Vaginal pharmaceutical compositions are described. These compositions contain (i) an active pharmaceutical ingredient selected from the group consisting of antimicrobial imidazoles and mixtures thereof, and (ii) a polysaccharide, wherein the pH of the composition is greater than 4.25 and less than about 8. In particularly preferred compositions, the active pharmaceutical ingredient includes metronidazole and the polysaccharide includes hypromellose. These compositions can be applied to vaginal tissue for treatment of various diseases, such as bacterial vaginosis, or for prophylaxis.

Description of the Invention

FIELD OF THE INVENTION

The invention relates to vaginal pharmaceutical compositions containing an antimicrobial imidazole, such as metronidazole, that can be used, for example, in treating bacterial vaginosis.

BACKGROUND

Normal vaginal flora is reported to be composed predominantly of Lactobacillus species, with an average pH of about 4.0. This low pH is reported to foster growth and maintenance of the acidophilic Lactobacilli that dominate the normal flora.

Metronidazole is an antibacterial compound that has been used to treat various microbial diseases, including bacterial vaginosis (BV). Metronidazole has been reported to be effective in treating BV when administered orally. For example, as of 1985, the Center for Disease Control recommended an oral dose of 500 mg of metronidazole twice daily for seven days.

MetroGel-Vaginal.RTM. (3M, St. Paul, Minn.) is a product containing 0.75% metronidazole, methylparaben, propylparaben, edetate disodium, Carbomer 934P, propylene glycol, water, and sodium hydroxide to pH 4.0. The Food and Drug Administration's Approved Drug Products and Therapeutic Equivalents (The "Orange Book") lists, for MetroGel-Vaginal.RTM., U.S. Pat. No. 5,536,743 ("the '743 patent"), Pat. No. 5,536,744 ("the '744 patent"), and Pat. No. 4,837,378 ("the '378 patent").

The '743 and the '744 patents describe compositions and methods directed to the treatment of bacterial vaginosis. These patents describe metronidazole in a buffered, non-flowing pharmaceutical composition having a pH value below 4.25. These patents repeatedly emphasize the criticality of the low pH of the composition. For instance, in Example 12 in each of these two patents, the clinical cure rate of MetroGel-Vaginal.RTM. (pH 4) was found to be superior to the same composition at pH 6. The conclusion was that these results "underscore clearly the advantage of the relatively lower pH value for the vaginal preparation."

The '378 patent is directed to aqueous metronidazole gels containing water-dispersible polycarboxylated vinyl polymers (such as Carbopol.RTM. (Noveon Pharmaceuticals, Cleveland, Ohio)) for the treatment of skin disorders.

U.S. Pat. No. 6,348,203 ("the '203 patent") is directed toward imidazole derivatives that can be used in the topical treatment of certain dermatological diseases. The '203 patent discloses compositions that are specially formulated and buffered to a pH that is within the physiologically tolerable range for dry or inflamed skin. The '203 patent, however, does not teach or suggest whether the disclosed compositions could be suitable for applying to vaginal tissue for treatment or prevention of vaginal diseases, let alone the appropriate dosage for vaginal treatment.

Romanian Patent No. 80,363, published Nov. 30, 1982, describes a vaginal gel containing antifungal, antiparasitic, and large amounts of antibacterial agents (such as metronidazole) in a Carbopol.RTM. 940 base.

Flagyl.RTM. (G.D. Searle & Co., Skokie, Ill.) is a pharmaceutical product that has been approved in Canada. In one form, it is a high-dose (500 mg) vaginal cream containing 10% metronidazole, glycerin, glyceryl monostearate, methylparaben, propylparaben, purified water, stearic acid, and triethanolamine for the treatment of trichomoniasis.

SUMMARY OF THE INVENTION

One embodiment of the invention is a vaginal pharmaceutical composition comprising (i) an active pharmaceutical ingredient selected from the group consisting of antimicrobial imidazoles and mixtures thereof, and (ii) a polysaccharide, wherein the pH of the composition is greater than 4.25 and less than about 8. In particularly preferred embodiments of the invention, the active pharmaceutical ingredient comprises metronidazole, the polysaccharide comprises hypromellose, or both. Another embodiment of the invention is a method for preparing a composition of the invention. The composition of the invention can be applied to vaginal tissue for treatment of certain diseases or for prophylaxis.

Unless otherwise indicated, all percentages refer to percent by weight of the composition.

DETAILED DESCRIPTION OF THE INVENTION

The inventors have unexpectedly discovered that certain compositions containing an antimicrobial imidazole, such as metronidazole, and a polysaccharide are highly effective in treating microbes in low doses and at a pH of greater than 4.25.

A preferred embodiment of the invention is a viscous vaginal pharmaceutical composition comprising an active pharmaceutical ingredient selected from the group consisting of antimicrobial imidazoles and mixtures thereof, and a polysaccharide, wherein the pH of the composition is greater than 4.25 and less than about 8. Advantageously, the composition does not require a buffering system.

The active pharmaceutical ingredient (API) of the composition is one or more antimicrobial imidazoles. Examples of suitable imidazoles include metronidazole, terconazole, clotrimazole, econazole, ketoconozole, miconazole, sulconazole, tioconazole, and the like. As used herein, "antimicrobial" refers to an agent that suppresses or kills bacteria, protozoa, or other microbes.

One of ordinary skill in the art would appreciate that the preferred amount of API in a given composition depends on the particular antimicrobial agent(s) used and other factors, such as the particular carrier used. For metronidazole, the preferred amount is about 0.1 to about 2 wt %, preferably about 0.5 to about 1 wt %, more preferably about 0.75 wt %. Preferred amounts of other imidazoles are as follows -- see Original Patent.

Likewise, the preferred quantity of API contained in a unit dose also depends on the particular antimicrobial agent(s) used and other factors, such as the particular carrier used. For metronidazole, the unit dose is generally at least about 20 mg, and is generally not more than about 375 mg. A preferred unit dose of metronidazole in a gel vehicle is in the range of about 20 to about 40 mg, more preferably about 37.5 mg. Preferred amounts of other imidazoles are as follows -- see Original Patent.

A unit dose can be administered one to three times daily (that is, at spaced intervals in a 24 hour period) for up to ten days. Thus, the total daily dose of metronidazole delivered can range from about 20 to about 375 mg, preferably about 20 to about 100 mg, more preferably about 20 to about 40 mg. In a gel form of a metronidazole composition, a daily dose in the range of about 30 to about 40 mg usually is sufficient. The total dose during the course of therapy for metronidazole compositions of the present invention is preferably in the range of about 100 mg to about 375 mg. The total dose of other APIs can be similarly calculated.

In a preferred embodiment, about 5 g of a gel containing 0.75% metronidazole is administered once or twice daily for a period of about five days, thereby delivering a total dose of about 185 mg to about 375 mg. Such doses are significantly lower than that described previously for oral administration of metronidazole. Lower doses decreases the risk of dose-related side effects.

For prophylactic purposes, the amount of metronidazole administered is preferably in the range of about 20 mg to about 80 mg, more preferably in the range of about 30 to about 40 mg per dose. For other APIs, the dosage can be adjusted downward in a like manner. These prophylactic amounts can be introduced intravaginally as a single dose or more than one dose, as desired, preferably twice a week on non-consecutive days.

The term "unit dose" as used in the specification and claims refers to a physically discrete amount of a pharmaceutical composition that is suitable for itemized administration to a patient. Over the course of treatment, a patient may receive one or more unit doses. The preferred unit dose will also depend on other factors well known by those of skill in the art, including, for example, the nature and severity of the disease, the weight, age, and health of the patient, etc.

In a preferred embodiment of the invention, the composition is sufficiently viscous that the composition stays adhered to the target tissue for a sufficient time to deliver an adequate amount of the API. The preferred viscosity will depend on factors such as the rate of penetration of the API, the quantity of the composition that is applied, whether the patient upright or lying down (for example, bedtime applications), etc.

The composition, which contains a polysaccharide, may be in the form of a gel, paste, cream, ointment, and the like. A gel is most preferred.

To achieve the desired viscosity, a sufficient amount of one or more polysaccharides may be used. Typically, about 0.25 to about 10 wt % polysaccharide (based on the total weight of the composition) is desirable, more preferably about 2.5 to about 7 wt %.

To increase the viscosity of the composition, the polysaccharide may be used in conjunction with one or more non-polysaccharide viscosifiers known in the art. In the absence of a non-polysaccharide viscosifier, the polysaccharide is preferably about 3 to about 4.5 wt %, more preferably about 3.5 wt %.

The polysaccharide of the invention is preferably a cellulose derivative, preferably a non-ionic cellulose ester, ether, hydroxy-ether, or hydroxy-ester, or a non-ionic starch derivative. The polysaccharide can be, for example, a methyl, ethyl, or propyl cellulose ester, ether, hydroxy-ether, or hydroxy-ester. Preferably, the polysaccharide is a hydroxyalkyl cellulose, more preferably hypromellose (also known as hydroxypropyl methylcellulose).

In a preferred embodiment, it is desirable to have a highly viscous composition without exceeding 3.5 wt % polysaccharide. For such an embodiment, it is therefore preferred to use a relatively high-viscosity polysaccharide, such as Methocel E10M, which has an apparent viscosity of 4646-7070 mPa by rotation and 7500-14,000 cP by Ubbelhode.

Examples of possible non-polysaccharide viscosifiers that could be used in conjunction with one or more polysaccharides include xantham gum, alginic acids and salts thereof, magnesium aluminum silicate, dextrins, sucrose and derivatives thereof, and mixtures thereof. The amount of non-polysaccharide viscosifier, if present, is about 0.1 to about 10 wt %.

In a preferred embodiment, the viscosity of the composition is substantially unaffected by changes in pH.

Preferred embodiments of the invention contain one or more pharmaceutically acceptable preservatives. As used herein, the term "preservative" includes an agent or a combination of agents that aids in stabilizing the composition, inhibiting microbe growth, or both. Examples of suitable preservatives include parabens (e.g., methyl, ethyl, propyl, and butyl esters of parahydroxybenzoic acid), propyl gallate, sorbic acid and its sodium and potassium salts, propionic acid and its calcium and sodium salts, "Dioxin" (6-acetoxy-2,4-dimethyl-m-dioxane), "Bronopol" (2-bromo-2-nitropropane-1,3-diol) and salicylanilides such as disbromosalicylanilide, tribromosalicylamilides, "Cinaryl" 100 and 200 or "Dowicil" 100 and 200 (Cis isomer of 1-(3-chloroallyl-3,5,7-triaza-1-azanidadamantane chloride), hexachlorophene, sodium benzoate, citric acid, ethylene diaminetetraacetic acid and its alkali metal and alkaline earth metal salts, butyl hydroxyanisol, butyl hydroxytoluene, phenolic compounds such as chloro- and bromocresols and chloro- and bromo-oxylenols, quaternary ammonium compounds like benzalkonium chloride, aromatic alcohols such as phenylethyl alcohol, benzyl alcohol, etc., chlorobutanol, quinoline derivatives such as iodochlorohydroxyquinolin, and the like. Additional examples of pharmaceutically acceptable preservatives can be found, for example, in Handbook of Pharmaceutical Additives (Synapse Information Resources, Inc.), which is incorporated herein by reference. A particularly preferred preservative system is a combination of methylparaben and propylparaben.

The total amount of preservative, when present, is preferably about 0.005 to about 2 wt %, more preferably about 0.1 wt %.

In a preferred embodiment of the invention, the pharmaceutical composition is water-based and contains a cosolvent. For the cosolvent, monohydric alcohols can be used, such as those having from 1 to 22 carbons per molecule, such as methanol, ethanol, propanol, isopropanol, butanol, hexanol, cetyl alcohol, stearyl alcohol, and the like. Dihydric and polyhydric alcohols can be used, such as those having from 2 to 22 carbons per molecule, such as propylene glycol, glycerin, hexanetriols, such as 1,2,6-hexanetriol, sorbitol, 1,3-butanediol, 2,3-butanediol, and the like. Polyethylene glycols and polypropylene glycols can be used, such as those having molecular weight in the range of about 100 to about 20,000. Esters of aliphatic monobasic and dibasic acids can be used, such as those having from 2 to 22 carbons per molecule, with (a) monohydric alcohols having from 1 to 20 carbons per molecule, (b) di- and polyhydric alcohols having from 2 to 20 carbons per molecule, and (c) sugar alcohols. Examples include isopropyl myristate, myristyl myristate, cetyl stearate, methyl stearate, isopropyl sebacate, methyl sebacate, sucrose monolaurate, sucrose monostearate, and the like. Propylene glycol, a polyethylene glycol, hexylene glycol, oleic acid, a polyoxyethylene, glycerin, or mixtures thereof are preferred. Propylene glycol is most preferred.

The preferred amount of cosolvent, when present, is about 0.5 to about 40 wt %, preferably about 3 wt %.

In a preferred embodiment of the invention, the pharmaceutical composition contains a chelating agent, such as those known to those skilled in the art. Preferably, the chelating agent is EDTA or a salt thereof. The composition preferably contains about 0.003 to about 1 wt % chelating agent, preferably about 0.02 to about 0.2 wt %, more preferably about 0.05 wt %.

The pH of the composition of the invention is not critical, but preferably ranges from 4.25 to about 8, more preferably from about 5 to about 6.5.

According to an embodiment of the invention, there is provided a viscous vaginal pharmaceutical composition comprising an aqueous gel of: about 0.75% metronidazole; about 3.5% hypromellose; about 3% propylene glycol; about 0.05% edetate disodium; about 0.08% methylparaben; about 0.02% propylparaben; and about 93% water, wherein the pH of the composition is from about 5 to about 6.

Another embodiment of the invention is a method for preparing a pharmaceutical composition according to the invention. Water is admixed with an antimicrobial imidazole, a polysaccharide, optionally, a chelating agent, optionally, a water-miscible cosolvent, and optionally, a preservative. Preferably, the composition that is formed is a gel. Optionally, the pH can be adjusted.

Preferably, the composition is prepared by, first, admixing a polysaccharide and water to form a first mixture. Second, an imidazole and, optionally, a cosolvent is dissolved in the first mixture to form a second mixture. Preferably, the second mixture is cooled to about room temperature prior to storage.

The temperature of the various components is not critical, but preheating the water to about 25.degree. C. to about 90.degree. C. expedites thorough mixing. Preheating the water to about 70.degree. C. to about 80.degree. C. has been found to be a particularly convenient temperature.

Another embodiment of the invention is a method for treating vaginal tissue comprising applying the composition of the invention to targeted vaginal tissue. As used herein, "vaginal tissue" includes the vagina, cervix, and vulva. For most applications, it is envisioned that the vagina will be the principal vaginal tissue that will be targeted. The composition of the invention may be applied to vaginal tissue either to treat diseased tissue or prophylactically.

In one embodiment, the composition of the invention is dispensed from an applicator that is inserted into the vagina and removed. Alternatively, the composition can be put into a vaginal insert, for example, that remains in the vagina as a means of controlling the dose. A vaginal insert of this type might be porous, have holes, or have other mechanisms known in the art to control dosing.

Claim 1 of 2 Claims

1. A viscous vaginal pharmaceutical composition comprising an aqueous gel consisting essentially of: about 0.75% metronidazole; about 3.5% hypromellose; about 3% propylene glycol; about 0.05% edetate disodium; and about 0.08% methylparaben; about 0.02% propylparaben; and about 93% water, wherein the pH of the composition is from about 5 to about 6.5.

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