WO1993020796A1

WO1993020796A1 - Method and composition for treating acne

Info

Publication number: WO1993020796A1
Application number: PCT/US1993/003325
Authority: WO
Inventors: Sreekant R. Nadkarni; Paul A. Laskar
Original assignee: Allergan, Inc.
Priority date: 1992-04-09
Filing date: 1993-04-07
Publication date: 1993-10-28
Also published as: ZA932483B; AU3975993A; IL105217A0

Abstract

The present invention provides topical compositions of a peroxide of an organic acid, e.g., benzoyl peroxide and clindamycin and its derivatives, such as clindamycin phosphate, which are useful for treating acne vulgaris. Such compositions may further include a surfactant including a sulfonic radical.

Description

METHOD AND COMPOSITION FOR TREATING ACNE

W OF THE INVENTION

This invention relates to a method and composition for treating acne vulgaris.

p ACKGROUNP OF THE ART

Acne vulgaris is an inflammatory disease of the sebaceous glands characterized by an eruption of the skin, often pustular in nature but not suppurative. Acne is a common affliction of the adolescent and affects a small but significant percentage of the adult population. Acne involvement results in unsightly lesions, particularly on the face, and in some cases results in severe scarring.

Various topical agents are utilized in the treatment of acne and these include sulfur, resorcinol, salicylic acid, benzoyl peroxide, retinoids and topical antibiotics. An effective anti-acne agent (or composition) must exhibit the following activites:

(a) a sebostatic activity so as to inhibit hyperseborrhea;

(b) a keratolytic and comedolytic activity so as to avoid hyperkeratosis of the follices and to permit removal of comedos;

(c) a bacteriostatic activity so as to inhibit the activity of Propionibacterium acnes.

Nevertheless, acne vulgaris is seldom cured and only can be contained with difficulty.

The antibiotic clindamycin has been used, topically, to treat acne vulgaris. (See U.S. Patent 3,969,516, to Stoughton.) Various references discuss the use of vehicle formulations to enhance the efficacy of topically-applied clindamycin. (See U.S. Patents 3,932,653;

3,989,816; 3,991,203; 4,132,781; 4,671,956; 4,746,675; 4,789,667; 4,803,228

SUBSTITUTE SHEET and 4,882,359.) Clindamycin salts, clindamycin derivatives, and various dosage forms of clindamycin have also been discussed as a treatment for acne vulgaris. (See U.S. Patent 3,849,396; 4,621,075 and 4,916,118.) Finally, combinations of clindamycin and other compounds active for the treatment of acne vulgaris are disclosed in U.S. Patents, 4,323,558; 4,505,896; 4,607,101; 4,906,617; 4,942,031 and 4,018,918.

Benzoyl peroxide has been suggested for treating acne vulgaris. (See U.S. Patent 4,387,107.) For many years, benzoyl peroxide has been proven to be a particularly powerful keratolytic and anti-seborrhic agent, as well as being endowed with antibacterial properties. Topical benzoyl peroxide compositions, including a vehicle to enhance the efficacy thereof, are known (See U.S. Patent 4, 411,893). Topical compositions of benzoyl peroxide combination with antibiotics are also known. (See U.S. Patents 4,407,794; 4,692,329 and 4,387,107)

Peroxides, other than benzoyl peroxide, have been suggested for treatment of acne vulgaris, alone, or in combination with other compounds useful in treating acne vulgaris. (See U.S. Patents 4,607,101 and 4,906,617.) These peroxides are suggested as having certain advantages, e.g. stability over benzoyl peroxide. U.S. Patent 4,671,956 identifies the problem of benzoyl peroxide decomposing coingredients in topical formulations to thereby cause itching upon application. It is suggested that this problem may be solved by including a sunscreen in the topical formulation to retard this decomposition effect of benzoyl peroxide.

I view of the above, it is apparent that there is a great deal of interest in formulating topical compositions for the treatment of acne vulgaris, such compositions utilizing as an active ingredient clindamycin or benzoyl peroxide, alone, or in combination with other active ingredients for the treatment of acne vulgaris. Furthermore, it is apparent that there are stability problems associated with topical compositions including benzoyl peroxide,

SUBSTITUTE SHEET alone, or in combination with other pharmacologically-active compounds.

Therefore, one object of the instant invention is to provide a method of treating acne vulgaris with a topical composition including benzoyl peroxide and clindamycin.

It is another object of the invention to provide compositions of benzoyl peroxide and clindamycin effective for use in the topical treatment of acne vulgaris.

It is another object of this invention to provide stable compositions for the topical treatment of acne vulgaris.

Another object of the invention is to provide topical compositions of benzoyl peroxide and clindamycin that are stable to storage over extended periods of time at ambient conditions.

Other objects and advantages of the instant invention will become apparent from a careful reading of the specification below.

SUMMARY OF THE INVENTION

The present invention provides a method for treating acne vulgaris by topically applying a composition of benzoyl peroxide and clindamycin in a therapeutically-effective amount. The antibiotic clindamycin (free base), or its pharmaceutically acceptable salts or prodrugs (e.g., clindamycin phosphate, clindamycin hydrocholoride), may be applied in an amount sufficient to provide from about 0.1 to about 10 percent, and preferably from about 0.5 to about 5 percent by weight, clindamycin. Benzoyl peroxide, which has keratolytic and antiseborrheic properties, may be present in an amount sufficient to provide from about 0.1 to about 30 percent, and preferably from about 2.5 to about 10 percent, by weight, benzoyl peroxide. The benzoyl peroxide may more preferably be used as hydrous benzoyl peroxide and may be suspended preferably in the

SUBSTITUTE SHEET -4-

form of micropartides. The above described topical composition may be in the form of a solution, gel, ointment, cream, a liquid suspension or emulsion or a stick base. The topical composition of this invention may further include a surfactant preferably comprising at least one sulfonic radical, e.g., long-chain alkyl sulfonates or alkyl aryl sulfonates. The surfactant may comprise from about 0.01 to about 5 percent, by weight, and preferably from 0.025 to about 1 percent, of the above topical composition. Surfactants which are useful in the method and composition of this invention include dioctyl sodium sulfosuccinate and sodium dodecylbenzenesulfonate.

DETAILED DESCRIPTION OFTHE INVENTION

The compositions of this invention are administered topically to treat acne vulgaris. That is, the compositions may be applied as a solution, gel, ointment, cream, a liquid suspension or emulsion or a stick base. Thus, it is preferred that such compositions indude a pharmaceutically acceptable carrier that enhances the efficacy of such topical administration.

Pharmaceutically acceptable carriers include conventional emulsifiers, such as fatty alcohols, glycol ethers and esters of fatty adds; conventional emollients, such as isopropyl and butyl esters of fatty adds, e.g. isopropyl myristate; humectants such as glycerin, propylene glycol, polyethylene glycol; and alcohols and acetone; oils such as mineral oil, petroleum oil, oil extracts from animal or vegetable sources; conventional stabilizers including antioxidants and preservatives. The formulation may also indude agents, such as urea, to improve the hydration of the skin. In addition to the foregoing conventional formulations, the topical compositions may indude penetration-enhancing agents such as 1-pyrrolidone and N- lower alkyl-2-pyrrolidones, such as N-methyl-2-pyrrolidone; and 1- substituted azacycloaIkan-2-ones such as, for example, 1-n- dodecylazacydoheptan-2-one and other compounds disdosed in U.S. Pat. No. 3,989,816. Longer chain sulfoxides, e.g., n-octyl methyl sulfoxide and hexamethylene-lauramide and the other penetration-

SUBSTITUTE SHEET -5-

enhandng agents disdosed in U.S. Patent No. 4,743,588, may also be included in the formulations of this invention. The amount of these compounds which may be used in the present invention ranges from about 0.1 to 25 percent and preferably about 1 to 15 percent by weight of the composition.

The amount of the composition to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the physidan.

In carrying out the novel method employing the topical route, the active ingredient(s) formulated, for example, as a gel or lotion or suspension, is applied to the affected area of the skin at a rate varying from 0.2 mg per square cm of skin surface per day up to 10 mg per square cm of skin surface per day until the appearance of the affected skin has returned to normal. The gel or lotion or suspension is generally applied for several days.

The topical compositions of this invention may be applied to the face of a patient with acne 2 to 4 times daily with the result that open and closed comedones are markedly reduced within two weeks

The invention is further illustrated by the following formulations and examples which are illustrative of a specific mode of practicing the invention and is not intended as limiting the scope of the daims.

The following gel formulations are prepared by dispersing a polyacrylic add, e.g. Carbomer 940, available from B.F. Goodrich, into water. To this dispersion is added a dispersion of hydrous

SUBSTITUTE SHEET benzoyl peroxide in a solution of clindamydn phosphate, edetate disodium and a surfactant comprising a sulfonate radical. The pH of the resulting dispersion may be buffered with NaOH and a mixture of dtric add monohydrate, and sodium dtrate dihydrate.

Formulation 1

Gel ∞ntaining dioctyl sodium sulfosuccinate and dtrate buffer

Percent Clindamycin phosphate 1.188

Hydrous benzoyl peroxide¹ 7.332

Carbomer 940² 0.900

Docusate sodium 0.150

Disodiumedetate 0.050 Qtric add monohydrate • 0.096

Sodium dtrate dihydrate 0.264

Sodium hydroxide 0.140

Purified water 89.860

Formulation 2

Gel containing sodium dode ylbenzenesulfonate and dtrate buffer.

Percent

Clindamycin phosphate 1.188 Hydrous benzoyl peroxide 7.332

Carbomer 940 0.900

Sodium dodecylbenzenesulfonate 0.170

Disodiumedetate 0.050

Sodium dtrate dihydrate 0.264 Citric add monohydrate 0.096

Sodium hydroxide 0.140

Purified water 89.860

¹Hydrous benzoyl peroxide includes about 70% by weight benzoyl peroxide as an active ingredient.

²Carbopol or carbomer resins are synthetic, high molecular acrylic acid cross- linked to different extents with a polyalkenyl ether (alkyl ethers of either sucrose or pentaerythritol).

SUBSTITUTE SHEET -7-

Formulation 3

Gel containing sodium dodecylbenzene sulfonate and dtrate buffer

Percent Clindamycin phosphate 1.188

Hydrous benzoyl peroxide 7.332

Carbomer 940 0.900

Sodium dodecylbenzenesulfonate 0.420

Disodiumedetate 0.050 Sodium dtrate dihydrate 0.264

Citric add monohydrate 0.096

Sodium hydroxide 0.140

Purified water 89.610

Formulation 4

Gel in propylene glycol and water containing dioctyl sodium sulfosuccinate and dtrate buffer

Percent Clindamycin phosphate 1.188

Hydrous benzoyl peroxide 7.332

Carbomer 940 0.900

Docusate sodium 0.150

Disodiumedetate 0.050 Sodium dtrate dihydrate 0.200

Citric add monohydrate 0.134

Sodium hydroxide 0.100

Propylene glycol 30.000

Purified water 59.946

EXAMPLE 1

Formulations of Examples 1 and 2 were tested for stability to storage in sealed ointment jars at 5° C. and 23° C. The results are reported in Table I below.

SUBSTITUTE SHEET TABLE I

Formulation 1

PERCENT CLINDAMYCIN REMAINING

1 month

2 months

3 months 6 months

PERCENT BENZOYL PEROXIDE REMAINING

5° C 23° C

1 month 95.7 96.4

2 months 96.9 97.9 3 months 105.5 103.7

6 months 101.1 99.0

Formulation 2

PERCENT CLINDAMYCIN REMAINING 5° C 23° C

1 month 99.1 94.4

2 months 99.9 92.5

3 months 101.3 89.6 6 months 100.3

PERCENT BENZOYL PEROXIDE REMAINING

5° C 23° C

1 month 97.6 96.1

2 months 98.2 97.3 3 months 101.8 101.9

6 months 97.6 97.9

As can be determined from the above data, the topical compositions of the invention, induding both dindamycin and benzoyl peroxide, surprisingly, are stable to storage. It is believed that this stability is a result of the stabilization of the topical compositions by the sulfonate radical-containing surfactant.

SUBSTITUTE SHEET EXAMFLE2

Formulations 3 and 4 were also tested for stability to storage as in Example 1 above. The results are reported in Table 2 below.

Formulation 4

PERCENT CLINDAMYCIN REMAINING

5° C 23° C 1 month 98.7 93.7

2 months 99.2 89.2

3 months 100.3 6 months 96.7

PERCENT BENZOYL PEROXIDE REMAINING

5° C 23° C

1 month 97.3 96.4

2 months 97.2 95.1

3 months 100.3 6 months 96.4

These topical compositions of the invention also showed excellent stability to storage.

SUBSTITUTE SHEET Formufction 5

Gel containing docusate sodium

The following gel formulation was prepared as described above except that no buffer was utilized:

Percent

Clindamycin phosphate 1.188

Hydrous benzoyl peroxide 7.332

Carbomer 940 0.900 Docusate sodium 0.150

Disodiumedetate 0.050

Sodium hydroxide 0.180

Purified water 90.20

EXAMPLE 3

Formulation 5 was tested for storage stability. The results are reported in Table 3, below

TABLE 3

Formulation 5

PERCENT CLINDAMYCIN REMAINING

5° C 23° C 1 month 98.7 98.3

2 months 95.9 96.7

3 months 100.6 90.7 6 months 101.2 PERCENT BENZOYL PEROXIDE REMAINING

5° C 23° C

1 month 97.5 97.5

2 months . 96.3 95.0

3 months 95.7 95.2

SUBSTITUTE SHEET -11-

Formttlation 6

A cream formulation without dioctyl sodium sulfosucdnate was prepared in the form of an oil-in-water emulsion. This cream formulation had the following composition:

Percent

Clindamycin phosphate 1.188

Hydrous benzoyl peroxide 7.332

Cetostearyl alcohol 4.000 Cetearyl octanoate 4.000

Glyceryl stearate and PEG-100 stearate³ 2.000

Carbomer 934P⁴ 0.500

Trolamine 0.500

Brij® 30 (laureth-4)5 0.250 Disodiumedetate 0.050

Purified water 80.180

EXAMPLE 4

Formulation 6 was tested for storage stability. The results are reported in Table 4 below.

³Glyceryl stearate and polyoxyethylene (100) stearate in combination is an acid- stable, self-emulsifying system available commercially as Arlacel®165 (ICI Americas).

⁴ Carbomer 934P is a high molecular weight polymer of acrylic acid cross-linked with a polyalkenyl polyether.

⁵Brij® 30 is a polyoxyethylene (4) lauryl ether and functions as an emulsifier

TE SHEET PERCENT BENZOYL PEROXIDE REMAINING

5° C 23° C

1 month

2 months 3 months

6 months

Further formulation work was done to obtain stable compositions containing 1.188 percent clindamycin phosphate (equivalent to 1 percent dindamycin) and 7.332 percent hydrous benzoyl peroxide (equivalent to 5 percent benzoyl peroxide, anhydrous) and 3-month stability data were collected for both the active ingredients in these formulations. The detailed compositions of the formulations and the results of stability evaluations are as follows:

Formulation 7

Carbomer gel containing 0.45% sodium metabisulfite and 0.05% docusate sodium

Percent

Clindamycin phosphate 1.188

Hydrous benzoyl peroxide 7.332

Sodium metabisulfite 0.450 Disodiumedetate 0.050

Docusate sodium 0.050

Carbomer 940 0.500

Triethanolamine 0.900

Sodium hydroxide 0.140 Purified water 89.890

Formulation 8

Carbomer gel containing 0.1% sodium metabisulfite, 0.1% propyl gallate and 0.1% docusate sodium in dtrate buffer (dtric add and sodium dtrate).

SUBSTΠΓUTE SH Percent

Clindamycin phosphate 1.188 Hydrous benzoyl peroxide 7.332 Sodium metabisulfite 0.100 Propyl gallate, 20% solution 0.500 Disodiumedetate 0.100 Citric add monohydrate 0.096 Sodium dtrate dihydrate 0.264 Carbomer 940 0.900 Docusate sodium 0.014 Sodium hydroxide 0.140 Purified water 89.280

Formulation 9

Carbomer gel containing 0.1% sodium metabisulfite, 0.1% propyl gallate, 0.025% docusate sodium and 5% glycerin in dtrate buffer (dtric add and sodium dtrate).

Percent

Clindamydn phosphate 1.188 Hydrous benzoyl peroxide 7.332 Sodium metabisulfite 0.100 Propyl gallate, 20% solution 0.500 Disodiumedetate 0.050 Citric add monohydrate 0.096 Sodium dtrate dihydrate 0.264 Docusate sodium 0.025 Carbomer 940 0.900 Sodium hydroxide 0.140 Glycerin 5.000 Purified water 84.405

EXAMPLE ?

Three-month stability data have been colleded on Formulations 7, 8 and 9 at refrigeration (5° C) and room (23° C) temperatures:

SUBSTITUTE SHEET PERCENT CLINDAMYCIN REMAINING

Temperature: 5° C

Temperature: 23° C

PERCENT BENZOYL PEROXIDE REMAINING

Temperature: 23° C

The compositions of further anti-acne gel formulations containing 1.19 percent dindamydn phosphate (equivalent to 1 percent dindamydn) and 5 percent benzoyl peroxide (on an anhydrous basis) are listed below:

SUBSTITUTE SHEET Formulation 10

Preparation containing microcrystalline cellulose, NF (Avicel RC-591) and colloidal magnesium aluminum silicate (Veegum HV) as gelling agents.

Percent

Preparation containing microcrystalline cellulose (Avicel RC-591) and methylcellulose (Methocel A4M) as gelling agents. Percent

Clindamycin phosphate 1.190

Benzoyl peroxide 5.000

Microcrystalline cellulose (Avicd RC-591) 2.500

Methylcellulose 0.500 Disodiumedetate 0.050

Sodium dodecyulbenzenesulfonate 0.050

Sodium dtrate 0.200

Purified water 93.210

SUBSTITUTE SHEET Formulation 12

Preparation containing hydroxypropylmethylcellulose (Methocel E4M) and xanthan gum (Keltrol T) as gelling agents.

Percent

Preparation containing colloidal magnesium aluminum silicate

(Veegum HV) and hydroxypropylmethylcellulose (Methocd E4M) as gelling agents. Percent

Clindamycin phosphate 1.190

Benzoyl peroxide 5.000

Colloidal magnesium aluminum silicate 2.000

Hydroxypropylmethylcdlulose 1.500 Disodiumedetate 0.050

Docusate sodium 0.050

Sodium dtrate 0.200

Purified water 90.010

SUBSTITUTE SHEET Foπnulation 14

Preparation containing colloidal magnesium aluminum silicate

(Veegum HV) and xanthan gum (Keltrol T) as gelling agents. Percent

Clindamycin phosphate 1.190

Benzoyl peroxide 5.000

Colloidal magnesium aluminum silicate 2.000

Xanthan gum 0.500 Disodiumedetate 0.050

Docusate sodium 0.050

Sodium dtrate 0.200

Purified water 91.010 EXAMPLE S

A 20 year old male applies 0.5 gms of Formulation to his face 4 times daily. After 10 days, the number of comedones begin to diminish. By the end of four weeks, the number of comedones declines significantly.

While particular embodiments of the invention have been described, it will be understood, of course, that the invention is not limited thereto since many obvious modifications can be made; and it is intended to include within this invention any such modifications as will fall within the scope of the appended daims. For example, it will be appredated by those skilled in the art that various pharmaceutically acceptable derivatives, salts and prodrugs of clindamycin may be used in place of clindamycin and dindamydn phosphate. For example, dindamydn hydrochloride, clindamycin palmitate hydrochloride may be substituted for clindamycin. Also, various forms of peroxides may be used in place of hydrous benzoyl peroxide; i.e., diaryl peroxide, alkyl aryl peroxide, cydoalkyl aryl peroxide may be substituted for hydrous benzoyl peroxide. For example, lauroyl benzoyl peroxide, cydohexyl carbanolyl benzoyl peroxide, Various sulfonate radical-containing surfactants may be used in place of diortylsodium sulfosucάnate and sodium dodecylbenzene sulfonate. For example, diammonium lauryl sulfosuccinate, disodium laureth sulfosuccinate, sodium

SUBSTITUTE SHEET alpha olefin sulfonate, sodium dodeyd diphenyl either disulfonate. Polyacrylic add, commerdally available under the trade name of Carbopols®, may be replaced by various other gelling agents, such as methylcellulose microcrystalline cellulose, hydroxypropyl metiiyl cellulose, colloidal magnesium aluminum silicate.

SUBSTITUTE SHEET

Claims

-19-CLAIMS:

1. A method of treating acne vulgaris in human patients comprising topically administering to said patients a composition comprising a therapeutically effective amount of benzoyl peroxide and dindamydn.

2. The method of daim 1 wherein said benzoyl peroxide and dindamydn are dispersed in a pharmaceutically acceptable carrier.

3. The method of daim 2 wherein said composition is a cream or a gel.

4. The method of claim 3 wherein said composition comprises from about 0.25 to 2 percent, by weight, clindamycin.

5. The method of claim 4, wherein said composition comprises from about 1 to 30 percent, by weight, benzoyl peroxide.

6. The method of claim 5 wherein said composition comprises a surfactant comprising a sulfonic radical.

7. The method of clam 6 wherein said surfactant is selected from the group consisting of dioctylsodium sulfosucdnate and sodium dodecylbenzene sulfonate.

8. The method of claim 7 wherein said surfactant comprises from about 0.01 to about 1 percent, by weight, of said composition.

9. The method of claim 8 wherein said composition further comprises a polyacrylic add polymer.

10. The method of claim 9, wherein said composition comprises about 1 percent, by weight, dindamydn, 5 percent, by

SUBSTITUTE SHEET weight, benzoyl peroxide, from about 0.1 to 0.2 percent, by weight, of a surfactant comprising a sulfonic add radical and about 0.1 to about 0.2 percent, by wdght, of a polyacrylic add.

11. A topical composition for treating acne vulgaris in human patients comprising a therapeutically effective amount of benzoyl peroxide and clindamycin.

12. The composition of daim 11 wherein said benzoyl peroxide and dindamydn are dispersed in a pharmaceutically acceptable carrier.

13. The composition of daim 12 wherein said composition is a cream or gd.

14. The composition of daim 13 wherein said composition comprises from about 0.25 to 2 percent, by wdght, clindamycin.

15. The composition of daim 14 wherein said composition comprises from about 2.5 to 20 percent, by wdght, benzoyl peroxide.

16. The composition of daim 15 wherein said composition comprises a surfactant comprising a sulfonic radical.

17. The composition of daim 16 wherein said surfactant is selected from the group consisting of dioctylsodium sulfosucdnate that sodium dodecylbenzene sulfonate.

18. The composition of claim 17 wherein said surfartant comprises from about .0.01 to about 1 percent, by weight, of said composition.

19. The composition of daim 18 wherein said composition further comprises a polyacrylic add polymer.

SUBSTITUTE SHEET

20. The composition of claim 19, wherein said composition comprises about 1 percent, by weight, clindamycin, 5 percent, by weight, benzoyl peroxide, from about 0.1 to 0.2 percent, by weight, of surfactant comprising a sulfonic and radical about 0.01 to about 0.2 percent, by weight, of a polyacrylic add.

SUBSTITUTE SHEET