Biodegradable intravitreal tyrosine kinase implants

Abstract

Biocompatible intraocular implants include a tyrosine kinase inhibitor and a biodegradable polymer that is effective to facilitate release of the tyrosine kinase inhibitor into the vitreous of an eye for an extended period of time. The therapeutic agents of the implants may be associated with a biodegradable polymer matrix, such as a matrix that is substantially free of a polyvinyl alcohol. The implants can be placed in an eye to treat or reduce the occurrence of one or more ocular conditions.

What is claimed: 
     
         1 . A method of improving vision or maintaining vision in a patient comprising
 placing a biodegradable intraocular implant into an eye of the patient, the implant comprising a TKI and a biodegradable polymer,   wherein the implant degrades at a rate effective to sustain release of an amount of the TKI from the implant effective to improve or maintain vision.   
     
     
         2 . The method of  claim 1 , wherein the TKI is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of halogen, NO 2 , CN, C 1  to C 4  alkyl and aryl; R 2  is selected from the group consisting of hydrogen, C 1  to C 8  alkyl, COCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and phenyl; R is selected from the group consisting of D, halogen, C 1  to C 8  alkyl, CF 3 , OCF 3 , OCF 2 H, CH 2 CN, CN, SR 2 , (CR 7 R 8 ) c C(O)OR 2 , C(O)N(R 2 ) 2 , (CR 7 R 8 ) c OR 2 , HNC(O)R 2 , HN—C(O)OR 2 , (CR 7 R 8 ) c N(R 2 ) 2 , SO 2  (CR 7 R 8 ) c N(R 2 ) 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, HN—CH═CH, —N(COR 2 )CH 2 CH 2 , HC═N—NH, N═CH—S, O(CR 7 R 8 ) d —R 6  and (CR 7 R 8 ) c —R 6 , —NR 2 (CR 7 R 8 ) d R 6  wherein R 6  is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one, N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3 acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl, 1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2-(N-methyl-2-aminoethyl)-1,3-dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R)-3-amino-I-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran, ethanolamine and alkyl-substituted derivatives thereof and wherein when c is 1 said CH 2  may be 
       
       
         
           
           
               
               
           
         
         and CH 2 CH 2 CH 2 ; provided said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower alkyl amino radicals wherein R 7  and R 8  may be selected from the group consisting of H, F and C 1 -C 4  alkyl or CR 7 R 8  may represent a carbocyclic ring of from 3 to 6 carbons, preferably R 7  and R 8  are H or CH 3 ,
 b is 0 or an integer of from 1 to 3; 
 a is 0 or an integer of from 1 to 5, preferably 1 to 3; 
 c is 0 or an integer of from 1 to 4, 
 d is an integer of from 2 to 5; 
 
         the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof. 
       
     
     
         3 . The method of  claim 2 , wherein the TKI is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 1 , wherein the TKI is provided in an amount from about 30% by weight to about 70% by weight of the implant. 
     
     
         5 . The method of  claim 1 , wherein the biodegradable polymer comprises a poly(lactide-co-glycolide). 
     
     
         6 . The method of  claim 5 , wherein the poly(lactide-co-glycolide) is provided in an amount from about 30% by weight to about 70% by weight of the implant. 
     
     
         7 . The method of  claim 5 , wherein the poly(lactide-co-glycolide) is a 75:25 poly(D,L-lactide-co-glycolide) having an inherent viscosity of 0.50 to 0.70 dl/g. 
     
     
         8 . The method of  claim 5 , wherein the poly(D, L-lactide) has a molecular weight of between about 1,500 and about 2,250, and wherein the implant is made by melt extrusion and comprises 50% by weight of the TKI and 50% by weight of the poly(D,L-lactide). 
     
     
         9 . The method of  claim 1 , wherein the implant releases the TKI for about 70 days at a substantially linear rate. 
     
     
         10 . The method of  claim 1 , wherein the method comprises administering the implant to the patient by at least one of intravitreal injection, subconjunctival injection, sub-tenon injections, retrobulbar injection, and suprachoroidal injection. 
     
     
         11 . The method of  claim 1 , wherein the biodegradable implant is placed in the vitreous of an eye. 
     
     
         12 . A method of improving vision or maintaining vision in a patient comprising:
 placing a biodegradable intraocular implant into the vitreous of an eye of the patient, the implant comprising a TKI and a biodegradable polymer,   wherein the implant releases TKI at a rate effective to sustain release of the TKI from the implant for at least about one week to about one year after the implant is placed in the vitreous of the eye to treat the ocular condition;   wherein the tyrosine kinase inhibitor is provided in an amount from about 30% by weight to about 70% by weight of the implant, and   wherein the biodegradable polymer comprises a poly(lactide-co-glycolide) in an amount from about 30% by weight to about 70% by weight of the implant.   
     
     
         13 . The method of  claim 12 , wherein the TKI is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of halogen, NO 2 , CN, C 1  to C 4  alkyl and aryl; R 2  is selected from the group consisting of hydrogen, C 1  to C 8  alkyl, COCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and phenyl; R is selected from the group consisting of D, halogen, C 1  to C 8  alkyl, CF 3 , OCF 3 , OCF 2 H, CH 2 CN, CN, SR 2 , (CR 7 R 8 ) c C(O)OR 2 , C(O)N(R 2 ) 2 , (CR 7 R 8 ) C OR 2 , HNC(O)R 2 , HN—C(O)OR 2 , (CR 7 R 8 ) C N(R 2 ) 2 , SO 2  (CR 7 R 8 ) c N(R 2 ) 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, HN—CH═CH, —N(COR 2 )CH 2 CH 2 , HC═N—NH, N═CH—S, O(CR 7 R 8 ) d —R 6  and (CR 7 R 8 ) C —R 6 , —NR 2 (CR 7 R 8 ) d R 6  wherein R 6  is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one, N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3 acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl, 1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2-(N-methyl-2-aminoethyl)-1,3-dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R)-3-amino-I-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran, ethanolamine and alkyl-substituted derivatives thereof and wherein when c is 1 said CH 2  may be 
       
       
         
           
           
               
               
           
         
         and CH 2 CH 2 CH 2 ; provided said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower alkyl amino radicals wherein R 7  and R 8  may be selected from the group consisting of H, F and C 1 -C 4  alkyl or CR 7 R 8  may represent a carbocyclic ring of from 3 to 6 carbons, preferably R 7  and R 8  are H or CH 3 ,
 b is 0 or an integer of from 1 to 3; 
 a is 0 or an integer of from 1 to 5, preferably 1 to 3; 
 c is 0 or an integer of from 1 to 4, 
 d is an integer of from 2 to 5; 
 the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof. 
 
       
     
     
         14 . The method of  claim 13 , wherein the TKI is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 12 , wherein the poly(lactide-co-glycolide) is a 75:25 poly(D,L-lactide-co-glycolide) having an inherent viscosity of 0.50 to 0.70 dl/g. 
     
     
         16 . A kit for treating an ocular condition, wherein the kit comprises:
 a container comprising an extended release implant comprising a therapeutic component including a TKI, and a drug release sustaining component; and   instructions for use.   
     
     
         17 . The kit of  claim 16 , wherein the TKI is represented by the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of halogen, NO 2 , CN, C 1  to C 4  alkyl and aryl; R 2  is selected from the group consisting of hydrogen, C 1  to C 8  alkyl, COCH 3 , CH 2 CH 2 OH, CH 2 CH 2 CH 2 OH and phenyl; R is selected from the group consisting of D, halogen, C 1  to C 8  alkyl, CF 3 , OCF 3 , OCF 2 H, CH 2 CN, CN, SR 2 , (CR 7 R 8 ) c C(O)OR 2 , C(O)N(R 2 ) 2 , (CR 7 R 8 ) c OR 2 , HNC(O)R 2 , HN—C(O)OR 2 , (CR 7 R 8 ) c N(R 2 ) 2 , SO 2  (CR 7 R 8   c N(R 2 ) 2 , OP(O)(OR 2 ) 2 , OC(O)OR 2 , OCH 2 O, HN—CH═CH, —N(COR 2 )CH 2 CH 2 , HC═N—NH, N═CH—S, O(CR 7 R 8 ) d —R 6  and (CR 7 R 8 ) c —R 6 , —NR 2 (CR 7 R 8 ) d R 6  wherein R 6  is selected from the group consisting of halogen, 3-fluoropyrrolidinyl, 3-fluoropiperidinyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyrrolinyl, pyrrolidinyl, methyl isonipecotate, N-(2-methoxyethyl)-N-methylamyl, 1,2,3,6-tetrahydropyridinyl, morpholinyl, hexamethyleneiminyl, piperazinyl-2-one, piperazinyl, N-(2-methoxyethyl)ethylaminyl, thiomorpholinyl, heptamethyleneiminyl, 1-piperazinylcarboxaldehyde, 2,3,6,7-tetrahydro-(1H)-1,4-diazepinyl-5(4H)-one, N-methylhomopiperazinyl, (3-dimethylamino)pyrrolidinyl, N-(2-methoxyethyl)-N-propylaminyl, isoindolinyl, nipecotamidinyl, isonipecotamidinyl, 1-acetylpiperazinyl, 3 acetamidopyrrolidinyl, trans-decahydroisoquinolinyl, cis-decahydroisoquinolinyl, N-acetylhomopiperazinyl, 3-(diethylamino)pyrrolidinyl, 1,4-dioxa-8-azaspiro[4.5]decaninyl, 1-(2-methoxyethyl)-piperazinyl, 2-pyrrolidin-3-ylpyridinyl, 4-pyrrolidin-3-ylpyridinyl, 3-(methylsulfonyl)pyrrolidinyl, 3-picolylmethylaminyl, 2-(2-methylaminoethyl)pyridinyl, 1-(2-pyrimidyl)-piperazinyl, 1-(2-pyrazinyl)-piperazinyl, 2-methylaminomethyl-1,3-dioxolane, 2-(N-methyl-2-aminoethyl)-1,3-dioxolane, 3-(N-acetyl-N-methylamino)pyrrolidinyl, 2-methoxyethylaminyl, tetrahydrofurfurylaminyl, 4-aminotetrahydropyran, 2-amino-1-methoxybutane, 2-methoxyisopropylaminyl, 1-(3-aminopropyl)imidazole, histamyl, N,N-diisopropylethylenediaminyl, 1-benzyl-3-aminopyrrolidyl 2-(aminomethyl)-5-methylpyrazinyl, 2,2-dimethyl-1,3-dioxolane-4-methanaminyl, (R)-3-amino-I-N-BOC-pyrrolidinyl, 4-amino-1,2,2,6,6-pentamethylpiperidinyl, 4-aminomethyltetrahydropyran, ethanolamine and alkyl-substituted derivatives thereof and wherein when c is 1 said CH 2  may be 
       
       
         
           
           
               
               
           
         
         and CH 2 CH 2 CH 2 ; provided said alkyl or phenyl radicals may be substituted with one or two halo, hydroxy or lower alkyl amino radicals wherein R 7  and R 8  may be selected from the group consisting of H, F and C 1 -C 4  alkyl or CR 7 R 8  may represent a carbocyclic ring of from 3 to 6 carbons, preferably R 7  and R 8  are H or CH 3 ,
 b is 0 or an integer of from 1 to 3; 
 a is 0 or an integer of from 1 to 5, preferably 1 to 3; 
 c is 0 or an integer of from 1 to 4, 
 d is an integer of from 2 to 5; 
 
         the wavy line represents a E or Z bond and pharmaceutically acceptable salts thereof. 
       
     
     
         18 . The kit of  claim 17 , wherein the TKI is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The kit of  claim 16 , wherein the tyrosine kinase inhibitor is provided in an amount from about 30% by weight to about 70% by weight of the implant, and wherein the drug release sustaining component comprises a poly(lactide-co-glycolide) in an amount from about 30% by weight to about 70% by weight of the implant. 
     
     
         20 . The kit of  claim 16 , wherein the ocular condition is glaucoma or proliferative vitreoretinopathy.