Impact of physical manipulation on in vitro and in vivo release profiles of oxycodone DETERx®: an extended-release, abuse-deterrent formulation.

OBJECTIVE

In vitro: To assess the effect of common crushing techniques on particle size reduction (PSR) and in vitro drug-release kinetics of oxycodone DETERx® (herein DETERx) and of a commercially available oxycodone extended-release (ER) tablet. In vivo: To evaluate the impact of the most effective manipulation method identified in the in vitro study and the effect of chewing on the pharmacokinetics (PK) of DETERx relative to oxycodone solution.

DESIGN

In vitro: Mechanical manipulation of dosage forms using common household utensils. In vivo: Open-label, randomized, active-controlled, crossover PK study.

SUBJECTS

In vivo: Forty-four healthy male and female volunteers.

METHODS

In vitro: DETERx capsule contents and marketed comparator tablets were subjected to manipulation (crushing) using 10 different household utensils. Particle size and dissolution analysis were conducted. In vivo: Subjects were randomly assigned to receive DETERx 40-mg capsules intact, crushed, or chewed or oxycodone solution. Serial blood samples were drawn for PK assessment.

RESULTS

In vitro: The utensils used to manipulate DETERx capsule contents were either ineffective in reducing the particle size or produced only a small change in the median particle size and dissolution rate relative to the marketed comparator. In vivo: DETERx intact capsules provided significantly lower Cmax and longer Tmax values than oxycodone solution. Manipulation of DETERx by crushing (using the most effective method established in vitro) or chewing resulted in bioequivalent plasma concentration-time profiles to the intact dosage form.

CONCLUSION

These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.