Use of Drug Release Testing to Evaluate the Retention of Abuse-Deterrent Properties of Polyethylene Oxide Matrix Tablets.

Abstract

Abuse-deterrent formulations (ADFs) using physical/chemical barrier approaches limit abuse by providing resistance to dosage form manipulation to limit drug extraction or altered release. Standardizing in vitro testing methods to assess the resistance to manipulation presents a number of challenges, including the variation in particle sizes resulting from the use of various tools to alter the tablet matrix (e.g., grinding, chipping, crushing). A prototype, direct-compression ADF using a sintered polyethylene oxide (PEO) matrix containing dextromethorphan, an enantiomeric form of the opioid, levorphanol, was developed to evaluate testing methodologies for retention of abuse-deterrent properties following dosage form tampering. Sintered PEO tablets were manipulated by grinding, and drug content and release were evaluated for the recovered granules. Drug content analysis revealed that higher amounts of drug were contained in the smaller size granules (< 250μm, 190% of the theoretical amount) compared with the larger particles (> 250μm, 55-75% of theoretical amount). Release testing was performed on various size granule fractions (> 850μm, 500-850μm, 250-500μm, and < 250μm) using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus. The USP type I and type II apparatus gave highly variable release results with poor discrimination among the release rates from different size granules. The observed sticking of the hydrated granules to the baskets and paddles, agglomeration of hydrated granules within the baskets/vessels, and ongoing PEO hydration with subsequent gel formation further altered the particle size and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules (minimal sticking and aggregation). Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500μm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500μm) provided rapid drug release that was unhindered by the hydrated granule matrix. Since < 500-μm size particles are preferred for nasal abuse, improved direct-compression ADF formulations should minimize the formation of these smaller-sized particles following tampering to maintain the product's abuse-deterrent features.