Patent EA-003670-B1 (EA)
Title: Biodegradable sustained-release alginate gels
Inventor: GOLDENBERG MERRILL SEYMOUR
IPC: A61K38/21
Filed: 1999-05-14
Abstract: 1. A sustained-release delayed gel composition, comprising: a) a biodegradable anionic polysaccharide; b) a leptin protein and analogs or derivatives thereof; and c) at least one bound polyvalent metal ion, wherein said biodegradable anionic polysaccharide is an alginate ester which is crosslinked with said polyvalent metal ion to provide a biodegradable, biocompatible alginate ester hydrogel which is formed in a time-delayed manner, is injectable, and results in no injection site reaction. 2. The 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 leptin 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 ion. 7. The composition of Claim 1 wherein the biologically active agent comprises a protein, and wherein the composition demonstrates improved bioavailability. 8. The composition of Claim 7 wherein the protein consist of at least 0.001 mg/ml. 9. The composition of Claim 7 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. 10. The composition of Claim 7 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. 11. The composition of Claim 1 wherein the biologically active agent is a complexed biologically active agent. 12. The composition of Claim 11 wherein the complexed biologically active agent is a precipitated protein. 13. The composition of Claim 12 wherein the precipitated protein is a zinc leptin precipitate. 14. A method of producing a sustained-release delayed gel composition, wherein said gel is biodegradable, comprising: mixing a biologically active agent and a hydrophilic polymer in a solvent to form a first mixture; mixing to the first mixture at least one bound polyvalent metal ion to form a second mixture wherein said biodegradable anionic polysaccharide is an alginate ester which is crosslinked with said polyvalent metal ion to provide a biodegradable, biocompatible alginate ester hydrogel which is formed in a time-delayed manner, is injectable. 15. The composition of Claim 14 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. 16. The composition of Claim 14 wherein the metal ion is selected from the group consisting of manganese, strontium, iron, magnesium, calcium, barium, copper, aluminum or zinc. 17. The composition of Claim 16 wherein the metal ion is calcium ion. 18. The composition of Claim 14 wherein the biologically active agent comprises a protein. 19. The composition of Claim 18 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. 20. The composition of Claim 18 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. 21. The composition of Claim 14 wherein the biologically active agent is a complexed biologically active agent. 22. The composition of Claim 21 wherein the complexed biologically active agent is a precipitated protein. 23. The composition of Claim 22 wherein the precipitated protein is a zinc leptin precipitate. 24. The method of Claim 22, wherein it further comprises producing a sustained-release delayed gel composition stage. 25. A pharmaceutical formulation comprising sustained-release delayed gel composition according to Claims 1-14 in a pharmaceutically acceptable carrier, diluent or adjuvant. 26. The pharmaceutical formulation of Claim 25, wherein the formulation is in a syringe.