Vaginal gel

Abstract

A composition having gel-like consistency contains metronidazole, terconazole, a physiologically acceptable thickener and water. The composition is useful for treating bacterial vaginosis as well as vulvovaginal candidiasis.

Claims

1. A composition having enhanced bioavailability of metronidazole, a gel-like consistency and comprising metronidazole, terconazole, a physiologically acceptable thickener, and water; wherein metronidazole is present in a concentration of at least 0.5 weight percent based on the weight of the composition, terconazole is present in a concentration of at least 0.4 weight percent, based on the weight of the composition, and in an amount sufficient to enhance bioavailability of metronidazole present and the metronidazole is present together with a buffer system which provides a buffered pH value for the composition in the range of 3.75 to 4.25, and metronidazole and terconazole are present in a mole ratio in the range of 3:1 to about 3.5:1.

2. The composition in accordance with claim 1, wherein metronidazole and terconazole are present in a mole ratio of about 3.5:1, respectively.

3. The composition in accordance with claim 1, wherein the amount of metronidazole present in the composition is in the range of about 0.75 weight percent to about 1 weight percent, based on the weight of the composition and the amount of terconazole present in the composition is in the range of about 0.6 weight percent to about 1.2 weight percent, based on the weight of the composition.

4. The composition in accordance with claim 1, wherein metronidazole concentration is about 0.9 weight percent, terconazole concentration is about 0.8 weight percent, the physiologically acceptable thickener is hydroxypropyl methyl cellulose, and the buffer system comprises citric acid and sodium citrate.

5. A method for treating bacterial vaginosis in a human patient which comprises introducing into the vagina of a patient in need of such treatment the composition of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) In the drawings,

(2) FIG. 1 is a graph showing bioavailability of metronidazole alone and in a combination with terconazole in a gel-like carrier; and

(3) FIG. 2 is a graph showing bioavailability of terconazole alone and in combination with metronidazole in the same gel-like carrier.

DESCRIPTION OF PREFERRED EMBODIMENTS

Definitions

(4) The term “buffer system” or “buffer” as used herein and in the appended claims refer to a solvent agent or agents which, when dissolved in water, stabilize the resulting solution against a major change in pH when acids or bases are added. A preferred buffer system for purpose of the present invention is a citric acid—sodium citrate system.

(5) The terms “unit dose” or “unit dosage form” as used herein and in the appended claims refers to physically discrete units of the present composition suitable for administration to human female subjects. Each unit contains a predetermined amount of metronidazole and terconazole calculated to produce the desired therapeutic effect. The unit dosage form to be administered to any given patient is dictated by and dependent on (1) the particular therapeutic effect to be achieved (2) and the release rate of the active agents from the particular composition utilized.

(6) The term “vagina” as used herein and the appended claims is inclusive of the vaginal region generally, including the vulva and the cervix.

(7) The quantity of the therapeutic composition introduced intravaginal, for treatment of bacterial vaginosis (BV) can vary widely, depending on age and physical condition of the patient, the extent of affliction, frequency of administration, and the like factors.

(8) The active ingredients in the present therapeutic compositions are metronidazole (1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole; M.W.171.156 g/mol) and terconazole cis-1-[p-[[2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazole-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-4-isopropylpiperazine; M.W. 532.462 g/mol). The terms “metronidazole” and “terconazole” as used herein and appended claims also includes analogs and derivatives thereof that exhibit therapeutic activity when used as described herein.

(9) Metronidazole and terconazole both are commercially available compounds.

(10) Suitable physiologically acceptable thickeners are cellulose derivatives such as hydroxypropyl methyl cellulose, hydroxy ethyl cellulose, sodium carboxymethyl cellulose, as well as the polyacrylic acid polymers cross-linked with polyacrylic acid polymers and commercially available from Lubrizol Corporation, Cleveland Ohio under the designations CARBOPOL 934, CARBOPOL 940, CARBOPOL 950, and the like.

(11) The present compositions can also contain optional preservatives, chelating agents, a cosolvent, viscosity stabilizes, and the like.

(12) Suitable preservatives are the lower alkyl esters of parahydroxybenzoic acid, e.g., methyl paraben, propyl paraben, and the like, sodium benzoate, ethylene diamine tetraacetic acid (EDTA), and the like.

(13) Suitable cosolvants are dihydric and polyhydric alcohols such as propylene glycol, glycerin, sorbitol, 1, 2, 6-hexane triol, and the like.

(14) A suitable viscosity stabilizer is methionine, and the like. In the gel-like compositions embodying the invention metronidazole and terconazole are present in a respective mole ratio in the range of about 3 to about 4, preferably about 3.5.

(15) The concentration of metronidazole present in the compositions is at least about 0.5 weight percent, based on the weight of the composition, preferably in the range of about 0.75 weight percent to about 1 percent weight, and more preferably about 0.9 weight percent.

(16) The concentration of terconazole present in the composition is at least about 0.4 weight percent, based on the weight of the composition, preferably in the range of about 0.6 weight percent to about 1.2 weight percent, more preferably about 0.8 weight percent.

(17) The quality of metronidazole contained in a unit dose generally is at least about 20 milligrams and not more than about 100 milligrams. A preferred unit dose of metronidazole in a gel vehicle is in the range of about 20 to about 60 milligrams, more preferably about 45 milligrams.

(18) The quantity of terconazole contained in a unit dose generally is at least about 16 milligrams and not more than about 80 milligrams. A preferred unit dose of terconazole in the gel vehicle is in the range of about 16 to about 50 milligrams, more preferably about 40 milligrams.

(19) Experimental compositions having the composition shown in Table 1, below, were prepared to determine bioavailability of metronidazole as well as terconazole from single entity gels as well as from a combination gel. These experimental gels were also used to treat women with mixed (concomitant) BV and VVC. The indicated percentages in Table 1 are percentages by weight.

(20) TABLE-US-00001 TABLE 1 Experimental Compositions Metronidazole + Metronidazole- Terconazole- terconazole gel only gel only gel (T1) (T2) (T3) Active ingredients Metronidazole  0.9%  0.9% 0 Terconazole  0.8% 0  0.8% Inactive ingredients Hypromellose, 2208,  2.5%  2.5%  2.5% USP Propylene glycol, USP   3%   3%   3% l-Methionine, USP 0.18% 0.18% 0.18% Methylparaben, NF 0.08% 0.08% 0.08% Propylparaben, NF 0.02% 0.02% 0.02% EDTA 0.05% 0.05% 0.05% Citric acid, USP 0.43% 0.43% 0.43% Sodium citrate, USP QS to pH 4.0 QS to pH 4.0 QS to pH 4.0 Purified water, USP QS to 100% QS to 100% QS to 100%

(21) A single dose crossover bioavailability study was conducted in healthy female volunteers using the preparations shown in Table 1, above. Five grams of each preparation was filled into a vaginal applicator and administered to each subject. Each applicator corresponded to 45 milligrams of metronidazole, or 40 milligrams of terconazole, or 45 milligrams of metronidazole and 40 milligrams of terconazole. Twenty-four (24) subjects were enrolled in the study of which twenty-one (21) completed the study. Subjects were housed from at least 12 hours prior to drug administration until 24 hours thereafter. Thereafter, subjects reported to the study facility at 36 hours, 48 hours, and 72 hours. The subjects were treated with each of these gels according to a randomization schedule.

(22) Plasma samples were obtained from the subjects within 90 minutes prior to dose administration (0 hr) and post-dose at hourly intervals starting with one hour after dose administration for the first twelve hours and thereafter at 14 hrs, 16 hrs, 24 hrs, 36 hrs, 48 hrs and 72 hrs in each study period.

(23) Three separate study periods were conducted. A washout period of seven days was maintained between study periods except in three instances between Study Period II and Study Period III due to menstruation. In those three instances the washout period was 14 days.

(24) A linear plot of observed mean metronidazole plasma concentration versus time for metronidazole+terconazole gel (T1) and metronidazole-only gel (T2) is shown in FIG. 1. The enhanced bioavailability of metronidazole in the presence of terconazole is clearly indicated.

(25) FIG. 2 is a linear plot of observed mean terconazole plasma concentration versus time for metronidazole+terconazole gel (T1) and terconazole-only gel (T3) and shows that bioavailability of terconazole is not enhanced by the presence of metronidazole.

(26) Table 2 and 3, below, present the observed pharmacokinetic parameters.

(27) TABLE-US-00002 TABLE 2 Metronidazole Bioavailability Mean ± SD (Untransformed Data) Metronidazole + Metronidazole- terconazole gel only gel Parameter (T1) (T2) (Unit) (N = 23) (N = 22) C.sub.max (ng/mL) 597.4 ± 167.5 348.3 ± 154.3 AUC.sub.0-t (hr .Math. ng/mL) 9286.8 ± 2562.8 7371.7 ± 2031.1 AUC.sub.0-∞ (hr .Math. ng/mL) 9396.2 ± 2593.4 7463.8 ± 2027.9

(28) The above data show that the maximum plasma concentration (C.sub.max) as well as the area under the curve (AUC) for metronidazole are much greater for metronidazole+terconazole gel (p<0.001 for all parameters). Metronidazole bioavailability was significantly enhanced by formulation together with terconazole.

(29) TABLE-US-00003 TABLE 3 Terconazole Bioavailability Mean ± SD (Untransformed Data) Metronidazole + Terconazole- terconazole gel only gel Parameter (T1) (T3) (Unit) (N = 23) (N = 23) C.sub.max (ng/mL) 18.7 ± 18.4 22.1 ± 20.3 AUC.sub.0-t (hr .Math. ng/mL) 285.9 ± 158.5 307.0 ± 180.7 AUC.sub.0-∞ (hr .Math. ng/mL) 320.3 ± 156.3 320.6 ± 183.2

(30) The data in Table 3 show that the bioavailability of terconazole was not significantly influenced by the presence of metronidazole.

(31) The compositions embodying the invention also are more effective than metronidazole alone for curing bacterial vaginosis (BV) infections in women with mixed (concomitant) BV and VVC.

(32) These same three experimental formulations were tested in women who met all clinical and laboratory criteria required to establish a diagnosis of both BV and VVC. Women were given a five-gram applicator full of gel at bedtime for 3 consecutive days. At 7-14 days they were evaluated for clinical cure of both BV and VVC.

(33) BV cure was defined as resolution of abnormal discharge, negative KOH whiff test for amines, and negative for presence of 20% or greater clue cells on examination of vaginal fluid wet mount. In these women with both BV and VVC, it was expected that the metronidazole+terconazole combination would cure significantly more BV than terconazole alone and provide similar cure rates to metronidazole alone for BV. However, the BV cure rate for these women was unexpectedly higher in women who used the metronidazole+terconazole combination gel compared to women who used the metronidazole-only gel as seen below in Table 4

(34) TABLE-US-00004 TABLE 4 BV Cure Rates Metronidazole + Metronidazole- Terconazole- BV Clinical Cure terconazole gel only gel only gel in Mixed Infection (T1) (T2) (T3) Number of subjects 82 84 83 BV Clinical Cure 54 (65.9%) 46 (54.8%) 38 (45.8%) 95% Confidence Interval (55.0%, 76.7%) (43.5%, 66.0%) (34.5%, 57.1%) Difference: Combination gel 11.1% 20.1% minus single-entity gel p-value (continuity 0.193 0.015 corrected chi-square)

(35) VVC cure was defined as resolution of all symptoms and signs attributable to VVC. In these women with both BV and VVC, it was expected that the metronidazole+terconazole combination would cure significantly more VVC than metronidazole alone and provide similar cure rates to terconazole alone for VVC. These expectations were correct, as seen in Table 5 below:

(36) TABLE-US-00005 TABLE 5 VVC Cure Rates Metronidazole + Metronidazole- Terconazole- VVC Clinical Cure terconazole gel only gel only gel in Mixed Infection (T1) (T2) (T3) Number of subjects 82 84 83 VVC Clinical Cure 53 (64.6%) 37 (44.0%) 52 (62.7%) 95% Confidence Interval (53.7%, 75.6%) (32.8%, 55.3%) (51.6%, 73.7%) Difference: Combination gel 20.6% 2.0% minus single entity gel p-value (continuity 0.012 0.918 corrected chi-square)