IE51097B1 - Stable benzoyl peroxide compositions - Google Patents

Abstract

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

Description

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 sehorrhoeic conditions.

Acne and seborrhoea are conditions of the human skin characterised by an excessive flow of sebum or skin oil from sebaceous glands, which are located in the pilosebaceous apparatus. The channel through which sebum reaches the skin surface is the duct of the fair 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 topical therapeutical agents are employed in the treat20 ment 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 or the thickened sebum, or to 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 skin, and with it the debris clogging the follicular openings. 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, US Patent Specification No 3,535,422 dis30 closes 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. - 2 51097 In addition, US 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 nonionic surface active agent that is soluble in the aqueous alcohol vehicle.

Prior art benzoyl peroxide compositions which contain merely finely divided benzoyl 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 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 1% to 30% by weight of benzoyl peroxide, water and an effective amount of dioctyl sodium sulphosuccinate as a stabilizing and surface active agent, the benzoyl peroxide having a particle size of - 3 51097 less than 150 microns.

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 ben10 zoyl 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 formations.

Accordingly, in another and preferred 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 1 to 30%, and preferably from 5 to. 15%, by weight, of micronized benzoyl peroxide having a particle size of less than 150 microns, preferably with the mean average particle size being less than 35 microns. The composition also contains dioctyl sodium sulphosuccinate which serves as a surface active agent as well as providing for the increased stability of the composition and this may be present in an amount bf from 0.1 to 3%, by weight, preferably from 0.1 to 1%, by weight of the composition. In addition, the composition advantageously contains a wetting agent in an amount of from 1.0 to 6.0% by weight and preferably from 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 - 4 51097 1n 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 5 to 15%, by weight of benzoyl peroxide. The benzoyl peroxide constituent of the composition should be high purity and preferably in the form of micronized finely divided crystalline 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, along-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 polyglycol 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 purpose. However, preferred gelling agents are pure micro-crystalline cellulose, colloidal magnesium aluminium silicate, hydroxypropyl methyl cellulose and the so-called hydrozylated vinylic polymers, particularly those disclosed in US Patent Specfication No 2,798,053. Among hydrozylated vinylic polymers of special interest herein are those described generally as interpolymers of a monomeric monoolefinic acrylic acid, and from 0.1 to 10% 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 polyther containing at least two allyl Other groups per oligosaccharide molecule. Commercially available interpolymers of this type are marketed under the name Carbopol (registered Trade Mark). These are described as being - 5 51097 polymers of acrylic acid cross-linked with about 1% of a polyallyl either 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 BF 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. Suit10 able neutralizing agents are the organic amines among which may be mentioned triethanolamine, triethylamine, isopropylamine and di isopropyl amine, and inorganic bases, among which may be mentioned NaOH, KCH and Ca(0H(2· The quantity of gelling agent that may be contained in the present gel compositions may also vary somewhat. Ordinarily, this will constitute from 0.5% to 15% by weight, and preferably from 1% to 5% by weight, based on the total weight of the finished compos iti on.

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 30 to 70%, based on the total weight of the finished product. It is also preferred to use demineralised water.

The alcohol employed in the aqueous alcohol gel vehicle must be at least partially 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 to 6 carbon atoms meet the foregoing criteria and are used in the formulation of the gel composition of the invention.

In such gel composition 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 or to 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. When these are used, they may be employed over a range of concentrations which may vary from 0.2% to 8% by weight.

The gel compositions 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 of alkalinity thereof, the pH of the composition being adjused 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, emollients and preservatives. -751097 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 per5 sons who have used the compositions of the present invention have shown a definite suppression of the acne eruption 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 continued for 45 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% ben25 zoyl 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. - 8 51097 EXAMPLE II 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 EXAMPLE III A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) Water Ethyl alcohol Polyoxyethylene (8) stearate Carboxy vinyl polymer (Carbopol 934) Hydroxypropylmethylcel 1ulose Dioctul sodium sulphosuccinate 2.50% by weight 11.35% by weight 70,00% by weight 5.00% by weight 10.50% by weight 0.45% by weight 0.20% by weight 20 EXAMPLE IV A gel composition was formed having the following ingredients: 25 Benzoyl peroxide (micronized) Water Ethyl alcohol Polyoxyethylene lauryl ether Carboxy vinyl polymer (Carbopol 941) Potassium hydroxide Dioctyl sodium sulphosuccinate 2.8 % by weight 16.8 % by weight 70.0 % by weight 5.0 % by weight 5.0 % by weight 0.2 % by weight 0.2 % by weight - 9 51097 EXAMPLE V A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 15.00% by weight Water 49.35% by weight 5 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 10 Dioctyl sodium sulphosuccinate 0.50% by weight EXAMPLE VI A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 5.00% by weight Water 76.47% by weight 15 Isopropyl alcohol 10.00% by weight Polyoxyethylene (20) sorbitan monolaurate .5.00% by weight Hydroxypropylmethylcellulose 1.50% by weight Xanthan gum 1.50% by weight Phosphoric acid 0.03% by weight 20 Di octyl sodium sulphosuccinate 0.50% by weight EXAMPLE VII A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) 8.00% by weight Water 68.74% by weight 25 Ethyl alcohol 15.00% by weight Prolyoxypropylenepolyoxyethylene polymer 5.00% by weight Hydroxypropylmethulcel1ulose 1.50% by weight Guar gum 1.50% by weight Tartaric acid 0.06% by weight 30 Dioctyl sodium sulphosuccinate 0,20% by weight - 10 S1097 EXAMPLE VIII A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) Water Ethyl alcohol Polyethylene glycol 400 laurate Microcrystalline cellulose Sodium carboxymethylcellulose Citric acid Dioctyl sodium sulphosuccinate EXAMPLE IX .002 by weight 52.732 by weight 24.002 by weight 5.002 by weight 2.502 by weight 0.502 by weight 0.072 by weight 0.202 by weight A gel compostion was formed having the following ingredients: Benzoyl peroxide (micronized) Water Isopropyl alcohol Alkyl polyglycol ether Sodium carboxymethylcellulose Sodium naphthalene sulphonic acidformaldehyde condensate Citric acid Dioctyl sodium sulphosuccinate Sulphur (micronized) .0 2 by weight 45.8 2 by weight 20.0 2 by weight 6.0 2 by weight 11.5 2 by weight 1.0 2 by weight 0.2 2 by weight 1.0 2 by weight 10.0 2 by weight EXAMPLE X A gel composition was formed having the following Ingredients: Benzoyl peroxide (micronized) 7.502 by weight Water 62.752 by weight Isopropyl alcohol 15.002 by weight Polyoxyethylene (20) oleyl ether 3.002 by weight Colloidal magnesium aluminium silicate 10.002 by weight Polyethyleneglycol polymer 1.502 by weight Citric acid 0.052 by weight Dioctyl sodium sulphosuccinate 0.202 by weight - 11 Si 097 EXAMPLE XI A gel composition was formed having the following ingredients: Benzoyl peroxide (micronized) Water Ethyl alcohol Alkyl polyglycol ether Colliodal magnesium aluminium silicate Hydroxypropylmethylcellulose Citric acid Dioctyl sodium sulphosuccinate .99% by weight 24.36% by weight 44.10% by weight 6.00% by weight 12.50% by weight 1.00% by weight 0.05% by weight 1.00% by weight

Claims (10)

1. A stable aqueous benzoyl peroxide composition comprising from 1% to 30% by weight of benzoyl peroxide, water and an effective amount of dioctyl sodium sulphosuccinate as a stabilizing and surface active agent, the benzoyl peroxide having a particle size of less than 150 microns.

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

3. A composition according to claim 1 or claim 2, wherein the dioctyl sodium supohsuccinate is present in an amount of from 0.1 to 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. Composition an effective amount of dioctyl sodium sulphosuccinate as a stabilizing agent. 18. A method according to claim 17, wherein the doictyl sodium sulphosuccinate is included so as to be present in an amount of from 0.1 to 3.0% by weight of the total composition.

5. A composition according to claim 4, which also includes from 0.5 to 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 keratolytic 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 1.0 to 6.0% by weight of a wetting agent. - 13 7 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 composition suitable for the treatment of acne and seborrhoeic conditions comprising: (a) from 1% to 30% by weight of micronized 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 0.1 to 3.0% by weight of di octyl sodium sulphosuccinate; (c) from 1.0 to 6.0% by weight of a wetting agent; (d) from 0.5% to 15% by weight of a gelling agent; (e) from 10% to 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 di octyl sodium sulphosuccinate, about 4.1% by weight of alkyl polyglycol ether, from 1% to 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 13 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 1. to 5% of a hydroxylated vinylic polymer gelling agent, about 15% by weight of alkanol, about 0.4% bv weight of sodium hydroxide and the balance water. -1451097 17. A method for stabilizing aqueous benzoyl peroxide compositions comprising from 1% to 30% by weight of benzoyl peroxide, the peroxide having a particle size of less than 150 microns, which method comprises including in a said

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