Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-07-13
2002-10-22
Wilson, James O. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000, C514S025000, C514S054000, C514S058000, C536S001110, C536S102000, C536S103000
Reexamination Certificate
active
06468989
ABSTRACT:
The invention pertains to the field of topically applied medications for treatment of skin and mucosal disorders. In particular, the invention pertains to aqueous gel compositions containing metronidazole as the active ingredient.
BACKGROUND OF THE INVENTION
Metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole, has long been known as an effective drug to treat a variety of disorders, and is especially well known for the treatment of various protozoal diseases. As a topical therapy, metronidazole has also been shown to be useful in treating various skin disorders, including acne rosacea, bacterial ulcers, and perioral dermatitis. See, Borgman, U.S. Pat. No. 4,837,378. Metronidazole has been found to have an anti-inflammatory activity when used topically to treat dermatologic disorders. See, Czernielewski, et al., U.S. Pat. No. 5,849,776. Metronidazole may also be used as an intravaginal therapeutic agent for the treatment of bacterial vaginosis. See, Borgman, U.S. Pat. No. 5,536,743.
Compositions containing metronidazole for treatment of dermatologic disorders are available in both cream and gel forms. One commercially available metronidazole cream product, NORITATE™ (Dermik Laboratories, Inc., Collegeville, Pa. 19426 USA) contains 1% metronidazole and is directed to be applied once daily to affected areas. A commercially available metronidazole gel product, METROGEL® (Galderma Laboratories, Inc. Fort Worth, Tex., 76133 USA), contains 0.75% and is applied twice daily to affected areas.
For the treatment of many dermatologic and mucosal disorders, it is often preferable to use a gel formulation rather than a cream or an ointment. Creams (typically oil in water emulsions) and ointments (typically petroleum jelly based compositions) are often comedogenic, acnegenic, or not cosmetically appealing to patients.
The oil-based cream and ointment metronidazole formulations have an advantage over gel-based formulations in that oil-based formulations may contain a concentration of metronidazole of 1%. Aqueous-based gel compositions are limited to a concentration of metronidazole of 0.75% because of the poor solubility of metronidazole in water. Because of this, metronidazole gel products must be applied on at least a twice daily basis.
Cyclodextrins, especially &bgr;-cyclodextrins, have been shown to enhance the solubility of various drugs in aqueous solutions. Yie W. Chien, Journal of Parenteral Science and Technology, 38(1):32-36 (January 1984), describes the increase in water solubility of MTZ by addition of niacinamide. The Chien article is incorporated herein by reference. The cyclodextrins and niacinamide enhance solubility by formation of a “cage” structure having an external hydrophilic face and an internal hydrophobic face.
A drug, such as metronidazole, is partially or completely enclosed within this cage structure, thereby increasing the solubility of the drug. Beta-cyclodextrin, (“BCD”) and various derivatives of BCD, including methylated and ethylated cyclodextrins, hydroxypropyl-&bgr;-cyclodextrin (referred to in this application as “HPCD”), and hydroxyethyl-&bgr;-cyclodextrin have been used to increase solubility of drugs.
Several authors have described the use of &bgr;-cyclodextrin in combination with metronidazole. Kata and Antal, Acta Pharmaceutica Hungarica, 54:116-122 (1984), disclose a marked increase in the rate of dissolution of metronidazole when dissolved in a solution containing BCD. The stability of the BCD/metronidazole solutions is not addressed. Also, use of &bgr;-cyclodextrin (“BCD”) is limited however due to its relatively low solubility in water and toxicity when administered internally.
Publications by other authors concerning the use of derivatives of BCD show that any increase in the solubility of a drug that is obtained by combining with the BCD derivative cannot be extrapolated to other drugs. Also, any increase in the solubility of a drug due to any particular derivative of BCD cannot be extrapolated to another derivative of BCD.
Pitha, U.S. Pat. No. 4,596,795, discloses that the solubility of the sex steroids testosterone, progesterone, and estradiol was greatly improved with HPCD and with poly-beta cyclodextrin, which are highly soluble in water, easily dissolving to 40% w/w solutions. However, solubility of the sex steroids was only marginally improved with BCD, which forms saturated aqueous solutions at about 2% w/w.
Stella, PCT application International Publication WO 91/11172, discloses that digoxin is five times more water soluble when combined with BCD than when it is combined with HPCD. Stella also discloses that testosterone and phenytoin are more water soluble when combined with BCD than when combined with HPCD.
Bodor, EP 0335545 B1, discloses that a 50% w/w concentration of HPCD increases the water solubility of several drugs, including chlordiazepoxide, dexamethasone, diazepam, estradiol, ethynylestradiol, medazepam, methotrexate, norethindrone, norethindrone acetate, norgestrel, oxazepam, phenytoin, and all-trans-retinol. Bodor further discloses that, in order to obtain a particular dissolved concentration of an estradiol compound, the concentration of HPCD must be maintained above 20% because, at levels less than this, the solutions are unstable and precipitation occurs.
Muller, WO 85/02767, discloses that certain hydroxyalkylated derivatives of BCD, including hydroxyethyl, hydroxypropyl, and dihydroxypropyl BCD, increase the solubility of various drugs in aqueous solution. Muller discloses that 10% HPCD increases the solubility of indomethacin, digitoxin, progesterone, dexamethasone, hydrocortisone, and diazepam in a phosphate buffer aqueous solution. No information was provided concerning the stability of these solutions. Muller further discloses that solutions of 4% hydroxypropyl-methyl-BCD increased the solubility of several compounds, including several imidazole compounds, and that solutions of 7% hydroxyethyl-BCD increased the solubility of indomethacin. The drugs dissolved in these solutions were found to be chemically stable, as determined by high pressure liquid chromatography. Muller does not address the problem of physical stability over time as described in Bodor regarding solutions containing less than 50% HPCD.
SUMMARY OF THE INVENTION
It has been surprisingly discovered that physically stable aqueous solutions of higher than 0.75% metronidazole (MTZ) w/w may be obtained by combining in the solution an amount of hydroxypropyl-betacyclodextrin (HPCD), preferably at a level less than 20%. It has further been surprisingly discovered that the combination of HPCD and niacinamide has a synergistic effect in increasing the solubility of MTZ in water. These discoveries permit the production of aqueous MTZ solutions, including gel solutions, at levels of 1% MTZ or higher. At such levels, MTZ may be effectively used as a topical medicament when applied only once daily.
In one embodiment, the invention is an aqueous solution having a concentration of MTZ higher than 0.75% w/w. The aqueous solution contains HPCD, or a combination of HPCD and niacinamide. Preferably, the level of HPCD is less than 20% and the concentration of niacinamide is less than that which, without HPCD, increases the concentration of MTZ to the level of that in the aqueous solution. Preferably, the solution is substantially free of MTZ solubility-enhancing agents other than HPCD or other than HPCD in combination with niacinamide. Preferably, the solution is an aqueous gel.
In another embodiment, the invention is a method for the manufacture of an aqueous solution of MTZ having a concentration greater than 0.75%. The method includes combining MTZ and HPCD, or MTZ, HPCD, and niacinamide, in a water based solution wherein the concentration of the final aqueous solution of MTZ is higher than 0.75%. Preferably, the level of HPCD is less than 20%, and the concentration of niacinamide is less than that which, by itself, increases the concentration of MTZ to the level of that in the aqueous solution. Preferably, a gelling agent is further combined with the MTZ a
Angel Arturo
Chang Yunik
Dow Gordon J.
Dow Pharmaceutical Sciences
Eisenberg, Esq Howard
Lewis Patrick
Wilson James O.
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