Chung Shih

Biodegradable block copolymers for delivery of proteins and water-insoluble drugs

Release of several drugs from new ABA-type biodegradable thermal gels, ReGel, including proteins and conventional molecules, are presented. These are biodegradable, biocompatible polymers that demonstrate reverse thermal gelation properties. Organic solvents are not used in the synthesis, purification, or formulation of these polymers. The unique characteristics of ReGel hinge on the following two key properties: (1) ReGel is a water soluble, biodegradable polymer at temperatures below the gel transition temperature; (2) ReGel forms a water-insoluble gel once injected. This is consistent with a hydrophobically bonded gel state where all interactions are physical, with no covalent crosslinking. An increase in viscosity of approximately 4 orders of magnitude accompanies the sol--gel transition. The gel forms a controlled release drug depot with delivery times ranging from 1 to 6 weeks. ReGels inherent ability to solubilize (400 to >2000-fold) and stabilize poorly soluble and sensitive drugs, including proteins is a substantial benefit. The gel provided excellent control of the release of paclitaxel for approximately 50 days. Direct intratumoral injection of ReGel/paclitaxel (OncoGel) results in a slow clearance of paclitaxel from the injection site with minimal distribution into any organ. Efficacies equivalent to maximum tolerated systemic dosing were observed at OncoGel doses that were 10-fold lower. Data on protein release (pGH, G-CSF, insulin, rHbsAg) and polymer biocompatibility are discussed.

Quantitative analysis of ester linkages in poly(dl-lactide) and poly(dl-lactide-co-glycolide)

A quantitative analytical method for determination of intact ester linkages in biodegradable poly(DL-lactide) (PLA) and poly(dl-lactide-co-glycolide) (PLGA) has been developed. The polymer backbone ester bonds were converted to amides by a facile reaction with n-butylamine under ambient conditions. The resulting amides were analyzed by gas chromatography. The amidation of both types of ester bonds was quantitative; reaction of the glycolate and lactate linkages was completed within 3 and 8 h, respectively. The method was free from interferences by lactic or glycolic acids and was tolerant of extraneous water. The values determined by this method were within 5% of those obtained by 1H-NMR. Application to the study of the hydrolysis of poly(dl-lactide-co-glycolide) was demonstrated where the degradation profiles of the glycolide and lactide linkages were simultaneously determined.

In vivo and in vitro release of ivermectin from poly(ortho ester) matrices. I. Crosslinked matrix prepared from ketene acetal end-capped prepolymer

Abstract Release of ivermectin from a crosslinked poly(ortho ester) matrix was studied both in vitro and in vivo in rats and dogs. A total of 32.8% of the loaded drug was covalently bonded to the polymer matrix. The release rate of the drug in vitro was initially slow but accelerated in the later stages of the studies. The rat plasma concentration of the drug was maintained fairly constant over a period of 6 months with a slight increase thereafter. Implant retrieval studies in dogs showed that the drug release may be controlled by matrix erosion.

Acid catalyzed poly (ortho ester) matrices for intermediate term drug delivery

The in vitro release of timolol maleate from poly(ortho ester) matrices was studied. Release profiles ranged from simple zero-order to complex multiphasic release patterns. The observed profile was dependent on both the polymer and the catalyst selected. Polymers that contained ⩾ 50 mol% ofcyclohexane-trans-1,4-dimethanol (CDM) in the backbone consistently gave linear drug release profiles. Multiphasic drug release profiles were associated with polymers of < 50 mol% of CDM and lipophilic acid catalysts. The nature of the drug release profile was related to the Tgof the polymer-drug-catalyst composite. A purely surface or bulk erosion-controlled drug release mechanism could not account for the observed drug release profiles. Linear release from devices of varied geometries suggested that diffusion through a rate controlling surface skin layer may be a limiting step in the overall drug release mechanism.