BENZOPHENANTHRIDINE ALKALOIDS FOR TOPICAL ACNE TREATMENT

Abstract: A method for topical treatment of P. acnes in mammals with a composition containing benzophenanthridine alkaloid and a skin penetration enhancer. Preferred alkaloids are selected from the group consisting of sanguinarine, chelerythrine, sanguilutine, sanguirubine, chelirubine and chelilutine. The penetration enhancer is selected from the group consisting of pyrrolidones, pyrroles, ethanol, propylene glycol, oleic acids, isopropyl myristate, 1-dodecylazacycloheptan-2-one, hexamethylene palmitamide, hexamethylene laurimide, dimethyl sulfoxide, dimethyl sulfone, N,N-dimethyl formamide, N,N-diethyl toluamide, caprolactam, aliphatic alcohols and aliphatic esters. The compositions may be in the form of liquids, lotions, gels, etc.

Description: BENZOPHENANTHRIDINE ALKALOIDS FOR TOPICAL ACNE TREATMENT BACKGROUND OF THE INVENTION The invention relates to the preparation and composition of a benzophenanthridine alkaloid with a skin penetration enhancer such that the benzo¬ phenanthridine alkaloid will be delivered topically to an acne lesion. The topical delivery of the alkaloid will provide an effective treatment against Proprionibacterium acnes. Acne is a chronic inflammatory disease of the pilosebaceous follicles typically with the onset at puberty. The sebaceous glands enlarge due to androgenic stimulation and colonization of the gland with primarily Proprionibacterium acnes (P. acnes) ensues. Acne affects approximately 80% of the population during adolescence. Topical acne treatments include: benzoyl peroxide, salicylic acid, povidone-iodine, sulfur- resorcinol, sulfur, vitamin A derivatives and antibiotics such as tetracycline. Systemic treatments include the oral administration of estrogen, tetracycline, minocycline and erythromycin. Effective treatments for acne must have several characteristics. First low minimum inhibitory concentration values and low minimum bactericidal concentration values of the an imicrobic are needed against P_^ acnes. Dosage levels which are effective and safe must be tolerated by both males and females. The treatment must be effective for all age groups affected by the disease. The treatment must penetrate the epidermal layer to effectively treat the P^ acnes in the sebaceous gland. Sources of benzophenanthridine alkaloids include five plant families: Papaveraceae, Fumariaccae, Rutaceae Capifoliaceace and Meliaceae. Two of the most important sources of benzophenanthridine alkaloid are found in the Papaveraceae plant family. These plant species are Sanσuinaria canadensis L. (bloodroot) and Maclea a spp. Sanquinaria canadensis L. contains the benzophenanthridine alkaloid sanguinarine, chelery¬ thrine, sanguilutine, chelilutine, sanguirubine, and chelirubine. These alkaloids are known as sanguinaria extract. The benzophenanthridine alkaloids can be isolated and purified on a commercial basis using the techniques and processes described in U.S. Patents 4,767,861; 4,769,452 and 4,878,533, for example. Macleaya spp. major alkaloid components are sanguinarine and chelerythrine. Patents describing an extract of these alkaloids include USSR Pat. No. 495,311 and German Pat. No. 2,856,577. Plants containing the mixture of benzo¬ phenanthridine alkaloids have been used in a variety of medical ailments. These treatments include antiplaque and treating gingivitis using benzophenanthridine alkaloid in combination with zinc chloride in U.S. Patent No. 4,145,412 and as an antimicrobial agent with zinc chloride U.S. in Patent No. 4,406,081. The following patents describe the use of benzo- phenanthridine alkaloid extracts in medical ailments: U.S. Patent No. 4,376,115; U.K. Pat. No. 2,042,336; German Pat. No. 2,901,406; Belgian Pat. No. 888,843. Vichkanova has described the antifungal and antimicrobial effects of sanguirythrine sulfate (Farmakal Toksikol.Moscow 32, 1969), a 1:1 combination of sanguinarine and chelerythrine. USSR Patent No. 230,387 describes the use of sanguirythrine as a topical antimicrobial treatment. Early patents disclose the use of sanguinaria, zinc chloride, and kerosene oil in equal portions to treat open sores (U.S. Pat. No. 201,331). U.S. Pat. No. 433,257 describes a salve of pulverized bloodroot. Armenian bole, powdered rosin, lard, and Stockholm tar for use in the treatment of piles. U.S. Pat. No. 2,344,830 discloses the use of a mixture of bloodroot, zinc chloride and stibnite to fix and outline diseased tissue for surgery. SUMMARY OF THE INVENTION The present invention is directed toward a safe and effective topical treatment of acne using the benzo- phenanthridine alkaloids in combination with skin penetration enhancers in ointments or lotions. This combination will improve the penetration of the epidermal layer by the benzophenanthridine alkaloid transdermally into the follicles containing the P^_ acnes. The benzophenanthridine alkaloid will be either in the iminium ion form as a mineral acid salt, organic salt or in the alkanolamine or base form (Figure 1) . The alkanolamine forms can be as the pseudohydroxylate or pseudoalcoholate. These forms have limited water and alcohol solubility in comparison to the iminium ion form (Table 1) . These compounds are ideal for transdermal drug delivery. This invention incorporates the benzophenanthridine alkaloid in a form compatible with the skin penetration enhancer to facilitate delivery of the alkaloid transdermally. The compositions used in this invention maybe in the form of liquids, lotions, gels, etc. The benzophenanthridine alkaloids include: sanguinarine, chelerythrine, sanguilutine, sanguirubine, chelirubine, and chelilutine, or combinations of any of these. The most effective formulation containing benzophenanthridine alkaloid against ~~ _ acnes requires the active agent to penetrate the epidermal layer. Skin penetration enhancers will assist the transdermal delivery of the benzophenanthridine alkaloid or mixture. These types of compounds act by penetrating the skin and decreasing the skin's resistance to drug passage. Thus, in the present invention, large quantities of benzo¬ phenanthridine alkaloid can be delivered to the acne lesion site. Typical skin penetration enhancers useful in the present invention include: pyrrolidones, pyrroles. ethanol, propylene glycol, oleic acids, isopropyl myristate, l-dodecylazacycloheptan-2-one, hexamethylene palmitamide, hexamethylene laurimide, dimethyl sulfoxide, N,N-dimethyl formamide, N,N-diethyl toluamide, eaprolactam and other aliphatic alcohols and esters. The effectiveness of a skin penetration enhancer must be able to solubilize the alkaloid and have a low water or body fluid solubility. The benzophenanthridine alkaloids as acid salts are soluble in water at one percent or less. Organic acid salt derivatives of the benzophenanthridine alkaloids such as the palmitate and benzoate can be used to increase alkaloid retention in the skin. TABLE 1: SOLUBILITY OF SANGUINARINE FORMS DRUG: Sanguinarine Chloride Solvent Solubility μg/ml Water 4,000 Methanol 10,000 Ethanol 2,000 Glycerin 12,000 Isopropyl Myristate 500 Acetone <50 N-methyl-2-pyrrolidone <10 N,N-dimethylformamide <500 Hexane <50 Mineral Oil <50 Isopropanol 200 Dimethyl Sulfoxide 5,000 DRUG: 8-Ethoxydihvdrosanguinarine (base form) Solvent Solubility μg/ml Water Methanol Ethanol Glycerin Isopropyl Myristate Acetone N-methyl-2-pyrrolidone N,N-dimethylformamide Hexane Mineral Oil Dimethyl Sulfoxide Ethyl Acetate ACTIVITY OF THE BENZOPHENANTHRIDINE ALKALOIDS AGAINST PROPRIONIBACTERIUM ACNES Initial research has demonstrated the in vitro minimum inhibitory concentrations (MIC) of aqueous solutions of sanguinarine chloride and chelerythrine chloride against P_;_ acnes to be 1.1 and 0.8 μg/ml respectively. In Table 2, seven P_;_ acnes strains isolated from the skin of human subjects and identified by standard biochemical testing were evaluated for antimicrobic sensitivity. The drugs used were aqueous solutions of sanguinarine chloride, chelerythrine chloride, tetracycline hydrochloride and doxycycline hyclate. TABLE 2: MINIMUM INHIBITORY CONCENTRATION OF SANGUINARINE CHLORIDE, CHELERYTHRINE CHLORIDE, TETRACYCLINE HYDROCHLORIDE AND DOXYCYCLINE HYCLATE en P. acnes strain VCEDW5-19-9 showed an increased MIC to tetracycline and doxycycline. However, the benzophenanthridine alkaloids MIC indicated no reduced sensitivity. The reported MIC for benzoyl peroxide against P. acnes is approximately 78 μg/ml. (Topical Acne Drug Product for Over-the-Counter Human Use; 21 CFR Part 333, March 23, 1982; using MIC as the basis for comparison.) Sanguinarine and chelerythrine are 78 times more effective than benzoyl peroxide against P. acnes. The antibiotics tetracycline and doxycycline are 3 and 6 times more effective than sanguinarine and chelerythrine. Sanguinarine has been shown to effective than benzoyl peroxide against P_;_ acnes. The antibiotics tetracycline and doxycycline are 3 and 6 times more effective than sanguinarine and chelerythrine. Sanguinarine has been shown to have antiinflammatory properties (U.S. Patent No. 4,737,503) and the toxicity studies on sanguinarine and benzophenanthridine alkaloids have demonstrated no animal or human tissue irritancy, sensitization, anaphylactic, mutagenic, cardiovascular, fertility or reproduction effects. PREPARATION OF FORMULATIONS CONTAINING BENZO- PHENANTHRIDINE ALKALOIDS FOR THE TREATMENT OF P.ACNES The pure compounds sanguinarine, chelerythrine or other benzophenanthridine alkaloids as the acid or organic acid salt may be dissolved in water, glycerin, propylene glycol or C ! -C 6 alcohol at a temperature of 20- 60°C. Higher temperatures will cause N-demethylation of the alkaloid salts. The preparations may contain 0.001 to 10% by weight benzophenanthridine alkaloid salt. The preferred concentration range is 0.01 to 5% by weight. Alternatively, the alkanolamine form or base form of the benzophenanthridine alkaloid can be dissolved in isopropyl myristate, N-methyl-2- pyrrolidone, 2-pyrrole, acetone or ethyl acetate at a concentration of 0.001 to 3% by weight. The alkanolamine form usually used will be the hydroxylate or alcoholate. These forms readily convert to the iminium ion at pH less than 7.0. Thus these forms can be incorporated into an ointment or lotion which is applied to the skin where the active form of the drug is generated at pH 5-6, the pH normally encountered in the epidermis. These preparations usually contain between 0.01 and 5% by weight benzophenanthridine alkaloid. These preparations are all free from metal salts such as zinc or tin. Basic ointment preparations for the treatment of P. acnes with benzophenanthridine alkaloids are listed below: EXAMPLE I Using another benzophenanthridine alkaloid, a formula against P. -acnes would be: The base forms of the benzophenanthridine alkaloids can be prepared in the following example for treatment of acne: EXAMPLE IV A typical lotion with the benzophenanthridine alkaloid is shown below: 10

Claims: WHAT IS CLAIMED IS: 1. A pharmaceutical composition for topical treatment of Proprionibacterium acnes infection sites in mammals, comprising: (a) benzophenanthridine alkaloid; and (b) a skin penetration enhancer. 2. A composition according to claim 1, wherein the alkaloid is selected from the group consisting of sanguinarine, chelerythrine, sanguilutine, sanguirubine, chelirubine and chelilutine. 3. A composition according to claim 1, wherein the penetration enhancer is selected from the group consisting of pyrrolidones, pyrroles, ethanol, propylene glycol, oleic acids, isopropyl myristate, 1- dodecylazacycloheptan-2-one, hexamethylene pal itamide, hexamethylene lauri ide, dimethyl sulfoxide, dimethyl sulfone, N,N-dimethyl formamide, N,N-diethyl toluamide, eaprolactam, aliphatic alcohols and aliphatic esters. 4. A composition according to claim 1, wherein the alkaloid is an acid salt. 5. A composition according to claim 1, wherein the concentration of the alkaloid is in the range of about 0.001 to 10% by weight, based on the total weight of the composition. 6. A composition according to claim 1, wherein the alkaloid is in the base form. 7. A composition according to claim 6, wherein the alkaloid is an alkanolamine derivative. 8. A composition according to claim 1, wherein the composition further comprises water. 9. A composition according to claim 7, wherein the alkaloid derivative is a hydroxylate, ethanolate or methanolate derivative. 10. A composition according to claim 1, wherein the alkaloid is a salt of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric salt, gluconic acid, benzoic acid and palmitic acid. 11. A pharmaceutical composition for reducing skin inflammation in mammals caused by Proprionibacterium acnes, comprising: (a) benzophenanthridine alkaloid; and (b) a skin penetration enhancer. 12. A composition according to claim 11, wherein the penetration enhancer is selected from the group consisting of sanguinarine, chelerythrine, sanguilutine, sanguirubine, chelirubine and chelilutine. 13. A composition according to claim 11, wherein the penetration enhancer is selected from the group consisting of pyrrolidones, pyrroles, ethanol, propylene glycol, oleic acids, isopropyl myristate, 1- dodecylazacycloheptan-2-one, hexamethylene palmitamide, hexamethylene laurimide, dimethyl sulfoxide, dimethyl sulfone, N,N-dimethyl formamide, N,N-diethyl toluamide, eaprolactam, aliphatic alcohols and aliphatic esters. 14. A composition according to claim 11, wherein the alkaloid is an acid salt. 15. A composition according to claim 11, wherein the concentration of the alkaloid is in the range of about 0.001 to 10% by weight, based on the total weight of the composition. 16. A composition according to claim 11, wherein the alkaloid is in the base form. 17. A composition according to claim 11, wherein the composition further comprises water. 18. A composition according to claim 17, wherein the alkaloid derivative is a hydroxylate, ethanolate or ethanolate derivative. 19. A composition according to claim 11, wherein the alkaloid is a salt of an acid selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric salt, gluconic acid, benzoic and palmitic acid.

Inventors: DUNN RICHARD L, GODOWSKI KENNETH C, HARKARADER RONALD J, WOLFF ELYSE D, DUNN, RICHARD, L., GODOWSKI, KENNETH, C., HARKARADER, RONALD, J., WOLFF, ELYSE, D.
Applicants: ATRIX LAB INC, ATRIX LABORATORIES, INC.
Application year: 1990
Main classification: A61K31
IPC codes: A61K31, A61K47