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 method of treatment modulating LHRH levels in a patient, comprising providing the patient with a therapeutically effective amount of a flowable delivery system comprising a biocompatible, biodegradable, non-hydrolyzed PLG low-burst copolymer material having a weight average molecular weight of about 10 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4-2.0 and from which a removed copolymer fraction characterized by a weight average molecular weight of about 4 kilodaltons to about 10 kilodaltons and a polydispersity index of about 1.4 to 2.5 has been separated, an organic solvent, and leuprolide or a peptide analogue thereof, which provides controlled release of the leuprolide or a peptide analogue thereof for a period of 30 days to 6 months.
2. The method of claim 1 , wherein the PLG low-burst copolymer material is prepared, without a step of hydrolysis of a higher molecular weight PLG copolymer material, from a starting PLG copolymer material by dissolving the starting PLG copolymer in a solvent, precipitating the low-burst copolymer material with a non-solvent, and collecting the PLG low-burst copolymer material.
3. The method of claim 1 , wherein the PLG low-burst copolymer material has the content of unreacted lactide and glycolide less than about 1.0 weight % and 0.1 weight % respectively.
4. The method of claim 1 , wherein the PLG low-burst copolymer material is prepared by separating a removed copolymer fraction characterized by a weight average molecular weight of about 4 kDa to about 10 kDa and a polydispersity index of about 1.4 to 2.5 from a starting PLG copolymer material, the method comprising dissolving the starting PLG copolymer material in a solvent to provide a solution, then precipitating the PLG low-burst copolymer material by contacting the solution with a nonsolvent and collecting precipitated PLG low-burst copolymer material, the method comprising no step of hydrolysis of a higher molecular weight PLG copolymer.
5. The method of claim 1 , wherein the organic solvent is N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, polyethylene glycol 200, polyethylene glycol 300, or methoxypolyethylene glycol 350.
6. The method of claim 1 , wherein the organic solvent is N-methylpyrrolidone.
7. The method of claim 1 , wherein the method suppresses testosterone biosynthesis.
8. The method of claim 1 , wherein the patient has prostate cancer.
9. The method of claim 1 , wherein the flowable delivery system is administered subcutaneously.