INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification ^• **: (11) International Publication Number WO 81/00206

Al A61K 31/78, 31/00, 47/00 (43) International Publication Date: 5 February 1981 (05.02.81)

(21) International Application Number. PCT/US 80/00967 (74) Agent MILLER, Austin, R.; Miller & Prestia, 1125 Land Title Building, Philadelphia, PA 19110 (US).

(22) International Filing Date: 24 July 1980 (24.07.80)

(81) Designated States: AT, DE, DK, GB, JP, NL, SE.

(31) Priority Application Number: 060,392

(32) Priority Date: 25 July 1979 (25.07.79) Published

With international search report

(33) Priority Country: US Before the expiration of the time limit for amen¬ ding the claims and to be republished in the event of the receipt of amendments

(71) Applicant DERMJJ LABORATORIES,INC. [US/US];

500 Virginia D rive, Fort Washington, PA 19034 (US) .

(72) Inventors: KLEIN,Robert, Warren; 1013UnionMeeting

Road, B lue B ell, PA 19422 (US) . FOXX, Mary, Eliza¬ beth; 18-01 Pheasant Hollow Drive, Plainsboro, NJ 08536 (US).

(54) Title: STABLE BENZOYL PEROXIDE COMPOSIΗON

(57) Abstract

Therap eutic alcoholic gel compositions for treating acne containing micronized benzoyl p eroxide and dioctyl sodium sul¬ fosuccinate having greater shelf life and stability.

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identifyStates party to the PCT on the frontpages of pamphlets publishing international appli- cations under the PCT.

AT Austria KP Democratic People's Republic of Korea

AU Australia LI Liechtenstein

BR Brazil LU Luxembourg

CF Central African Republic MC Monaco

CG Congo MG Madagascar

CH Switzerlan MW Malawi

CM Cameroon NL Netherlands

DE Germany, Federal Republic of NO Norway

DK Denmark RO Romania

El Finland SE Sweden

FR France SN Senegal

GA Gabon SU Soviet Union

GB United Kingdom TD Chad

HU Hungary TG Togo

JP Japan US United States of America

STABLE BENZOYL PEROXIDE COMPOSITION

Field of the Invention

This invention relates to aqueous gel compositions which contain benzoyl peroxide that are useful in con¬ nection with the treatment of acne and sebhorreic con¬ ditions .

Prior Art

Acne and sebhorrea are conditions of the human skin characterized by an excessive flow of sebum or skin oil, from the sebaceous glands which are located in the pilosebaceous apparatus. The channel through which sebum reaches the skin surface is the duct of the hair follicle. The presence of excess amounts of sebum in the duct and on the skin acts to block or stagnate the continuous flow of sebum fro ^' m the follicle duct, thus producing a thickening of sebum which becomes a solid plug known as a comedone. When this occurs, hyper- - keratinization of the follicular opening is stimulated, thus completely closing the duct. The usual result is a papule, pustule or a cyst, which are often contaminated with bacteria that cause secondary infections. These occurrences characterize the disease today known as acne, and in lesser severity, sebhorrea.

Many topical therapeutical agents are employed in the treatment of acne and sebhorrea to prevent the block¬ ing of the follicular ducts , to reopen the duct once it has become blocked, to act against the infecting bacteria or the thickened sebum, or to provide combinations of each of these actions. It is well known to use sulfur as a mild cutaneous irritant to remove the horny layer of the skin, and with it the debris clogging the follicular openings. Benzoyl peroxide gel compositions have been found to be effective in the treatment of acne, sebhorrea, and the associated secondary infections.

U. S. Patent Number 3,535,422 discloses a therapeutic

composition for the treatment of acne comprising a uniform dispersion of benzoyl peroxide in a fluid medium containing water and at least ^ς one organic emollien IT. S. Patent Number 4,056,611 discloses a therapeuti composition for the treatment of acne comprising a stable dispersion of finely divided particles of benzoyl peroxid in an aqueous alcohol vehicle having a single phase. The single phase of the composition is non-lipid and contains a non-ionic surface active agent that is soluble in the aqeuous alcohol vehicle.

Prior art benzoyl peroxide compositions which contain merely finely divided benzoyl peroxide particles in an emulsion of water and certain select emollients provides the disadvantage that when the water content of the emulsion evaporates there remains most of the organic emollients and the large benzoyl peroxide particles on the surface of the skin near and in contact with the acne sites which may cause irritation.

Additionally, the use of large amounts of non-ionic surface active agents in such compositions, unless ex¬ tremely fine particles of benzoyl peroxide are utilized, would cause a likelihood of irritation from the benzoyl peroxide.

Also, because of the powerful oxidizing properties of benzoyl peroxide, the inclusion of this substance in a conventional ointment or emulsion results in unstable compositions that soon display an unacceptable loss in keratolytic potency.

_< Summary of the Invention

The present invention relates to novel therapeutic compositions containing micronized particles of benzoyl peroxide in an aqueous alcoholic gel vehicle having greater stability and shelf life. It has been surprisingly found that in an aqueous alcoholic gel vehicle the utilization of micronized benzoyl peroxide having a particular size of less than 150 microns in combination with dioctyl sodium sulfo¬ succinate as the surface active agent results in a com-

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position which displays full stability with respect to the benzoyl peroxide component even when subjected to temperatures higher than those normally expected in the ordinary use of the product. Also, the alcoholic gel of the present invention upon evaporation allows a uniform release of the micronized benzoyl peroxide so as to obviate the burning and erythema experienced with other harsh gel formulations.

The aqueous alcoholic gel composition of the present invention contains from about 1 to about 30%, and pref¬ erably from about 5-15%, by weight, of micronized benzoyl peroxide having a particle size of less than 150 microns with the mean average particle size being less than 35 microns . Dioctyl sodium sulfosuccinate which serves as a surface active agent as well as providing for the increased stability of the composition is present in the amount of about 0.1 to about 37o, by weight, preferably about 0.1 to .1%, by weight of composition. The composi¬ tion also advantageously contains a wetting agent in an amount of about 1.0 to about 6.07o by weight and pref¬ erably about 3-67o by weight.

Detailed Description

The therapeutic gel composition of the present in- vention must contain sufficient benzoyl peroxide to be therapeutically effective, and should not contain more peroxide than can be uniformly dispersed in the vehicle to form a smoothly sπreadable composition. Such con¬ siderations dictate that the composition contain at least 17o and not more than 307. by weight of benzoyl peroxide, and preferably that the composition contain from about 5 to about 157o by weight benzoyl peroxide. The benzoyl peroxide constituent of the composition should be high purity and in the form of micronized finely divided crystalline particles having a mean average particle size of less than 35 microns. The aqueous gel composition of the present invention advantageously includes a wetting agent such as the esters of polyols and sugars, the products of the condensation of ethylene oxide with

fatty acids, fatty alcohols, long-chain alkyl phenols, long-chain mercaptans , long-chain amides, polyethers of polyhydroxylated fatty alcohols and alkyl polyglycol ethers in an amount of from 3 to 67,, by weight. Alkyl polyglycol ether when utilized in about the same amounts as the dioctyl sodium sulfosuccinate has been found to provide the composition with extraordinary shelf life. Another important component of the present compo¬ sition is the gelling agent. These may be selected both as to type and quantity to give products of various vis¬ cosities. In the preferred form of this invention, the gelling agent is selected so as to produce an elegantly formed and stable gel. A variety of gelling agents may be used for the present purposes. However, preferred gelling agents are pure micro-crystalline cellulose, colloidal magnesium aluminum silicate, hydroxypropyl methyl cellulose and the so-called hydroxylated vinylic polymers, particularly, those disclosed in the U.S. Patent No. 2,798,053. Among those hydroxylated vinylic polymers of special interest herein are described gen¬ erally as interpolymers of a monomeric monoolefinic acrylic acid, and from about 0.1 to about 107. by weight based on the total monomer of a monomeric polyether of an oligosaccharide in which the hydroxyl groups which are modified are esterified with allyl groups with said polyether containing at least two allyl ether groups per oligosaccharide molecule. Commercially available inter¬ polymers of this type are marketed under the trade name "Carbopol". These are described as being polymers of acrylic acid cross-lined with about 17. of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule. These polymers have molecular weight in the order of magnitude of 1,000,000. Such polymers are available from the B. F. Goodrich Chemical Company and are sold under the trademark, "Carbopol 934", "Carbopol 940" and "Carbopol 941".

The various Carbopols are distinguished from each other by the manufacturer on the basis of their viscosity. The polymers are gelled by neutralizing them with an

a a ne mater a . u ta e neutra z ng agents are organic amines among which may be mentioned triethanol- amine, triethylamine, isopropylamine, diisopropylamine, etc. and inorganic bases, among which may be NaOH, KOH, Ca(0H) ₂ , etc.

The quantity of gelling agent that may be contained in the present compositions may also vary somewhat. Ordinarily, this will constitute about 0.57 to about 157. by weight, and preferably about 17. to about 57, by weight, based on the total weight of the finished composition.

The compositions of the present invention will also ordinarily contain substantial aqueous components. When water is present, it may also vary dependent on the nature of the product desired. Usually this will con- stitute between about 30-707., based on the total weight of the finished product. It is also preferred to use demineralized water.

The alcohol employed in the aqueous alcohol gel vehicle must be soluble in water, serve as a cosolvent for the surface active agent and wetting agent in the vehicle and also as an antiseptic and drying agent when applied to the skin. Alkyl alcohols having from 1-6 carbon atoms meet the foregoing criteria and are used in the formulation of the composition of the invention. The compositions with from 10-807, by weight of one or more of these alcohols is sufficient to insure that the surface active agents and wetting agents will dissolve therein.

It is sometimes advantageous to add additional therapeutically active ingredients to the present compo¬ sitions which may serve to augment the activity of the benzoyl peroxide or to supplement them. A variety of materials may be used for this purpose. Of special interest as an auxiliary skin treating agent is the keratolytic agents and especially salicylic acid. When these are used, they may be employed over a range of concentrations which may vary from about 0.27, to about 87, by weight.

The composition may also advantageously contain

from 1-257, by weight of finely divided, micronized or colloidal sulfur. Sulfur is an antimicrobial and keralytic agent that has long been used in the treatment of acne. Although it is not known precisely how sulfur exerts its keratolytic effect on the skin, it is believed that the hydrogen sulfide, which is formed when sulfur is in contact with animal tissue, reacts with alkali in tissue fluids to produce active sulfides, which in turn, promote keratosis. The combination of sulfur with benzoyl peroxide produces significantly greater keratosis than either substance will when used alone.

If desired, minute amounts of a compatible acid base may be added to the composition to adjust the re¬ lative acidity or alkalinity thereof, the pH of the composition usually being adjusted to within the range 3.5 and 7.5, preferably 5-6.5.

In addition, for purposes of formulating more ele¬ gant products', additional additives may be incorporated into the present composition. Typical among these may be emulsifying agents, emollients, preservatives, etc. The gel composition of the present invention is applied topically to the skin of the patient by rubbing the gel in one or more times daily depending on the skin condition to provide drying, desquamative and antiseptic effects. Almost all persons who use the compositions of the present invention show a definite suppression of the acne eruption within the first few weeks of treatment. Moreover, the compositions of this invention have been demonstrated to be markedly more effective and faster acting than benzoyl peroxide containing emulsions or gel formulations of comparative strength previously known in the art.

The following examples are representative but not limited of therapeutic compositions prepared in accor- dance with the invention:

OMPI

EXAMPLE I

495.0 mg. of purified water was mixed and 15.0 mg. of Carbopol 940 (a carboxy vinyl polymer, acid form, of B. F. Goodrich Co.) were added to the water while stirring. Stirring of the mixture was continued for 45 minutes. Then 4.095 mg. of sodium hydroxide in 4.91 ml. of purified water was added thereto. Stirring of the mixture was continued for 10 minutes, whereupon 150.0 mg. of ethyl alcohol, 0.50 mg. of perfume and 0.50 mg. of methyl salicylate was added. To the stirred mixture was then added a mixture comprising 210.0 mg. of wet pack micronized benzoyl peroxide (507, benzoyl peroxide - 507, water), 2.0 mg. of dioctyl sodium sulfosuccinate, 41.0 mg. of alkyl polyglycol ether and 41.0 mg. of purified water. The mixture was ^' stirred for 30 more minutes until a smooth and elegant gel mixture was obtained.

EXAMPLE II

Benzoyl peroxide (micronized) 5.467 by weight

Water 40.697o by weight

Ethyl alcohol 44.107o by weight

Polyoxyethylene lauryl ether 6.007= by weight

Colloidal magnesium aluminum silicate 2.507o by weight

Hydroxypropylmethylcellulose 1.007, by weight

Citric acid 0.057 by weight

Dioctyl sodium sulfosuccinate 0.2 7 by weight

EXAMPLE III

Benzoyl peroxide (micronized) 2.507 by weight

Water 11.357. by weight

Ethyl alcohol 70.007. by weight

Polyoxyethylene (8) stearate 5.007o by weight

Carboxy vinyl polymer

(Carbopol 934) 10.507 by weight Hydroxypropylcellulose 0.457, by weight Dioctyl sodium sulfosuccinate 0.207, by weight

EXAMPLE IV

Benzoyl peroxide (micronized) 2.87o by weight

Water 16.87= by weight

Ethyl alcohol 70.07= by weight

Polyoxyethylene lauryl ether 5,.07, by weight

Carboxy vinyl polymer

(Carbopol 941) 5.07= by weight Potassium hydroxide 0.27= by weight Dioctyl sodium sulfosuccinate 0.27= by weight

EXAMPLE V

Benzoyl peroxide (micronized) 15.007= by weight

Water 49.357, by weight

Ethyl alcohol 25.007= by weight

Polyoxyethylene (40) stearate 5.507= by weight

Colloidal magnesium aluminum silicate 4. .507= by weight Sodium carboxymethylcellulose 0 . . 607= by weight Citric acid 0 , .057= by weight Dioctyl sodium sulfosuccinate 0 . .507 by weight

EXAMPLE VI

Benzoyl peroxide (micronized) 5.007= by weight

Water 76.477 by weight

Isopropyl alcohol 10.007= by weight

Polyoxyethylene (20) sorbitan monolaurate 5.007= by weight Hydroxypropylmethylcellulose 1.507= by weight Xanthan gum 1.507= by weight Phosphoric acid 0.037= by weight Dioctyl sodium sulfosuccinate 0.507= by weight

EXAMPLE VII

Benzoyl peroxide (micronized) 8.007= by weight

Water 68.747= by weight

Ethyl alcohol 15.007 by weight

Polyoxypropylenepolyoxyeth lene polymer 5.007= by weight Hydroxypropylmethylcellulose 1.507, by weight Guar gum 1.507= by weight Tartaric acid 0.067= by weight Dioctyl sodium sulfosuccinate 0.207= by weight

EXAMPLE VIII

Benzoyl peroxide (micronized 15.007= by weight

Water 52.737= by weight

Ethyl alcohol 24.007= by weight

Polyethylene glycol 400 laurate 5.007= by weight

Microcrystalline cellulose 2.507 by weight

Sodium carboxymethylcellulose 0.507 by weight

Citric acid 0 . 077= by weight Dioctyl sodium sulfosuccinate 0 . 207= by weight

EXAMPLE IX

Benzoyl peroxide (micronized) 15, 07= by weight Water 45 87= by weight Isopropyl alcohol 20, 07= by weight Alkyl polyglycol ether 6.07= by weight Sodium carboxymethylcellulose 11, 57= by weight Sodium naphthalene sulfonic acid- formaldehyde condensate 1, 07= by weight Citric acid 0.27= by weight Dioctyl sodium sulfosuccinate 1, 07= by weight Sulfur (micronized) 10.07= by weight

EXAMPLE X

Benzoyl peroxide (micronized) 7 ,507= by weight

Water 62, 757= by weight

Isopropyl alcohol 15 007= by weight Polyoxyethylene (20) oleyl ether 3 007= by weight Collodial magnesium aluminum silicate 10, 007= by weight

Polyethylene gylcol polymer 1, 507= by weight

Citric acid 0.057= by weight

Dioctyl sodium sulfosuccinate 0.207= by weight

O

EXAMPLE XI

Benzoyl peroxide (micronized) 10.997= by weight

Water 24.367= by weight

Ethyl alcohol 44.107= by weight Alkyl polyglycol ether 6.007 by weight Collodial magnesium aluminum silicate 12.507, by weight

Hydroxypropylmethylcellulose 1.007= by weight

Citric acid 0.057= by weight Dioctyl sodium sulfosuccinate 1.007= by weight