Enhanced Degradation of Lactide-co-Glycolide Polymer with Basic Nucleophilic Drugs

Abstract

The purpose of this study was to examine the degradative effect of weakly basic nucleophilic drugs on a lactide-co-glycolide (PLGA) polymer in a microsphere formulation. Biodegradable PLGA microspheres of two second-generation atypical antipsychotics, Risperidone and Olanzapine, were manufactured using a solvent extraction/evaporation technique. The effect of drug content, buffer pH and temperature on polymer molecular weight and degradation, were examined via a series of experiments and compared against a control (Placebo PLGA microspheres). In comparison to Placebo microspheres, significant polymer molecular weight reduction was observed upon encapsulation of varying levels of either Risperidone or Olanzapine. There was excellent correlation between the extent of molecular weight reduction during manufacture and the amount of encapsulated drug in the microspheres. Subsequent studies on polymer degradation showed: the following (a) the Placebo and Olanzapine microspheres followed pseudo first order kinetics, (b) Risperidone microspheres exhibited biphasic degradation profiles, and (c) polymer degradation was dependent on temperature, not pH. The findings of these studies show that encapsulation of weakly basic nucleophile type drugs into PLGA can accelerate the biodegradation of the PLGA and have major implications on the design of polymeric microsphere drug delivery systems.

Formulation of Bioerodible Ketamine Microparticles as an Analgesic Adjuvant Treatment Produced by Supercritical Fluid Polymer Encapsulation

“…In the current study, it is likely that the delayed hydration process of ester end-capped PLGAs [43] influenced the rate of polymer hydration in vitro and subsequently facilitated the release of ketamine out of the microparticles. This is in agreement with the findings by others that the encapsulation of weakly basic drugs into PLGA can accelerate the biodegradation of PLGA [44,45]. Additionally, the acids may also produce local lowering of the pH [35] to accelerate ketamine release.…”

Polymer degradation and drug delivery in PLGA‐based drug–polymer applications: A review of experiments and theories

“…For basic drugs, however, there are conflicting views of the impact on degradation. One viewpoint is that degradation will be accelerated; basic drugs, such as tertiary amine or nucleophilic drugs, catalyze the matrix degradation that will accelerate the release rate because of a bulk erosion of the matrix . An opposite viewpoint is that drug release can be suppressed; basic drugs can neutralize the generating acid from polymer hydrolysis so as to minimize the autocatalytic effect, thereby leading to a slower degradation rate and consequent reduced drug release rates …”

“…One viewpoint is that degradation will be accelerated; basic drugs, such as tertiary amine or nucleophilic drugs, catalyze the matrix degradation that will accelerate the release rate because of a bulk erosion of the matrix. 17,76,77 An opposite viewpoint is that drug release can be suppressed; basic drugs can neutralize the generating acid from polymer hydrolysis so as to minimize the autocatalytic effect, thereby leading to a slower degradation rate and consequent reduced drug release rates. 43,78,79 As an example of the studies to address the impact of drug-polymer interaction on the release behavior, Klose et al 34 reported in vitro release behaviors of lidocaine and ibuprofen drugs from PLGA-based polymers at pH 7.4 as Complete drug release in 20 days shown in Table V.…”

The gut microbiome influences the bioavailability of olanzapine in rats

“… Drug name, IUPAC name, and structure Dosage Physiochemical properties Mol.wt. Log P pKa Solubility (H 2 O) Olanzapine 2-methyl-4-(4-methylpiperazin-1-yl)-10H-thieno [2,3b] [1,5]benzodiazepine Target: 10 mg/day 312 g/mol 2 7.37 a 0.039 mg/ml Risperidone 3- [2- [4-(6-fluoro-1,2-benzoxazol-3-yl) piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydro-pyrido [1,2-a]pyrimidin-4-one Range: 2–10 mg/day 410 g/mol 3.49 8.24 a 0.064 mg/ml b Log P: partition co-efficient; a [18] ; b [19] …”