Biodegradable pH/thermosensitive hydrogels for sustained delivery of biologically active agents

Abstract

The present invention relates generally to the development of pharmaceutical compositions which provide for sustained release of biologically active polypeptides. More specifically, the invention relates to the use of pH/thermosensitive, biodegradable hydrogels, consisting of a A-B di block or A-B-A tri block copolymer of poly(d,l- or l-lactic acid) (PLA) or poly(lactide-co-glycolide) (PLGA) (block A) and polyethylene glycol (PEG) (block B), with ionizable functional groups on one or both ends of the polymer chains, for the sustained delivery of biologically active agents.

What is claimed is:  
     
         1 . A pharmaceutical composition for the sustained administration of an effective amount of a biologically active agent, or a derivative, analog, fusion, conjugate, or chemically modified form thereof, comprising an injectable biodegradable polymeric matrix into which said biologically active agent has been incorporated, said polymeric matrix having reverse thermal gelation properties and pH-responsive gelation/de-gelation properties.  
     
     
         2 . The composition of  claim 1 , wherein said polymeric matrix is a biodegradable block copolymer comprising: 
 (a) 20% to 80% by weight of a hydrophobic A polymer block and;    (b) 20% to 80% by weight of a hydrophilic B polymer block comprising a polyethylene glycol having an average molecular weight of between 500-10,000;    wherein said copolymers have ionizable functional groups on one or both ends of the polymer chains.    
     
     
         3 . The composition of  claim 2 , wherein said ionizable functional groups have a pK a  in the range of 3-8.  
     
     
         4 . The composition of  claim 2 , wherein said hydrophobic A polymer block is a poly(α-hydroxy acid) having an average molecular weight of between 1000-20,000.  
     
     
         5 . The composition of  claim 4 , wherein said poly(α-hydroxy acid) is selected from the group consisting of poly(lactide)s (d,l- or l-forms), poly(glycolide)s, polyanhydrides, polyorthoesters, polyetheresters, polycaprolactone, polyesteramides, polycarbonate, polycyanoacrylate, polyurethanes, polyacrylate, blends and copolymers thereof.  
     
     
         6 . The composition of  claim 5 , wherein said poly(α-hydroxy acid) is poly lactide-co-glycolide (PLGA).  
     
     
         7 . The composition of  claim 6 , wherein said block copolymer is a tri block copolymer having a configuration selected from the group consisting of A-B-A or B-A-B block segments.  
     
     
         8 . The composition of  claim 7 , wherein said hydrophobic A polymer block comprises 74% by weight of said block copolymer and said hydrophilic B polymer block comprises 26% by weight of said block copolymer.  
     
     
         9 . The composition of  claim 8  further comprising an excipient which will vary the lower critical solution temperature and increase the rate of gelation of said block copolymer.  
     
     
         10 . The composition of  claim 1 , wherein said biologically active agent is a protein selected from the group consisting of interferon consensus, interleukins, erythropoietins, granulocyte-colony stimulating factor (GCSF), stem cell factor (SCF), leptin (OB protein), interferons (alpha, beta, gamma), tumor necrosis factor (TNF), tumor necrosis factor-binding protein (TNF-bp), interleukin-1 receptor antagonist (IL-1ra), brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), neurotrophic factor 3 (NT3), fibroblast growth factors (FGF), neurotrophic growth factor (NGF), bone growth factors such as osteoprotegerin (OPG), granulocyte macrophage colony stimulating factor (GM-CSF), megakaryocyte derived growth factor (MGDF), keratinocyte growth factor (KGF), thrombopoietin, platelet-derived growth factor (PGDF), novel erythropoiesis stimulating protein (NESP), tissue plasminogen activator (TPA), urokinase, streptokinase and kallikrein.  
     
     
         11 . The composition of  claim 1 , wherein said biologically active agent is a small molecule.  
     
     
         12 . A method for the parenteral administration of a biologically active agent, or a derivative, analog, fusion, conjugate, or chemically modified form thereof, in a biodegradable polymeric matrix to a warm blooded animal with the resultant sustained release of said agent concomitant with biodegradation and clearance from injection site of said polymeric matrix, which comprises: 
 (a) providing an injectable liquid polymeric matrix having reverse thermal gelation properties and pH-responsive gelation/degelation properties, and into which a biologically active agent has been incorporated;    (b) maintaining said liquid polymeric matrix at a temperature below the lower critical solution temperature of said polymeric matrix; and    (c) injecting said liquid parenterally into said animal, thus forming a gel depot of said agent and polymeric matrix as the temperature of said liquid is raised in the body of said animal above the lower critical solution temperature of the polymeric matrix.    
     
     
         13 . The method of  claim 12 , wherein said polymeric matrix is a biodegradable block copolymer comprising: 
 (a) 20% to 80% by weight of a hydrophobic A polymer block and;    (b) 20% to 80% by weight of a hydrophilic B polymer block comprising a polyethylene glycol having an average molecular weight of between 500-10,000;    wherein said copolymers have ionizable functional groups on one or both ends of the polymer chains.    
     
     
         14 . The method of  claim 13 , wherein said hydrophobic A polymer block is a poly(α-hydroxy acid) having an average molecular weight of between 1000-20,000.  
     
     
         15 . The method of  claim 14 , wherein said poly(α-hydroxy acid) is poly lactide-co-glycolide (PLGA).  
     
     
         16 . The method of  claim 15 , wherein said block copolymer is a tri block copolymer having a configuration selected from the group consisting of A-B-A or B-A-B block segments.  
     
     
         17 . The method of  claim 16 , wherein said hydrophobic A polymer block comprises 74% by weight of said block copolymer and said hydrophilic B polymer block comprises 26% by weight of said block copolymer.  
     
     
         18 . The method of  claim 17  further comprising an excipient which will vary the lower critical solution temperature and increase the rate of gelation of said block copolymer.  
     
     
         19 . The method of  claim 12 , wherein said biologically active agent is a protein selected from the group consisting of interferon consensus, interleukins, erythropoietins, granulocyte-colony stimulating factor (GCSF), stem cell factor (SCF), leptin (OB protein), interferons (alpha, beta, gamma), tumor necrosis factor (TNF), tumor necrosis factor-binding protein (TNF-bp), interleukin-1 receptor antagonist (IL-1ra), brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), neurotrophic factor 3 (NT3), fibroblast growth factors (FGF), neurotrophic growth factor (NGF), bone growth factors such as osteoprotegerin (OPG), granulocyte macrophage colony stimulating factor (GM-CSF), megakaryocyte derived growth factor (MGDF), keratinocyte growth factor (KGF), thrombopoietin, platelet-derived growth factor (PGDF), novel erythropoiesis stimulating protein (NESP), tissue plasminogen activator (TPA), urokinase, streptokinase and kallikrein.  
     
     
         20 . The method of  claim 12 , wherein said biologically active agent is a small molecule.