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Claims for Patent: 8,946,276

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Claims for Patent: 8,946,276

Title:High dosage mucoadhesive metronidazole aqueous-based gel formulations and their use to treat bacterial vaginosis
Abstract: The present disclosure provides mucoadhesive aqueous-based gel formulations of metronidazole useful for a variety of purposes, including intravaginal application as a therapeutic approach towards the treatment of individuals suffering from and/or diagnosed with bacterial vaginosis.
Inventor(s): Nordsiek; Michael T. (Wayne, PA), Balaji; Kodumudi S. (Landsdale, PA)
Assignee: Watson Laboratories, Inc. (Salt Lake City, UT)
Application Number:13/536,960
Patent Claims: 1. A method of treating a subject suffering from and/or diagnosed with bacterial vaginosis (BV), comprising applying intravaginally to the subject an aqueous-based gel comprising one or more gelling polymers, about 1.3 wt % metronidazole (MTZ), and water, wherein the amount of aqueous-based gel applied in a single application contains about 65 mg MTZ, the aqueous-based gel being free of dextrins, cyclodextrins, niacin, and niacinamide, and surfactants.

2. The method of claim 1, wherein the levels of MTZ from the aqueous-based gel measured in the stratum corneum and receiver fluid in an in vitro Franz cell skin permeation experiment carried out with human cadaver skin are at least about 25-55 fold higher and at least about 1-20 fold lower, respectively, when normalized for concentration, than the MTZ levels measures from a gel having the formulation of 0.75 wt % MTZ, 3.0 wt % propylene glocol, 0.02 wt % propyl paraben, 0.08 wt % methyl paraben, 0.05 wt % disodium EDTA, 2% Carbomer 974P, sodium hydroxide and water, pH 4 ("MGV").

3. The method of claim 1, in which the aqueous-based gel has a viscosity ranging from about 200,000 mPa to about 400,000 mPa, measured at 25.degree. C. using the controlled shear rate method, a Bohlin CVO 100 rheometer and the rheometer settings of Table 11.

4. The method of claim 1, in which the aqueous-based gel has a degree of mucoadhesion ranging within about +10% of that of MG33PB.

5. The method of claim 1, in which the aqueous-based gel comprises about 30 wt % to about 60 wt % water.

6. The method of claim 1, in which the aqueous-based gel is stable for a period of at least 6 months at 25.degree. C.

7. The method of claim 1, in which the aqueous-based gel includes about 1 wt % to about 3 wt % total gelling polymers and about 40-50 wt % of a solvent system for the MTZ.

8. The method of claim 7 in which the solvent system comprises one or more solvents having a staturated MTZ solubility at 25.degree. C. of at least about 20 mg/g.

9. The method of claim 8 in which the solvent system comprises one or more solvents having a saturated MTZ solubility at 25.degree. C. of at least about 50 mg/g and optionally one or more solvents having a saturated MTZ solubility at 25.degree. C. in a range of about 20 mg/g to about 25 mg/g.

10. The method of claim 9 in which the solvent system comprises one or more lower aromatic alcohols, and optionally one or more lower aliphatic diols and/or one or more polyoxyalkylenes having a molecular weight ranging from about 200 to about 400 ("lower polyoxyalkylene").

11. The method of claim 10 in which the solvent system comprises one or more lower aromatic alcohols, one or more lower aliphatic diols, and/or one or more lower polyoxyalkylenes.

12. The method of claim 11 in which the solvent system comprises one or more lower aromatic alcohols, one or more lower aliphatic diols, and one or more lower polyoxyalkylenes.

13. The method of claim 10 in which the one or more lower aromatic alcohols are selected from the group consisting of benzyl alcohol, 2-methylbenzyl alcohol, phenoxyethanol, and mixtures thereof.

14. The method of claim 10 in which the one or more lower alkylene diols are selected from the group consisting of ethane-1,2-diol (ethylene glycol), propane-1,2-diol (propylene glycol), and mixtures thereof.

15. The method of claim 10 in which the one or more lower polyoxyalkylenes are selected from the group consisting of polyoxyethylene (polyethylene glycol), polyoxypropylene, (polypropylene glycol) and mixtures thereof.

16. The method of claim 10 in which one or more lower aliphatic diols and the one or more lower polyoxyalkylenes are included in the solvent system in a total lower aliphatic diol to total lower polyoxyalkylene weight ratio ranging from about 1:1 to about 1:2.

17. The method of claim 10 in which the solvent system comprises about 3.5 wt % to about 5 wt % total lower aromatic alcohols and about 95 wt % to about 95.5 wt % of a mixture of the one or more lower alkylene diols and the one or more lower polyoxyalkylenes.

18. The method of claim 17 in which the weight ratio of total lower alkylene diols to total lower polyoxyalkylenes ranges from about 1:1 to about 1:1.67.

19. The method of claim 18 in which the solvent system consists of benzyl alcohol, propane-1,2-diol and PEG 400.

20. The method of claim 10 in which the solvent system consists of about 3.5 wt % to about 5 wt % benzyl alcohol and about 95 wt % to about 96.5 wt % of a mixture of propane-1,2-diol and PEG 400, wherein the weight ratio of the propane-1,2-diol to PEG 400 ranges from about 1:1 to about 1:1.67.

21. The method of claim 1 in which the aqueous-based gel further comprises one or more preservatives.

22. The method of claim 21 in which the one or more preservative is an ester of 4-hydroxy benzoic acid.

23. The method of claim 22 in which the one or more preservatives are selected from the group consisting of methyl 4-hydroxybenzoate, propyl 4-hydroxybenzoate, and mixtures thereof.

24. The method of claim 1 in which the aqueous-based gel has a pH in the range about pH 3.0 to about pH 5.0.

25. The method of claim 24 in which the aqueous-based gel has a pH of about pH 4.0.

26. The method of claim 1 in which the one or more gelling polymer is selected from the group consisting of a hydroxyethylcellulose, a carbomer, a polycarbophil, and mixtures thereof

27. The method of claim 1 in which the aqueous-based gel is applied once per day for a period of one to five days.

28. The method of claim 1 in which the aqueous-based gel is applied once per day for a period of one day.

29. The method of claim 1 in which the aqueous-based gel is applied once per day for a period of five days.

30. The method of claim 1 in which the aqueous-based gel comprises about 1.3 wt % MTZ, about 2 wt % polycarbophil AA-1, about 2 wt % benzyl alcohol, about 15 wt % propane-1,2-diol, about 25 wt % PEG 400, about 0.02 wt % methyl 4-hydroxybenzoate, and about 0.08 wt % propyl 4-hydroxybenzoate.

31. The method of claim 30 in which the aqueous-based gel is applied once per day for a period of one to five days.

32. The method of claim 30 in which the aqueous-based gel is applied once per day for a period of one day.

33. The method of claim 30 in which the aqueous-based gel is applied once per day for a period of five days.

34. A method of treating a subject suffering from and/or diagnosed with bacterial vaginosis (BV), comprising applying intravaginally to the subject an amount of an aqueousbased gel for a number of applications sufficient to achieve a clinical cure, wherein the aqueous-based gel comprises one or more mucoadhesive polymers, about 1.3 wt % metronidazole (MTZ), and water, and has one or more features or characteristics selected from the following group: the levels of MTZ from the aqueous-based gel measured in the stratum corneum and receiver fluid in an in vitro Franz cell skin permeation experiment carried out with human cadaver skin are at least about 25-55-fold higher and at least about 1-20-fold lower, respectively, when normalized for concentration, than the MTZ levels measured from MGV; a viscocity ranging from about 200,000 mPa to about 400,000 mPa, measured at 25.degree. C. using the controlled shear rate method, a Bohlin CVO 100 rheometer and the rheometer settings of Table 11; a degree of mucoadhesion ranging within about .+-.10% of that of MG33PB; comprises about 30 wt % to about 60 wt % water; is stable for a period of at least 6 months at 25.degree. C.; and includes about 1 wt % to about 3 wt % total mucoadhesive polymers and about 40 wt % to 45 wt % of a solvent system for the MTZ; wherein the amount of the aqueous-based gel applied in a single application contains about 65 mg MTZ, and the aqueous-based gel is free of dextrins, cyclodextrins, niacin, niacinamide and surfactants.

35. The method of claim 34 in which an amount of the aqueous-based gel is applied for a number of applications sufficient to achieve a therapeutic cure.

36. The method of claim 34, wherein the amount of the aqueous-based gel comprises about 30% to about 60% water.

37. The method of claim 36, wherein the aqueous-based gel is applied once per day for a period of one to five days.

38. The method of claim 36, wherein the aqueous-based gel is applied once per day for a period of five days.

39. A method of treating bacterial vagninosis (BV) comprising administering to a subject suffering from and/or diagnosed with BV a treatment that comprises an intravaginal administration of an aqueous-based gel composition comprising about 65 mg metronidazole (MTZ), wherein the concentration of MTZ in the aqueous-based gel is about 1.3 wt % and the aqueous-based gel is free of dextrins, cyclodextrins, niacin, niacinamide and surfactants.

40. The method of claim 39, wherein the step of administering comprises administering a unit dose of the aqueous-based gel composition, which unit dose contains about 65 mg MTZ.

41. The method of claim 39, wherein the aqueous-based gel composition comprises one or more mucoadhesive gelling polymers, about 1.3% by weight MTZ, a solvent system for MTZ, and water.

42. The method of claim 41, wherein the aqueous-based MTZ gel composition comprises about 1.3 wt % MTZ, about 1 wt % to about 3 wt % of one or more mucoadhesive gelling polymers, about 30 wt % to about 60 wt % of a solvent system for the MTZ, and about 30 wt % to about 60 wt % water.

43. The method of claim 41, wherein the solvent system comprises one or more lower aromatic alcohols, one or more lower aliphatic diols and/or one or more polyoxyalkylenes having a molecular weight ranging from about 200 to about 400.

44. The method of claim 43, wherein the one or more lower aromatic alcohols are selected from the group consisting of benzyl alcohol, phenoxyethanol, and mixtures thereof.

45. The method of claim 43, wherein the one or more lower aliphatic diols are selected from the group consisting of ethane-1,2-diol (ethylene glycol), propane-1,2-diol (propylene glycol), and mixtures thereof.

46. The method of claim 43, wherein the one or more lower polyoxyalkylenes are selected from the group consisting of polyoxyethylene (polyethylene glycol), polyoxypropylene (polypropylene glycol), and mixtures thereof.

47. The method of claim 43, wherein the solvent system consists of benzyl alcohol, propane-1,2-diol and PEG 400.

48. The method of claim 41, wherein the aqueous-based MTZ gel composition further comprises one or more preservatives, where the one or more preservatives are optionally esters of 4-hydroxy benzoic acid.

49. The method of claim 41, wherein the aqueous-based MTZ gel composition has a pH in the range about pH 3.0 to about pH 5.0.

50. The method of claim 41, wherein the aqueous-based MTZ gel composition has a pH of about pH 4.0.

51. The method of claim 41, wherein the one or more mucoadhesive gelling polymers are selected from the group consisting of a hydroxyethylcellulose, a carbomer, a polycarbophil, and mixtures thereof.

52. The method of claim 41, wherein the aqueous-based MTZ gel composition comprises about 1.3 wt % MTZ, about 2 wt % polycarbophil AA-1, about 2 wt % benzyl alcohol, about 15 wt % propane-1,2-diol, about 25 wt % PEG 400, about 0.02 wt % methyl 4-hydroxybenzoate, and about 0.08 wt % propyl 4-hydroxybenzoate.

53. The method of claim 39, wherein the treatment comprises two or more intravaginal administrations of an aqueous-based gel composition comprising about 65 mg MTZ, wherein the concentration of MTZ is about 1.3 wt %.

54. The method of claim 53, wherein the aqueous-based gel composition is applied once per day for a period of two to five days.

55. The method of claim 54, wherein the aqueous-based gel composition is applied once per day for a period of five days.
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