Title of Invention

AN ANHYDROUS COMPOSITION FORMULATED FOR TROPICAL DELIVERY

Abstract An anhydrous composition formulated for topical delivery comprising: (a) ethanol, (b) propylene glycol, (c) polyethylene glycol, (d) glycerin, and (e) ketoconazole, wherein the composition is formulated as a gel.
Full Text FIELD OF THE INVENTION
The present invention relates to topical anhydrous skin
preparations having high therapeutic efficacy, low toxicity, and the ability to
target or enhance delivery of active agents to the skin, thereby resulting in an
improved, high therapeutic index. The invention further relates to methods for
making and using such compositions.
BACKGROUND OF THE INVENTION
Alcohols, polyols (such as, for example, propylene glycol),
surfactants (such as, for example, sodium lauryl sulfate), preservatives (such
as, for example, parabens, such as methyl paraben), acids (such as, for
example, sorbic acid), and solvents, singly or in topical preparations, are
known either to induce irritation, sensitization, or allergic skin reactions and/or
to be skin penetration enhancers. Humectants (such as for examples,
glycerin), solvents (such as, for example, polyethylene glycol), sunscreens
(such as, for example, zinc oxide), and surfactants are among the entities
known to retard skin penetration of active agents. See, Angleini, G. Contact
Dermatitis 7, 1981; Belmonte, J. Pharm Sc/67: 517,1978; Catanzaro, J.M. J
Am Acad Dermatol 24(1), 1981; Cooper, J. Pharm Sci73:1153, 1984;
Faucher, J Am Oil Chem Soc 56: 776, 1979; Lahti, A. Contact Dermatitis 29,
1993; Trancik, R. J., Contact Dermatitis 8, 1982; Wahlberg, J.E. Acta Derm
Venereol 64, 1984; Zatz, J. L. J Soc Cosmet Chem 34: 327, 1983.
Patel et al., U.S. Patent No. 4,855,294, disclose a composition
containing glycerin and a method for reducing skin irritation properties of a

transdermal (i.e., delivery by actual passage of a drug through the skin or
mucosal tissue) drug enhancer composition.
Glucocorticosteroid-based compositions have been used since
the 1940's to treat inflammations of the skin. World Patent Publication No.
W092/18113 discloses a liquid solution containing an antifungal agent and a
steroid for use as a mouthwash. Hogi, F. Mykosen 23(8): 426,1980 reports
on the activity of ketoconazole in the presence of triaminolene acetonide.
Ketoconazole compositions have more recently been proved to be effective in
the treatment of mycotic infections.
Skin diseases are often characterized by the combination of
both inflammatory-conditions and fungal infections, since inflammatory
processes of the skin create predisposing conditions for the growth and
proliferation of pathogenic microorganisms. Therefore, a single drug-therapy
with an antiinflammatory or an antifungal agent alone is often insufficient to
treat various skin diseases.
U.S. Patent No. 5,654,293 and EP Patent Publication No. 0 680
328 describe a topical oil in water emulsion and pharmaceutical composition
respectively comprising ketoconazole and an acetonide glucocorticosteroid
having a pH above 2.5 and below 6.
However, the stability problems involved combining a 17-ester
steroid with an imidazole antifungal agent are known from U.S. Patent Nos.
5,002,938 and 5,110,809. The preparation of a formulation containing both
ketoconazole and a glucocorticosteroid was hindered by the destabifization of
the steroid in the presence of ketoconazole. There continues to be an unmet
clinical need for topically stable, efficacious, and nontoxic therapies targeted
to the skin for the treatment of skin disorders. Therefore, applications of and
the opportunity for new methods for making these compositions are needed.
SUMMARY OF THE INVENTION
According to an embodiment of the present invention, there are
provided anhydrous compositions for topical delivery of one or more
medicaments. These compositions comprise:
(A) a penetration
enhancer/solvent selected from the group
consisting of alcohol, propylene glycol, or a
combination thereof;
(B) a humectant/solvent selected
from the group consisting of polyethylene glycol,
glycerin, sorbitol, xylitol, or any combination of any
of the foregoing; and
(C) an anhydrous vehicle.
According to an alternate embodiment of the present invention,
there are provided anhydrous compositions for topical delivery of one or more
medicaments which comprise:
(A) a penetration
enhancer/solvent selected from the group
consisting of alcohol, propylene glycol, or a
combination thereof;
(B) a humectant/solvent selected
from the group consisting of polyethylene glycol,
glycerin, sorbitol, xylitol or any combination of any
of the foregoing;
(C) an anhydrous vehicle; and
(D) one or more medicaments.
According to another embodiment of the present invention, there
are provided
methods for topically delivering one or more medicaments to an animal, such
as a mammal or a human patient, in need of the medicaments. The methods
comprise topically administering to the animal compositions as described
above.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the present invention typically are creams,
gels, ointments, lotions or liquids. These compositions are anhydrous in that
no water is added. However, a certain amount of water associated with the
various components may be contained in the composition. Typically, this will
be less than 10 percent by weight, based upon 100 percent by weight of total
composition. Preferably, the present compositions are completely anhydrous.
Penetration enhancers/solvents suitable for use in the present
invention are alcohols, including, but not limited to, ethanol, propylene glycol,
or a combination thereof. Suitable humectants/solvents for use herein,
include, but are not limited to, polyethylene glycol, glycerin, sorbitol, xylitol or
any combination of any of the foregoing. Suitable anhydrous vehicles for use
herein include, but are not limited to, alcohols which may be the same as or
different than the alcohol penetration enhancer. Non-limiting examples of
such alcohols are isobutanol and isopropyl alcohol.
Medicaments which may be delivered topically in the present
compositions include, but are not limited to, antifungal agents, antibacterial
agents, antiviral agents, antiacne agents, antiaging agents, antipruritic agents,
photoprotection agents, skin pigment modulators, hair growth enhancers, hair
growth inhibitors, hair removal agents, antidandruff agents, anti-seborrheic
agents, anti-psoriasis agents, exfoliating agents, wound heaiing agents, anti-
ectoparasitic agents, sebum modulators, immunomodulators, hormones,
botanicals, moisturizers, astringents, cleansers, sensates, antibiotics, anti-
irritants, anesthetics, analgesics, steroids, anti-inflammatories, tissue healing
substances, tissue regenerating substances, vitamins including, but not
limited to, retinoids and the like, amino acids, peptides, minerals, hydroxy
acids, including, but not limited to, alpha hydroxy acids and beta hydroxy
acids, or any combination of any of the foregoing.
Non-limiting examples of steroids are glucocorticosteroids and
particularly desonide. A non-limiting example of an antifungal agent is
ketoconazole. A non-limiting example of an antibiotic is erythromycin.
Other components which may be contained in the compositions
of the present invention include, but are not limited to, emollients, chelating
agents, pH adjusters, antioxidants, gelling agents, viscosifiers, colorants,
fragrances, UV stabilizers, sunscreens, or any combination of any of the
foregoing.
Non-limiting examples of pH adjusters are malic acid, lactic acid,
citric acid, glycolic acid, benzoic acid, ascorbic acid, or any combination of
any of the foregoing. Non-limiting examples of antioxidants are propyl gallate,
ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butyiated
hydroxytoluene (BHT), tocopherol, such as alpha-tocopherol, or any
combination of any of the foregoing. A non-limiting example of a viscosifier is
hydroxypropyl cellulose.
The amounts of each of the components of the present
composition are typically those amounts effective to accomplish the purpose
of that ingredient. For example, the amount of penetration enhancer is
typically a penetration enhancing effective amount. Preferably, the
compositions include from about 1.0 to about 50 percent by weight of
penetration enhancer/solvent, from about 10 to abolit 80 percent by weight of
humectant/solvent, from 0 to about 10 percent by weight of emollient and
aesthetic enhancer combined, from 0 to about 2 percent by weight of
chelating agent and pH adjuster combined, from 0 to about 2 percent by
weight of antioxidant, from 0 to about 5 percent by weight of gelling agent and
viscosrfier combined, and an anhydrous vehicle, based upon 100 percent by
weight of total composition.
Preferably, the amount of hydroxypropyl cellulose gelling agent
will range from 0 to about 3 percent by weight, based upon 100 percent by
weight of total composition.
Preferred amounts of specific medicaments are from about
0.0001 to about 20 percent by weight, preferably from about 0.5 to about 3
percent by weight, and most preferably about 2 percent by weight of an
antifungal agent and particularly ketoconazole; from about 0.0001 to about 10
percent by weight, preferably from about 0.01 percent to about 2.0 percent by
weight, and most preferably about 0.05 percent by weight, of a
glucocorticosteroid and particularly desonide; preferably from about 0.001 to
about 0.5 percent by weight, and most preferably from about 0.02 to about 0.1
percent by weight of a vitamin and particularly an all- trans retinoic acid,
tretonoin; and preferably from about 0.01 to about 10 percent by weight, and
most preferably from about 0.1 to about 3 percent by weight of an antibiotic
and particularly erythromycin, based upon 100 percent by weight of total
composition.
The amount of the penetration enhancer, solvent and vehicle
may be balanced to solubilize the medicament.
The compositions of the present invention are administered
topically in therapeutically effective amounts of the medicament incorporated
therein.
The compositions of the present invention may be prepared by
mixing the penetration enhancer/solvent, humectant/solvent, and anhydrous
vehicle in a primary vessel until uniform. Medicaments or active agents can
then be added and mixed until uniform. Any chelating agents, pH adjusters,
antioxidants, emollients, aesthetic enhancers, fragrances, UV stabilizers,
sunscreens, colorants and the like can then be added and mixed until uniform.
Viscosifiers and gelling agents may then be added and mixed until uniform.
The final product may then be packaged.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples illustrate the invention without limitation.
All amounts are given by percent by weight based upon 100 percent by
weight of total composition, unless noted otherwise.
Example 1
An anhydrous composition for topical administration of
ketoconazole and desonide was prepared having the formulation of Table 1
below.
Comparative Examples 1A-C
Compositions having the formulations of Tables 2-4 below were
prepared.
Example 2
An anhydrous composition for topical administration of all-trans
retinoic acid also known as tretinoin, was prepared having the formulation of
Table 5 below.
Example 3
An anhydrous composition for topical administration of erythromycin
was prepared having the formulation of Table 6 below.
Example 4 and Comparative Example 4A: Skin Inflammation Assay
Topically applied phorbol esters are known inducers of skin
inflammation. Corticosteroids are known to be highly effective in lowering
phorbol ester (e.g. TPA) induced inflammation in a dose dependent fashion.
Therefore, this model was used to evaluate the relative anti-inflammatory
activity of corticosteroids.
Dose response studies to reduce skin inflammation (TPA ear
edema in a murine model) were conducted with the compositions of Example
1 (Example 4) and Comparative Example 1A (Comparative Example 4A).
Results are illustrated in Table 7 below.
The composition of Example 1 (Example 4) (ED50 = 0.0015%)
was topically three times more active and more potent in its skin anti-
inflammatory activity than that of Comparative Example 1A (Comparative
Example 4A)(ED50 = 0.0054%)
Example 5 and Comparative Examples 5A and 5B: Skin Antifungal Assay
Microbiological in vitro cadaver skin zone of inhibition studies
were conducted to measure antifungal activity and to demonstrate biological
activity on the human skin using the compounds of Example 1 (Example 5),
Comparative Example 1A (Comparative Example 5A), and NIZORAL® cream
(2% ketoconazole cream) (Janssen Pharmaceutica) (Comparative Example
5B). Results are illustrated in Table 8 below.
Only a partial zone of inhibition was noted for this organism where it
continued to grow; no clear zone resulted.
T. rubrum is a major organism known to cause skin fungal
disorders including tinea corporis, tinea cruris, and tinea pedis. Results
indicated that the composition of Example 1 (Example 5) demonstrated
significant skin antifungal (clear zone) activity against the common
dermatophyte T. rubrum. The composition of Comparative Example 1A
(Comparative Example 5A) and NIZORAL® cream (Comparative Example 5B)
did not demonstrate clear zone antifungal activity for T. rubrum in this study.
P. ovale has been implicated as playing a major role in the
etiology of various dermatoses, such as Seborrheic Dermatitis. The
composition of Example 1 (Example 5) also demonstrated outstanding
antifungal activity against the yeast, P. ovale, while that of Comparative
Example 1A (Comparative Example 5A) and NIZORAL® cream (Comparative
Example 5B) only showed minimal activity.
Examples 6 and 7 and Comparative Examples 6A-E and 7A: Measurement of
Targeted and Enhanced Delivery to Skin
Franz cell diffusion studies using human cadaver skin were
conducted to demonstrate cutaneous bioavailability of medicaments like
ketoconazole and desonide using the compositions of Example 1 (Examples 6
and 7), NIZORAL® cream (Comparative Examples 6A, 6C, and 6E),
DesOwen® cream (0.05% desonide cream) (Galderma) (Comparative
Examples 7B, 7C, and 7E), Example 1A (Comparative Examples 6B and 7A),
and Comparative Example 1B (Comparative Examples 6D and7F).
Results are illustrated in Tables 9 and 10 below.
The composition of Example 1 demonstrated targeted delivery
of ketoconazole and desonide to the cutaneous compartments. It delivered
greater amount of ketoconazole to the epidermis and dermis but less to the
receptor versus NIZORAL® cream. A comparable amount of desonide from
the composition of Example 1 was delivered to the epidermis and to the
dermis and less to the receptor versus DesOwen® cream (Comparative
Examples 7B, 7C, and 7E). Diminished amounts of ketoconazole and
desonide medicaments in the receptor compartment of the composition of
Example 1 may clinically translate to lower systemic absorption of the drugs
and, thereby, lower systemic drug toxicity. The composition of Comparison
Example 1A versus NIZORAL® and DesOwen® creams delivered less
ketoconazole to the epidermis and dermis but a greater amount to the
receptor versus NIZORAL® cream.
Overall results indicate that the composition of Example 1
resulted in targeted delivery of the drugs to the skin with greater amounts of
medicaments to the intended sites of the epidermis and dermis versus that of
Comparative Example 1A, NIZORAL®cream and DesOwen® cream. The
data demonstrates better targeted delivery to the skin and more
pharmacologic effects due to the composition of Example 1. Moreover, the
composition of Example 1 demonstrated positively less permeation through
the skin into the receptor that could clinically translate into lower systemic
toxicity. In contrast, the composition of Comparative Example 1A results
indicate greater permeation of ketoconazole into the receptor fluid that could
exhibit negative clinical, toxic systemic effects.
Example 8 and Comparative Examples 8A and 8B: Cumulative Irritation Test
Dermal irritation studies of the compositions of Example 1
(Example 8), Comparative Example 1B (Comparative Example 8A), and
Comparative Example 1C (Comparative Example 8B) were conducted on
albino rabbits to determine relative irritation using mean grades of erythema
and edema. Results are illustrated in Table 11.
As shown in Table 11, the composition of Example 1 was less
irritating than that of Comparative Examples 1B and 1C (p alone did not singly reduce irritations.
In addition, the combination of the diminished irritation the
composition of Example 1 and its enhanced efficacy translated into an
improved, high Therapeutic Index.
Example 9: Repeated Patch Insult Test
The vehicle composition of Example 1, i.e., the composition
without ketaconazole or desonide, was evaluated for the potential to induce
contact dermal sensitization in human subjects.
A total of 216 male and female subjects were evaluated over a
period of six weeks. After selection, a semi-occlusive patch with test material
was applied nine times over three weeks. Following a rest period and test site
observation, a challenge test was conducted.
During the induction phase, three subjects exhibited low-level
reactions. Two other subjects exhibited dryness only. Original test sites
exhibited no reactions on subjects during the rest period and at the challenge.
Only two subjects exhibited low-level reactions at the challenge phase.
These clinical results indicate that the vehicle composition of
Example 1, after repeated application, did not induce contact dermal
sensitization in human subjects.
All patents, publications, applications, and test methods
mentioned herein are hereby incorporated by reference.
Many variations of the present invention will suggest themselves
to those skilled in the art in light of the above, detailed description. All such
obvious variations are within the full intended scope of the appended claims.
We Claim:
1. An anhydrous composition formulated for topical delivery
comprising:
(a) ethanol,
(b) propylene glycol,
(c) polyethylene glycol,
(d) glycerin, and
(e) ketoconazole,
wherein the composition is formulated as a gel.
2. The composition as claimed in claim 1, wherein the ketoconazole
is solubilized.
3. The composition as claimed in claim 1, wherein the amount of
ketoconazole is 0 to 2 percent by weight.
4. The composition as claimed in claim 1, wherein the amount of
polyethylene glycol is 10 to 20 percent by weight.
5. The composition as claimed in claim 4, wherein the amount of
polyethylene glycol is 20 percent by weight.
6. The composition as claimed in claim 1, wherein the amount of
propylene glycol is 20 percent by weight.
7. The composition as claimed in claim 1, wherein the amount of
glycerin is 20 to 30 percent by weight.
8. The composition as claimed in claim 7, wherein the amount of
glycerin is 20 percent by weight.
9. The composition as claimed in claim 1, wherein the imposition
further comprises PPG-15 stearyl ether.
10. The composition as claimed in claim 9, wherein the amount of
PPG-15 stearyl ether is 0 to 2 percent by weight.
11. The composition as claimed in claim 10, wherein the amount of
PPG-15 stearyl ether is 2 percent by weight.
12. The composition as claimed in claim 1, wherein the composition
further comprises hydroxypropyl cellulose.
13. The composition as claimed in claim 12, wherein the amount of
hydroxypropyl cellulose is 1.5 to 2 percent by weight.
14. The composition as claimed in claim 1, wherein the composition
further comprises ascorbic acid.

15. The composition as claimed in claim 14, wherein the amount of
ascorbic acid is 0 to 0.3 percent by weight.
16. The composition as claimed in claim 15, wherein the amount of
ascorbic acid is 0.3 percent by weight.
17. The composition as claimed in claim 1, wherein the composition
further comprises butylated hydroxytoluene.
18. The composition as claimed in claim 17, wherein the amount of
butylated hydroxytoluene is 0 to 0.1 percent by weight.
19. The composition as claimed in claim 18, wherein the amount of
butylated hydroxytoluene is 0.1 percent by weight.
20. The composition as claimed in claim 1, wherein the composition
further comprises citric acid.
21. The composition as claimed in claim 20, wherein the amount of
citric acid is 0 to 0.1 percent by weight.
22. The composition as claimed in claim 21, wherein the amount of
citric acid is 0.1 percent by weight.

23. The composition as claimed in claim 1, wherein the composition
further comprises one or more colorants.
24. An anhydrous composition formulated for topical delivery
comprising:
(a) propylene glycol,
(b)polyethylene glycol,
(c) glycerin,
(d)ethanol,
(e) ketoconazole,
(f) PPG-15 stearylethr,
(g)hydroxypropyl cellulose,
(h) ascorbic acid,
(i) butylated hydroxytoluene, and
(j) citric acid,
wherein the composition is formulated as a gel.
25. An anhydrous composition formulated for topical delivery
consisting essentially of:
(a) propylene glycol,
(b) polyethylene glycol,
(c) glycerin,
(d)ethanol,
(e) ketoconazole,
(f) PPG-15 stearyl ether
(g)hydroxypropyl cellulose,
(h) ascorbic acid,
(i) butylated hydroxytoluene,
(j) citric acid, and
(k)one or more colorants,
wherein the composition is formulated as a gel.
26. A composition as claimed in any one of claims 1, 24 or 25 for use
a medicament.
27. The composition as claimed in claim 1, wherein the composition
further comprises a steroid.
28. The composition as claimed in claim 27, wherein the steroid is a
glucocorticosteroid.
29. The composition as claimed in claim 28, wherein the
glucocorticosteroid is desonide.
30. The composition as claimed in claim 29, wherein the amount of
desonide is 0.0001 to 10 percent by weight.
31. The anhydrous composition as claimed in claim 24, further
comprising desonide.

An anhydrous composition formulated for topical delivery comprising:
(a) ethanol,
(b) propylene glycol,
(c) polyethylene glycol,
(d) glycerin, and
(e) ketoconazole,
wherein the composition is formulated as a gel.

Documents:

in-pct-2000-181-kol-abstract.pdf

in-pct-2000-181-kol-assignment.pdf

in-pct-2000-181-kol-claims.pdf

in-pct-2000-181-kol-correspondence.pdf

in-pct-2000-181-kol-description (complete).pdf

in-pct-2000-181-kol-examination report.pdf

in-pct-2000-181-kol-form 1.pdf

in-pct-2000-181-kol-form 13.pdf

in-pct-2000-181-kol-form 18.pdf

in-pct-2000-181-kol-form 2.pdf

in-pct-2000-181-kol-form 26.pdf

in-pct-2000-181-kol-form 3.pdf

in-pct-2000-181-kol-form 5.pdf

in-pct-2000-181-kol-granted-abstract.pdf

in-pct-2000-181-kol-granted-assignment.pdf

in-pct-2000-181-kol-granted-claims.pdf

in-pct-2000-181-kol-granted-correspondence.pdf

in-pct-2000-181-kol-granted-description (complete).pdf

in-pct-2000-181-kol-granted-examination report.pdf

in-pct-2000-181-kol-granted-form 1.pdf

in-pct-2000-181-kol-granted-form 13.pdf

in-pct-2000-181-kol-granted-form 18.pdf

in-pct-2000-181-kol-granted-form 2.pdf

in-pct-2000-181-kol-granted-form 26.pdf

in-pct-2000-181-kol-granted-form 3.pdf

in-pct-2000-181-kol-granted-form 5.pdf

in-pct-2000-181-kol-granted-reply to examination report.pdf

in-pct-2000-181-kol-granted-specification.pdf

in-pct-2000-181-kol-granted-translated copy of priority document.pdf

in-pct-2000-181-kol-reply to examination report.pdf

in-pct-2000-181-kol-specification.pdf

in-pct-2000-181-kol-translated copy of priority document.pdf


Patent Number 236050
Indian Patent Application Number IN/PCT/2000/181/KOL
PG Journal Number 38/2009
Publication Date 18-Sep-2009
Grant Date 17-Sep-2009
Date of Filing 01-Aug-2000
Name of Patentee JOHNSON & JOHNSON CONSUMER COMPANIES, INC.
Applicant Address 199 GRANDVIEW ROAD, SKILLMAN, NJ
Inventors:
# Inventor's Name Inventor's Address
1 BURNETT, KATHARINE, M. 77 HAAS ROAD, BASKING RIDGE, NJ 07920
2 KURTZ, ELLEN, S. 7 STARK COURT, RINGOES, NJ 08551
PCT International Classification Number A61K 47/00
PCT International Application Number PCT/US1999/28661
PCT International Filing date 1999-12-03
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 09/205,474 1998-12-04 U.S.A.