Low-burst polymers and methods to produce polymer
A PLG copolymer material, termed a PLG(p) copolymer material, adapted for use in a controlled release formulation for a bioactive material is provided, wherein the formulation exhibits a reduced “initial burst” effect when introduced into the tissue of a patient in need thereof. A method of preparation of the PLG copolymer material is also provided, as are methods of use.
1. A controlled release formulation, comprising:
an organic solvent;
a peptide bioactive agent useful for modulating LHRH levels; and
a biocompatible, biodegradable, linear poly(DL-lactide-co-glycolide) (PLG) copolymer comprising a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4 to about 2.0;
wherein:
a low-molecular weight copolymer fraction having a weight average molecular weight of about 10 kilodaltons or less and comprising unreacted, residual lactide and glycolide monomers has been removed from the PLG copolymer; and
the controlled release formulation is formulated to release the peptide bioactive agent for a period of 30 days to 6 months.
2. The controlled release formulation of claim 1 , wherein the peptide bioactive agent is leuprolide or an analog thereof.
3. The controlled release formulation of claim 1 , wherein the PLG copolymer comprises less than about 1.0 weight % residual lactide monomer.
4. The controlled release formulation of claim 1 , wherein the PLG copolymer comprises about 0.5 weight % or less residual lactide monomer and about 0.1 weight or less residual glycolide monomer.
5. The controlled release formulation of claim 1 , wherein the PLG copolymer is not a product of hydrolysis of a higher molecular weight copolymer.
6. The controlled release formulation of claim 1 , wherein the PLG copolymer was prepared by a ring-opening polymerization reaction of lactide and glycolide.
7. The controlled release formulation of claim 1 , wherein the organic solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, dimethylsulfoxide, and combinations thereof.
8. The controlled release formulation of claim 7 , wherein the organic solvent is N-methylpyrrolidone.
9. The controlled release formulation of claim 1 , wherein the PLG copolymer is 85/15 poly(DL-lactide-co-glycolide).
10. The controlled release formulation of claim 1 , wherein the PLG copolymer comprises a terminal ester group and a terminal hydroxyl group.
11. A method of modulating LHRH levels in a patient, comprising administering to the patient a therapeutically effective amount of a controlled release formulation, comprising:
an organic solvent;
a peptide bioactive agent; and
a biocompatible, biodegradable, linear poly(DL-lactide-co-glycolide) (PLG) copolymer comprising a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4 to about 2.0,
wherein:
a low-molecular weight copolymer fraction having a weight average molecular weight of about 10 kilodaltons or less and comprising unreacted, residual lactide and glycolide monomers has been removed from the PLG copolymer; and
the controlled release formulation forms an in situ solid or semi-solid depot with the body of the patient that provides for the controlled release of the peptide bioactive agent for a period of 30 days to 6 months.
12. The method of claim 11 , wherein the administration of the controlled release formulation suppresses testosterone biosynthesis in the patient.
13. The method of claim 11 , wherein the patient has prostate cancer.
14. The method of claim 11 , wherein the peptide bioactive agent is leuprolide or an analog thereof.
15. The method of claim 11 , wherein the PLG copolymer comprises about 1.0 weight % or less residual lactide monomer and/or about 0.1 weight % or less residual glycolide monomer.
16. The method of claim 11 , wherein the linear PLG copolymer is not a product of hydrolysis of a higher molecular weight copolymer.
17. The method of claim 11 , wherein the linear PLG copolymer was prepared by a ring-opening polymerization reaction of lactide and glycolide.
18. The method of claim 11 , wherein the organic solvent is selected from the group consisting of N-methylpyrrolidone, N,N-dimethylacetamide, dimethylsulfoxide, and combinations thereof.
19. The method of claim 11 , wherein the linear PLG copolymer is 85/15 poly(DL-lactide-co-glycolide).
20. The method of claim 11 , wherein the linear PLG copolymer comprises a terminal ester group and a terminal hydroxyl group.