Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-23
2004-05-11
Tate, Christopher (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S165000, C514S859000, C514S055000, C530S427000, C528S183000
Reexamination Certificate
active
06734210
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new water-soluble salts of azelaic acid.
1. Technical Field
This patent relates to new salts of azelaic acid with polycations, the processes for obtaining them and to therapeutic uses of these new salts. More particularly, the invention relates to salts deriving from the reaction between azelaic acid and polycations such as chitosan, their production process, and pharmaceutical compositions that contain them as active principles.
2. Background of the Invention
Azelaic acid is a naturally occurring straight-chained, 9-carbon atom saturated dicarboxylic acid obtained by oxidation of oleic acid and by chemical, physical or biological oxidation of free and esterified fatty acids. It is found also in small amounts in the urine of normal individuals (Mortensen P. B. Dicarboxylic acids and the lipid metabolism. Danish Med Boll 1984; 31:121-145). In vitro, azelaic acid has been shown to be a competitive inhibitor of a number of oxidoreduction enzymes such as tyrosinase (Nazzaro-Porro M., Passi S., Morpugro G., Breatimach A. S. Identification of tyrosinase inhibitors in cultures of Pityrosporum, and their melanocytotoxic effect. In: Klaus S. N. (Ed). Pigment Cell, Vol1, Basel: Karger, 1979; 234-243.), thioredoxin reductase (Schallreuter K. U., Wood J. M. Azelaic acid as a competitive inhibitor of thioredoxin reductase in melanoma cells. Cancer Letters 1987;36:297-305.), DNA polymerase (Galhaup I. Azelaic acid: mode of action at cellular and subcellular levels. In: Breathnach A. S., Graupe K., Stingl G. (Eds.) Azelaic acid: A New Therapeutic Agent. Acta Derm Venereol Stockh 1989; 43 (Suppl): 75-82.) and also of mitochondrial oxidoreductases in the respiratory chain. (Passi S., Picardo M., Nazzaro-Porro M., Breathnach A. S. et al. Antimitrochondrial effect of medium chain length (C8-C13) dicarboxylic acids. Biochem Pharmacol 1984; 33:103-108.) In addition, azelaic acid is a potent inhibitor of 5-alpha-reductase (Stamatidas D., Bulteau-Portois M. C., Moszowicz I. Inhibition of 5-alpha reductase activity in human skin by zinc and azelaic acid. Br. J Dermatol 1988;118: 627-632.) Azelaic acid is a scavenger of toxic oxygen species and also inhibits oxyradical activity in cell cultures. (Passi S., Picardo M., De Luca C. et al. Scavenging activity of azelaic acid on hydroxyl radicals in vitro. Free Rad Res Comm 1991; 11:329-339. Passi S., Picardo M., Zompetta C., et al. Oxyradicals scavenging activity of azelaic acid in biological systems. Free Rad Res Comm 1991;15: 17-28.)
Azelaic acid has been used clinically for many years in the treatment of acne vulgaris as well as in hyperpigmentary skin disorders. (Fitton A. and Goa, K. L. Azelaic acid: A Review of its Pharmacological Properties and Therapeutic Efficacy in Acne and Hyperpigmentary Skin Disorders. Drugs 41 (5): 180-798, 1991) It has recently been studied for the treatment of papulopustular rosacea (Maddin, S. A comparison of topical azelaic acid 20% cream and topical metronidazole 0.75% cream in the treatment of patients with papulopustular rosacea. J Am Acad Dermatol 1999;40: 961-965)
While azelaic acid has been used primarily in the treatment of dermatological conditions, because of some of its mechanisms of action, it could have further clinical utility in conditions unrelated to the skin. Azelaic acid has been shown to have antiproliferative and cytotoxic action on the following tumor cell lines: human cutaneous malignant melanoma (Zaffaroni N., Villa R., Silvestro L et al. Cytotoxic activity of azelaic acid against human primary melanoma cultures and established cell lines. Anti Can Res 1990;10:1599-1602.), human choroidal melanoma (Breatimach A. S., Robins E. J., Patzhold H. C. et al. Effect of dicarboxylic acids (C6,C9) on human choroidal melanoma in cell culture. Invest Ophthal Vis Sci 1989;30: 491-498), human squamous cell carcinoma (Paetzold H. C., Breathnach A. S., Robins E. J., et al. Effect of dicarboxylic acids (C6C9) on a human squamous carcinoma line in culture. Histo Histopathol 1989;4: 167-171.) and fibroblastic lines (Geier G., Haushild T., Bauer R et al. Der Einfluss von Azelainsaure auf das Wachstum von Melanomazelikulturen im Vergleich zu Fibroblastemkulturen. Hautartz 1986;37: 146-148.). Azelaic acid would also be expected to have utility in the prevention and treatment of skin cancer as well as solar keratosis. Because of its mechanism of action as a potent inhibitor of 5-alpha reductase, azelaic acid may be applicable to the treatment and prevention of benign enlargement as well as cancer of the prostate and other conditions in which 5-alpha reductase is elevated.
While azelaic acid is somewhat soluble in water, cosmetic oils and alcohols, each of these solvents has serious limitations. Thus, water only marginally dissolves azelaic acid so that a water and azelaic acid solution would contain a maximum of about 0.24% by weight (w/w) azelaic acid, not likely enough to be effective. Azelaic acid has little or no solubility in cosmetic oils. Alcohols are good solvents but are unsatisfactory because large amounts of alcohol e.g., isopropyl alcohol, in a topical composition have the undesirable side effect of drying the skin. Indeed, some alcohols e.g., ethyl alcohol, render azelaic acid unstable at normal temperatures resulting in a totally ineffective composition. For the dermatological use of azelaic acid, the problem of solubility in suitable solvents remains.
U.S. Pat. No. 4,292,326 (Nazzaro-Porro, Sep. 29, 1981), U.S. Pat. No. 4,386,104 (Nazzaro-Porro, May 31, 1983), and U.S. Pat. No. 4,818,768 (Nazzaro-Porro, Apr. 4, 1989) describe azelaic acid as well as other dicarboxylic acids in the treatment of acne and melanocyclic hyperpigmentary dermatoses. The azelaic acid is dispersed in a cream base. These patents do not disclose the use of new azelaic acid salts of the present invention made with chitosan.
U.S. Pat. No. 4,713,394 (1Thomfeldt, Dec. 15, 1987) and U.S. Pat. No. 4,885,282 (Thornfeldt, Dec. 5, 1989) describe azelaic acid as well as other dicarboxylic acids used in the treatment of non-acne inflammatory dermatoses and infectious cutaneous diseases such as rosacea, perioral dermatitis, eczema, seborrheic dermatitis, psoriasis, tinea cruris, flat warts, and alopecia areata. One of Thomfeldt's formulations comprises azelaic acid disposed in a large proportion of ethanol. While ethyl alcohol dissolves azelaic acid, it also renders the azelaic acid unstable at normal temperatures meaning that it will not provide a marketable product. Thornfeldt's second formulation comprises a complete dispersion of azelaic acid. These patents do not disclose the use of new azelaic acid salts made with chitosan.
Venkateswaran U.S. Pat. No. 5,549,888 teaches a solution of active ingredients which includes azelaic acid and is partially solubilized by a glycol. It uses glycol in combination with ethyl alcohol to solubilize the azelaic acid. As stated previously, the presence of ethyl alcohol with azelaic acid can destabilize the azelaic acid. Moreover, because the composition contains ethyl alcohol, formulation of a non-drying, aesthetically pleasing formulation would be difficult. Venkateswaran also teaches that the formulation has a pH between 2.5 and 4.0. This low pH range can have an irritating effect on the skin. Again, this patent also does not teach the use of new azelaic acid salts made with chitosan. Indeed, a search of the patent as well as the scientific literature does not reveal any prior use of the salts of azelaic acid that are the object of this present invention.
The art has yet to find a formulation for completely solubilizing azelaic acid at normal temperatures without sacrificing the stability of the solubilized azelaic acid. Solubilized azelaic acid must remain stable at normal temperatures in order to provide a marketable product.
Without a stable, completely solubilized formula of azelaic acid, the benefits of azelaic acid are unavailable to many users who experience the burning, stinging and redness of the skin associated with exposure to hi
Tate Christopher
Teller Roy
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