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Claims for Patent: 6,699,492

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Claims for Patent: 6,699,492

Title: Quinolone carboxylic acid compositions and related methods of treatment
Abstract:The present invention relates to the use of quinolone carboxylic acid formulations in the treatment of ocular and periocular infections. The present invention also relates to sustained release compositions comprising specific quinolone carboxylic acid compounds. The invention also relates to quinolone carboxylic acid compositions and methods of preparing the same.
Inventor(s): Roy; Samir (San Ramon, CA), Chandrasekaran; Santosh Kumar (Moraga, CA), Imamori; Katsumi (Chiba, JP), Asaoka; Takemitsu (Chiba, JP), Shibata; Akihiro (Chiba, JP), Takahashi; Masami (Tokyo, JP), Bowman; Lyle M. (Pleasanton, CA)
Assignee: InSite Vision Incorporated (Alameda, CA) SSP Co., Ltd. (Tokyo, JP)
Application Number:10/126,513
Patent Claims: 1. A topical ophthalmic broad spectrum antibiotic composition comprising: from about 0.005% to about 10% by weight, based upon the total weight of the composition, of a quinolone carboxylic acid derivative of formula (I), ##STR5##

wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R.sup.2 is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and monodispersed particles having a particle size of 30 .mu.m and below of a crosslinked carboxy containing polymer; wherein said topical ophthalmic broad spectrum antibiotic composition is nonirritating to ocular tissue.

2. The composition of claim 1, wherein said broad spectrum antibiotic composition provides sustained release of said quinolone carboxylic acid derivative of formula (I), and wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.

3. The composition of claim 1, consisting essentially of a quinolone carboxylic acid derivative of formula (II), wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R.sup.2 is a hydrogen atom or an amino group which may be substituted by ore or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and a carboxy containing polymer, and wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.

4. The composition of claim 1, wherein said carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition, and wherein said quinolone carboxylic acid derivative of formula (I) comprises particles prepared by micronization.

5. The composition of claim 4, wherein said carboxy containing polymer contains up to about 40% by weight of non-carboxyl containing monoethylenically unsaturated monomers.

6. The composition as in claim 2, wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.007% to about 5% by weight based upon the total weight of the composition.

7. The composition of claim 6, wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.

8. The composition as in claim 2, further comprising one or more excipients.

9. The composition as in claim 2, in which said quinolone carboxylic acid derivative of formula (I) is a pro-drug form of said quinolone carboxylic acid derivative of formula (I).

10. The composition as in claim 2, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-1,4-diazepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihy dro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.

11. The composition as in claim 2, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1,4-dihydro-4-oxoquinotine-3-carbo xylic acid, a salt thereof, or hydrochloride thereof.

12. The composition of claim 1, further comprising a solubilizer.

13. The composition of claim 12, wherein said solubilizer is hydroxypropyl-.beta.-cyclodextrin.

14. The composition of claim 13, wherein said hydroxypropyl-.beta.-cyclodextrin is about 5.0% to about 20.0% by weight of said composition, based on the total weight of said composition.

15. The composition of claim 1, further comprising a lightly crosslinked polymer of acrylic acid.

16. The composition of claim 15, wherein said lightly crosslinked polymer of acrylic acid comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.

17. The composition of claim 16, wherein said lightly crosslinked polymer of acrylic acid comprises from about 0.5% to about 1.0% by weight of said composition, based on the total weight of said composition.

18. The composition of claim 1, wherein said crosslinked carboxy containing poiymer is a lightly crosslinked polymer of acrylic acid.

19. A topical ophthalmic broad spectrum antibiotic composition comprising: from about 0.005% to about 10% by weight, based upon the total weight of the composition, of a micronized quinolone carboxylic acid derivative of formula (I), ##STR6##

wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R.sup.2 is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and monodispersed particles having a particle size of 30 .mu.n and below of a crosslinked carboxy containing polymer.

20. The composition of claim 19, wherein said broad spectrum antibiotic composition provides sustained release of said quinolone carboxylic acid derivative of formula (I).

21. The composition of claim 19, wherein said carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.

22. The composition of claim 19, wherein said carboxy containing polymer contains up to about 40% by weight of non-carboxyl containing monoethylenically unsaturated monomers.

23. The composition of claim 19 wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.

24. The composition as in claim 19, further comprising one or more excipients.

25. The composition as in claim 19, which said quinolone carboxylic acid derivative of formula (I) is a pro-drug form of said quinolone carboxylic acid derivative of formula (I).

26. The composition as in claim 19, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.

27. The composition as in claim 19, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carbo xylic acid, a salt thereof, or hydrochloride thereof.

28. The composition of claim 19, wherein said crosslinked carboxy containing polymer comprises a lightly crosslinked polymer of acrylic acid.

29. The composition of claim 19, wherein said crosslinked carboxy containing polymer is a lightly crosslinked polymer of acrylic acid.

30. The composition of claim 29, wherein said lightly crosslinked polymer of acrylic acid comprises from about 0.1% to about 6.5% by weight of said compositions based on the total weight of said composition.

31. The composition of claim 30, wherein said lightly crosslinked polymer of acrylic acid comprises from about 0.5% to about 1.0% by weight of said composition, based on the total weight of said composition.

32. A topical ophthalmic broad spectrum antibiotic composition comprising: a micronized quinolone carboxylic acid derivative of formula (I), ##STR7##

wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R.sup.2 is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and monodispersed particles having a particle size of 30 .mu.m and below of a crosslinked carboxy containing polymer.

33. A method of treating or preventing a bacterial infection in the ocular or periocular region comprising: delivering to the ocular or periocular region a topical ophthalmic broad spectrum antibiotic composition comprising from about 0.005% to about 10% by weight, based upon the total weight of the composition, of a micronized quinolone carboxylic acid derivative of formula (I), ##STR8##

wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in viva, R.sup.2 is a hydrogen atom or an amino group which may be substituted by one or two tower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms and particles having a particle size of 30 .mu.m and below of a crosslinked carboxy containing polymer.

34. The method of claim 33, wherein said composition provides sustained release of said quinolone carboxylic acid derivative of formula (I).

35. The method of claim 33, wherein said crosslinked carboxy containing polymer comprises from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.

36. The method of claim 33, wherein said crosslinked carboxy containing polymer contains up to about 40% by weight of non-carboxyl containing monoethylenically unsaturated monomers.

37. The method of claim 33, wherein said composition is in the form of an ointment or instillant.

38. The method of claim 33, wherein said particles have an average diameter less than about 10 microns.

39. The method as in claim 33, wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.007% to about 5% by weight based upon the total weight of the composition.

40. The method of claim 33, wherein said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight based upon the total weight of the composition.

41. The method of claim 33, wherein said composition further comprises one or more excipients.

42. The method as in claim 33, in which said quinolone carboxylic acid derivative of formula (I) is a pro-drug form of said quinolone carboxylic acid derivative of formula (I).

43. The method as in claim 33, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.

44. The method as in claim 33, wherein said quinolone carboxylic acid derivative of formula (I) is the free acid 8-chloro-1-cyclopropyl-6-fluoro7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1, 4-diazepin-1-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof.

45. The method as in claim 33, wherein said infection is an infection of Grain positive bacteria, Gram negative bacteria, or a mixed infection of Gram positive and Gram negative bacteria.

46. The method as in claim 33, wherein said infection is an infection of a bacteria selected from the group consisting of Escherichia coil, Salmonella typhi, Shigella flexneri, Klebsiellia pneumonia, Proteus vulgaris, Proteus rettgeri, Haemophilus influenzae, Pseudomonos aeruginosia, Serratia marcescens, Moraxella morganii Moraxella lacunata, Moraxella cararrhalis, Bacillus subtilis, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus pyogenes, Streptococcus pneumoniae, Enterococcus faecalis Micrococcus lysodeikticus, and combinations thereof.

47. The method of claim 33, wherein said infection is a mixed infection of Gram negative bacteria and Gram positive bacteria.

48. A method of preparing a sustained release topical ophthalmic delivery system comprising from about 0.005% to about 10% by weight, based upon the total weight of the composition, of a quinolone carboxylic acid derivative of formula (I), said method comprising: preparing a micronized topical ophthalmic broad spectrum antibiotic composition comprising a quinolone carboxylic acid derivative of formula (I), ##STR9##

wherein R.sup.1 is a hydrogen atom, an alkyl group, an aralkyl group, an ester residual group which can be hydrolyzed in vivo, R.sup.2 is a hydrogen atom or an amino group which may be substituted by one or two lower alkyl groups, X is a hydrogen atom or a halogen atom, Y is CH.sub.2, O, S, SO, SO.sub.2, or N--R.sup.3, wherein R.sup.3 is a hydrogen atom or a lower alkyl group, and Z is an oxygen atom or two hydrogen atoms; and combining said micronized topical ophthalmic broad spectrum antibiotic composition comprising a quinolone carboxylic acid derivative of formula (I) with a carboxy containing polymer.

49. The method of claim 48, wherein said carboxy containing polymer present from about 0.1% to about 6.5% by weight of said composition, based on the total weight of said composition.

50. The method of claim 48, further comprising packaging said topical ophthalmic broad spectrum antibiotic composition.

51. The method of claim 48 wherein said carboxy containing polymer comprises a lightly crosslinked polymer of acrylic acid which is present from about 0.5% to about 4.5% by weight, based upon the weight of said composition, and said quinolone carboxylic acid derivative of formula m is present from about 0.02%-2.5% by weight, based upon the total weight of the composition; and wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof, or the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, a salt thereof or hydrochloride thereof.

52. The method of claim 48, wherein said carboxy containing polymer is a lightly crosslinked polymer of acrylic acid which is present from about 0.5% to about 4.5% by weight, based upon the weight of said composition, and said quinolone carboxylic acid derivative of formula (I) is present from about 0.02%-2.5% by weight, based upon the total weight of the composition; and wherein said quinolone carboxylic acid derivative of formula (I) is the free acid (R)-(+)-7-(3-amino-2, 3, 4, 5, 6, 7-hexahydro-1H-azepin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, a salt thereof, or hydrochloride thereof, or the free acid 8-chloro-1-cyclopropyl-6-fluoro-7-(2, 3, 4, 5, 6, 7-hexahydro-5-oxo-1H-1,4-diazepin-1-yl)-1, 4-dihydro-4-oxoquinolinea-3-carboxylic acid, a salt thereof or hydrochloride thereof.

53. The method of claim 48, wherein said quinolone carboxylic acid derivative of formula (I) is present as particles having an average diameter less than about 10 microns, and wherein said particles are prepared by micronization of said quinolone carboxylic acid.
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