Biodegradable sustained-release alginate gels

Abstract

The present invention relates to sustained-release formulations using biodegradable alginate delayed gels or particles and methods thereof.

We claim:  
     
         1 . A sustained-release delayed gel composition, comprising: 
 a) a hydrophilic polymer;    b) a biologically active agent; and    c) at least one bound polyvalent metal ion, wherein said gel is biodegradable.    
     
     
         2 . The sustained-release composition of  claim 1  wherein the bound polyvalent metal ion is a mixture of bound and unbound polyvalent metal ion.  
     
     
         3 . The sustained-release delayed gel of  claim 1  further comprising excipients for stabilizing the biologically active agent or the hydrophilic polymer.  
     
     
         4 . The composition of  claim 1  wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, tartrates, citrates, chlorides, carbonates or hydroxides thereof.  
     
     
         5 . The composition of  claim 4  wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.  
     
     
         6 . The composition of  claim 5  wherein the metal ion is calcium.  
     
     
         7 . The composition of  claim 1  wherein the proton donor is from an acid source.  
     
     
         8 . The composition of  claim 7  wherein the acid source is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.  
     
     
         9 . The composition of  claim 1  wherein the hydrophilic polymer is a polyanion.  
     
     
         10 . The composition of  claim 1  wherein the hydrophilic polymer is a polysaccharide.  
     
     
         11 . The composition of  claim 10  wherein the polysaccharide is an acidic polysaccharide.  
     
     
         12 . The composition of  claim 11  wherein the polysaccharide is alginate.  
     
     
         13 . The composition of  claim 12  wherein the alginate contains at least 30% guluronic acid.  
     
     
         14 . The composition of  claim 12  wherein the alginate consist of at least 0.05% by weight.  
     
     
         15 . The composition of  claim 1  wherein the biologically active agent comprises a protein, and wherein the composition demonstrates improved bioavailability.  
     
     
         16 . The composition of  claim 15  wherein the protein consist of at least 0.001 mg/ml.  
     
     
         17 . The composition of  claim 15  wherein the protein is selected from the group consisting of hematopoietic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.  
     
     
         18 . The composition of  claim 15  wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF, insulin and analogs or derivatives thereof.  
     
     
         19 . The composition of  claim 1  wherein the biologically active agent is a complexed biologically active agent.  
     
     
         20 . The composition of  claim 19  wherein the complexed biologically active agent is a precipitated protein.  
     
     
         21 . The composition of  claim 20  wherein the precipitated protein is a zinc leptin precipitate.  
     
     
         22 . A method of producing a sustained-release delayed gel composition, wherein said gel is biodegradable, comprising the steps of: 
 a) mixing a biologically active agent and a hydrophilic polymer in a solvent to form a first mixture;    b) mixing to the first mixture at least one bound polyvalent metal ion to form a second mixture.    
     
     
         23 . A method of  claim 22  further comprising the step of c) mixing to the second mixture at least one proton donor capable of releasing the bound polyvalent metal ion.  
     
     
         24 . The method of claims  22  wherein the first mixture is concentrated before mixing the proton donor or bound polyvalent metal ion.  
     
     
         25 . The method of  claim 22  wherein the bound polyvalent metal ion is a salt selected from the group consisting of acetates, phosphates, lactates, citrates, tartrates, chlorides, carbonates or hydroxides thereof.  
     
     
         26 . The method of  claim 22 , wherein said method provides for a substantially constant blood level of said biologically active agent over time in the patient.  
     
     
         27 . The composition of  claim 25  wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc.  
     
     
         28 . The composition of  claim 27  wherein the metal ion is calcium.  
     
     
         29 . The composition of  claim 24  wherein the proton donor is from an acid source.  
     
     
         30 . The composition of  claim 29  wherein the slow dissolving acid is selected from the group consisting of buffers, esters, slowly dissolving acids or lactones.  
     
     
         31 . The composition of  claim 30  wherein the acid source is δ-gluconolactone.  
     
     
         32 . The composition of  claim 22  wherein the hydrophilic polymer is a polyanion.  
     
     
         33 . The composition of  claim 22  wherein the hydrophilic polymer is a polysaccharide.  
     
     
         34 . The composition of  claim 33  wherein the polysaccharide is an acidic polysaccharide.  
     
     
         35 . The composition of  claim 34  wherein the polysaccharide is alginate.  
     
     
         36 . The composition of  claim 35  wherein the alginate contains at least 30% guluronic acid.  
     
     
         37 . The composition of  claim 35  wherein the alginate consist of at least 0.05% by weight.  
     
     
         38 . The composition of  claim 22  wherein the biologically active agent comprises a protein.  
     
     
         39 . The composition of  claim 38  wherein the protein consist of at least 0.001 mg/ml.  
     
     
         40 . The composition of  claim 38  wherein the protein is selected from the group consisting of hematopoetic factors, colony stimulating factors, anti-obesity factors, growth factors, trophic factors, and antiinflammatory factors.  
     
     
         41 . The composition of  claim 38  wherein the protein is selected from the group consisting of leptin, G-CSF, SCF, BDNF, GDNF, NT3, GM-CSF, IL-1ra, IL2, TNF-bp, MGDF, OPG, interferons, erythropoietin, KGF and analogs or derivatives thereof.  
     
     
         42 . The composition of  claim 22  wherein the biologically active agent is a complexed biologically active agent.  
     
     
         43 . The composition of  claim 42  wherein the complexed biologically active agent is a precipitated protein.  
     
     
         44 . The composition of  claim 43  wherein the precipitated protein is a zinc leptin precipitate.  
     
     
         45 . The method of  claim 22  further comprising the step of isolating the sustained-release composition.  
     
     
         46 . The sustained-release product produced by the method of claims  22  or  45 .  
     
     
         47 . A pharmaceutical formulation comprising the sustained-release composition according to claims  1 ,  2 ,  3  or  46  in a pharmaceutically acceptable carrier, diluent or adjuvant.  
     
     
         48 . The pharmaceutical formulation of  claim 47 , wherein the formulation is in a syringe.  
     
     
         49 . A method of treating an indication with a sustained-release composition according to claims  1 ,  2 ,  3  or  46  in a pharmaceutically acceptable carrier, diluent or adjuvant.  
     
     
         50 . A method of treatment of a disorder selected from the group consisting of excess weight, diabetes, high blood lipid level, artherial sclerosis, artherial plaque, the reduction or prevention of gall stones formation, insufficient lean tissue mass, insufficient sensitivity to insulin, and stroke, with a sustained-release composition according to claims  1 ,  2 ,  3 , or  46  in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is leptin, an analog or derivative thereof  
     
     
         51 . A method of treating a disorder selected from the group consisting of hematopoietic cell deficiencies, infection, and neutropenia with a sustained-release composition according to claims  1 ,  2 ,  3 , or  46  in a pharmaceutically acceptable carrier, diluent, or adjuvant wherein the biologically active agent is G-CSF, an analog or derivative thereof.  
     
     
         52 . A method of treating inflammation with a sustained-release composition according to claims  1 ,  2 ,  3 , or  46  in a pharmaceutically acceptable carrier, diluent, or adjuvant, wherein the biologically active agent is an IL-1ra, an analog or derivative thereof.  
     
     
         53 . A sustained-release composition, comprising: 
 a) a hydrophilic polymer;    b) a biologically active agent; and    c) at least one precipitating agent; characterized in that the biologically active agent is co-precipitated within the hydrophilic polymer, wherein said composition is in the form of a gel particle, and wherein said particle is biodegradable.    
     
     
         54 . The composition of  claim 53  wherein the precipitating agent is selected from the group consisting of polyvalent metal ions or salts, acetates, citrates, chlorides, carbonates or hydroxides thereof.  
     
     
         55 . The composition of  claim 54  wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, aluminium or zinc.  
     
     
         56 . The composition of  claim 55  wherein the precipitating agent is a polyvalent ion selected from the group consisting of zinc, calcium or a combination thereof.  
     
     
         57 . The composition of  claim 53  wherein the hydrophilic polymer is a polysaccharide.  
     
     
         58 . The composition of  claim 57  wherein the polysaccaharide is alginate.  
     
     
         59 . A method of producing a sustained-release composition, comprising the steps of: 
 a) dissolving a biologically active agent and a hydrophilic polymer with a solvent to form a first mixture;    b) dissolving at least one precipitating agent in a solvent to form a second mixture;    c) adding the first mixture with the second mixture; and    d) co-precipitating the biologically active agent with the hydrophilic polymer to form a co-precipitated gel particle, wherein said particle is biodegradable.    
     
     
         60 . The method of  claim 59  further comprising the step of isolating the co-precipitated particle.  
     
     
         61 . The sustained-release product produced by the method of claim  60 .  
     
     
         62 . A pharmaceutical formulation according to claims  53  in a pharmaceutically acceptable carrier, diluent or adjuvant.  
     
     
         63 . A method of treating an indication with a sustained-release composition according to  claim 53  in a pharmaceutically acceptable carrier, diluent or adjuvant.