Pharmaceutical delivery system and method of use

• US 20060134174A1
• Filed: 12/21/2005
• Published: 06/22/2006
• Est. Priority Date: 12/22/2004
• Status: Abandoned Application

• Current Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Original Assignee: Bausch & Lomb Incorporated (Bausch Health Cos., Inc.)
• Inventors: Jani, Dharmendra, Bartels, Stephen
• Application Number:
  US11/313,856
• Publication Number:
  US 20060134174A1
• Time in Patent Office: Days
• US Class Current: 424/427
• CPC Class Codes: A61F 9/0008 Introducing ophthalmic products into the ocular cavity or retaining products therein putting in contact lenses A61F9/0061; introducing or retaining media in cavities of the body in general A61M31/00
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine

Abstract

The present invention includes a pharmaceutical delivery system comprising a fused pyrrolocarbazole and a biodegradable polymer matrix configured to be inserted into the eye of the patient.

Claims

1. A pharmaceutical delivery system comprising a fused pyrrolocarbazole and a biodegradable polymer matrix configured to be inserted into the eye of the patient.

2. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is selected from the group consisting of an indolocarbazole and an indenocarbazole and mixtures thereof.

3. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is a compound defined by the following formula and salts thereof and prodrugs thereof and mixtures of the compound, salt and prodrug thereof:

4. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is one or more compounds defined by Formula II and salts thereof and prodrugs thereof and mixtures of the compounds, salts and prodrugs thereof:

5. The pharmaceutical delivery system of claim 4, wherein R1 is an alkyl of 1-4 carbons, substituted with —

OH or —

OR4 wherein R4 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

R2 is H; and

R3 is alkyl of 1-4 carbons, substituted with —

OR5, —

OR8, —

CH₂OR7, —

S(O)yR6 or —

SR8; and

wherein R5 is alkyl of 1-4 carbons or aryl;

R6 is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R7 is H or alkyl of 1-4 carbons; and

R8 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed.

6. The pharmaceutical delivery system of claim 4, wherein R1 is —

CH₂CH₂CH₂OH or —

CH₂CH₂CH₂OCOCH₂N(CH₃)₂;

R2 is H; and

R3 is —

CH₂OR7 wherein R7 is alkyl of 1-4 carbons.

7. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is selected from the groups consisting of compounds represented in Table I and salts thereof and prodrugs thereof and mixtures of the salts and prodrugs thereof:

8. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is of the following formula and salts thereof and prodrugs thereof and mixtures of the compound, salts and prodrugs therof:

9. The pharmaceutical delivery system of claim 1, wherein the fused pyrrolocarbazole is a compound of the following formula and salts thereof and prodrugs thereof and mixtures of the compound, salts and/or prodrugs thereof:

10. The pharmaceutical delivery system of claim 1, wherein the biodegradable polymer matrix is in the form of an implant.

11. The pharmaceutical delivery system of claim 1, wherein the biodegradable polymer is in the form of microspheres.

12. The pharmaceutical delivery system of claim 1, wherein the amount of active ingredient is present in the biodegradable polymer matrix is a minimum of about 10 wt. % and a maximum of about 80 wt. % based upon the total weight of the biodegradable polymer matrix.

13. The pharmaceutical delivery system of claim 1, wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polylactate polyglycolic acid, polyglycolate and copolymers thereof.

14. The pharmaceutical delivery system of claim 1, wherein the biodegradable polymer is a poly(lactic-co-glycolic acid) polymer system or poly(lactate-co-glycolate) polymer system wherein the ratio of lactic and/or lactate monomers to glycolic and/or glycolate monomers is a minimum of about 30:

70 and a maximum of about 70;

30.

15. The pharmaceutical delivery system of claim 1, wherein the weight average molecular weight of the biodegradable polymer is a minimum of about 1 kD and a maximum of about 1000 kD.

16. The pharmaceutical delivery system of claim 1, wherein the system is configured to maintain the concentration of fused pyrrolocarbazole in the vitreous that is a minimum of about 10 ng/ml.

17. The pharmaceutical delivery system of claim 1, that is configured to maintain the effective concentration of fused pyrrolocarbazole in the vitreous that is at least about 50 times greater than the concentration of the fused pyrrolocarbazole in the blood of the patient.

18. The pharmaceutical delivery system of claim 1, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.

19. The pharmaceutical delivery system of claim 1, wherein the anti-angiogenesis agent is released from the pharmaceutical delivery system at rate that is a minimum of about 5 ng per day and a maximum of about 1 mg per day.

39. The method of claim 19, wherein the angiogenesis agent is released from the pharmaceutical delivery system at rate that is a minimum of about 5 ng per day and a maximum of about 1 mg per day.

20. A method for treating angiogenic disorders in the eye of a patient, which comprises administering to a host in need of such treatment a pharmaceutical delivery system comprising a biodegradable polymer matrix and a therapeutically effective amount of a fused pyrrolocarbazole.

21. The method of claim 20, wherein the fused pyrrolocarbazole is selected from the group consisting of an indolocarbazole and an indenocarbazole and mixtures thereof.

22. The method of claim 20, wherein the fused pyrrolocarbazole is defined by the following Formula I and salts thereof and prodrugs thereof:

23. The method of claim 20, wherein the fused pyrrolocarbazole is defined by the following Formula II and salts thereof and prodrugs thereof:

24. The method of claim 23, wherein R1 is an alkyl of 1-4 carbons, substituted with —

OH or —

OR4 wherein R4 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed;

R2 is H; and

R3 is alkyl of 1-4 carbons, substituted with —

OR5, —

OR8, —

CH₂OR7, —

S(O)yR6 or —

SR8; and

wherein R5 is alkyl of 1-4 carbons or aryl;

R6 is H, alkyl of 1-4 carbons or aryl of 6-10 carbons;

R7 is H or alkyl of 1-4 carbons; and

R8 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed.

25. The method of claim 23, wherein R1 is —

CH₂CH₂CH₂OH or —

CH₂CH₂CH₂OCOCH₂N(CH₃)₂;

R2 is H; and

R3 is —

CH₂OR7 wherein R7 is alkyl of 1-4 carbons.

26. The method of claim 20 wherein the fused pyrrolocarbazole is selected from the group consisting of the compounds represented in Table I and salts thereof and prodrugs thereof and mixtures of such compounds, salts and/or prodrugs thereof:

27. The method of claim 20, wherein the fused pyrrolocarbazole is a compound of the following formula and salts thereof and prodrugs thereof and mixtures of the compound, salts and/or prodrugs:

28. The method of claim 20, wherein the fused pyrrolocarbazole is of the following formula and salts and prodrugs thereof and mixtures of the compound, salts and/or prodrugs thereof:

29. The method of claim 20, wherein the biodegradable polymer matrix is in the form of an implant.

30. The method of claim 20, wherein the biodegradable polymer matrix is in the form of a microsphere.

31. The method of claim 20 wherein the amount of active ingredient is present in the biodegradable polymer matrix is a minimum of about 10 wt. % and a maximum of about 80 wt. % based upon the total weight of the biodegradable polymer matrix.

32. The method of claim 20, wherein the biodegradable polymer is selected from the group consisting of polylactic acid, polylactate polyglycolic acid, polyglycolate and copolymers thereof.

33. The method of claim 20, wherein the biodegradable polymer is a poly(lactic-co-glycolic acid) polymer system or poly(lactate-co-glycolate) polymer system wherein the ratio of lactic and/or lactate monomers to glycolic and/or glycolate monomers is a minimum of about 30:

70 and a maximum of about 70;

30.

34. The method of claim 20, wherein the weight average molecular weight is a minimum of about 1 kD and a maximum of about 1000 kD.

35. The method of claim 20, wherein the pharmaceutical delivery system is configured to maintain the concentration of fused pyrrolocarbazole in the vitreous that is a minimum of about 10 ng/ml.

36. The method of claim 20, that is configured to maintain the effective concentration of fused pyrrolocarbazole in the vitreous that is at least about 50 times greater than the concentration of the fused pyrrolocarbazole in the blood of the patient.

37. The method of claim 20, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.

38. The method of claim 20, wherein the angiogenesis agent is released from the pharmaceutical delivery system at rate that is a minimum of about 5 ng per day and a maximum of about 1 mg per day.

40. A method for treating an inflammatory disorder in the eye of a patient, which comprises administering to a host in need of such treatment a pharmaceutical delivery system comprising a drug-eluting polymer matrix and a therapeutically effective amount of a fused pyrrolocarbazole.

41. The method of claim 40, wherein the pharmaceutical delivery system is configured to maintain the concentration of fused pyrrolocarbazole in the vitreous that is a minimum of about 10 ng/ml.

42. The method of claim 40, that is configured to maintain the effective concentration of fused pyrrolocarbazole in the vitreous that is at least about 50 times greater than the concentration of the fused pyrrolocarbazole in the blood of the patient.

43. The method of claim 40, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.

44. The method of claim 40, wherein the inflammatory disorder is edema.