GB2054375A

GB2054375A - Stable benzoyl peroxide composition

Info

Publication number: GB2054375A
Application number: GB8024458A
Authority: GB
Original assignee: Dermik Laboratories Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 1979-07-25
Filing date: 1980-07-25
Publication date: 1981-02-18
Also published as: IT8068161A0; IE51097B1; GB2054375B; CH644758A5; ATA907180A; SE451666B; PH16734A; AU6075580A; AU540640B2; JPS56500888A; AR221949A1; AT379309B; ES494336A0; DE3049722T1; ZA804349B; DE3049722C2; FR2462424A1; JPH0327532B2; DK132081A; FR2462424B1

Abstract

Therapeutic alcoholic gel compositions for treating acne containing micronized benzoyl peroxide and dioctyl sodium sulfosuccinate having greater shelf life and stability.

Description

SPECIFICATION Stable benzoyl peroxide composition This invention relates to stable aqueous benzoyl peroxide compositions, and in particular to aqueous gel compositions which contain benzoyl peroxide that are suitable for the treatment of acne and sebor rhoeic conditions.

Acne and seborrhoea are conditions of the human skin characterised 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 surfaces is the duct of the hair follicle. The presence of an excess amount of sebum in the follicle duct and on the skin acts to block or stagnate the continuous flow of sebum from the duct, thus producing a thickening of sebum which becomes a solid plug known as a comedo. When this occurs, hyperkeratinization of the follicular opening is stimulated, thus completely closing the duct. The usual result is a papule, pustule or a cyst, often contaminated with bacteria that cause secondary infection. These occurrences characterise the disease today known as acne, and in lesser severity seborrhoea.

Many topicai therapeutical agents are employed in the treatment of acne and seborrhoea to prevent the blocking of the follicular ducts, to reopen the ducts once they have become blocked, to act against the infecting bacteria orthethickened sebum, orto provide combinations of each of these actions. Thus, it is well known to use sulphur as a mild cutaneous irritant to remove the horny layer of the skin, and with it the debris clogging the follicularopenings. In addition, benzoyl peroxide gel compositions have been found to be effective in the treatment of acne, seborrhoea, and associated secondary infections.

Thus, for example, U.S. Patent Specification No.

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 one organic emollient.

In addition, U.S. Patent Specification No. 4,056,611 discloses a therapeutic composition for the treatment of acne comprising a stable dispersion of finely divided particles of benzoyl peroxide 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 aqueous alcohol vehicle.

Prior art benzoyl peroxide compositions which contain merely finely divided benzoyl peroxide particles in an emulsion of water and certain selected emollients possess 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 extremely fine particles of benzoyl peroxide are utilised, can give rise to the 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.

We have now found surprisingly that stable aqueous benzoyl peroxide compositions useful in the preparation of aqueous gel compositions which contain benzoyl peroxide can be prepared using an effective amount of dioctyl sodium sulphosuccinate as a stabilizing and surface active agent.

Accordingly, in its broadest aspect the present invention provides a stable aqueous benzoyl peroxide composition comprising from about 1% to about 30% by weight of benzoyl peroxide, water and an effective amount of dioctyl sodium sulphosuccinate as a stabilizing and surface active agent.

More particularly, the present invention relates to compositions containing micronized particles of benzoyl peroxide in an aqueous alcoholic gel vehicle having greater stability and shelf life.

We have found surprisingly 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 sulphosuccinate as the surface active agent results in a composition 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 upon evaporation can allow a uniform release of the micronized benzoyl peroxide so as to obviate the burning and erythema experienced with other harsh gel formulations.

Accordingly, in another and preffered aspect the invention provides an aqueous alcoholic gel composition suitable for the treatment of acne and seborrhoeic conditions. The aqueous alcoholic gel composition of the present invention contains from about 1 to about 30%, and preferably from about 5 to 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. The composition also contains dioctyl sodium sulphosuccinatewhich serves as a surface active agent as well as providing for the increased stability of the composition and this is present in an amount of from about 0.1 to about 3%, by weight, preferably from about 0.1 to 1%, by weight of the composition.

In addition, the composition advantageously contains a wetting agent in an amount of from about 1.0 to about 6.0% by weight and preferably from about 3 to 6% by weight.

The therapeutic gel composition of the present invention 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 spreadable composition. Such considerations dictate that the composition contain at least 1% and not more than 30% by weight of benzoyl peroxide, and preferably that the composition contain from about 5 to about 15%, by weight of benzoyl peroxide. The benzoyl peroxide constituent of the composition should be high purity and in the form of micronized finely divided crystal line particles having a mean average particle size of less than 35 microns.

The gel composition of the present invention advantageously includes a wetting agent such as an ester of a polyol or a sugar, a condensation product of ethylene oxide with a fatty acid, a fatty alcohol, a long-chain alkyl phenol, a long-chain mercaptan or a long-chain amide, a polyether of a polyhydroxylated fatty alcohol or an alkyl polyglycol ether in an amount of from 3 to 6%, by weight. An alkyl poiyg- lycol ether when utilized in about the same amount as the dioctyl sodium sulphosuccinate has been found to provide the composition with very good shelf life.

Another important component of the present composition is the gelling agent. This may be selected both as to type and quantity to give products of various viscosities. 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 aluminium silicate, hydroxypropyl methyl cellulose and the so-called hydroxylated vinylic polymers, particularly, those disclosed in U.S. Patent Specification No. 2,798,053.Among hydroxylated vinylic polymers of special interest herein are those described generally as interpolymers of a monomeric monoolefinic acrylic acid, and from about 0.1 to about 100/o by weight based on the total monomer of a monomeric poiyether 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 oligosaccaride molecule. Commercially available interpolymers of this type are marketed under the trade name "Carbopol". These are described as being polymers of acrylic acid cross-linked with about 1% of a polyailyl 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, and are available from the B. F. Goodrich Chemical Company, being sold under the trade names "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 alkaline material. Suitable neutralizing agents are the organic amines among which may be mentioned triethanolemaine, triethylamine, isopropylamine and diisopropylamine, and inorganic bases, among which may be mentioned NaOH, KOH and Ca(OH)2.

The quantity of gelling agent that may be contained in the present gel compositions may also vary somewhat. Ordinarily, this will constitute from about 0.5% to about 15% by weight, and preferably from about 1% to about 5% 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 constitute between from about 30 to 70%, 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 at least partially soluble in water, serve as a cosolventforthe 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 to 6 carbon atoms meet the foregoing criteria and are used in the formulation of the gel composition of the invention. In such gel compositions the provision of from 10 to 80% by weight of one or more of these alcohols is sufficient to ensure that the surface active agents and wetting agents will dissolve therein.

It is sometimes advantageous to add additional therapeutically active ingredients to the gel compositions of the invention, which may serve to augment the activity of the benzoyl peroxide orto supplement it. A variety of materials may be used for this purpose, but of special interest as auxiliary skin treating agents are other keratolytic agents, and especially salicylic acid. When these are used, they may be employed over a range of concentrations which may vary from about 0.2% to about 8% by weight.

The gel composition may also advantageously contain sulphur, in particular from 1 to 25% by weight of finely divided, micronized or colloidal sulphur. Sulphur is an antimicrobial and keratolytic agent that has long been used in the treatment of acne. Although it is not known precisely how sulphur exerts its keratolytic effect on the skin, it is believed that the hydrogen sulphide, which is formed when sulphur is in contact with animal tissue, reacts with alkali in tissue fluids to produce active sulphides, which in turn, promote keratosis. The combination of sulphur with benzoyl peroxide produces significantly greater keratosis than either substance will produce when used alone.

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

In addition, for the purpose of formulating more elegant products, additional additives may be incorporated into the present composition. Typical among these may be, for example, emulsifying agents, emollient and preservatives.

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 have used the compositions of the present invention have shown a definite suppression of the acne erruption within the first few weeks of treatment. Moreover, the gel 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.

Following is a description by way of example to illustrate compositions prepared in accordance with the present invention: EXAMPLE 1 495.0 mg of purified water were stirred 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 contined for45 minutes. Then 4.095 mg of sodium hydroxide in 4.91 ml of purified water were 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 were added. To the stirred mixture was then added a mixture comprising 210.0 mg of wet pack micronized benzoyl peroxide (50% benzoyl peroxide - 50% water), 2.0 mg of dioctyl sodium sulphosuccinate, 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 A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 5.46% by weight Water 40.69% by weight Ethyl Alcohol 44.10% by weight Polyoxyethylene lauryl ether 6.00% by weight Colloidal magnesium aluminium silicate 2.50% by weight Hydroxypropylmethylcellulose 1.00% by weight Citric acid 0.05% by weight Dioctyl sodium sulphosuccinate 0.2% by weight EXAMPLEIII A gel composition was formed having the following ingredients:: Benzoyl peroxide (mirconized) 2.50% by weight Water 11.35% by weight Ethyl alcohol 70.00 /O by weight Polyoxyethylene (8) stearate 5.00% by weight Carboxyvinyl polymer (Carbopol 934) 10.50% by weight Hydroxypropylcellulose 0.45% by weight Dioctyl sodium sulphosuccinate 0.20% by weight EXAMPLE A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 2.8% by weight Water 16.8% by weight Ethyl alcohol 70.0% by weight Polyoxyethylene lauryl ether 5.0% by weight Carboxyvinyl polymer(Carbopol 941) 5.00/c byweight Potassium hydroxide 0.2% by weight Dioctyl sodium sulphosuccinate 0.2% by weight EXAMPLE V A gel composition was formed having the following ingredients:: Benzoyl peroxide (micronized) 1 5.000/c by weight Water 49.35% by weight Ethyl alcohol 25.00% by weight Polyoxyethylene (40) stearate 5.50% by weight Colloidal magnesium aluminium silicate 4.50% by weight Sodium carboxymethylcellulose 0.60% by weight Citric acid 0.05% by weight Dioctyl sodium sulphosuccinate 0.50% by weight EXAMPLE Vl A gel composition was formed having the following ingredients:: Benzoyl peroxide (micronized) 5.00% by weight Water 76.47% by weight Isopropyl alcohol 10.C3% by weight Polyoxyethylene (20) sorbitan monolaurate 5.000/c by weight Hydroxypropylmethylcel lu lose 1.50% by weight Xanthan gum 1.50% by weight Phosphoric acid 0.03% by weight Dioctyl sodium sulphosuccinate 0.50% by weight EXAMPLE VII A gel composition was formed having the following ingredients:: Benzoyl peroxide (micronized) 8.000/c by weight Water 68.74% by weight Ethyl alcohol 15.00% by weight Prolyoxypropylenepolyoxyethylene polymer 5.000/c by weight Hydroxypropylmethylcellulose 1.50% by weight Guargum 1.50% by weight Tartaric acid 0.06% by weight Dioctyl sodium sulphosucinate 0.20% by weight EXAMPLE Vlil A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 15.00% by weight Water 52.73% by weight Ethyl alcohol 24.00% by weight Polyethylene glycol 400 laurate 5.00% by weight Microcrystalline cellulose 2.50% by weight Sodium carboxymethylcellulose 0.50% by weight Citric acid 0.07% by weight Dioctyl sodium sulphosuccinate 0.20% by weight EXAMPLE A gel composition was formed having the following ingredients:: Benzoyl peroxide (micronized) 15.0% by weight Water 45.8% by weight Isopropyl alcohol 20.00/c by weight Alkyl polyglycol ether 6.0% by weight Sodium carboxymethylcellulose 11.5% by weight Sodium naphthalene sulphonic acid formaldehyde condensate 1.0% by weight Citric acid 0.2% by weight Dioctyl sodium sulphosuccinate 1.0% by weight Sulphur (micronized) 10.0% by weight EXAMPLEX A gel composition was formed having the following ingredients: : Benzoyl peroxide (micronized) 7.50% by weight Water 62.75% by weight Isopropyl alcohol 15.00% by weight Polyoxyethylene (20) oleyl ether 3.00% by weight Colloidal magnesium aluminium silicate 10.000/c by weight Polyethylene glycol polymer 1.50% by weight Citric acid 0.05% by weight Dioctyl sodium sulphosuccinate 0.20% by weight EXAMPLEXI A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 10.99% by weight Water 24.36% by weight Ethyl alcohol 44.10% by weight Alkyl polyglycol ether 6.00% by weight Colloidal magnesium aluminium silicate 12.50% by weight Hydroxypropylmethylcellulose 1.00% by weight Citric acid 0.05% by weight Dioctyl sodium sulphosuccinate 1.00% by weight

Claims

1. A stable aqueous benzoyl peroxide composition comprising from about 1% to about 30% by weight of benzoyl peroxide, water and an effective amount of dioctyl sodium sulphosuccinate as a stabilizing and surface active agent.

2. A composition according to claim 1, wherein the benzoyl peroxide has a particle size of less than 150 microns with a mean average particle size in the composition of less than 35 microns.

3. A composition according to claim 1 or claim 2, wherein the dioctyl sodium sulphosuccinate is present in an amount of from about 0.1 to about 3.0% by weight of the composition.

4. A composition according to any one of the preceding claims, which also includes a gelling agent.

5. A composition according to claim 4, which also includes from about 0.5 to about 15% by weight of a gelling agent.

6. A composition according to claim 4 or claim 5, wherein the gelling agent is colloidal magnesium aluminium silicate, hydroxypropylmethylcellulose, microcrystalline cellulose or a hydroxylated vinylic polymer.

7. A composition according to any one of the preceding claims, which also includes another keratolyic agent in addition to benzoyl peroxide.

8. A composition according to any one of the preceding claims, which also includes sulphur.

9. A composition according to any one of the preceding claims, which also includes a wetting agent.

10. A composition according to claim 8, which also includes from about 1.0 to about 6.0% by weight of a wetting agent.

11. A composition according to claim 9 or claim 10, wherein the wetting agent is an alkyl polyglycol ether.

12. A composition according to any one of the preceding claims, which also includes a lower alkanol.

13. A composition according to claim 12, wherein the alkanol is ethyl alcohol or isopropyl alcohol.

14. A composition according to claim 12 or claim 13 in the form of an aqueous alcoholic gel composi tion suitable for the treatment of acne and sebor rhoeic conditions comprising: (a) from about 1% to about 30 /O by weight of mic ronized benzoyl peroxide having a particle size of less than 150 microns with a mean average particle size in the composition of less than 35 microns; (b) from about 0.1 to about 3.0% by weight of dioctyl sodium sulphosuccinate; (c) from about 1.0 to about 6.0% by weight of a wetting agent; (d) from about 0.5 to about 15% by weight of a gelling agent; (e) from about 10% to about 80% of a lower alkyl alcohol; and (f) water.

15. A composition according to claim 12 or claim 13 comprising about 10% by weight of micronized benzoyl peroxide, about 0.2% by weight of dioctyl sodium sulphosuccinate, about 4.1% by weight of alkyl polygylcof ether, from about 1% to about 5% of a hydroxylated vinylic polymer gelling agent, about 15% by weight of alkanol, about 0.4% by weight of sodium hydroxide and the balance water.

16. A composition according to claim 12 or claim 13 comprising about 5% by weight of micronized benzoyl peroxide, about 0.2% by weight of dioctyl sodium sulphosuccinate, about 4.1% by weight of alkyl polyglycol ether, from about 1% to about 5% of a hydroxlated vinylic polymer gelling agent, about 15% by weight of alkanol, about 0.4% by weight of sodium hydroxide and the balance water.

17. A method for stabilizing aqueous benzoyl peroxide compositions, which method comprises including in a said composition an effective amount of dioctyl sodium sulphosuccinate as a stabilizing agent.

18. A method according to claim 17, wherein the dioctyl sodium sulphosuccinate is included so as to be present in an amount of from 0.1 to 3.0 /O by weight of the total composition.

19. An aqueous alcoholic gel substantially as hereinbefore described with reference to the specific Examples.