Pharmaceutical delivery system and method of use
First Claim
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1. A pharmaceutical delivery system comprising a fused pyrrolocarbazole and a pharmaceutical delivery device selected from the group consisting of reservoir devices and drug infusion device, wherein the pharmaceutical delivery device is sized and configured to be inserted into the eye of the patient.
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Abstract
The present invention includes a pharmaceutical delivery system comprising a fused pyrrolocarbazole and a pharmaceutical delivery device that is selected from the group consisting of reservoir device and drug infusion device. The pharmaceutical delivery systems are sized and configured to be inserted into the eye of the patient.
51 Citations
48 Claims
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1. A pharmaceutical delivery system comprising a fused pyrrolocarbazole and a pharmaceutical delivery device selected from the group consisting of reservoir devices and drug infusion device, wherein the pharmaceutical delivery device is sized and configured to be inserted into the eye of the patient.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
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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.
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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:
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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)nSOyR5;
—
CH2SR5;
or alkyl of 1-8 carbons, preferably an alkyl of 1-4 carbons, substituted with —
OH, —
OR5, —
OR8, —
CH2OR7, —
SOyR6 or —
SR6; and
whereinR5 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.
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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 —
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.
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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.
- OH or —
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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.
- CH2CH2CH2OH or —
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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—
CH2OCH32 —
CH2CH2CH2OH—
H—
CH2OCH(CH3)23 —
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—
CH2OCH2CH37 —
CH2CH2CH2OH—
H—
CH2OCH2CH2CH38 —
CH2CH2CH2OH—
H—
CH2OCH2CH2CH2CH3 9 —
CH2CH2CH2OH—
H—
CH(CH3)OCH2CH310 —
CH2CH2CH2OH—
H(chiral) —
CH(CH3)OCH2CH311 —
CH2CH2CH2OH—
H(chiral) —
CH(CH3)OCH2CH312 —
CH2CH2CH2OH—
H—
CH(CH3)OCH313 —
H—
CH2OCH2CH314 —
CH2CH2CH2OH—
H—
CH(CH3)O—CH2CH2CH2CH3 15 —
CH2CH2CH2OH—
H—
CH(CH3)O—CH(CH3)2 16 —
CH2CH2CH2OH—
H—
CH2OC(CH3)317 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2NH2 18 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2NH2— CH2CH2CH2CH2NH2 19 —
CH2CH2CH2OCOCH2—
H—
CH2OCH(CH3)2—
CH2NH220 —
CH2CH2CH2OCOCH2—
H—
CH2OCH(CH3)2—
CH2CH2N(CH3)221 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2N(CH2)2 22 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2CH2CH2 23 —
CH2CH2OH—
H—
CH2SCH2CH324 —
CH2CH2CH2OH—
H—
CH2SCH2CH325 —
CH2CH2CH2OH—
H—
CH2S(O)CH(CH3)226 —
CH2CH2OH—
H—
CH2OH27 —
H—
H—
CH2OH28 —
H—
H—
CH2OCH2CH329 —
H—
H—
CH2OCH(CH3)230 —
CH2CH2CH2OH—
H—
CH(OH)CH331 —
CH2CH2CH2OH—
H—
CH(OH)CH2CH332 —
H—
H—
CH(OH)CH333 —
H—
H(+/−
) —
CH(OCH3)CH334 —
CH2CH2CH2OH—
CH2OH—
CH2OCH(CH3)2
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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:
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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:
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10. The pharmaceutical delivery system of claim 1, wherein the delivery device is a drug reservoir delivery device.
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11. The pharmaceutical delivery system of claim 10, wherein the drug reservoir delivery device has a drug impermeable portion that surrounds at least a portion of a drug core comprising a fused pyrrolocarbazole, wherein the drug impermeable portion defines a reservoir and restricts flow of fused pyrrolocarbazole from the reservoir.
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12. The pharmaceutical delivery system of claim 10, wherein the drug impermeable portion defines a wall, layer or coating.
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13. The pharmaceutical delivery system of claim 11, wherein the drug impermeable portion is made of silicone.
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14. The pharmaceutical delivery system of claim 11, further comprising a drug permeable portion that surrounds at least a portion of a drug core, wherein the drug impermeable portion further defines the reservoir and allows passage of fused pyrrolocarbazole through the drug permeable portion.
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15. The pharmaceutical delivery system of claim 14, wherein the drug permeable portion defines a wall, layer or coating.
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16. The pharmaceutical delivery system of claim 14, wherein the drug permeable portion is made of silicone.
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17. The pharmaceutical delivery system of claim 1, wherein the pharmaceutical delivery device comprises:
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a holder made of a material impermeable to passage of a pharmaceutical agent and including at least one opening for passage of the active agent therethrough;
a drug core contained into which the fused pyrrolocarbazole is received; and
a preformed disc made of an expandable material permeable to passage of the fused pyrrolocarbazole, the disc contained in the holder and disposed between the drug core and the at least one opening in the holder, wherein a groove is formed in the holder in the vicinity of the disc.
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18. 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.
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19. 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.
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20. 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.
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21. 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.
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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.
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22. 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 pharmaceutical delivery device selected from the group consisting of a reservoir device and a drug infusion device, wherein the pharmaceutical delivery device is sized and configured to be inserted into the eye of a patient and a therapeutically effective amount of a fused pyrrolocarbazole.
- View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43)
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23. The method of claim 22, wherein the fused pyrrolocarbazole is selected from the group consisting of an indolocarbazole and an indenocarbazole and mixtures thereof.
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24. The method of claim 22, 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.
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25. The method of claim 22, 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 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.
-
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26. The method of claim 25, 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.
- OH or —
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27. The method of claim 25, wherein R1 is —
- CH2CH2CH2OH or —
CH2CH2CH2OCOCH2N(CH3)2;
R2 is H; and
R3 is —
CH2OR7 wherein R7 is alkyl of 1-4 carbons.
- CH2CH2CH2OH or —
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28. The method of claim 22, 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—
CH2OCH32 —
CH2CH2CH2OH—
H—
CH2OCH(CH3)23 —
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—
CH2OCH2CH37 —
CH2CH2CH2OH—
H—
CH2OCH2CH2CH38 —
CH2CH2CH2OH—
H—
CH2OCH2CH2CH2CH3 9 —
CH2GH2CH2OH—
H—
CH(CH3)OGH2CH310 —
CH2CH2CH2OH—
H(chiral) —
CH(CH3)OCH2CH311 —
CH2CH2CH2OH—
H(chiral) —
CH(CH3)OCH2CH312 —
CH2CH2CH2OH—
H—
CH(CH3)OCH313 —
H—
CH2OCH2CH314 —
CH2CH2CH2OH—
H—
CH(CH3)O—CH2CH2CH2CH3 15 —
CH2CH2CH2OH—
H—
CH(CH3)O—CH(CH3)2 16 —
CH2CH2CH2OH—
H—
CH2OC(CH3)317 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2NH2 18 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2NH2— CH2CH2CH2CH2NH2 19 —
CH2CH2CH2OCOCH2—
H—
CH2OCH(CH3)2—
CH2NH220 —
CH2CH2CH2OCOCH2—
H—
CH2OCH(CH3)2—
CH2CH2N(CH3)221 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2N(CH2)2 22 —
CH2CH2CH2OCO——
H—
CH2OCH(CH3)2CH2CH2CH3 23 —
CH2CH2OH—
H—
CH2SCH2CH324 —
CH2CH2CH2OH—
H—
CH2SCH2CH325 —
CH2CH2CH2OH—
H—
CH2S(O)CH(CH3)226 —
CH2CH2OH—
H—
CH2OH27 —
H—
H—
CH2OH28 —
H—
H—
CH2OCH2CH329 —
H—
H—
CH2OCH(CH3)230 —
CH2CH2CH2OH—
H—
CH(OH)CH331 —
CH2CH2CH2OH—
H—
CH(OH)CH2CH332 —
H—
H—
CH(OH)CH333 —
H—
H(+/−
) —
CH(OCH3)CH334 —
CH2CH2CH2OH—
CH2OH—
CH2OCH(CH3)2
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29. The method of claim 22, 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:
-
30. The method of claim 22, wherein the fused pyrrolocarbazole is of the following formula and salts and prodrugs thereof and mixtures of the compound, salts and/or prodrugs thereof:
-
31. The method of claim 22, wherein the delivery device is a drug reservoir delivery device.
-
32. The method of claim 31, wherein the drug reservoir delivery device has a drug impermeable portion that surrounds at least a portion of a drug core comprising a fused pyrrolocarbazole, wherein the drug impermeable portion defines a reservoir and restricts flow of fused pyrrolocarbazole from the reservoir.
-
33. The method of claim 32, wherein the drug impermeable portion defines a wall, layer or coating.
-
34. The method of claim 32, wherein the drug impermeable portion is made of silicone.
-
35. The method of claim 32, further comprising a drug permeable portion that surrounds at least a portion of a drug core, wherein the drug permeable portion further defines the reservoir and allows passage of fused pyrrolocarbazole through the drug permeable portion.
-
36. The method of claim 32, wherein the drug permeable portion defines a wall, layer or coating.
-
37. The method of claim 32, wherein the drug permeable portion is made of poly(vinyl alcohol).
-
38. The method of claim 32 wherein the pharmaceutical delivery system comprises:
-
a holder made of a material impermeable to passage of a pharmaceutical agent and including at least one opening for passage of the active agent therethrough;
a drug core contained in the holder and including fused pyrrolocarbazole; and
a preformed disc made of an expandable material permeable to passage of the fused pyrrolocarbazole, the disc contained in the holder and disposed between the drug core and the at least one opening in the holder, wherein a groove is formed in the holder in the vicinity of the disc.
-
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39. The method of claim 22, 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 22, 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 22, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.
-
42. The method of claim 22, 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.
-
43. The method of claim 22, 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.
-
23. The method of claim 22, wherein the fused pyrrolocarbazole is selected from the group consisting of an indolocarbazole and an indenocarbazole and mixtures thereof.
-
44. 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 pharmaceutical delivery device selected from the group consisting of reservoir devices and drug infusion device and a therapeutically effective amount of a fused pyrrolocarbazole.
- View Dependent Claims (45, 46, 47, 48)
-
45. The method of claim 44, 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.
-
46. The method of claim 44, 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.
-
47. The method of claim 44, wherein the effective concentration of fused pyrrolocarbazole in the vitreous of is maintained for a minimum of 6 weeks.
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48. The method of claim 44, wherein the inflammatory disorder is edema.
-
45. The method of claim 44, 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.
Specification
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Current AssigneeBausch & Lomb Incorporated (Bausch Health Cos., Inc.)
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Original AssigneeBausch & Lomb Incorporated (Bausch Health Cos., Inc.)
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InventorsBartels, Stephen
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Application NumberUS11/314,843Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current424/427CPC Class CodesA61F 9/0008 Introducing ophthalmic prod...A61K 31/407 condensed with other hetero...