesion enhancing agents include copolymers of methylvinyl ether and maleic
anhydride (Gantrez polymers), polyethylene glycol, and polyvinyl pyrrolidone,
=
gelatin, low molecular weight polyisobutylene rubber, copolymer of acrylsan
alkyl/octylacrylamido (Dermacryl 79), and/or various aliphatic resins and =
aromatic resins.
= The terms "washable," "washing" or "removed by Washing" when used
with respect to the adhesive formulations of the present invention refers.to
the
ability of the adhesive formulation to be removed by the.application of a
washing
solvent using a normal or medium amount of washing force. :The required force
to remove-the formulations by washing should not cause significant skin
irritation or abrasion. Generally, gentle washing forae accompanied by the
application of an appropriate, washing solvent is sufficient to remove the
adhesive formulations disclosed herein. The solvents which can be used for
removing by washing the formulations of the present invention are numerous,
but preferably are chosen from comenonly.acceptable solvents including the
volatile solvents listed herein. Preferred washing solvents do not
significantly
irritate human skin and are generally available to the average subject.
Examples of washing solvents include but are not limited to water, ethanol,
methanol, isopropyl alcohol, acetone, ethyl acetate, propanol; or combinations
thereof. In aspect of the invention the washing solvents can be selected from
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the group consisting of water, ethanol, isopropyl alcohol, or combinations
thereof. Surfactants can also be used in some embodiments.
, An acceptable length of time for a "drying time" refers to the
time it takes
for the formulation to form a non-messy solidified Surface after application
on
skin under standard skin and ambient conditions, and with standard testing
procedure. it is noted that the word "drying time" as used herein does not
mean
the time it takes to completely evaporate off the volatile solvent(s).
Instead, it
means the time it takes to form the non-messy solidified surface as described
above..
."Standard skin" is defined as dry, healthy human skin with a surface
temperature of between about 30 C to about 36 C. Standard ambient
conditions are defined by the temperature range of from 20 C to 25 C and a
relative humidity range of from 20% to 80%. The term "standard skin", in no
way
limits the types of skin or skin conditions on which the formulations of the
- 15 present invention can be used. The formulations of the present invention
can
be used to treat all types of "skin," including undamaged (standard skin),
=
= diseased skin, or damaged skin. Although skin conditions having different
characteristics can be treated using the formulations of the present
invention,
the use of the term "standard skin" is used merely as a standard to test the
compositions of the varying embodiments of the present invention. As a
practical matter, formulations that perform well (e.g:, solidify, provide .
= therapeutically effective flux, etc.) on standard skin can also perform
well
diseased or damaged skin.
. The "standard testing procedure" or "standard testing condition"
is as
follows: to standard skin at standard ambient conditions is applied an =
approximately 0.1 mm layer of the adhesive solidifying formulation.and the
drying time is Measured. The drying time is defined as the time it takes far
the
formulation to form 'a non-messy surface *such that the formulation does not
lose
mass by adhesion to a piece of 100% cotton cloth pressed onto the formulation
surface with a pressure of between about 5 and about 10 g/cm2 for 5 seconds.
"Solidified layer" describes the solidified or dried layer of an adhesive
solidifying formulation after at least a portion of the volatile solvent
system has
=
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=
evaporated. The solidified layer remains adhered to the skin, and is
preferably
capable of maintaining good contact with the subject's skin for substantially
the
entire duration of application under standard skin and ambient conditions. The
solidified layer also preferably exhibits sufficient tensile strength so that
it can be
pieces (as opposed to a layer with weak tensile strength that breaks into many
small pieces or crumbles when removed from the skin).
.The use of the term "substantially! when referring to the evaporation of
the volatile solvents means that a majority of the volatile solvents which
were
Concentrations, amounts, and other numerical data may be expressed or
format is used merely for convenience and brevity and thus should be
interpreted flexibly to include not only the numerical values explicitly
recited as
the limits of the range, but also to include all the individual numerical
values or .
sub-ranges encompassed within that range as if eaoh numerical value and sub-
=.2.0 mm" Should be interpreted to include not only the explicitly recited
valUes of
about Ø01 mm to about 2.0 mm, but also include individual values and sub-
ranges within the indicated range. Thus, included in this numerical range are
individual values Such as 0.5, 0.7, and 1.5, and sub-ranges such as from 0.5
to
= reciting only one numerical value. Furthermore, Such an interpretation
should
apply regardless of the breadth of the range or the characteristics being
described. =
As used herein, a plurality of drugs, compounds, and/or solvents may be
=
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= =
be construed as a de facto equivalent of any other member of the same list
solely based on their presentation in a common group without indications to
the
contrary.
With these definitions in mind, the present invention is drawn generally to
5 a formulation for treating an infection, comprising a drug that is
effective for
treating an infection, a solvent vehicle, and a solidifying agent. The solvent
vehicle can comprise a volatile solvent system including at least one volatile
solvent, and a non-volatile solvent system including at least one non-volatile
solvent, wherein the non-volatile solvent system is capable of facilitating
delivery
10 of the drug at therapeutically effective rates over a sustained period
of time.
The formulation can have a viscosity suitable for application and adhesion to
a
skin surface prior to evaporation of the volatile solvent system. The
formulation .
applied to the skin surface can form a solidified layer after at least partial
evaporation of the volatile solvent system. Further, the drug can continue to
be
15 delivered after the volatile solvent system is at least substantially
evaporated.
In another embodiment, a method of treating a.skin infection can
comprise applying a solidifying adhesive formulation to an infected skin
surface.
The solidifying adhesive formulation can comprise a drug that is effective for
treating a skin infection, a solvent vehicle, and a solidifying agent. The
solvent
20 system can comprise a volatile solvent system including at least one
volatile
solvent, and a non-volatile solvent system including at least one non-volatile
solvent. The non-volatile solvent system cante capable of facilitating the
delivery of the drug at therapeutically effective rates over a sustained
period of
time. The formulation can have a viscosity suitable for application and
adhesion
to the skin surface prior to evaporation of the volatile solvent system.
Additional
steps include solidifying the formulation to form a solidified layer on the
infected
=
skin surface by at least partial evaporation of the volatile solvent system,
and =
dermally delivering the drug from the solidified layer to the infected skin
site at
therapeutically effective rates over a sustained period of time.
In another embodiment, a solidified layer for treating an infection can
comprise a drug that is effective for treating a skin infection; a non-
volatile
solvent system including at least one non-volatile solvent, wherein the non-
.
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=
volatile solvent system facilitates the delivery of the drug at
therapeutically
effective rates over a sustained period of time; and a solidifying agent. The
solidified layer can be stretchable by 5% (or even 10%) in one direction
without
cracking, breaking, and/or separating from a skin surface to which the layer
is
applied.
In still another embodiment, a formulation for treating an infection can
comprise a drug selected from the group consisting of acyclovir, valacyclovir,
pencyclovir, or combinations thereof; a solvent vehicle comprising a volatile
solvent system including at least one volatile solvent, and a non-volatile
solvent
system comprising a non-volatile solvent; and a solidifying agent. The non-
=
volatile solvent can be selected from the group consisting of oleic acid,
isostearic acid, olive oil, or combinations thereof. The solidifying agent can
be
selected from. the group consisting of ethyl acrylate-methyl methacrylate-
trimethylammonioethyl methacrylate chloride copolymers, butyl and methyl
methacrylate copolymers, ethyl cellulose, and mixtures and copolymers thereof.
The formulation can have a viscosity suitable for application to a skin
surface
prior to evaporation of the volatile solvent system, can form a solidified, -
coherent, flexible, and continuous layer after at least partial evaporation of
the
volatile solvent system, and the drug can be continued to be delivered at a
therapeutically effective rate after the volatile solvent, system is at least
substantially all evaporated.
In another embodiment, a formulation for treating an infection can
comprise a drug selected from the group; consisting of econazole, terbinafine,
or.
'combinations thereof; a solvent vehicle comprising a volatile solvent system
including at least one volatile solvent and a non-volatile solvent system
comprising at least one non-volatile solvent, and a solidifying agent. The non-
volatile solvent can be selected from the group consisting of
tetrahydroxypropyl
pthylenediamine, oleic acid, isostearic acid, olive oil, or combinations
thereof.
The solidifying agent can be selected from the group consisting of ethyl
=
acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride
copolymers, butyl and methyl methacrylate copolymers, ethyl cellulose, and
mixtures and copolymers thereof. The formulation can have a viscosity suitable
=
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for application to a skin surface prior to evaporation of the volatile solvent
system, can form a solidified, coherent, flexible, and continuous layer after
at
least partial evaporation of the volatile solvent system, and the drug can be
continued to be delivered at a therapeutically effective rate after the
volatile
solvent system is at least substantially all evaporated.
In another embodiment, an adhesive solidifying formulation for treating -a
nail infection can comprise a drug that is effective for treating a nail
infection, a
solvent vehicle, and a solidifying agent. The solvent vehicle can comprise a
volatile solvent system including at least one volatile solvent, and a non-
volatile
solvent system including at least one non-volatile solvent; Wherein the non-
volatile solvent system is capable of facilitating delivery of the drug at a
therapeutically effective rate over a sustained period of time. The
formulation -
has a viscosity suitable for application and adhesion to a nail surface prior
to
evaporation of the volatile solvent system, and when applied to the nail
surface,
it forms a solidified. layer after at least partial evaporation of the
volatile solvent
system. Further, the drug continues to be delivered to the hail after the
volatile
solvent system is at least substantially evaporated. =
In another embodiment, a method of treating nail fungal infection can
comprise applying to a nail surface with a fungal infection, and optionally.
surrounding skin, a layer of an adhesive solidifying formulation. The
formulation
can comprise an anti-fungal drug,a solvent vehicle including a Volatile
solvent..
system comprising at least one volatile solvent, and a non-volatile solvent
.systern.comprising.at least one non-volatile solvent, and a solidifying
agent.
The non-volatile solvent system can be capable of facilitating delivery of the
=
anti-fungal drug at a therapeutically effective rate over a sustained period
of
time, and can have a viscosity suitable for application and adhesion to a nail
- surface prior to evaporation of the volatile solvent system. Further, the
.
formulation applied to the nail surface can form a solidified layer after at
least
=
partial evaporation of the volatile solvent system, and the drug can continue
to
be delivered from the solidified layer to the nail after the volatile solvent
system
is at least substantially evaporated. Additional steps can include keeping the
=
. .
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23
solidified layer on said nail surface for a treatment period of at least 4
hours, and
removing the solidified layer after the treatment period.
In another embodiment, a formulation for treating dermatitis or psoriasis
(such as hand dermatitis) can comprise a drug, a solvent vehicle., and a '
15 . flexible, and continuous layer after at least partial evaporation of the
volatile
=
solvent system. Additionally, the drug can continue to.be delivered at the
therapeutically effective rate after the volatile solvent system is at least
substantially all evaporated
While the ,formulations, methods, and solidified layers of the current
= and methods of the current invention are expected to be particularly
beneficial
for treating hand dermatitis and psoriasis. =
In still another embodiment, a solidified layer for treating alopecia can
comprise
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=
24
=
In an alternative embodiment, a method of treating alopecia can comprise
applying a layer of an adhesive formulation to a skin surface suffering from
alopecia (hair loss). The formulation can comprise a drug capable of
stimulating
hair growth when delivered to a hair follicle of a subject suffering from
alopecia,
a solvent vehicle,. and a solidifying agent. The solvent vehicle can comprise
a
volatile solvent system including at least one volatile solvent, and a non-
volatile
solvent system including at least one non-volatile solvents, wherein the non-
'
volatile solvent system is preferably capable of facilitating topical delivery
of the
drug at a therapeutically effective rate over a sustained period of time. The
formulation can have a viscosity suitable for application and adhesion to the
skin surface prior to evaporation of the volatile solvent system. Other steps
include solidifying the formulation to form a solidified layer on the skin
surface
by at least partial evaporation of the volatile solvent system; and topically
delivering the drug from the solidified layer to the skin at therapeutically
effective
rates over.a sustained period of time. =
In another embodiment, a solidified layer for delivering a drug for treating =
alopecia=can comprise a drug capable of stimulating hair growth when delivered
to a hair follicle of a subject suffering from alopecia, a non-volatile
solvent
system including at least One non-volatile solvent, wherein the non-volatile
solvent system is capable of facilitating the delivery of the drug at
therapeutically
effective rates over a sustained period of time, and:a solidifying agent. The
= solidified layer can have sufficient flexibility and adhesion to the skin
'surface so
= that it can maintain good contact with the skin surface to which it was
originally
applied for at least most of the intended duration of the application.. '
In another embodiment, a formulation for treating a subject suffering from
= alopecia can comprise a drug, a solvent vehicle, and a solidifying agent.
The = = -
drug can include a member selected from the group consisting.of clobetasol
propionate, clobetasol, derivatives thereof, and combinations thereof. The
solvent vehicle can comprise a volatile solvent system including at least one
volatile solvent, and a non-:volatile solvent system comprising at least one
= solvent selected from the group consisting of propylene glycol, glycerol,
and
, combinations thereof, and at least one solvent selected from the group
. .
=
=
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=
consisting of isostearic acid, oleic acid, and combinations thereof. The =
. solidifying agent can include a member selected from the group consisting
of
polyvinyl alcohol, fish gelatin, gluten, casein, zein, and combinations
thereof.
The formulation can have a viscosity suitable for application and adhesion to
a
5 skin surface prior to evaporation of the volatile solvent system, and,
after being
applied to a skin surface as a layer, can form a solidified, coherent,
flexible, and
continuous layer after at least partial evaporation of the volatile solvent
system.
The continues to be topically delivered at the therapeutically effective rate
after =
the volatile solvent system is at least substantially all evaporated.
10 In another embodiment, a method for treating alopecia can comprise
applying to a skin area of a subject suffering from alopecia a 0.01 mm to 2 mm
thick layer of an adhesive solidifying formulation. The formulation can
comprise
a drug including at least one .member selected from the group consisting of
clobetasol propionate, clobetasol, and combinations thereof, a volatile
solvent
15 System including at least one volatile solvent. Other ingredients can
comprise a
non-volatile solvent system including at least one solvent selected from the
*group consisting of propylene glycol, glycerol, and combinations thereof, and
at
least one solvent selected from the group consisting of isostearic acid, oleic
acid, and combinations thereof. A solidifying agent can also be present can
20 include at least one member selected from the .group consisting of
polyvinyl .
alcohol, fish gelatin, gluten, casein, zein, and combinations thereof. The
formulation can have a viscosity suitable for application and adhesion to the
= .-
palm skin surface prior to evaporation of the volatile solvent system, and can
form' a solidified, coherent and flexible, layer after at least partial
evaporation of =
25 the volatile solvent system. The drug can continue to be topically
delivered at
the therapeutically effective rate after the volatile 'solvent system is.at
least
substahtially all evaporated: Other steps include leaving the formulation on
the
skin surface for an intended application period of at least 2 hours, and
removing
the solidified, coherent and flexible layer from the skin surface after the
intended.
application period.
In another embodiment, an adhesive solidifying formulation for treating
photo damaged human skin can comprise an immune modulating agent, and at
=
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26
=
least one member selected from the group consisting of isostearic acid,
tnacetin, sorbitan monolaurate, and combinations thereof.
In another embodiment, a solidified layer for treating photo damaged
human skin can comprise an immune modulating agent, a non-volatile solvent
system, and a solidifying agent. The non-volatile solvent system can comprise
at least one non-volatile solvent, and the system can be capable of
facilitating
the delivery of the immune modulating agent at a therapeutically effective
rate
over a sustained period of time. The solidified layer can be capable of
adhering
to a human skin surface for at least two hours.
= In further detail, the present invention is related to a formulation
comprising an immune activator, a volatile solvent system comprising at least
one volatile solvent (defined as water or solvents more volatile than water),
a
non-volatile solvent system comprising one or more non-volatile solvent
(defined
as less volatile than water), and a solidifying agent. Before application to
the
skin, the formulation is in its initial, less-than-solid form, such as cream;
gel,.
paste, or ointment. After applying a layer of such a formulation on the skin
area
to be treated, the evaporation of the volatile solvent(s), with the help from
the =
solidifying agent, can convert the formulation layer into a soft, flexible,
coherent
= solid layer that is optionally peelable. The non-volatile solvent system
stays in
the formulation for substantially.the entire duration of the application and
serves
=
as vehicle solvent for delivering the drug into the skin (a fraction of the
non-. -=
volatile solvent(s) may be absorbed by skin during the application). The soft,
flexible, coherent solid layer is designed to adhere to the skin for, a
substantial
duration, preferably longer than 2 hours. Optionally, an emollient and/or a
moisturizing substance can be included in the formulation for providing
beneficial moisturizing effect as well as soothing the skin and minimizing the
possible irritation caused by the immune activator.
The, formulations of the present invention provide several advantages = =
over the Aldara cream. First, the immune activating agent in the formulations
of
the present invention is "anchored" on the skin surface to be treated, and
thus is
not as susceptible to unintentional removal. The optional emollient and/or
moisturizing agent(s) can moisturize and sooth the skin to provide additional
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=
= 27
treatment benefits. The optional emollient and/or moisturizing agent(s) may
also offset the possible irritation caused by the immune activating agent.
Furthermore, the physical barrier provided by the solidified layer and water
retention property of the moisturizing agent can help maintain moisture in
and/or
on the surface of the skin. This is believed to be valuable because hydration
of
the skin is believed to increase th.e permeability of the skin, which in turn
can
increase the absorption of the immune activating agent. Therefore,
formulations
containing both immune activator and moisturizing agent can be synergistic.
= 10 . Thus, the present invention is related to formulations that
are typically in
the initial form of semi-solids (including creams, gels, pastes, ointments,
and
other viscous liquids), which can be easily applied onto the skin as a layer,
and
can, after evaporation of at least some of the volatile solvent(s), quickly
(from 15
seconds to about 5 minutes under standard skin and ambient conditions as set
forth above) to moderately quickly (from about 4 to. about 15 minutes under
standard skin and ambient conditions) change into a solidified layer (Which is
optionally also peelable), e.g., a coherent and soft solid layer, for drug
delivery.
The solidified layer thus formed is capable of delivering drug over a
sustained
period of time, e.g., hours to tens of hours, so that most of the drug
absorption
occurs after the solidified layer is formed.
Additionally, the solidified layer typically adheres to the skin, but has a
solidified, minimally-adhering, outer surface which is formed relatively soon
after
application and which does not substantially transfer to or otherwise soil
clothing
or other objects that a subject is wearing or that the solidified layer may
inadvertently contact. The solidified _layer can also be formulated such that
it is
highly flexible and stretchable, and thus, is capable of maintaining good
contact
= with a skin surface, even if the skin is stretched during normal daily
activities.
The formulations of the present invention can be applied and used-on
various types of human body or skin surfaces. In one embodiment, the skin
surface being treated can be what is traditionally referred to as "skin." The
skin
surface can be an epidermal layer of the skin. In another embodiment, the skin
surface that can be treated is a mucosal surface, such as lips, oral mucosal,
=
CA 02633489 2011-11-17
28
genital mucosa, nasal mucosa, or anal mucosa. In another embodiment, the
skin surface being treated can be a finger or toe nail surface. In yet another
embodiment, the skin surface being treated is a wounded skin surface. In yet
another embodiment, the skin surface Is a bed sore or a skin surface with one
or
more lesions or open sores.
In selecting the various components that can be used, e.g., drug, solvent
vehicle of volatile sOivent system and non-volatile solvent system,
solidifying
agent(s), etc., many variations can be considered. For example, the volatile
- solvent system may be one or more volatile solvents (at least as volatile
as
water, including water). In one embodiment of the present Invention, the
volatile
solvent system can include a member of ethanol, isopropyl alcohol, water,
dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1,
difluoroethane,
1,1,1,2 tetrafluorethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3
hexafluoropropane, ethyl acetate, acetone, or combinations thereof. In another
embodiment of the present invention, the volatile solvent system can include
denatured alcohol, methanol, propanol, isobutene, pentane, hexane,
methyl ethyl ketone, butanol, butyl alcohol, acetyl monoglycerides, alkyl
dioxolanes, coriander oil, diethylene glycol monoethyl ether, milk, olive
alcohol, vinyl acetate, hexylene glycerol, methacrylic acid, or
combinations thereof. The volatile solvent system can include a mixture
of combination of any of the volatile solvents set forth in the
embodiments above. These volatile solvents should be chosen to be
compatible with the rest of the formulation. = Itis desirable to use an
appiopriate -
weight percentage of the volatile-solvent(s) in the formulatidn. Too much of
the
.25 - volatile solvent system prolongs the drying time. Too little of the
volatile solvent
system can make it difficult to spread the formulation on the skin. For most
formulations, the weight percentage of the volatile solvent(s) can be from
about
10 wt% to about 85 wt%, and more preferably from about 20 .ivrio to about 50
wt%.
The non-volatile solvent System can also be chosen or formulated to be
compatible with the solidifying agent, the drug, the volatile solvent, and any
other ingredients that May be present. For example, the solidifying agent can
be chosen so that it is dispersible or soluble in the non-volatile solvent
system.
Most non-volatile solvent systems and solvent vehicles as a whole can be
CA 02633489 2011-11-17
29
formulated appropriately after experimentation. For instance, certain drugs
have good solubility in poly ethylene glycol (PEG) having a molecular weight
of
400 (PEG 400, non-volatile solvent) but poor solubility in glycerol (non-
volatile
solvent) and water (volatile solvent). However, PEG 400 cannot effectively
dissolve poly vinyl alcohol (PVA), and thus, is not very compatible alone with
PVA as the only solidifying agent. In order to dissolve sufficient amount of
an =
active drug and use PVA as a solidifying agent at the same time, a non-solvent
system including PEG 406 and glycerol (compatible with PVA) in an appropriate
ratio can be formulated, achieving a compatibility compromise. As a further '
example of compatibility, non-volatile solvent/solidifying agent
incompatibility is
observed when Span 20 is formulated into a formulation containing PVA..With
this combination, Span 20 can separate out of the formulation and form an oily
-layer on the surface of the solidified layer. Thus, appropriate solidifying
agent/non-volatile solvent selections are desirable in developing a viable
formulation and compatible combinations.
Non-volatile solvent(s) that can be used alone or in combination to form
= non-volatile solvent systems can be selected from a variety of
pharmaceutically
acceptable liquids. In one embodiment of the present invention, the nth-
Volatile
solvent system can Include glycerol, propylene glycol, isostearic acid, Oleic
acid,
propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate,
.
sorbitan monooleate, sorbitan monopalmitate, or combinations thereof.
In another embodiment the non-volatile solvent system can include benzoic
= acid, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol,
fatty acids such as coconut oil, fish oil, palm oil, grape seed oil, isopropyl
myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan
.fatty acid
surfactants, triethyl citrate, or combinations thereof. In a further
embodiment, =
the non-volatile solvent system can include 1,2,6-hexanetriol, alkyltriols,
alkyldiols, tocopherol, p-propenylanisole, anise oil,
apricot oil, dimethyl isosorbide, alkyl glucoside,
' 30 benzyl alcohol, bees wax, benzyl benzoate, butylene glycol,
caprylic/capric
triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil,
clove
oil, coconut oil, cocoa butter, cocoglycerides, coriander oil, corn oil,
=
CA 02633489 2011-11-17
so
corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin,
diacetylated monoglycerides, diethanolamine, diglycerides, ethylene
glycol, eucalyptus oil, fat, fatty alcohols, flavors, liquid sugars ginger
= extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP
palmitate, lemon oil, lime oil, limonene, monoacetin, monoglycerides,
nutmeg oil, octyldodecanol, orange oil, palm oil,
peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle
oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable
oil,
vegetable shortening, wax, 2-(2-(octadecyloxy)ethoxy)ethanol,
benzyl benzoate, butylated hydroxyanisole, candelilldwax, carnauba wax,
ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxy stearate, PEG-7
hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone,
dimethyl phthalate, PEG fatty acid esters such as PEG-stearate, PEG-
=
oleate, PEG-laurate, PEG fatty acid diesters such as PEG-dioleate, PEG-
distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid
esters such as PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl
oleate, lanolin, lauric diethanolamide, lauryl lactate, lauryl sulfate,
medronic acid, multisteroi extract, myristyl alcohol, neutral oil, PEG-octyl
phenyl ether, PEG -alkyl ethers such as PEG-cetyl ether, PEG-stearyl ether,
PEG- sorbitan fatty acid esters such as PEG-sorbitan diisosterate, PEG-
sorbitan
monostearate, propylene glycol fatty acid esters Such as propylene glycol
stearate, pippylene glycol, caprylate/caprate, sodium pyrrolidone carboxyiate,
sorbitol, squalene, stear-o-wet, triglycerides, alkyl aryl polyether alcohols,
polyoxYethylene derixiativos of sorbitan-ethers, saturated polyglycolyzed.C8-
C10
glycerides, N-methyl pyrrolidone, honey, polyoxyethylated glycerides, dimethyl
sulfoxide, azone and related compounds, dimethylformamide, N-methyl =
formamaide, fatty acid ester* fatty alcohol ethers, alkyl-amides (N,N-
dimethylalkylamides),.N-methyl pyrrolidone related compounds, ethyl oleate, .
.
polyglycerized fatty acids, glycerol monooleate, glyceryl monomyristate,
glycerol
esters of fatty acids, silk amino acids, PPG-3 benzyl ether myristate, Di-PPG2
myreth 10-adipate, honeyquat, sodium pyroglutamic acid, abyssinica oil,
dimethicone, macadamia nut oil, limnanthes alba seed oil, cetearyl alcohol,
=
CA 02633489 2011-11-17
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PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydro-
lyzed wheat protein, iso-amyl acetate, chlorobutanol, turpentine, cytopenta-
_ siloxane, or combinations thereof. In yet a further embodiment the non-
volatile solvent system can include a combination or mixture of non-volatile
solvents set forth in any of the above discussed embodiments.
Certain volatile and/or non-volatile solvent(s) that are irritating to the
skin _
may be desirable to use to achieve the desired solubility and/or permeability
of
the drug. It is also desirable to add compounds that are both capable of
preventing or reducing skin irritation and are compatible with the
formulation.
For example, in a formulation where the solvent (either non-volatile or
volatile) is
capable of irritating the skin, it would be helpful to use a non-volatile
solvent that
is capable of reducing skin irritation. Examples of solvents that are known to
be
may also be used.
The formulations of the current invention may also contain two or more
non-volatile solvents that independently are not adequate non-volatile
solvents
for a drug but when formulated together become an adequate non-volatile
solvent. One possible reason for these initially non adequate non-volatile
solvents to become adequate non-volatile solvents when formulated together
may be due to the optimization of the ionization state of the drug to a
physical
form Which has higher flux or the non-volatile solvents act in so-me other .
synergistic manner. One further benefit of the mixing of the non-volatile
solvents is that it may optimize the pH of the formulation or the skin tissues
under the formulation layer to minimize irritation. Examples of suitable
combinations of non-volatile solvents that result in an adequate non-volatile.
solvent system include but are not limited to isostearic acid /trolamine,
isostearic
acid/diisopropyl amine, oleic acid/trolamine, and propylene glycoVisostearic
acid.
The selection of the solidifying agent can also be carried out in
consideration of the other components present in the solidifying adhesive
formulation. An appropriate solidifying agent is compatible with the
formulation
such that the.formulation is in liquid or semi-liquid state, e.g. cream,
paste, gel,
=
=
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32
ointment, etc., before any evaporation of the volatile solvent(s) and becomes
a
soft, coherent solid after the evaporation of at least some of the volatile
solvent(s). The solidifying agent can be selected or formulated to be
compatible
with the drug and the solvent vehicle (including the volatile solvent(s) and
the
non-volatile solvent system),. as well as provide desired physical properties
to
the solidified layer once it is formed. Depending on the drug, solvent
vehicle,
and/or other components that may be present, the solidifying agent can be
selected from a variety of agents. In one embodiment, the solidifying agent
can
include polyvinyl alcohol with a MW range of 20,000-70,000 (Amresco), esters
. 10 of polyvinylmethylether/maleic anhydride copolymer (ISP Gantrez ES-425
and
Gantrez ES-225) with a MW range of 80,000-160,000, neutral copolymer of
= butyl methacrylate and methyl .methacrylate.degussa Plastoid B) with a
MW.
range of 120,000-180,000, dimethylaminoethyl methacrylate-butyl methacrylate-
methyl methacrylate copolymer (degussa Eudragit E100) with a MW range of
100,000-200,000, ethyl acrylate-methyl methacrylate-trimethylammonioethyl
methacrylate chloride copolymer with a MW greater than 5,000 or similar MW to
Eudragit RLPO (Degussa), Zein (prolamine) with a MW greater than 5,000
=-=
(Zein, MW around 35,000, Freeman industries), pregelatinized starch having a
MW similar to Instant Pure-Cote B793 (Grain Processing Corporation), ethyl
cellulose with a MW greater than 5,000 or a MW similar to AquaIon EC N7, N10,
N14, N22, N50, or N100 (Hercules), fish gelatin having a MW range of 20,000-
250,000 (Norlanci Products), gelatin, other animal sources with a MW range
greater than 5,000, acrylates/octylacrylamide copolymer With a MW range -
greater than 5,000 or a MW similar to National Starch and Chemical Dermacryl
79.
In another embodiment, the solidifying agent can include ethyl cellulose,
hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose,
hydroxypropy' I methyl cellulose; carboxymethyl cellulose, methyl cellulose;
. poIyether amides, corn starch, 'pregelatinized corn starch, polyether
amides,
shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate
phthalate, or combinations thereof. In a further embodiment, the solidifying
agent can include ammonia methacrylate, carrageenan, cellulose acetate
=
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33
phthalate aqueous such as CAPNF from Eastman, carboxy polymethylene,
cellulose acetate (microcrystalline), cellulose polymers, divinyl benzene
styrene,
ethylene vinyl acetate, silicone, guar gum, guar rosin, gluten, casein,
calcium
caseinate, ammonium caseinate, sodium caseinate, potassium caseinate,
methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose,
acrylate, PEG/PVP, xantham gum, trimethyl siloxysilicate, maleic
acid/anhydride
colymers, polacril in, poloxamer, polyethylene oxide, poly glactic acid/poly-I-
lactic
acid, turpene resin, locust bean gum, acrylic copolymers, polyurethane
dispersions, dextrin, polyvinyl alcohol-polyethylene glycol co-polymers,
1.0 methyacrylic acid-ethyl acrylate copolymers such as BASF's Kollicoat
polymers,
- .methacrylic acid and methacrylate based polymers such as
poly(methacrylic
acid), or combinations thereof. In yet a further embodiment, the solidifying
agent can include a combination of solidifying agents set forth in the any of
the
above discussed embodiments. Other polymers may also be suitable as the
solidifying agent, dependingon the solvent vehicle components, the drug, and
the specific functional requirements of the given formulation.
In one embodiment of the present invention, the solidifying agent
includes a methacrylic polymer or copolymer such as methyacrylic acid-ethyl
acrylate copolymer, butyl and methyl methacrylate copolymer, aminoalkyl
methacrylate copolymer, and/or an ammonioalkyl methacrylate copolymer. In
another embodiment, the solidifying agent includes polyvinyl alcohol or a
polyvinyl alcohol copolymer such as polyvinyl alcohol-polyethylene glycol
copolymer.
The non-volatile solvent system and the Solidifying agent are preferably
õ
compatible with one Other. Compatibility can be defined as i) the solidifying
agent does not substantially negatively influence the function of the non-
volatile
solvent system; ii) the solidifying agent can hold the non-volatile solvent
system
in the solidified layer so that substantially no non-volatile solvent oozes
out of
=
the layer, and iii) the Solidified layer formed with the selected non-volatile
solvent system and the solidifying agent has acceptable flexibility, rigidity,
tensile strength, elasticity, and adhesiveness. The weight ratio of the non-
volatile solvent system to the solidifying agent. can be from about 0.1:1 to
about
=
=
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34
1 0:1 , or more preferably from about 0.5:1 to about 2:1. In some embodiments,
the non-volatile solvent system makes up about 20-60% of the total weight of
the formulation,
The thickness of the formulation layer applied on the skin should also be -
appropriate for a given formulation and desired drug delivery considerations.
If
the layer is too thin, the amount of the drug may not be sufficient to support
sustained delivery over the desired length of time. If the layer is too thick,
it may
take too long to form a non-messy outer surface of the solidified layer. If
the
drug is very potent and the solidified layer has very high tensile strength, a
layer
as thin as 0.01 mm may be sufficient. If the drug has rather lop potency and
the
solidified layer has low tensile strength, a layer as thick as 2-3 mm may be
desirable. Thus, for most drugs and formulations, the appropriate thickness
can
be from about 0.01 min to about 3 mm, 0.1 mm to about 2 mm, or from about
0.2 mm to about 0.4 mm. In one embodiment, the formulations of the present
invention can have sufficient gas volatile solvents such that the formulation
can
be contained in a pressurized container and applied to the skin by spraying.
In
another embodiment, the formulation can be sprayed on a skin surface of a
'
subject experiencing alopecia.
The formulations of the present invention can be applied over a variety of
skin surfaces of subjects suffering from alopecia. Generally, the skin surface
= can be any size; however, in one embodiment, it can be desirable to limit
the
. area to no more than 100 cm2, and often, no more than 20 cm2,.partiCularly
if
the active drug is a corticosteroid. The desirability of limiting the skin
area is
= based on fact that though the cortiCosterpid is delivered topically, a
good portion
of the delivered drug may enter the systemic circulation Which, if at high
enough
quantities, can cause undesirable side effects. Therefore, it can be desirable
to
. achieve a balance of good topical effect and minimum systemic drug
absorption.
Since the acting site of the corticosteroids is the hair follicles which exist
somewhat deep under the skin surface, the drug needs to travel along a
relatively long path through the skin, and thus, the subject can experience
some
systemic uptake. This being stated, a significant number of alopecia subjects
=
only have relatively small skin area where they are experiencing alopecia.
=
=
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Therefore, a limitation on the skin treatment area can stratify the treatment
need
of those subjects, while minimizing systemic side effects. Even for s'ubjects
who
alopecia skin areas are larger, a limitation on treatment skin area may still
make
sense as it altows the alopecia skin areas to be treated portion by portion
with
5 minimized potential of systemic side effects. Treating large alopecia
skin areas
portion by portion is possible because the treatment of each portion is
expected
to be periodical instead of continuous.
The flexibility and stretchability of a solidified layer, optionally in the
form
of a peel, can be desirable in some applications. High flex and stretch are
10 particularly advantageous when the area being treated is involved in
frequent
stretching or movement, such as the lips or corners of the mouth. Traditional
ointments, creams, gels, pastes or the like are often not suitable for
treatment of
these areas because they are easily removed by licking the lips or. through --
contact with food during eating. In contrast, the solidifying compositions of
the
15 present invention can be formulated so as to provide adequate
flexibility and
stretching while not being easily licked, rubbed, or scraped off. It is also
worth
noting that the solidified layers of the present invention do not always peed
to
.
be stretchable, though some elasticity is preferred.
A further feature of a formulation is related to the drying time. If a
20 formulation dries too quickly, the user may not have sufficient time to
spread the
formulation into a thin layer on the skin surface before the formulation is
solidified, leading to poor skin contact. If the formulation dries too slowly,
the
subject may have to Wait a long time-before resuming* normal activities (e.g.
putting clothing on, eating, talking, etc) that may remove un-solidified
25 formulation. Thus, it is desirable for the drying time to be longer than
about 15
seconds but shorter than about 15 minutes, and preferably from about 0.5
minutes to about 5.minutes.
One way for conveniently using the formulations of the present invention
is to apply the formulation on the skin to be treated within an hour of
sleeping
30 and remove the solidified layer within an hour after waking.
Another way is to apply the formulation within an hour after waking and
remove the solidified layer within an hour of sleeping. .
;
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3.6
. .
When using the formulations of the present invention to treat the
dermatological condition of photo damaged skin, it can be advantageous to
apply the formulation so as to cover a skin area slightly beyond the damaged
skin area. Therefore, one embodiment of the current invention is to apply the
formulation at least 1-2 mm beyond the damaged skin area.
Other benefits of the solidified layers of the present invention include the
presence of a physical barrier that can be formed by the material itself. This
physical barrier can protect the infected area against contacting objects or
sources which cause irritation, pain, or further infections. For example, the
solidified layer can act as a barrier against friction with a diaper, or as a
protective barrier against urine and/or fecal matter. Additionally, upon
volatile
solvent system evaporation, the dosage form is relatively thick and can
contain
much more active drug than a typical layer of.traditional cream, gel, lotion,
=
ointment, paste, etc., and further, is not as subject to unintentional
removal.
These and other advantages can be summarized by the following non-
limiting application embodiments. The solidified layers of the present
invention
can be prepared in an initial form that is easy to apply as a semisolid dosage
form. Additionally, upon volatile solvent evaporation, the formulation layer
applied to the skin is relatively thick and can contain much more active drug
than a typical layer of traditional cream, gel, lotion, ointment, paste, etc.,
and
further, is resistant to unintentional removal. After the evaporation of the
volatile solvent(s) and the formation of the solidified layer, the.drug in the
solidified layer can be delivered at therapeutically effective rates over
sustained
periods of time. Further, as the solidified layer remains adhesive to skin
and,
=
easy removal of the solidified layer can occur, usually without the aid of a
solvent or surfactant. In some embodiments, the adhesion to skin and
elasticity =
of the material is such that the solidified layer will not separate from the
skin
upon skin stretching at. highly stretchable skin areas, such as over joints
and
muscles. For example, in one embodiment, the solidified layer can be stretched
by 5% or even 10% or greater in at least one direction without cracking,
breaking, and/or separating form a skin surface to "which the layer is
applied.
=
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37
As a further note, it is a unique feature that the solidified layers of the
present invention can keep a substantial amount of the non-volatile solvent
system, which is optimized for delivering the drug, on the body surface. This
feature can provide unique advantages over existing products. For example,
5. Penlac is a product widely used for treating nail fungal infections. It
contains the
drug ciclopirox, volatile solvents (ethyl acetate and isopropyl), and a
polymeric
substance. After being applied on the nail surface, the volatile solvents
quickly
evaporate and the formulation layer solidifies into a hard lacquer. The drug
molecules are immobilized in the hard lacquer layer and are substantially
unavailable for delivery into the nail. As a result, it is believed that the
delivery
of the drug is not sustained over a long period of time. As a result, without
=
being bound by any particular theory, it is believed that this is at least one
of the
reasons why Penlac, while widely used, has an efficacy rate of only about 10%.
Conversely, in the solidified layer of the present invention, the drug
molecules
are quite mobile in the non-volatile solvent system which is in contact with
the
skin surface, e.g., skin; nail, mucosa', etc., surface, thus ensuring
sustained
=
delivery: = - =
=EXAMPLES
=
The following examples illustrate the embodiments of the invention that
are presently best known. However, it is to be understood that the following
are
only exemplar)/ or illustrative of the application of the principles of the
present -
invention. = Numerous modifications and alternative compositions, methods, and
=
systems may be devised by those skilled in the art without departing from the
spirit and scope of the present invention. The appended claims are intended to
cover such modifications and arrangements. Thus, while the present.invention
has been described above with particularity, the following examples provide
further detail in connection with what are presently deemed to be the most
practical and preferred embodiments of the invention.
=
=
=
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38
Example 1 =
Hairless mouse skin (HMS) or human epidermal membrane (HEM) is
used as the model membranes as noted for the in vitro flux studies described
in
herein. Hairless mouse skin (HMS) is used as the model membrane for the in
Example 2 =
26 Formulations of acyclovir in various non-volatile solvent systems are
evaluated. Excess acyclovir is present. The transdermal flux of acyclovir from
the test formulations through HMS is presented in Table 1 below.
Table 1
=
Non-volatile solvent system = = =
(Skin Flux*mcg/cm2/11)
lsostearic Acid 0.1 - 0.09
=
lsostearic Acid Li- 10% Trolamine 2.7 t 0.6 =
lsostearic Acid + 30% Trolamine . 7 2
Olive Oil = 0.3 t 0.2
Olive Oil + 11% Trolamine 3 t 3
=
= Olive Oil 4 30%
Trolamine 0.3 t 0.2
Oleic Acid '0.4 t 0.3
Oleic Acid + 30% Trolamine 14 t 5 =
Ethyl Oleate 0.2 t 0.2
Ethyl Oleate + 10% Trolamine 0.2 0.2
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39 ,.
=
= * Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be 'between 4-8 hours.
As indicated, significant enhancement of acyclovir skin flux is achieved with
isostearic acid or oleic acid mixed with trolamine. Relatively significant
flux
enhancement (e.g., 10 fold) is observed when trolarnine is added to olive oil,
oleic acid, and isostearic acid and no appreciable flux enhancement is
observed
when trolamine is added to ethyl oleate. This surprising result may be the
result
of an additive or even synergistic enhancement effect of trolaminefiatty acid
=
combination resulting in much higher acyclovir flux values.
Examples 3-6
=
Prototype adhesive solidifying formulations are prepared as follows.
Several acyclovir solidifying formulations are prepared in accordance with
embodiments of the present invention in accordance with Table 2, as follows:
= Table 2
=
Example 3 = 4 5 6
% by weight
= Ethanol .. 21 25 28
29.5
Eudragit RL- 15 18 = 20
P0* =21.0 -
=
Isostearic Acid 31 36 39
42.0
Trolamine 30 18 10
4.7
Acyclovir 3 = 3 = .. 3
2.8. =
* degussa polymer. -
=
In Examples 3-6, the compositions in Table 2 are prepared as follows. Eudragit
RL-PO and ethanol are combined in a glassiarand _heated with stirring until
the
=RL-PO is dissolved. The isostearic 'acid and trolamine is added to the RL-
.
PO/ethanol mixture and the mixture is vigorously stirred.. Once a uniform
mixture is obtained, acyclovir is added to the mixture and the formulation is
vigorously mixed. =
=
=
=
=
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=
Examples 7-8
= Two acyclovir adhesive solidifying formulations are prepared in
accordance with embodiments of the present invention in accordance with Table
3, as follows:
5 Table 3
Example 7 = 8
% by weight
Ethanol 26 21
Eudragit RL-PO 44 15
lsostearic Acid 26 31
Diisopropanol Amine 2
Neutrol TE Polyol 30 .
=
Acyclovir 2 3
=
The compositions of Examples 7 and 8 as shown in Table 3 are prepared as
follows. Eudragit RL-P0 and ethanol are combined in a glass jar and heated
with stirring until the RL-PO is dissolved. The isostearic acid and
diisopropanol
10 amine or Neutrol TE Polyol (BASF) is added to the RL-PO/ethanol mixture
and
the mixture is vigorously stirred. Once.a uniform mixture is obtained,
acyclovir
is added to the mixture and the formulation is vigorously mixed.
Examples 9-10
15 Two acyclovir solidifying formulations are prepared in
accordance.with
= embodiments of the present invention in accordance with Table 4, as
follows:
= Table 4 = .
. .
Example 9 10
=% by weight
=
Ethanol 59.6 58 =
= Ethyl cellulose
= ECN7* 19.9
=
Ethyl cellulose .19
=
==
ECN100* = --
=
Trolamine 7.6 9
Isostearic Acid 7.7 0 9
Acyclovir 5.2 5
* Hercules Aqualon N type ethyl cellulose.
In Examples 9-10.the compositions in Table 4 are prepared as follows. EC7 or
20 EC100 and ethanol are combined in a glass jar and heated with stirring
until the
=
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=
=
=
solid cellulose is dissolved. The isostearic acid and trolamine is added to
the
cellulose/ethanol mixture and the mixture is vigorously stirred. Once a
uniform
mixture is obtained, acyclovir is added to the mixture and the formulation is
=
vigorously mixed.
Example 11
The formulations of Examples. 3-10 are tested in a hairless mouse skin
(HMS) in vitro model described in Example 1. Table 5 shows data obtained
using the experimental process outlined above.
=
Table 5¨ Steady-state flux (J) of Acyclovir through HMS
Formulation J* Ratio to
(pg/cm2/h) Control
Example 3 12 5 - 6
Example 4 19 -.J..- 1 8
Example 5 8 * 1 4
= Example 6 1 1 0.5
Example 7 0.7 0.3 0.35
Example 8 . 1 0.9 0.5 -
Example 9 2 1 1
=
Example 10 19 *7 8
=
Zovirax Cream= 2 0.4 1
* Skin flux measurements represent the mean and standard
. deviation of three determinations. Flux measurements reported were
=
= determined .from the linear region of the cumulative amount versus time
=plots. The linear region was observed to be between 4-8 hours. If
experimental conditions allowed the steady state flux would extend
beyond the 8 hours measured.
= The formulations of the invention shown above generally provide for
significant
penetration of the active ingredient, and further, the formulations of
Examples 3- =
5 and 10 are found to be much greater in permeability than the marketed
= product Zovirax Cream (control). The quantity of acyclovir that permeated
across the HMS stratum corneum over time for Examples 3, 4, and Zovirax
Cream are shown in FIG. 1. Each value shown indicates the mean *SD of at
least three experiments.
Examples 3:6 show the impact of the trolamine to isostearic acid (ISA)
ratio on acyclovir flux enhancement. The optimal ISA:trolamine ratio is 1:1 to
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2:1 and ratio greater than 4:1 show a significant decrease in the acyclovir
skin .
flux. Additions of diisopropanol amine and Neutral. in place of trolamine
(Examples 7 and 8) in the formulation show a significant decrease in acyclovir
flux values. This may be due to a specific chemical interaction between
trolamine and ISA creating an environment within the formulation which
facilitates higher skin flux. Examples 9 and 10 utilize a different
solidifying agent
to evaluate the impact of the solidifying agent on acyclovir flux.
Surprisingly,
Example 9 shows a significant decrease in acyclovir skin flux, but Example 10,
which differed from Example 9 only by the molecular weight of the solidifying -
= 10 agent, shows no 'impact on acyclovir skin flux compared to a similar
1SA:trolamine ratio in Example 3.
As can be seen from FIG. 1, Examples 3 and 4 show sustained delivery
of acyclovir up to 8 hours, it is reasonable to assume based on the drug load
and the continued presence of the non volatile solvent that the delivery of
acyclovir would continue at the reported flux values for as long as the
subject
desires to leave the adhesive solidifying formulation affixed to the skin.
=
=
Example 12
. .
A formulation similar to Example 4 (with no acyclovir) is applied onto a .
human skin surface, resulting in a thin; transparent, flexible, and
stretchable
film. After a few minutes Of-evaporation of the volatile solvent (ethanol), a
solidified adhesive layer that is peelable is formed. The stretchable film has
good adhesion to the skin and did not separate from the skin, and could easily
= be peeled away from the skin. The absence of acyclovir is expected to'
have
minimal to no impact on the physical and wear properties of the,, coherent
solid
because it is present at such low concentration, when present.
= =
Examples 13-14
Anti-fungal formulations are prepared and a qualitative assessment of
-30 peel flexibility and viscosity are evaluated. The formulatiOn
components are
presented in Table 6 below.
Table 6
=
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Example 13 14
Components Parts by Weight
Eudragit RL-PO 3.8 4.2
Isostearic Acid 2 2.2
Ethanol 5.3 3.8
Neutral TE Polyol 1 1 =
Econazole 0.09 = 0.1
The formulation in Example 13 has a low viscosity that was lower than may be
desirable for application on a nail or skin surface. The time to form a
solidified
peel with this formulation is longer than the desired drying time. The
formulation.
in Example 1.4 had an increase in the amount of solidifying agent (Eudgragit
RL-
'PO) and decrease in amount of ethanol, which improves the viscosity and
drying time. Example 14 has a viscosity suitable for application and an
improved drying time. =
Example 15
Formulations of betamethasone.dipropionate (BDP) in various non-
=
volatile solvent systems are evaluated following procedure described in
Example1. Excess BDP is present. The permeation of BDP from the test
formulations through HEM is presented in Table 7 below.
= Table 7. Non volatile solvents for betamethasone dipropionate
= Non-volatile solvent Skin
Flux*
system = - (ng/cm2/h)
= Propylene Glycol 195.3 t
68.5 =
= Triacetin = 4.6 t 2.8
= Light Mineral Oil 11.2 3.1
.
=
Oleic Acid 8.8 t 3.3
Sorbitan Monolaurate 30.0 t 15.9
Labrasol 12.2 t 6.0
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 6-28 hours. If the
experiment was continued it is anticipated the steady state would
continue.
=
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=
= Active enzymes in the skin convert BDP to betamethasone. The steady state
flux values reported in Table 7 are quantified using external betamethasone
standards and are reported as amount of betamethasone permeating per unit
area and time. As seen from the results triacetin, labrasol, oleic acid, and
light
mineral oil have flux values close to 10 ng/cm2/hr. Addition of solidifying
agents
and other components could possibly decrease the flux and therefore the above
mentioned solvents would not be an ideal non-volatile solvent'. However,
sorbitan monolaurate and propylene glycol have average.flux of 30 ng/cm2/hr
and. 195 ng/cm2/hr, .respectively, and Therefore are good candidates for non-
volatile solvent. = = =
Example 16
= Formulations of clobetasol propionate in various non-volatile solvent
systems are evaluated. All solvents have 0.1% (w/w) clobetasol propionate.
The permeation of clobetasol from the test formulations through HEM is
presented in Table 8 below.
=
Table 8- Non volatile solvents for clobetasol propionate
Non-volatile solvent Skin Flux*
. = system (ng/cm2/h) =
=
Propylene Glycol 3.8 1.- 0.4 =
= = Glycerol 7.0 4.1
Light Mineral Oil . 31.2 3.4
lsostearic Acid (ISA) 19.4 3.2
Ethyl Oleate 19.4 1.6 =
Olive Oil 13.6 3.3
Propylene Glycol/ISA .0:1) 764.7 193.9
-
* Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 6-28 hours. If the
=experiment was continued it is anticipated the steady state would
continue. .
=
=
All the pure non-volatile solvents studied have an average flux of less than
40
ng/cm2/hr over the 30 hour time period. Propylene glycol and glycerol have the
lowest permeation for clobetasol propionate. A mixture of propylene glycol and
. =
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isostearic acid in weight ratio of 9:1 have significantly higher flux than
either of
the solvents alone or the other solvents tested. The average flux is 20 times
higher than that with light mineral oil which is the best non-mixed solvent.
=
Hence, for clobetasol propionate propylene glycol/isostearic acid combination
is
an ideal non-volatile solvent.
Examples 17-22
= Adhesive solidifying formulations containing 0.05% (w/w) clobetasol
0
propionate with propylene glycol and isostearic acid as non volatile solutions
and various solidifying agents are prepared. The formulations are prepared
from
the ingredients as shown in Table 9.
=
Table 9 - Solidifying formulation components
Percent Percent
Percent Percent rc
Example Polymer Propylene Isostearic Pe
Polytner Ethanol
Wateernt
Glycol Acid
17 Polyvinyl = 20 30 19.6 0.4 30
Alcohol
18. Shellac 50 . 30 19.6 0.4 0
Dermacryl 65.76 21.16 12.76 0.26 0
19 79 =
Eudragit 50 30 19.6 0.40
=
E100 =
21 Eudragit 50 30 19.6 0.40 9
=
RLPO
22 Gantrez 14.3 57.1 28 0.6 0 =
S97
15 Each
of the compositions shown above are studied for flux of clobetasol
propionate as shown in Table 10 as follows: =
Table 10 - Steady state flux of clobetasol propionate through human
Cadaver skin at 35 C
Skin Flux*
Formulation
= (ng/cm2/h)
. . Example 17 87.8 21.4
Example 18 9.7 2.4
Example 19 8.9 0.8
Example 20 3.2 1.7
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= Example 21 20.2
18.6
Example 22 147.5 38.8
* Skin flux measurements represent the mean and standard
= deviation of three determinations. Flux measurements reported were
determined from the linear region of the cumulative amount versus time
plots. The linear region was observed to be between 6-28 hours. If the =
=
experiment was continued it is anticipated the steady state would
continue.
. As seen from Table 10 formulation described in Example 17 that contains
=
polyvinyl alcohol as solidifying agents has high flux of clobetasol
propionate.
Polyvinyl alcohol is known to form stretchable films (if formulated with
appropriate plasticizer) and it is likely that this formulation will have
acceptable
wear properties. The toughness of the resulting film can be modified by adding
. appropriate plasticizers if needed. Tackiness can also be modified by adding
appropriate amounts of tackifier or by adding appropriate amounts of another
= Regarding formulation described in Example 22, a higher percentage of
ethanol is needed to dissolve the polymer. However, the polymer used in
Example 22 provides the highest flux of dobetasol propionate among the
solidifying agents studied. The wear properties of this formulation can be
modified by adding appropriate levels of other ingredients including but not
limited to plasticizers, taCkifiers, non-volatile solvents and or solidifying
agents.
Example 23-25 = =
"
. Placebo formulations containing Gantrez ES 425 as a tackifier were
prepared for wear studies by volunteers. The formulations are shown as .
examples in Table 11. All the formulations have Polyvinyl alcohol as the .
solidifying agent. The amount of propylene glycol in the formulations was = -
decreased from 19.6% (w/w) to 8.7% (w/w), and the amount of glycerol was
increased by the same amount to keep the total non-volatile ratio constant.
Keeping the non-volatile ratio constantis. important as it determines the
drying
time and the duration of delivery. The placebo formulations are worn on the
palms of hand and percentage adherence of the film formed after evaporation of
=
volatile solvents was observed after 5-6 hours.
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Table 11 - Placebo formulations (%w/w ingredients)
Ingredient Example 23 Example 24 Example 25
Polyvinyl Alcohol 21.7% 21.7% 21.7%
Water 32.6% 32.6% 32.6%
Glycerol 8.7% 13.0% 19.6%
Propylene Glycol 19.6% 15.2% 8.7%
=
Gantrez ES 425 4.3% 4.3% 4.3%
Oleic acid 4.3% 4.3% 4.3%
Ethanol 8.7% 8.7% 8.7%
Wear study results on 3 volunteers show that 70-80% of solidified layer aS
described in Example 23 stayed on palms after a duration of 5-6 hours.
However, greater than 90% of solidified layer as shown in Example 25 stayed
on palms of the volunteers. These examples demonstrate that glycerol is a
better plasticizer that propylene glycol for the polyvinyl alcohol polymer. It
also
shows that the ratio of non-volatile solvent is critical in selecting the
formulation
for treatment of hand dermatitis. .
= Example 26
A formulation with the following composition: 10.4% polyvinyl alcohol,
=
10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90, 10.4%
glycerol, 27.1 % water, and 31.3% ethanol was applied ontci a human skin
surface at an elbow joint and a finger joint, resulting in a thin,
transparent,
flexible, and stretchable film. = After a few minutes of evaporation of the
volatile =
solvents (ethanol and water), a solidified peelable layer that was peelable
was
formed. The stretchable film had good adhesion to the skin and did not
separate
from the skin on joints when bent, and could easily be peeled away from the
=
skin.
Examples 27-28
=
=
Adhesive peelable formulations containing 0.05.% (w/w) clobetasol =
propionate and 0.15% (w/w) clobetasol propionate with polyvinyl alcohol as
25* solidifying polymer are prepared for in-vitro flux evaluation.
Propylene glycol and =
oleic acid are the non volatile solvents selected for facilitation of
clobetasol
propionate delivery. As shown in Example 12, glycerol is added as the non
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48
volatile solvent for its plasticizing properties. Ratios of ingredients used
in the
two formulations are shown in Table 12.
Table 12 - Clobetasol Propionate peel formulations*
Ingredient Example 27 Example 28
Polyvinyl Alcohol 22.7% 22.7%
Water 34.1% 34.0%
= Glycerol 17.3%
17.2%
Propylene Glycol 7.7% 7.7%
Gantrez ES 425 4.5% 4.5%
Oleic acid . 4.5% 4.5%
=
= * . Ethanol 9.1%
9.1%
=
Clobetasol Propionate 0.05% 0.15%
* Numbers do not add to 100% because of rounding in the second decimal.
= Both of the compositions shown above are studied for flux of clobetasol
propionate on cadaver skin from three donors. The permeation results are as
shown in Table 13. Commercial clobetasol ointment (0.05% w/w) was used as a
control formulation.
=
Table 13 - Steady state flux of clobetasol propionate through human . .
cadaver skin at 35 C
= Control Example 27
Example 28
Skin Donor J* J* Crig/ J*
Crig/
= =
cm /h) cm /h) cm
/h).
Donor 1 = ' = 22.4 2.1
8.8 1.9 29.2 8.2
= Donor 2 ' 20.0 2.5
7.6 2.5 18.5 6.4
Donor 335.0 4.7 19.3 5.9
24.8 7.7
=
Mean +/- SD (n=3.donors) 26.8 7.5 1-
1.9 6.5 24.2 8.0
= =
* Skin flux measurements represent the mean and standard deviation of
three determinations. Flux measurements reported are determined from the =
linear region of the cumulative amount versus time plots. The linear region
are
observed to be between 6-28 hours. If the experiment is continued, it is
anticipated the steady state would continue.
=
= =
As seen from Table 13 formulation described in Example 27 that contained
polyvinyl alcohol as a solidifying agent and 0.05% clobetasol propionate had
46% flux of clobetasol propionate when compared to the control formulation.
Increasing the clobetasol propionate concentration drug concentration to 0.15%
(w/w) increased the steady state flux and the flux values were 94% Of the
=
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= 49
control formulation. It is expected that longer duration of application with
the
peel formulation would increase cumulative delivery in-vivo resulting in
effective
treatment of dermatitis.
Example 29
Adhesive solidifying formulations containing 0.05% (w/w) clobetasol
propionate with fish gelatin as solidifying agent are prepared for in-vitro
flux
evaluation. Propylene glycol, isostearic acid, and oleic acid are used as non-
volatile solvents to facilitate delivery of clobetasol. Talc is added as a
filler to
reduce the drying time the formulation. Ratio of ingredients used in the
formulation is shown in Table 14.
Table 14: Clobetasol Propionate formulations*
Ingredient = Example 29
Fish Gelatin 29.4%
Water 22.0%
Ethanol 14.7% =
Propylene Glycol 17.6%
lsostearic acid = 2.2% .
Oleic acid 2.2%
Talc 11.8%
Clobetasol Propionate 0.05%
* Numbers do not add to 100% because of rounding in the second decimal.
=
Unlike the polyvinyl based formulations shown in previous examples, the fish
gelatin based formulation shown in Example 29 is a water washable formulation
and can be easily removed by subjects suffering from hand dermatitis. Steady
state flux across human cadaver skin from 3 donors with formulation as
described in Example 29 is compared to the commercial clobetasol ointment.
The permeation results are _shown in Table 15.
Table 15 - Steady state flux of clobetasol Propionate through human
cadaver skin at 35 C
=
Control. Example 29 -
Skin Donor
= J* (ng/ cm2/h) J* (Ag/ cm2/h)
Donor 1 39.2 9.2
46.1 14.3 =
Donor 2 35.6 2.1 52.9 22.3
Donor 3 - 35.6 5.7 79.7 18.4
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= Mean -II- SD (n--.3 donors) 36.8 5.8 59.6 22.3 -
*Skin flux measurements represent the mean and standard.
deviation of three determinations. Flux measurements reported are
determined from the linear region of the cumulative amount versus time
.
plots. The linear region are observed to be between 6-28 hours. If the
experiment is continued, it is anticipated the steady state would continue.
=
As seen from Table 15, formulation described in Example 29 has 62% higher
steady state flux when compared to the commercial ointment. Higher steady
state flux would is expected to reduce inflammation in difficult to treat
dermatitis
and psoriasis cases.
=
=
Example 30 =
Adhesive solidifying formulations containing 0.05% (w/w) clobetasol
propionate with fish gelatin as solidifying polymer are prepared for in-vitro
flux
evaluation. Propylene glycol, and isostearic acid are used as non-volatile
solvents to facilitate delivery of clobetasol. Fumed silica is added as a
filler to =
=
reduce the drying time the formulation. Ratio of ingredients used in the
formulation is shown in Table 16.
= Table 16: Clobetasol Propionate formulations*
= Ingredient Example 30
Fish Gelatin 32.2%
=
== Water 24.2%
Ethanol = 16.1%
Propylene Glycol 19.3%
=
. Isostearic acid 4.8%
Fumed Silica 3.2%
= Clobetasol Propionate . .
0.05%
* Numbers do not add to 100% because of rounding in the second. decimal.
=
The fish gelatin based formulation shown in Example 30 is a watel= washable
formulation and can be easily removed by subjects suffering from hand
=
dermatitis. Steady state flux across human cadaver skin from 4 donors.with
formulation as described in Example 30 is compared to the commercial
clobetasol ointment. The permeation results are shown in Table 17. .
=
=
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51
Table 17 - Steady state flux of clobetasol propionate through human
cadaver skin at-35 C
Control Example
'30
Skin Donor
J* (ng/ cm2/h) J* (ng/ cm2/h)
= Donor 1 28.2
7.8 20.7 12.8
Donor 2 30.1 14.9 30.6
13.8
Donor 3 36.2 - 6.2 93.4
7.5
= Donor 4 33.6
3.9 101.4 8.5
Mean +/- SD (n.3 donors) 32.0 8.5 61.5 1-
38.9
*Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported are
= 5 - determined from the liner region of the cumulative amourti
versus time
plots. The linear region are observed to be between 6-28 hours. If the
experiment is continued, it is anticipated the steady state would continue.
=
As seen from Table 17, on an average, formulation described in Example 30
has at-least similar or better steady state flux when to compared to the
steady
state flux with the commercial ointment. Unlike talc used in Example 29, fumed
silica had a low density and is expected to have a less potential to separate
from the formulation.
=
Example 31 "
. .
Example 29 and 30 indicate that fish gelatin, a protein based solidifying
agent (polymer) based formulations is preferred polymer of choice fdr delivery
of
Corticosteroid drugs. However, fish.gelatin based forrriulations take a longer
time
to dry. Alternate adhesive formulations containing 9.05% (w/w).clobetasol =
propionate with zein, a. corn based protein, as solidifying polymer are,
prepared
for in-vitro flux 'evaluation. Propylene glycol, and.isostearic acid are used
as =
non-volatile solvents to facilitate delivery of clobetasol. Unlike fish
gelatin, which
has poor solubility in ethanol, zein, is soluble in ethanol, and hence zein
based
formulations have a lower drying time. Ratio of ingredients used in' the =
.
formulation is shown in Table 18. =
Table 18: Clobetasol Propionate formulations with zein''
Ingredient = Example 31
Zein 36.3%
Propylene Glycol 21.8% =
lsostearic acid 5.5%
Ethanol 36.3% =
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Clobetasol Propionate 0.05%
* Numbers do not add to 100% because of rounding in the second decimal.
Steady.state flux across human cadaver skin with formulation as described in
Example 31 is compared to the skin flux with a commercial clobetasol ointment.
The permeation results are shown in Table 19. =
Table 19 - Steady state flux of clobetasol propionate through human
cadaver skin at 35 C
Control Example 31
. . J* (ng/ cm2/h) J* (ng/ cm2/h)
Cadaver skin = = . 17.2 4.1 14.8
1Ø
*Skin flux measurements represent the mean and standard
deviation of three determinations. Flux measurements reported are
determined from the linear region of the cumulative amount versus time
plots. The linear region are observed to be between 6-28 hours. If the
experiment is continued, it is anticipated the steady state would continue.
As seen from Table 19, the formulation described in Example 31 has
comparable steady state flux to the commercial ointment (Ratio 86%). This
ratio
is significantly higher than the ratio of formulation in Example 27, a
polyvinyl .
_ .
alcohol based formulation, which has a ratio at 46%. This example
demonstrates that formulation with-protein based solidifying agents preserve -
flux of corticoteroids better than polyvinyl based formulations The wear
properties of formulation in Example 31 can be improved by the addition of
plasticizers and fillers.
= = .
Example 32 = =
.To demonstrate the ability of the solidified solidifying formulations to -
reduce the transepidermal water loss (TEWL) the.f011owing experiment was
conducted.
Placebo PVA formulation similar to the formulation-described in Example
= 28 was applied to the top of the hand and the TEWL was measured on a site
immediately adjacent to the solidified layer and on top of the solidified
peel. The
=
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TEWL measurement of the site covered by the solidified layer was 33% lower
=
than the untreated skin site. =
Placebo Plastoid B formulation similar to the formulation described in
Example 20 was applied to the top of the hand and the TEWL was measured on
a side immediately adjacent to the solidified layer and on top of the
solidified
peel. The TEWL measurement on the site covered by the solidified layer was
30% lower than the untreated skin site.
Example 33-36
Adhesive solidifying formulations containing the following components
are made:
Table 20 - Imiquimod peelable formulation ingredients
Example
Ingredients*
= 33 34 I 35 36
PVA 10.1
Plastoid B** 17.5
EUdragit RL PO 16.2 24.8
Pemulen TR-2 0.3
=
Water 52.9.
=
lsopropanol = 35.1
Ethanol = 32.4 38.6
ISA (lsostearic Acid) 16.8 23.4 23.1
27.6
. Salicylic Acid 15.2 16.4 16.
= Trolainine 1.7 =
Triacetin = 3.5 3.5
4.1
= Imiquimod '3.0 4.1 4.0 4.8
* Ingredients are noted as weight percent.
= =
** Polymer from Degussa
These formulations are applied to HMS skin as described in Example 1, and the -
imiquimod flux is measured. A summary of the results from in vitro flux
studies
carried out with the formulations in Examples 33-38 are listed in Table 21.
. .
=
Table 21 - Steady-state flux of lmiquimod through hairless mouse skin
from various adhesive peelable formulations at 35 C
Average flux Ratio to
= Formulation = mcg/cm2/h* =
'Control**
Example 33 . 1 1 1.1
Example 34 4.5 0.4 5
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54
=
Example 35 3.8 0.5 = 4.2
Example 36 0.8 * 0.2 0.9
Aldara 0.9 0.02 1 =
* The flux values represent the mean and SD of three determinations
** Ratio to control calculated by dividing the flux value for each Example
=
- by the flux value for Aldara control flux.
= =
In vitro flux of Examples 33-36 is substantially higher than that of the
Aldara control.
The scope of the claims should not be limited by the preferred
embodiments set forth in the examples, but should be given the
broadest interpretation consistent with the description as a whole.
= . =
. .
=
=
=
=
= . =
=
= =
. .
=
= =
= =
. - =
= = = =
. = = =
= = . - =
= =
=
= = =
. =
.=
= =
= =
=
=
== = =
=
