Controlled drug delivery system using the conjugation of drug to biodegradable polyester

A method of preparing a sustained controlled release system wherein a drug molecule to be released is directly conjugated to a biodegradable polyester polymer via a covalent bond, comprising the steps of:

• 1) forming an activated drug molecule solution by activating a drug molecule by mixing with coupling agents selected from the group consisting of bis(2-oxo-3-oxazolydinyl)phosphonic chloride (BOP—Cl), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBroP), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), dicyclohexyl carbodiimide, disuccinimidyl carbonate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), bis(2-oxo-3-oxazolydinyl)phosphin, diisopropyl carbodiimide (DIPC), 2-(1H-benzotrioxazolyl)-1,1,3,3-tetramethyl-uronium tetrafluoroborate (TBTU), 2-(5-norboren)-2,3-dicarboxyimido)-1,1,3,3-tetramethyluronium tetrafluoroborate (TNTU), para-nitrophenylchloroformate, and O-(N-succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU), bases, and optionally, additives;
• 2) directly conjugating the activated drug molecules resulting from step 1) with a biodegradable polyester polymer by adding a polymer to said activated drug molecule solution of step 1 and
• 3) purifying the polymer-molecule conjugate resulting from step 2.