Antifungal/steroid topical compositions

• US 6,075,056 A
• Filed: 10/03/1997
• Issued: 06/13/2000
• Est. Priority Date: 10/03/1997
• Status: Expired due to Term

• Current Assignee: Mylan Bertek Pharmaceuticals, Inc. (Pfizer Inc.)
• Original Assignee: Penederm, Inc. (Pfizer Inc.)
• Inventors: Chaudhuri, Bhaskar, Quigley, John W. Jr., Hou, Sui Yuen Eddie
• Primary Examiner(s): Dees, Jose' G.
• Assistant Examiner(s): PRYOR, ALTON NATHANIEL
• Application Number:
  US08/943,574
• Time in Patent Office: 984 Days
• Field of Search: 514/649
• US Class Current: 514/649
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone

Abstract

Stable topical formulations comprising an antifungal agent and an antiinflammatory steroid are disclosed, useful for treating fungal diseases and their related inflammation.

Claims

1. A topical antifungal composition comprising:

a) a therapeutically effective amount of an antifungal compound of the formula;

##STR5## wherein;

R¹, R², and R³ are independently hydrogen or lower alkyl;

X is --(CH₂)_n --;

in which n is 0, 1 or 2;

Y is --C.tbd.C--R⁴, or aryl;

in which R⁴ is lower alkyl; and

Ar is aryl;

or a pharmaceutically acceptable salt thereof;

b) a therapeutically effective amount of an antiinflammatory steroid; and

c) pharmaceutically acceptable excipients sufficient to form a topical composition.

2. The composition of claim 1, wherein the therapeutically effective amount of the antifungal compound is an amount between about 0.5% and 5% by weight of the total composition and the therapeutically effective amount of the antiinflammatory steroid is an amount between about 0.001% and 2.5% by weight of the total composition.

3. The composition of claim 2, wherein the composition is formulated as a cream, ointment, gel, lotion, foam, powder, aerosol, spray, shampoo, or liquid solution.

4. The composition of claim 3, wherein the composition is a cream.

5. The composition of claim 4 having a pH of about 3.5 to about 7.0, wherein the pharmaceutically acceptable excipients comprise:

at least one solvent, at least one emollient, at least one humectant, at least one preservative, and at least one emulsifier; and

optionally including an acid, base, or buffering agent to adjust the pH.

6. The composition of claim 5, wherein:

the solvent is chosen from one or more of propylene glycol, butylene glycol, hexylene glycol, polyethylene glycols, polypropylene glycols, and polyurethane compounds;

the emollient is chosen from one or more of white petrolatum, mineral oil, propylene glycol dicaprylate, lower fatty acid esters and lower alkyl ethers of propylene glycol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, stearic acid, cetyl esters wax, spermaceti wax, and white wax;

the humectant is chosen from glycerin and sorbitol; and

the emulsifier is chosen from one or more of glyceryl monostearate, glyceryl monoleate, stearic acid, polyoxyethylene cetyl ether, polyoxyethylene cetostearyl ether, polyoxyethylene stearyl ether, and polyethylene glycol stearate;

wherein the optional acid is chosen from hydrochloric acid and phosphoric acid, the optional base is chosen from diethanolamine, triethanolamine, and sodium hydroxide, the optional buffering agent is chosen from monobasic sodium phosphate and dibasic sodium phosphate, and the preservative is chosen from benzyl alcohol, sodium benzoate and parabens.

7. The composition of claim 6, wherein the antiinflammatory steroid is betamethasone, betamethasone dipropionate, fluocinonide, fluocinoline acetonide, hydrocortisone, methylprednisolone, clobetasol, or beclomethasone.

8. The composition of claim 7, wherein a solvent is a hydroxy-terminated polyurethane compound chosen from polyolprepolymer-2, polyolprepolymer-14, and polyolprepolymer-15.

9. The composition of claim 8, wherein Ar is optionally substituted naphthyl, R¹ and R³ are hydrogen, and R² is methyl.

10. The composition of claim 9, wherein Y is optionally substituted phenyl or --C.tbd.C--R⁴.

11. The composition of claim 10, wherein Ar is 1-naphthyl, n is 0, and Y is 4-t-butylphenyl or a pharmaceutically acceptable salt thereof.

12. The composition of claim 10, wherein the cream is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 2-10 Glyceryl monostearate, self 1-10 emulsifying type Triethanolamine 0.1-1.0 White petrolatum 1-10 Propylene glycol 5-20 Propylene glycol dicaprylate 5-20 Cetyl alcohol 1-10 Stearic acid 1-10 Polyolprepolymer-2 0-5 Polyoxyethylene (23) cetyl ether 1-10 Benzyl alcohol 0.5-3 Sodium benzoate 0-0.5 Steroid 0.01-2.5 Antifungal 0.5-5 ______________________________________

13. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 5 Glyceryl monostearate, self 3 emulsifying type Triethanolamine 0.5 White petrolatum 4 Propylene glycol 10 Propylene glycol dicaprylate 5 Cetyl alcohol 6 Stearic acid 5 Polyolprepolymer-2 1 Polyoxyethylene (23) cetyl ether 4 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

14. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 5 Glyceryl monostearate, self 5 emulsifying type Triethanolamine 0.3 White petrolatum 4 Propylene glycol 7 Propylene glycol dicaprylate 10 Cetyl alcohol 4 Stearic acid 3 Polyoxyethylene (23) cetyl ether 2 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

15. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 5 Glyceryl monostearate, self 5 emulsifying type Triethanolamine 0.3 White petrolatum 4 Propylene glycol 7 Propylene glycol dicaprylate 10 Cetyl alcohol 4 Stearic acid 3 Polyolprepolymer-2 1 Polyoxyethylene (23) cetyl ether 2 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

16. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 5 Glyceryl monostearate, self 3 emulsifying type Triethanolamine 0.5 White petrolatum 4 Propylene glycol 10 Propylene glycol dicaprylate 5 Cetyl alcohol 6 Stearic acid 5 Polyoxyethylene (23) cetyl ether 4 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

17. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 7 Glyceryl monostearate, self 4 emulsifying type Triethanolamine 0.3 White petrolatum 3 Propylene glycol 5 Propylene glycol dicaprylate 7 Cetyl alcohol 5 Stearic acid 4 Polyolprepolymer-2 1 Polyoxyethylene (23) cetyl ether 3 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

18. The composition of claim 12, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs Glycerin 7 Glyceryl monostearate, self 4 emulsifying type Triethanolamine 0.3 White petrolatum 3 Propylene glycol 5 Propylene glycol dicaprylate 7 Cetyl alcohol 5 Stearic acid 4 Polyoxyethylene (23) cetyl ether 3 Benzyl alcohol 1 Sodium benzoate 0.2 Betamethasone dipropionate 0.064 Butenafine hydrochloride 1 ______________________________________

19. The composition of claim 10, wherein the cream is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs White petrolatum 1-20 Propylene glycol 2-20 Cetearyl alcohol 1-10 Polyolprepolymer-2 0-3 Stearic acid 1-10 Mineral oil 5-20 Ceteareth-30 1-10 Benzyl alcohol 0.5-3 Steroid 0.01-2.5 Antifungal 0.5-5 ______________________________________

wherein an acid or base is added in quantity sufficient to adjust the pH of the cream to about 3.5 to 7.0.

20. The composition of claim 19, wherein the antiinflammatory steroid is betamethasone dipropionate and the antifungal is butenafine hydrochloride.

21. The composition of claim 10, wherein the cream composition is:

space="preserve" listing-type="tabular">______________________________________ Ingredients Wt % ______________________________________ Water qs to 100% White petrolatum 8 Propylene glycol 3 Cetearyl alcohol 6 Polyolprepolymer-2 1 Stearic Acid 4 Mineral oil 8 Ceteareth-30 8 Dibasic sodium 0.5 phosphate Phosphoric acid 0.02 Benzyl alcohol 1 Betamethasone 0.064 dipropionate Butenafine HCl 1 ______________________________________

22. The composition of claim 10, wherein the cream is:

##STR6## wherein an acid or base is added in quantity sufficient to adjust the pH of the cream to about 3.5 to 7.0.

23. The composition of claim 22, wherein the antiinflammatory steroid is betamethasone dipropionate and the antifungal is butenafine hydrochloride.

26. An article of manufacture, comprising:

(A) the topical composition of claim 1, in combination with;

(B) labeling instructions for application of said topical composition for the treatment of fungal diseases.

24. A method of treating a fungal disease, comprising application to the skin of a mammal in need of such treatment a topical composition comprising:

a) an effective amount of an antifungal compound of the formula;

##STR7## wherein;

R¹, R², and R³ are independently lower alkyl;

X is --(CH₂)_n --;

in which n is 0, 1 or 2;

Y is --C.tbd.C--R⁴, or aryl;

in which R⁴ is lower alkyl; and

Ar is aryl;

or a pharmaceutically acceptable salt thereof;

b) an effective amount of an antiinflammatory steroid;

c) amounts of pharmaceutically acceptable excipients sufficient to form a topical composition.

25. The fungal disease of claim 24 which is chosen from tinea pedis, tinea capitis, tinea corporis, tinea versicolor, nail fungal diseases, scalp disorders, tinea cruris, and candidiasis.