Methods of making pharmaceutical compositions with enhanced stability
The present invention provides for a stabilized biodegradable polymeric composition useful as a controlled release delivery system for peptide agents. The compositions of the present invention comprise a) a beneficial salt of a luteinizing hormone releasing hormone (LHRH) analog formed with a strong acid that minimizes or prevents the interaction/reaction between the LHRH and the polymer in an organic solution; b) a biodegradable polymer; c) a pharmaceutically acceptable organic solvent; and d) optionally one or more excipients. The present invention also relates to a method of manufacturing and a method of use thereof.
1. A method of forming an injectable polymeric composition comprising the steps of,
(a) dissolving a biodegradable polymer selected from the group of polylactide, poly(lactic acid), poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide) in a pharmaceutically acceptable organic solvent to form a polymer solution and,
(b) mixing the polymer solution with a salt of a luteinizing hormone releasing hormone (LHRH) analogue formed with a strong acid selected from the group consisting of methanesulfonic acid, hydrochloric acid, and sulphuric acid.
2. The method of forming the injectable polymeric composition in claim 1 , wherein the pharmaceutically acceptable organic solvent is selected from the group consisting of N-methyl-2-pyrrolidone (NMP) and Dimethyl sulfoxide (DMSO).
3. The method of forming the injectable polymeric composition in claim 1 , wherein the LHRH analogue is an LHRH agonist selected from the group consisting of leuprorelin, buserelin, gonadorelin, deslorelin, fertirelin, histrelin, lutrelin, goserelin, nafarelin, triptorelin, enfuvirtide, and thymosin α1.
4. The method of forming the injectable polymeric composition in claim 1 , wherein the LHRH analogue is an LHRH antagonist selected from the group consisting of cetrorelix and abarelix.
5. The method of forming the injectable polymeric composition in claim 1 , wherein the biodegradable polymer has an average molecular weight of between 2,000 and 100,000 Dalton.
6. The method of forming the injectable polymeric composition in claim 1 , wherein the biodegradable polymer is manufactured with a dodecanol (or lauryl alcohol) as an initiator resulting in the polymer with one hydroxyl end group at one end and one dodecyl ester group at the other end.
7. The method of forming the injectable polymeric composition in claim 1 , wherein the biodegradable polymer is manufactured with a 1,6-hexanediol as an initiator resulting in the polymer with one hydroxyl group at both ends of the polymer.
8. A method of forming an injectable polymeric composition comprising the steps of,
(a) dissolving a biodegradable polymer selected from the group of polylactide, poly(lactic acid), poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide) in N-methyl-2-pyrrolidone to form a polymer solution and,
(b) mixing the polymer solution with a salt of a luteinizing hormone releasing hormone (LHRH) analogue formed with a strong acid selected from the group consisting of methanesulfonic acid, hydrochloric acid, and sulphuric acid, wherein percentage of the biodegradable polymer in the injectable polymeric composition is 40-60% w/w, percentage of the salt of the luteinizing hormone releasing hormone in the injectable polymeric composition is 0.01-40% w/w, and percentage of N-methyl-2-pyrrolidone in the injectable polymeric composition is 30-80% w/w,
wherein the injectable polymeric composition does not contain excess of the strong acid.
9. The method of forming an injectable polymeric composition in claim 8 , wherein the biodegradable polymer has an average molecular weight between 8,000 and 50,000 Dalton.
10. A method of forming an injectable polymeric composition comprising the steps of,
(a) dissolving a biodegradable polymer selected from the group consisting of poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide), having the ratio of lactide:glycolide or lactic acid:glycolic acid of from 50:50 to 100:0, in N-methyl-2-pyrrolidone to form a polymer solution and,
(b) mixing the polymer solution with a salt of a luteinizing hormone releasing hormone analogue formed with a strong acid selected from the group consisting of methanesulfonic acid, hydrochloric acid, and sulphuric acid,
wherein percentage of the biodegradable polymer in the injectable polymeric composition is 30-60% w/w, percentage of the salt of the luteinizing hormone releasing hormone in the injectable polymeric composition is 0.01-40% w/w, and percentage of N-methyl-2-pyrrolidone in the injectable polymeric composition is 30-80% w/w,
wherein the injectable polymeric composition does not contain excess of the strong acid.
11. The method of forming an injectable polymeric composition in claim 10 , wherein the poly(lactide-coglycolide) or poly(lactic acid-co-glycolic acid) has a ratio of lactide:glycolide or lactic acid:glycolic acid of 85:15.
12. The method of forming an injectable polymeric composition in claim 10 , wherein the poly(lactide-coglycolide) or poly(lactic acid-co-glycolic acid) has an average molecular weight between 15,000 and 50,000 Dalton.