Pharmaceutical composition with improved stability
The present invention provides an injectable composition for controlled release drug delivery and the process of making the same, where the composition comprises: a lactate-based polymer having a weight average molecular weight between 5,000 and 50,000 dalton, an acid number of less than 3 mgKOH/g and the content of residual lactide monomers in the lactate-based polymer of less than about 0.3% by weight; a pharmaceutically acceptable organic solvent; and a bioactive substance or a salt thereof that contains an amino acid serine in the molecular structure that is capable of reacting with lactide monomer to form a conjugate; and where the composition reduces the formation of the conjugate.
1 . An injectable composition for controlled release drug delivery comprising:
a polylactide (PLA) polymer having a weight average molecular weight between 5,000 and 50,000 dalton, an acid number of less than 3 mgKOH/g, and a residual lactide monomer less than or equal to 0.3% by weight;
N-methylpyrrolidone (NMP); and
a bioactive substance or a salt thereof that contains an amino acid serine in the molecular structure that is capable of reacting with lactide monomer to form a conjugate,
with the proviso that no acid additive is added in making the injectable composition.
2 . The composition of claim 1 wherein the PLA is dissolved in the NMP to form a PLA solution in the NMP, and the concentration of the PLA in the MNMP solution is 57.5% to 60% by weight.
3 . The composition of claim 1 wherein the polylactide (PLA) polymer comprises less than or equal to 0.2% by weight of the residual lactide monomer.
4 . The composition of claim 1 wherein the polylactide (PLA) polymer comprises less than or equal to 0.1% by weight of the residual lactide monomer.
5 . The composition of claim 1 wherein the polylactide (PLA) polymer comprises less than 0.03% by weight of the residual lactide monomer.
6 . The composition of claim 1 wherein the bioactive substance is selected from the group consisting of leuteinizing hormone releasing hormone (LHRH), LHRH analogs, agonists, and antagonists, or salt thereof.
7 . The composition of claim 1 wherein the bioactive substance is leuprolide or a salt thereof.
8 . The composition of claim 1 wherein the bioactive substance is leuprolide acetate or leuprolide mesylate.
9 . The composition of claim 1 wherein the polylactide (PLA) polymer has an acid number of less than 2 mgKOH/g.
10 . The composition of claim 1 wherein the polylactide (PLA) polymer has an acid number of less than 1 mgKOH/g.
11 . The composition of claim 1 wherein the polylactide (PLA) polymer has a molecular weight of 14.6K to 15.7K.
12 . The composition of claim 1 wherein the polylactide (PLA) polymer has a polydispersity from about 1.7 to 2.1.
13 . An injectable composition for controlled release drug delivery consisting of:
a polylactide (PLA) having a weight average molecular weight between 5,000 and 50,000 dalton, an acid number of less than 2 mg KOH/g, and a residual lactide monomer less than or equal to 0.2 by weight;
N-methylpyrrolidone (NMP); and
leuprolide mesylate,
wherein the polylactide (PLA) is dissolved in the NMP to form a polylactide (PLA) solution in the NMP, and the concentration of the polylactide (PLA) in the MNMP solution is 57.5% by weight.
14 . A process for making the injectable composition for controlled release drug delivery of claim 1 comprising:
purifying a polylactide (PLA) polymer having a weight average molecular weight between 5,000 and 50,000 dalton and an acid number of less than 3 mgKOH/g to remove residual lactide monomers to a level of less than or equal to 0.3% by weight; and
combining the purified polylactide (PLA) polymer with N-methylpyrrolidone (NMP) and the bioactive substance or a salt thereof that contains an amino acid serine in the molecular structure that is capable of reacting with lactide monomer to form a conjugate,
with the proviso that no acid additive is added in making the injectable composition.