Implantable polymeric device for sustained release of dopamine agonist

Abstract

The present invention provides compositions, methods, and kits for treatment of Parkinson's disease and other conditions for which treatment with a dopamine agonist is therapeutically beneficial. The invention provides a biocompatible nonerodible polymeric device which releases dopamine agonist continuously with generally linear release kinetics for extended periods of time. Dopamine agonist is released through pores that open to the surface of the polymeric matrix in which it is encapsulated. The device may be administered subcutaneously to an individual in need of continuous treatment with dopamine agonist.

1 . An implantable device for administration of a dopamine agonist to a mammal in need thereof, comprising a dopamine agonist and a biocompatible, nonerodible polymeric matrix, 
 wherein said dopamine agonist is encapsulated within said matrix, and wherein when said implantable device is implanted subcutaneously in said mammal, said dopamine agonist is continuously released in vivo over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state.    
     
     
         2 . An implantable device according to  claim 1 , wherein the polymeric matrix comprises ethylene vinyl acetate copolymer (EVA).  
     
     
         3 . An implantable device according to  claim 2 , wherein said EVA comprises about 33% vinyl acetate.  
     
     
         4 . An implantable device according to  claim 1 , comprising about 10 to about 85% dopamine agonist.  
     
     
         5 . An implantable device according to  claim 4 , wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.  
     
     
         6 . An implantable device according to  claim 5 , wherein said dopamine agonist is apomorphine.  
     
     
         7 . An implantable device according to  claim 1 , wherein the sustained period of time is at least about 3 months.  
     
     
         8 . An implantable device according to  claim 1 , wherein the implantable device is produced by an extrusion process.  
     
     
         9 . An implantable device according to  claim 8 , comprising dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length.  
     
     
         10 . An implantable device according to  claim 9 , wherein said implantable device releases about 0.1 to about 10 mg of dopamine agonist per day in vitro at steady state.  
     
     
         11 . An implantable device according to  claim 1 , further comprising an anti-inflammatory agent encapsulated within said matrix.  
     
     
         12 . An implantable device according to  claim 11 , wherein said anti-inflammatory agent is a steroid.  
     
     
         13 . An implantable device according to  claim 11 , wherein said anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (“NSAID”).  
     
     
         14 . An implantable device according to  claim 11 , wherein said anti-inflammatory agent is an antihistamine.  
     
     
         15 . An implantable device according to  claim 1 , further comprising an antioxidant encapsulated within said matrix.  
     
     
         16 . An implantable device for administration of a dopamine agonist to a mammal in need thereof, comprising a dopamine agonist and a biocompatible, nonerodible polymeric matrix, 
 wherein said dopamine agonist is encapsulated within said matrix, and    wherein when said implantable device is subcutaneously implanted in a mammal, said dopamine agonist is continuously released in vivo over a sustained period of time through pores that open to the surface of said matrix at a rate of at least about 0.1 mg of dopamine agonist per day at steady state.    
     
     
         17 . An implantable device according to  claim 16 , wherein the polymeric matrix comprises EVA.  
     
     
         18 . An implantable device according to  claim 17 , wherein said EVA comprises 33% vinyl acetate.  
     
     
         19 . An implantable device according to  claim 16 , comprising about 10 to about 85% dopamine agonist.  
     
     
         20 . An implantable device according to  claim 16 , wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.  
     
     
         21 . An implantable device according to  claim 20 , wherein said dopamine agonist is apomorphine.  
     
     
         22 . An implantable device according to  claim 16 , wherein the sustained period of time is at least about 3 months.  
     
     
         23 . An implantable device according to  claim 16 , wherein the implantable device is produced by an extrusion process.  
     
     
         24 . An implantable device according to  claim 16 , further comprising an anti-inflammatory agent encapsulated within said matrix.  
     
     
         25 . An implantable device according to  claim 24 , wherein said anti-inflammatory agent is a steroid.  
     
     
         26 . An implantable device according to  claim 24 , wherein said anti-inflammatory agent is a NSAID.  
     
     
         27 . An implantable device according to  claim 24 , wherein said anti-inflammatory agent is an antihistamine.  
     
     
         28 . An implantable device according to  claim 18 , further comprising an antioxidant encapsulated within said matrix.  
     
     
         29 . A method for administration of a dopamine agonist to a mammal in need thereof, the method comprising administering at least one implantable device subcutaneously, 
 wherein each of said at least one implantable devices comprises a dopamine agonist encapsulated within a biocompatible, nonerodible polymeric matrix,    wherein said dopamine agonist is continuously released in vivo from each of said at least one implantable devices over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state.    
     
     
         30 . A method according to  claim 29 , wherein said at least one implantable device comprises a multiplicity of individual implantable devices, and wherein the combination of said implantable devices continuously releases dopamine agonist in vivo over a sustained period of time at a rate that results in a plasma level of at least about 0.05 ng/ml at steady state.  
     
     
         31 . A method according to  claim 29 , wherein the polymeric matrix comprises EVA.  
     
     
         32 . A method according to  claim 31 , wherein said EVA comprises about 33% vinyl acetate.  
     
     
         33 . A method according to  claim 29 , wherein each of said at least one implantable devices comprises at about 10 to about 85% dopamine agonist.  
     
     
         34 . A method according to  claim 33 , wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.  
     
     
         35 . A method according to  claim 34 , wherein said dopamine agonist is apomorphine.  
     
     
         36 . A method according to  claim 29 , wherein said mammal has Parkinson's disease.  
     
     
         37 . A method according to  claim 29 , wherein said mammal has toxin- or disease-induced parkinsonism.  
     
     
         38 . A method according to  claim 29 , wherein said mammal has a condition selected from the group consisting of erectile dysfunction and restless leg syndrome.  
     
     
         39 . A method according to  claim 29 , wherein the sustained period of time is at least about 3 months.  
     
     
         40 . A method according to  claim 29 , wherein each of said at least one implantable devices is produced by an extrusion process.  
     
     
         41 . A method according to  claim 40 , wherein each implantable device comprises dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length.  
     
     
         42 . A method according to  claim 41 , wherein each implantable device releases at least about 0.1 mg of dopamine agonist per day in vitro.  
     
     
         43 . A method according to  claim 29 , wherein each of said at least one implantable devices is subcutaneously implanted at a site selected from the group consisting of the upper arm, the back, and the abdomen.  
     
     
         44 . A method according to  claim 29 , further comprising administration of an anti-inflammatory agent.  
     
     
         45 . A method according to  claim 44 , wherein said anti-inflammatory agent is encapsulated in at least one of said at least one implantable devices.  
     
     
         46 . A method according to  claim 44 , wherein said anti-inflammatory agent is encapsulated within a biocompatible, nonerodible polymeric matrix that does not comprise said dopamine agonist, and wherein said method comprises administration of said polymeric matrix comprising said anti-inflammatory agent subcutaneously.  
     
     
         47 . A method according to  claim 44 , wherein said anti-inflammatory agent is administered via a route selected from the group consisting of local injection, systemic injection, subcutaneous injection, and oral administration.  
     
     
         48 . A method according to  claim 44 , wherein said at least one implantable devices further comprises an antioxidant.  
     
     
         49 . A kit comprising at least one implantable device comprising a dopamine agonist encapsulated within a biocompatible, nonerodible polymeric matrix, wherein when said at least one implantable device is implanted subcutaneously in a mammal, said dopamine agonist is continuously released in vivo from each of said at least one implantable devices over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state and instructions for use in a method of administration of a dopamine agonist to a mammal in need thereof.  
     
     
         50 . A kit according to  claim 49 , wherein said at least one implantable device comprises a multiplicity of individual implantable devices, and wherein when the combination of said implantable devices is implanted subcutaneously in a mammal, said implantable devices continuously release dopamine agonist in vivo over a sustained period of time at a rate that results in a plasma level of at least about 0.05 ng/ml at steady state.  
     
     
         51 . A kit according to  claim 49 , wherein said implantable device releases dopamine agonist at a rate of at least about 0.1 mg per day in vitro.  
     
     
         52 . A kit according to  claim 49 , wherein each of said implantable devices comprises EVA.  
     
     
         53 . A kit according to  claim 52 , wherein said EVA comprises about 33% vinyl acetate.  
     
     
         54 . A kit according to  claim 49 , wherein each of said implantable devices comprises about 10 to about 85% dopamine agonist.  
     
     
         55 . A kit according to  claim 54 , wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.  
     
     
         56 . A kit according to  claim 55 , wherein said dopamine agonist is apomorphine.