Drug eluting pharmaceutical delivery system for treatment of ocular disease and method of use

• US 20060134175A1
• 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: Bartels, Stephen
• Application Number:
  US11/314,120
• Publication Number:
  US 20060134175A1
• 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 drug-eluting polymer matrix configured to be inserted into the eye of the patient.

Claims

1. A pharmaceutical delivery system comprising a fused pyrrolocarbazole and a drug-eluting 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:

wherein;

R1 and R2 are the same or different and are independently selected from H, or alkyl of 1-8 carbons, preferably an alkyl of 1-4 carbons, substituted with —

OH, or —

OR4 where R4 is an alkyl of 1-4 carbons, aryl, preferably phenyl or naphthyl, or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R3 is —

CH₂OH;

—

CH₂OR7;

—

(CH₂)_nSR5;

—

(CH₂)_nSO_yR5;

—

CH ₂SR₅;

or alkyl of 1-8 carbons, preferably an alkyl of 1-4 carbons, substituted with —

OH, —

OR5, —

OR8, —

CH₂OR7, —

SO_yR6 or —

SR6; and

wherein

R5 is alkyl of 1-4 carbons or aryl, preferably phenyl or naphthyl;

R6 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, preferably phenyl or naphthyl, or heteroaryl;

R7 is H or alkyl of 1-4 carbons;

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

n is an integer of 1-4; and

y is 1 or 2, with the proviso that when R1 is —

(CH₂)₃OH and R2 is H, then R3 cannot be —

CH₂OH,

—

CH₂OCH₂CH₃, or —

CH₂SCH₂CH₃.

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:

R₁ and R₂ are the same or different and are independently selected from —

H, or alkyl of 1-8 carbons, substituted with —

OH or —

OR4 where R4 is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R3 is —

CH₂OH;

—

CH₂OR7;

—

(CH₂)nSR5;

—

(CH₂)nSOyR5;

—

CH₂SR₅;

or alkyl of 1-8 carbons substituted with —

OH, —

OR5, —

OR8, —

CH₂OR7, —

S(O) yR6 or —

SR6; 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;

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

n is an integer of 1-4; and

y is 1 or 2.

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 up 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:

TABLE 1 CMPD NO R1 R2 R3 1 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₃ 2 —

CH₂CH₂CH₂OH —

H —

CH₂OCH(CH₃)₂ 3 —

CH₂CH₂CH₂OH —

H —

CH₂O—

CH(CH₃)CH₂CH₃ 4 —

CH₂CH₂CH₂OH —

H (S)—

CH₂O—

CH(CH₃)CH₂CH₃ 5 —

CH₂CH₂CH₂OH —

H (R)—

CH₂O—

CH(CH₃)CH₂CH₃ 6 —

CH₂CHOHCH₃ —

H —

CH₂OCH₂CH₃ 7 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₂CH₂CH₃ 8 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₂CH₂CH₂CH₃ 9 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)OCH₂CH₃ 10 —

CH₂CH₂CH₂OH —

H (chiral) —

CH(CH₃)OCH₂CH₃ 11 —

CH₂CH₂CH₂OH —

H (chiral) —

CH(CH₃)OCH₂CH₃ 12 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)OCH₃ 13 —

H —

CH₂OCH₂CH₃ 14 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)O—

CH₂CH₂CH₂CH₃ 15 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)O—

CH(CH₃)₂ 16 —

CH₂CH₂CH₂OH —

H —

CH₂OC(CH₃)₃ 17 —

CH₂CH₂CH₂OCO—

CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 18 —

CH₂CH₂CH₂OCO—

CH₂NH₂—

CH₂CH₂CH₂CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 19 CH₂CH₂CH₂OCOCH₂—

CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 20 CH₂CH₂CH₂OCOCH₂—

CH₂CH₂N(CH₃)₂ —

H —

CH₂OCH(CH₃)₂ 21 CH₂CH₂CH₂OCO—

CH₂N(CH₂)₂ —

H —

CH₂OCH(CH₃)₂ 22 —

CH₂CH₂CH₂OCO—

CH₂CH₂CH₂ —

H —

CH₂OCH(CH₃)₂ 23 —

CH₂CH₂OH —

H —

CH₂SCH₂CH₃ 24 —

CH₂CH₂CH₂OH —

H —

CH₂SCH₂CH₃ 25 —

CH₂CH₂CH₂OH —

H —

CH₂S(O)CH(CH₃)₂ 26 —

CH₂CH₂OH —

H —

CH₂OH 27 —

H —

H —

CH₂OH 28 —

H —

H —

CH₂OCH₂CH₃ 29 —

H —

H —

CH₂OCH(CH₃)₂ 30 —

CH₂CH₂CH₂OH —

H —

CH(OH)CH₃ 31 —

CH₂CH₂CH₂OH —

H —

CH(OH)CH₂CH₃ 32 —

H —

H —

CH(OH)CH₃ 33 —

H —

H (+/−

) —

CH(OCH₃)CH₃ 34 —

CH₂CH₂CH₂OH —

CH₂OH CH₂OCH(CH₃)₂

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 drug eluting polymer matrix is made from siloxane copolymer that is polymerized with a fused pyrrolocarbazole.

11. The pharmaceutical delivery system of claim 10, wherein the drug eluting polymer matrix is made from a fluorinated side-chain siloxane copolymer polymerized in a mixture with a fused pyrrolocarbazole.

12. The pharmaceutical delivery system of claim 11, wherein the fluorinated side-chain siloxane copolymer is represented by Formula I below:

wherein the R₁ groups may be the same or different selected from the group consisting of C_1-7 alkyl and C_6-10 aryl;

the R₂ group is a C_1-7 alkylene;

x is a natural number less than 26;

p and q may be the same or different natural numbers less than 100 and z is a natural number less than 11.

13. The pharmaceutical delivery system of claim 12, wherein said one or more monomers are selected from the group consisting of methyl methacrylate, N,N-dimethylacrylamide, acrylamide, N-methylacrylamide, 2-hydroxyethyl methacrylate, hydroxyethoxyethyl methacrylate, hydroxydiethoxyethyl methacrylate, methoxyethyl methacrylate, methoxyethoxyethyl methacrylate, methoxydiethoxyethyl methacrylate, poly(ethylene glycol) methacrylate, methoxy-poly(ethylene glycol) methacrylate, methacrylic acid, sodium methacrylate, glycerol methacrylate, hydroxypropyl methacrylate, N-vinylpyrrolidione and hydroxybutyl methacrylate.

14. The pharmaceutical delivery system of claim 12, wherein the R₁ groups may be the same or different selected from the group consisting of C_1-7 alkyl and C_6-10 aryl;

the R₂ group is a C_1-7 alkylene;

x is a natural number less than 26;

p and q may be the same or different natural numbers less than 100 and z is a natural number less than 11.

15. 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.

16. 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.

17. 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.

18. The pharmaceutical delivery system of claim 1, 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.

19. 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 drug-eluting polymer matrix and a therapeutically effective amount of a fused pyrrolocarbazole.

20. The method of claim 19, wherein the fused pyrrolocarbazole is selected from the group consisting of an indolocarbazole and an indenocarbazole and mixtures thereof.

21. The method of claim 19, wherein the fused pyrrolocarbazole is defined by the following Formula I and salts thereof and prodrugs thereof:

R1 and R2 are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

OH, or —

OR4 where R4 is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R3 is —

CH₂OH;

—

CH₂OR7;

—

(CH₂)nSR5;

—

(CH₂)nS(O)yR5;

—

CH₂SR5;

or alkyl of 1-8 carbons substituted with —

OH, —

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;

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

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R1 is (CH₂)₃OH and R2 is H, then R3 cannot be —

CH₂OH, alkyl of 1-8 carbons substituted with —

OH or —

SR8 , wherein R6 is alkyl of 1-4 carbons;

—

(CH₂)nSR5, wherein n is 1 and R5 is alkyl of 1-4 carbons;

or —

CH₂SR5, wherein R5 is alkyl of 1-4 carbons.

22. The method of claim 19, wherein the fused pyrrolocarbazole is defined by the following Formula II and salts thereof and prodrugs thereof:

R₁ and R₂ are the same or different and are independently selected from H, or alkyl of 1-8 carbons, substituted with —

H, —

OH or —

OR4 where R4 is an alkyl of 1-4 carbons, aryl or the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and

R3 is —

CH₂OH;

—

CH₂OR7;

—

(CH₂)nSR5;

—

(CH₂)nSOyR5;

—

CH₂SR₅;

or alkyl of 1-8 carbons substituted with —

OH, —

OR5, —

OR8, —

CH₂OR7, —

S(O) yR6 or —

SR6; 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;

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

n is an integer of 1-4; and

y is 1 or 2;

with the proviso that when R1 is —

(CH₂)₃OH and R2 is —

H, then R3 cannot be —

CH₂OH, —

CH₂OCH₂CH₃, or —

CH₂SCH₂CH₃.

23. The method of claim 22, 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.

24. The method of claim 22, wherein R1 is —

CH₂CH₂CH₂OH or —

CH₂CH₂CH₂OCOCH₂N(CH₃)₂;

R2 is H; and

R3 is —

CH₂OR7 wherein R7 is alkyl of 1-4carbons.

25. The method of claim 19 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:

CMPD NO R1 R2 R3 1 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₃ 2 —

CH₂CH₂CH₂OH —

H —

CH₂OCH(CH₃)₂ 3 —

CH₂CH₂CH₂OH —

H —

CH₂O—

CH(CH₃)CH₂CH₃ 4 —

CH₂CH₂CH₂OH —

H (S)—

CH₂O—

CH(CH₃)CH₂CH₃ 5 —

CH₂CH₂CH₂OH —

H (R)—

CH₂O—

CH(CH₃)CH₂CH₃ 6 —

CH₂CHOHCH₃ —

H —

CH₂OCH₂CH₃ 7 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₂CH₂CH₃ 8 —

CH₂CH₂CH₂OH —

H —

CH₂OCH₂CH₂CH₂CH₃ 9 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)OCH₂CH₃ 10 —

CH₂CH₂CH₂OH —

H (chiral) —

CH(CH₃)OCH₂CH₃ 11 —

CH₂CH₂CH₂OH —

H (chiral) —

CH(CH₃)OCH₂CH₃ 12 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)OCH₃ 13 —

H —

CH₂OCH₂CH₃ 14 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)O—

CH₂CH₂CH₂CH₃ 15 —

CH₂CH₂CH₂OH —

H —

CH(CH₃)O—

CH(CH₃)₂ 16 —

CH₂CH₂CH₂OH —

H —

CH₂OC(CH₃)₃ 17 —

CH₂CH₂CH₂OCO—

CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 18 —

CH₂CH₂CH₂OCO—

CH₂NH₂—

CH₂CH₂CH₂CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 19 —

CH₂CH₂CH₂OCOCH₂—

CH₂NH₂ —

H —

CH₂OCH(CH₃)₂ 20 —

CH₂CH₂CH₂OCOCH₂—

CH₂CH₂N(CH₃)₂ —

H —

CH₂OCH(CH₃)₂ 21 —

CH₂CH₂CH₂OCO—

CH₂N(CH₂)₂ —

H —

CH₂OCH(CH₃)₂ 22 —

CH₂CH₂CH₂OCO—

CH₂CH₂CH₃ —

H —

CH₂OCH(CH₃)₂ 23 —

CH₂CH₂OH —

H —

CH₂SCH₂CH₃ 24 —

CH₂CH₂CH₂OH —

H —

CH₂SCH₂CH₃ 25 —

CH₂CH₂CH₂OH —

H —

CH₂S(O)CH(CH₃)₂ 26 —

CH₂CH₂OH —

H —

CH₂OH 27 —

H —

H —

CH₂OH 28 —

H —

H —

CH₂OCH₂CH₃ 29 —

H —

H —

CH₂OCH(CH₃)₂ 30 —

CH₂CH₂CH₂OH —

H —

CH(OH)CH₃ 31 —

CH₂CH₂CH₂OH —

H —

CH(OH)CH₂CH₃ 32 —

H —

H —

CH(OH)CH₃ 33 —

H —

H (+/−

) —

CH(OCH₃)CH₃ 34 —

CH₂CH₂CH₂OH —

CH₂OH —

CH₂OCH(CH₃)₂

26. The method of claim 19, 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:

27. The method of claim 19, wherein the fused pyrrolocarbazole is of the following formula and salts and prodrugs thereof and mixtures of the compound, salts and/or prodrugs thereof:

28. The method of claim 19, wherein the pharmaceutical delivery system is a drug eluting polymer matrix that is cured as a mixture with fused pyrrolocarbazole.

29. The method of claim 28, wherein the drug eluting polymer matrix is made from a siloxane copolymer.

30. The method of claim 28, wherein the drug eluting polymer matrix is made from a fluorinated side-chain siloxane copolymer polymerized with fused pyrrolocarbazole.

31. The method of claim 30, wherein the fluorinated side-chain siloxane copolymer is represented by Formula I below:

wherein the R1 groups may be the same or different selected from the group consisting of C_1-7 alkyl and C_6-10 aryl;

the R₂ group is a C_1-7 alkylene;

x is a natural number less than 26;

p and q may be the same or different natural numbers less than 100 and z is a natural number less than 11.

32. The method of claim 31, wherein said one or more monomers are selected from the group consisting of methyl methacrylate, N,N-dimethylacrylamide, acrylamide, N-methylacrylamide, 2-hydroxyethyl methacrylate, hydroxyethoxyethyl methacrylate, hydroxydiethoxyethyl methacrylate, methoxyethyl methacrylate, methoxyethoxyethyl methacrylate, methoxydiethoxyethyl methacrylate, poly(ethylene glycol) methacrylate, methoxy-poly(ethylene glycol) methacrylate, methacrylic acid, sodium methacrylate, glycerol methacrylate, hydroxypropyl methacrylate, N-vinylpyrrolidione and hydroxybutyl methacrylate.

33. The method of claim 31, wherein the R₁ groups may be the same or different selected from the group consisting of C_1-7 alkyl and C_6-10 aryl;

the R₂ group is a C_1-7 alkylene;

x is a natural number less than 26;

p and q may be the same or different natural numbers less than 100 and z is a natural number less than 11.

34. The method of claim 19, 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.

35. The method of claim 19, 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.

36. The method of claim 19, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.

37. 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.

38. 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.

39. The method of claim 38, 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.

40. The method of claim 38, 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.

41. The method of claim 38, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.

42. The method of claim 38, wherein the inflammatory disorder is edema.