Biodegradable drug delivery systems for the sustained release of proteins

Abstract

Biodegradable drug delivery systems, such as extruded implants, for the sustained delivery of a protein to an ocular region of the eye or intraarticular region in the body are described. The drug delivery systems may be used to treat a variety of ocular and medical conditions, including macular degeneration. Methods for using and making the drug delivery systems are also described. The drug delivery systems can be in the form of extruded filaments configured for placement in an ocular region such as the vitreous body or anterior chamber of the eye.

What is claimed is: 
     
         1 . An extruded biodegradable intraocular implant comprising a biodegradable polymer matrix and a protein associated with the biodegradable polymer matrix, wherein the biodegradable polymer matrix comprises a first poly(D,L-lactide-co-glycolide) and a second poly(D,L-lactide-co-glycolide), the first poly(D,L-lactide-co-glycolide) having an ester end group and a D,L-lactide:glycolide ratio of about 75:25, and the second poly(D,L-lactide-co-glycolide) having an acid end group and a D,L-lactide:glycolide ratio of about 50:50, wherein the implant provides continuous release of the protein in a biologically active form for about 90 days after placement of the implant in an eye of a mammal, wherein the protein comprises a bispecific antibody, wherein the bispecific antibody binds vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF). 
     
     
         2 . The implant of  claim 1 , wherein the weight to weight ratio of first poly(D,L-lactide-co-glycolide) to second poly(D,L-lactide-co-glycolide) is about 90:10. 
     
     
         3 . An implant according to  claim 2 , wherein the protein is therapeutically effective for reducing at least one symptom of an ocular condition selected from the group consisting of ocular tumors, ocular neovascularization, choroidal neovascularization, macular degeneration, diabetic macular edema and diabetic retinopathy. 
     
     
         4 . An implant according to  claim 3 , wherein the implant effectively inhibits or reduces the activity of VEGF or PDGF in vivo in an eye of a mammal, and wherein the implant provides continuous release of the bispecific antibody in a biologically active form for at least 30, 60, or 90 days after placement of the implant in an eye of a mammal. 
     
     
         5 . An extruded biodegradable intraocular implant comprising about 8.8% by weight RG502H, which is a poly(D,L-lactide-co-glycolide) having an acid end group, an inherent viscosity of 0.16-0.24 dl/g (0.1% in chloroform at 25° C.), and a D,L-lactide:glycolide ratio of about 50:50; about 79.7% by weight RG752S, which is a poly(D,L-lactide-co-glycolide) having an ester end group, an inherent viscosity of 0.16-0.24 dl/g (0.1% in chloroform at 25° C.), and a D,L-lactide:glycolide ratio of about 75:25; about 10% by weight of a bispecific antibody that binds vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF); about 0.1% by weight polysorbate 20; and about 1.4% by weight sodium phosphate, wherein the implant effectively inhibits or reduces the activity of VEGF and PDGF in vivo, and wherein the implant provides continuous release of the bispecific antibody in a biologically active form for at least 30, 60, or 90 days after placement of the implant in an eye of a mammal in an eye of a mammal. 
     
     
         6 . An apparatus for injecting an intraocular implant into the eye of a mammal, said apparatus comprising i) an elongate housing having a longitudinal axis; and ii) a cannula extending longitudinally from the housing, said cannula having a proximal end, a distal sharp end, and a lumen extending there through, the cannula further comprising an implant as defined by  claim 1 , wherein the implant is located within the lumen of the cannula. 
     
     
         7 . A method for treating an ocular condition in an eye of a mammal in need thereof, the method comprising placing in the eye of the mammal an implant according to  claim 1 , thereby treating the ocular condition. 
     
     
         8 . The method of  claim 7 , wherein the ocular condition is selected from the group consisting of ocular tumors, ocular neovascularization, choroidal neovascularization, and macular degeneration, diabetic macular edema and diabetic retinopathy. 
     
     
         9 . The method of  claim 8 , wherein the implant is placed in the vitreous body of the eye. 
     
     
         10 . The method of  claim 9 , wherein the mammal is a human. 
     
     
         11 . The method of  claim 10 , wherein the implant effectively treats the ocular condition for at least 4 weeks after the implant is placed in the eye. 
     
     
         12 . The method of  claim 11 , wherein the implant effectively treats the ocular condition for about 90 days after the implant is placed in the eye. 
     
     
         13 . A method for making a biodegradable intraocular implant that provides continuous release of a protein in a biologically active form for at least 90 days after placement of the implant in an eye of a mammal, the method comprising:
 a. providing a dry powder comprising a bispecific antibody and, optionally, one or more excipients, salts, buffering agents, preservatives, polyelectrolytes, or combination thereof; wherein the bispecific antibody binds vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF);   b. blending the dry powder with at least two poly(D,L-lactide-co-glycolide) copolymers to form a mixture wherein one of the copolymers has an ester end group and the other copolymer has an acid end group;   c. extruding the mixture at a temperature between 60° C. and 90° C. to form a filament;   d. cutting the filament to form an implant 0.5 to 10 mm in length suitable for placement in an ocular region of an eye.   
     
     
         14 . The method of  claim 13 , wherein the biodegradable intraocular implant effectively treats an ocular condition. 
     
     
         15 . The method of  claim 14 , wherein the ocular condition selected from the group consisting of ocular tumors, ocular neovascularization, choroidal neovascularization, and macular degeneration, diabetic macular edema and diabetic retinopathy.