In Vitro Evaluation of Poly(D,L-lactide-co-glycolide) In Situ Gels and Pharmacokinetics Following Subcutaneous Injection in Rats for Model Drugs

TL;DR

This study evaluates how drug properties and formulation factors affect drug release from in situ gels and establishes a correlation between in vitro and in vivo drug release for celecoxib.

Contribution

The study provides a point-to-point in vitro–in vivo correlation for celecoxib ISGs and highlights the impact of drug solubility and polymer properties on drug release.

Findings

Sustained in vitro drug release was observed, with release rates influenced by drug solubility and polymer properties.

A point-to-point in vitro–in vivo correlation was established for celecoxib ISGs following subcutaneous injection in rats.

Abstract

Background/Objectives. This research supports the development of long-acting injectables (LAIs) via in situ gel (ISG) technology by illustrating the influence of drug properties and formulation variables on in vitro drug release (Part 1), and providing an example of a point-to-point in vitro–in vivo correlation (IVIVC) for celecoxib ISGs (Part 2). Methods/Results. Part 1 evaluated the in vitro release (IVR) for ISGs containing 10 mg/g of five model drugs—paracetamol, theophylline, felbinac, indomethacin, and celecoxib—using two different poly(D,L-lactide-co-glycolide) (PLGA) grades with lactide/glycolide ratios (L/G) of 50:50 or 85:15 in N-methyl-2-pyrrolidone (NMP) at polymer/solvent ratios of 30/70% or 40/60% (w/w). The results demonstrated sustained IVR, with approximately 80% of the drug released within 1 to 5 days for the sparingly soluble compounds paracetamol and theophylline ISGs, and within 1.5 to 11 days, 3 to over 20 days, and 19 to 74 days for the slightly soluble compounds felbinac, indomethacin, and celecoxib, respectively. The IVR rate increased with decreasing polymer lipophilicity and concentration and with increasing drug solubility in the IVR medium. In Part 2, the pharmacokinetics of celecoxib ISGs were assessed following subcutaneous (SC) injection in rats. A point-to-point IVIVC was established between the fraction of drug absorbed derived via deconvolution (deconvoluted Fabs) and the fraction dissolved (observed Fdiss) obtained in Part 1, based on Korsmeyer–Peppas fitting and release phase-specific scaling. Conclusions. In summary, this research highlights the significant impact of drug solubility, polymer grade, and concentration on the IVR rates of ISGs and provides an example of a point-to-point IVIVC for celecoxib ISGs with varying polymer concentrations and grades, following SC injection in rats.

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