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 a flowable delivery system comprising: an organic solvent, a bioactive agent and a biocompatible, biodegradable, non-hydrolyzed linear PLG low-burst copolymer material having a weight average molecular weight of about 15 kilodaltons to about 50 kilodaltons and a polydispersity index of about 1.4 to about 1.8 and which low-burst linear copolymer material is free of a 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.
2. The controlled release formulation of claim 1 , wherein the PLG low-burst copolymer material comprises copolymer molecular chains wherein a predominant proportion of the molecular chains comprise predominantly lactate or lactide residues in at least one end domain of each molecular chain and predominantly glycolate or glycolide resides in an internal domain of each molecular chain.
3. The controlled release formulation of claim 1 , wherein the bioactive agent is leuprolide, octreotide, brimonidine, latanoprost, latanoprost acid, travoprost, travoprost acid, brinzolamide, dorzolamide, betaxolol, terbinafine, risperidone or rapamycin.
4. The controlled release formulation of claim 1 , wherein the bioactive agent is a steroid, a prostaglandin, an analgesic, an antiviral, or an antibiotic.
5. The controlled release formulation 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 controlled release formulation of claim 1 , wherein the bioactive agent is leuprolide or leuprolide acetate and the organic solvent is N-methyl pyrrolidone.
7. The controlled release formulation of claim 1 wherein the content of unreacted lactide and glycolide in the PLG low-burst copolymer material is less than about 1.0 weight % and 0.1 weight % respectively.
8. The controlled release formulation of claim 1 , wherein the linear PLG copolymer material has a weight average molecular weight of about 15 kilodaltons to about 21 kilodaltons.
9. The controlled release formulation of claim 1 , wherein the linear PLG low-burst copolymer material comprises terminal carboxyl groups that are capped as esters.
10. The controlled release formulation of claim 1 , comprising a linear chain extended PLG low-burst copolymer in place of the linear PLG low-burst copolymer material, the linear chain extended PLG low-burst copolymer being the product of the linear PLG low-burst copolymer material and a diol which caps as ester groups the terminal carboxyl groups of two molecules of the linear PLG low-burst copolymer material.