US3265571A

US3265571A - Thixotropic acne vulgaris composition

Info

Publication number: US3265571A
Application number: US446709A
Authority: US
Inventors: Joseph Z Krezanoski
Original assignee: Barnes Hind Pharmaceuticals Inc
Current assignee: Barnes Hind Pharmaceuticals Inc
Priority date: 1965-04-08
Filing date: 1965-04-08
Publication date: 1966-08-09
Anticipated expiration: 1983-08-09
Also published as: DE1617320C3; GB1038608A; DK108264C; DE1617320B2; DE1617320A1; SE347157B

Description

United States Patent 3,265,571 THHXOTRGPIC ACNE VULGARIS COMPOSiTlON Joseph Z. Krezanoski, Sunnyvale, Calif., assignor to Barnes-Hind Pharmaceuticals, Inc., a corporation of California N0 Drawing. Filed Apr. 8, 1965, Ser. No. 446,709 7 Claims. (Cl. 167-53) This application is a continuation-in-part of application Serial No. 277,133, filed May 1, 1963, and now abandoned.

This invention relates to an improved therapeutic composition, and more particularly to a composition wherein sodium thiosulfate is combined with fibrous boehmite for topical application. In accordance with one embodiment of the invention a formulation particularly adapted for" treatment of tinea versicolor is provided. In accordance with another embodiment a formulation containing hydnocortisone for the treatment of the inflammatory types of acne and acne rosacea is provided. Another embodiment of the invention provides a formulation for those skin maladies associated with hyperplasia of the infected sebaceous gland, such as acne vulgaris and seborrheic dermatitis.

Excessive oiliness of the skin and associated hormonal changes occurring during adolescence, as well as diet, have frequently been implicated in the predisposition to the development of acne vulgaris. At the present time, there are no specific measures or therapeutic compositions which entirely eliminate acne vulgaris and associated skin conditions. Most of the therapeutic measures, therefore, are of a palliative nature which assist in keeping the conditions under control. Some of the preparations commonly employed in treating acne vulgaris and seborrheic dermatitis consist of White lotion, aluminum acetate solutions (e.g. Burows solution), phenolated calamine lotion, sulphur lotion, calcium-zinc oxide and sulphur lotion as well as salicylic acid and resorcinol incorporated in a variety of oleaginous and/or hydroalcoholic vehicles. These preparations in general provide for two major actions: (a) the kerotolytic (peeling) effect; and (b) the antibacterial effect.

It is known that a certain amount of measurable beneficial effect occurs pursuant to the use of these products. Some of the disadvantages of currently employed preparations, in the treatment of such skin maladies, may be listed as follows:

(21) Many of the preparations consist of an oleaginoustype base. It may be shown that adding additional oils to the skin which already suffers from excessive oilness is detrimental.

(b) The pH of many preparations presently employed is usually in the alkaline region and may be as high as 10. It is well known that vehicles having an alkaline pH may often contribute significantly to the irritated condition already prevailing in a highly exacerbating stage of acne vulgaris.

(c) In some instances alcohol vehicles containing 60% or more of alcohol are employed as vehicles for salicylic acid, resorcinol, and some antibacterial agents which could otherwise not be properly and adequately dispersed for dermatological use. Alcohol could increase the irritating effect also where the skin is already highly inflamed and, further, upon the evaporation of alcohol, the crystalline residue may irritate the skin.

(d) Many of the preparations contain granular particles. Such preparations are not desirable for use for aesthetic reasons and their effectiveness is reduced by the fact that the medicinal agent is bound up in the particles and not fully available, as in the case of a solution or colloidal dispersion.

In accordance with the present invention, a novel Patented August 9, 1966 ice formulation for the treatment of acne vulgaris is provided. Formulations are also provided for the treatment of tinea versicolor and for the treatment of inflammatory types of acne and acne rosacea.

One object of this invention is to provide an effective therapeutic agent for the treatment of acne vulgaris.

Another object of this invention is to provide a treatment agent for skin maladies associated with hyperplasia of the infected sebaceous gland such as acne vulgaris and seborrheic dermatitis as well as tinea versicolor and acne and acne rosacea which is of a thixotropic nature. This physical characteristic greatly enhances the dispersion stability of the formulations.

A further object of the invention is to provide a formulation wherein all of the ingredients are in solution and/ or colloidal dispersion and which is therefore free from large granular or crystalline materials.

Still another object of this invention is to provide a therapeutic agent low in alcohol content for the treatment of skin maladies associated with hyperplasia of the infected sebaceous gland.

A still further object of the invention is to provide a treatment agent for skin maladies associated with hyperplasia of the infected sebaceous gland as well as tinea versicolor and acne and acne rosacea which is nonoily and which has a substantially physiological pH.

Another object of this invention is to provide a method of forming a stable therapeutically active dermatological preparation containing resorcinol ancl/ or salicylic acid wherein the active ingredients are in solution and/ or colloidal dispersion and wherein the preparation is thixotropic, is free of oil and-contains little alcohol.

A still further object of the invention is to provide a preparation of sodium thi-osulfate which is stable in storage but which releases nascent sulfur when used on the ski-n.

Other objects will be apparent from the balance of the specification which follows.

In accordance with the present invention, it has been found that an effective therapeutic agent for the treatment of skin maladies associated with hyperplasia of the infected sebaceous gland can be provided by preparing an aqueous lotion or cream which combines fibrous boehmite, sodium thiosulfate, salicylic acid, and resorcinol in a small amount of alcohol. In addition, chelating agents may advantageously be employed in the composition as well as cooling and perfuming agents such as menthol and camphor.

The function of the fibrous boehmite in all of the disclosed formula-tions is to act as a dispersing and thickening agent for the mixture. The fibrous boehmite forms a gel matrix so that the other ingredients are held in suspension and/ or solution in a thixotropic mixture. If one attempted to form the mixture without the fibrous boehmite, or if one attempts to substitute conventional aluminum hydroxide gel, the components deposit out as crystals. By the incorporation of fibrous boehmite, we have been able to maintain all of the active ingredients in solution or colloidal dispersion. Formulations prepared two years ago have shown no sign of forming solid deposits.

The sodium thiosulfate, salicylic acid and resorcinol are not only effective therapeutic agents but the sodium thiosulfate stabilizes the salicylic acid and the resorcinol.

Through the adsorption of these active ingredients, one is able to maintain them in colloidal dispersion.

Although the invention is not predicated on the theory of its operation, it is believed that the sodium thiosulfate is adsorbed onto the aluminum fibrils of the boehmite lattice and released as nascent sulfur when the lotion is rubbed into the skin.

The fibrous boehmite comprises boehmite which is stabilized with about 9% of acetic acid, the balance of D the composition being substantially entirely aluminum oxide. The fibrous boehmite which is employed is fully described in United States Patent 2,915,475, so it will not be further described here. The fibrous boehmite may be employed in concentrations of from 0.5 to in the composition. The sodium thiosulfate can be employed in concentrations of from 0.5 to 30%, and preferably from 0.5 to and the salicylic acid and resorcinol can be employed in concentrations of from 0.1 to 5%, if used. If menthol and camphor are used, they can each be employed in concentrations of from 0.01 to 1%. These two substances may be omitted from the formulation without detracting from its therapeutic utility. The amount of alcohol which is used can vary from 10 to and either ethyl or isopropyl alcohol or a mixture of isopropyl alcohol and propylene glycol can be employed. As a chelating agent, it is preferred to use disodium ethylene diamine tetracetic acid in a concentration of about 0.1% to 0.5% although other chelating agents well known to those skilled in the art may be employed. The disodium ethylene diamine tetracetic acid is sometimes hereinafter referred to as sodium EDTA.

The following basic formulation has been prepared and tested clinically for eifectivness:

Percent Fibrous boehmite 3 Sodium thiosulfate a- 8 Salicylic acid 2 Resoreinol 2 Menthol 0.1 Camphor 0.1 Isopropyl alcohol 25 Disodium EDTA 0.1

All parts are by weight and the balance of the composition is water. The results of the clinical evaluation are summarized in Table 1.

Another formulation, similar to the above, but varying somewhat in composition, was also prepared and tested clinically:

Percent Fibrous boehrnite 3 Sodium thiosulfate 2 Salicylic acid 1 Resoreinol 1 Menthol 0.1 Camphor 0.1 Isopropyl alcohol 25 Disodium EDTA 0.1

The clinical data are summarized in Table 2.

Table 1 Efficacy Condition Treated Number Number Doctors Patients X 0 1 2 NR Acne Vulgaris. 13 342 27 201 53 4 Acne Cystic 2 9 6 1 Acne Rosaeca. 4 4 2 1 Seborrheic Eczema 1 1 1 Miliaria 1 1 l Verruca Plaua 1 1 Tinea Versicolor 1 1 Totals 1 23 359 211 56 5 1 11 doctors participatedfigure reflects multiple conditions treated. N R results unknown.

X=condition worsened.

0 =no improvement. 1 =improvement. 2=marked improvement.

1 15 doctors participated-figure reflects multiple conditions treated.

A formulation which has been found highly efiicacious in the treatment of tinea versicolor is as follows:

. Percentage Sodium EDTA 0.25 Colloidal alumina 3.5 Sodium thiosulfate, U.S.P 25.0 Salicylic acid, U.S.P. 1.0 Menthol 0.05 Isopropyl alcohol, N.F. 10.0 Propylene glycol 10.0

Sodium hydroxide 50% solution, q.s. to adjust pH to 6.0. De-ionized water, q.s., ad.,

The order of compounding the formulations is as follows:

The fibrous boehmite is first dispersed in 50 ml. of water. The sodium thiosulfate is dissolved separately in an additional 16 ml. of water and added to the dispersed fibrous boehmite. Separately, the salicylic acid, resorcinol (if used), hydrocortisone (if used), menthol and camphor are dissolved in isopropyl alcohol or a mixture of isopropyl alcohol and propylene glycol and added gradually to the dispersion with vigorous agitation. The pH may now be adjusted, if necessary, by the addition of an alkali such as sodium hydroxide. The unique features of the above formulations may be described as follows:

(a) The addition of sodium EDTA and, in turn, the incorporation of sodium thiosulfate, stabilizes the product at a pH of 5.5. Specifically, the sodium EDTA chelates all of the trace metals which would cause the normal development of color in the presence of salicylic acid and/or resorcinol. Furthermore, the sodium thiosulfate prevents the oxidative decomposition of both the salicylic acid and resorcinol.

(b) The fibrous boehmite employed in this formulation is in the form of a polymer stabilized with acetic acid. Pursuant to application of the composition to the skin, small amounts of aluminum ion are released to provide for an astringent protein precipitating activity desirable in acne therapy. The aluminum ion also precipitates and inactivates the short chain fatty acids known to be generated and produced by the microbial flora often residing in active comedones as described by John S. Strauss and Albert M. Kligman, Arch. Derm., 82, 779-790 (1960). It has been shown by Strauss et al. that the short chain fatty acids abounding in acne lesions are in a major way contributory to the inflammation encountered in acne lesions. The basic formulations presented above are compatible with aluminum chloride and aluminum potassium sulfate and these latter salts can be added in concentrations ranging from 0.5% to 5.0% to increase the activity ascribed to the aluminum ion.

(c) These formulations embodying sodium thiosulfate allow for the release of nascent sulfur at the site of the inflamed acne lesion, according to the following equation:

It may be noted from the above equation that hydrogen ions are necessary for the decomposition of the thiosulfate ion. The hydrogen ions are generated at the acne lesion site as short chain fatty acids according to Strauss sulfate in these formulations, we have selective deposition of sulfur in situ (at the precise site of dermal affliction, the acne lesion) in an active colloidal form, not possible by ordinary topical application of native sulphur dispersions in ordinary vehicles now commonly employed with some measure of benefit. It should be noted that sulphur dioxide is another by-product of the reaction, and that it is dissipated. Some measurable transient antibacterial activity may be ascribed to sulphur dioxide. The other end-product is water. It maybe noted from the above equation that hydrogen ions are actually dissipated, thus reducing the hyperacidity associated with comedones, a beneficial effect.

(d) It has been shown that the fibrous boehmite provides a stabilizing effect on the sodium thiosulfate, presumably by physical adsorption at the surface of the fibrous boehmite preventing it from undergoing chemical decomposition. Such chemical decomposition may be ex pected to occur in ordinary vehicle-s. Furthermore, the rate of the above reaction is slow enough pursuant to application of the product to the skin so as not to cause any undesirable odor formation in actual use. In these formulations we are able to maintain in colloidal dispersion and in solution the salicylic acid, the resorcinol, and, in turn, the sodium thiosulfate which could not be so formulated into a stable preparation without the aid of the fibrous boehmite. For example, compounding according to either of the above two formulations without the aid of the fibrous boehmite results in incomplete solubility and separation of crystalline material which does not make such a preparation available for therapeutic use. The other possible alternative to maintaining this precise composition in an acceptable form would be by resorting to an oil-water emulsion. As pointed out earlier, oils are contraindicated in acne.

(e) The normal pH of the aqueous fraction of sweat on the skin has been shown to be between 4.0 and 6.5. In these formulations, it has been possible to adjust to a pH of 5.5 or in the range of 5 to 6 which is entirely compatible with normal physiological skin conditions.

(f) The product is translucent, and when applied to the skin, dries to form a practically crystal-clear film which is substanti-ative to the skin. The substantiativity of the formulation comes about by virtue of a net positive charge and the extremely large surface area associated with the stabilized fibrous boehmite particles.

(g) The positive charge associated with the fibrous boehmite particles allows for the adsorption of the thiosulfate and salicylate ions as well as the resorcinol which, pursuant to application to the skin, is held in a surface film to the afflicted epidermal layers.

(h) The practically clear film formed on the skin does not interfere with normal transpiration, is not occlusive in any sense since it is miscible with water and, therefore, does not interfere with normal physiological processes occurring in the skin.

(i) The above formulations are rapidly drying, thereby providing an element of convenience in normal practical use.

(j) The above formulations are compatible with a variety ofadditional components oftentimes employed in the therapy of various types of acne. For example, hexachlorophene 0.1-2.0%; parachlorometaxylenol 0.1-2.5%; phenol 0.1-2.0%; hydrocortisone 0.25-2.5%; nonionic detergents, 0.1-20%; cationic detergents, such as benzalkonium chloride, 0.010.l%; sulfur l15%; coal tar 110%; ichthyol 115%; tannic acid 120%; or balsam Peru 110%.

A typical formulation incorporating hydrocortisone and which is highly effective in treating inflammatory types of acne and acne rosacea is as follows:

Percentage Sodium EDTA 0.25 Colloidal alumina 4.0

' Percentage Sodium thiosulfate, U.S.P 8.0 Menthol, U.S.P 0.1 Carnphor, U.S.P 0.1 Salicylic acid, U.S.P 2.0 Isopr-opyl alcohol, N.F. 25.0

Sodium hydroxide 50% solution, qis. to adjust pH to 5.0.

Hydroco-ntisone acetate De-ionized water q.s., ad.,

(k) The above formulations when applied to the skin lend themselves extremly well to covering with cosmetics of choice either by the patient or as recommended by the physician. There is no incompatibility or covering problem with these formulations such as is always associated with ioalamine, titanium dioxide, zinc oxide, or iron pigment-containing formulations.

I claim:

1. A thixotropic composition for treating skin maladies associated with hyperplasia of the infected sebaceous gland comprising an aqueous mixture having a physiological pH and containing Percent Fibrous boehmite 0.5 to 10 Sodium thiosulfate 0.5 to 15 Resorcinol 0.1 to 5 Salicylic acid 0.1 to 5 and Alcohol 10 to 25 all percentages being by Weight.

2. The composition of claim 1 which also contains from about 0.1 to 1.0% of menthol and from about 0.1 to 1.0% camphor.

3. A thixotropic composition for treating skin maladies associated with hyperplasia of the infected sebaceous gland comprising an aqueous mixture having a physiological pH and containing Percent Fibrous boehmite 3 Sodium thiosulfate 8 Salicylic acid 2 Resorcinol 2 Menthol 0.1 Camphor 0.1 Isopropyl alcohol 25 and Disodium ethylene diamine tetracetic acid 0.1

all percentages being by weight.

5. thixotropic composition for treating skin maladies comprlsmg an aqueous mixture having a physiological pH and containing Percent Fibrous boehmite 0.5 to 10 Sodium thiosulfate 0.5 to 30 Alcohol 10 to 25 all percentages being by weight.

6. A thixotropic composition for treating skin maladies Percent comprising an aqueous mixture having a physiological pH Sodium EDTA 0.25 and containing Colloid-a1 alumina 4.0

Percent Sodium thi'osulfate, U.S.P 8.0

Sodium EDTA 0.25 5 Menthol, U.S.P 0.1

Colloidal alumina 3.5 Camphor, U.S.P 0.1

Sodium thiosulfiate, U.S.P 25.0 Salicylic acid, U.S.P 2.0

Salicylic acid, U.S.P 1.0 Isopropyl alcohol, N.F 25.0

Menthol 0.05 Sodium hydroxide 50% solution, q.s. to adjust Isopropyl alcohol, N.F 10.0 10 pH to 5.0%.

Propylene glycol 10.0 Hydrocortisone acetate 0.5

Sodium hydroxide 50% solution, q.s. to adjust De-ionized water, q.s., ad., 100%.

H t 6.0 D d q'S ad 100% References Cited by the Examiner 15 Merck Index, Merck and Co., Rahway, NJ. (196-),

pp. 532 and 863.

7. A thixotropic composition for treating skin maladies JULIAN S. LEVHT Primary Examiner. comprising an aqueous mixture having a physiological pH i and o tai i VERA C. CLARKE, Asszstant Examiner.

all percentages being by weight.

Claims

1. A THIXOTROPIC COMPOSITION FOR TREATING SKIN MALADIES ASSOCIATED WITH HYPERPLASIA OF THE INFECTED SEBACEOUS ALCOHOL 10 TO 25