Mechanistic Evaluation of Polyethylene Oxide for Physical Barrier Type Abuse Deterrent Formulations: Techniques and In vitro methods

Abstract

Abuse deterrent formulations (ADF) are designed to mitigate misuse and abuse of prescription narcotics. One mechanism of an ADF is to increase the tablet strength to reduce ease of tablet comminution while increasing the difficulty of drug extraction. Polyethylene oxide (PEO) is a popular polymer used in these complex opioid products. PEO provides these abuse resistance properties while providing extended release of the opioid drug. Evaluation of the manufacturing process and material attributes of this polymer is important to improve upon the next generation of abuse deterrent products. In addition, methods to assess abuse deterrence of these products in vitro is challenging, but important for product development and generic abuse deterrent product approvals. Thus, this dissertation seeks to determine the best evaluation methods for these products and establishes an in vitro method to assess a formulation's ability to prolong nasal absorption when nasally insufflated. Key results of this study show that heating tablets with PEO will significantly increase the strength of the tablet and key variables such as PEO composition, particle size distribution, high initial tablet solid fraction, and 1 h sinter time were found to be the optimal sintering conditions. It was also demonstrated that this sintering process could be monitored by near infrared spectroscopy to predict sintering end points. Finally, the in vitro nasal insufflation studies demonstrated that for each type of physical manipulation employed (i.e. cutting, grinding, milling), discreet particle size distributions were formed regardless of formulation. One exception occurred with milling where one drug product resulted in a much greater particle size distribution than the other milled tablets. A vertical diffusion cell was then used to assess release rate of drug from the comminuted dosage form. It was demonstrated that the VDC method was discriminant with respect to particle sizes of comminuted particles and formulation variables such as molecular weight of PEO used.