Failure Modes of Peo Based Abuse Deterrent Opioids and Promethazine Hydrochloride Tablets
Abstract
Opioid addiction has become a global epidemic and a national health crisis in recent years. In 2016, approximately 64,000 Americans under 50 years old were killed because of opioid overdoses. The aim of developing an abuse deterrent opioid is to render any form of manipulation that encourages abuse challenging and therefore, non-profitable. With this goal, the Food and Drug Administration (FDA) is extensively supporting research into the development of abuse deterrent technologies and prioritizing their production as a public health necessity. Abuse deterrent approaches include but are not limited to the following: (1) using a physical barrier (e.g., Polyethylene oxide PEO) that basically limit the release of the drugs in the blood or the digestive tract and prevent mechanical alteration of the drugs by crushing, grating, grinding, chewing etc, (2) using chemical barriers that employ gelling agents that prevent the aqueous or organic extraction of the drugs, and (3) combining the drug with an antagonist that blocks the post-abuse euphoriaPEO is a popular polymer used as a matrix in these complex opioid products. The polymer is responsible for the abuse deterrent properties as well as extended release behavior of opioid drugs. PEO hinders the extraction of Opioid drugs from Abuse Deterrent Formulations (ADF), makes it challenging to be injected, and resists mechanical stress and pulverization when crushed. PEO can be subjected to thermal processing such as thermal curing, compression molding, melt extrusion, and injection molding owing to its thermoplasticity.Assessment of the impact of using various manufacturing processes to develop ADFs and the effect of using various grades of this polymer is essential to improve upon the next generation of ADFs. There are three main categories of premarket studies: Category 1 – laboratory based (in-vitro manipulations and drug extractions), category 2 – pharmacokinetic and category 3 –clinical. These studies are required by the FDA to demonstrate that a given formulation exhibit abuse deterrent properties before a drug product is released to the market. In vitro laboratory based manipulation and extraction studies which are used to assess AD properties of these products are challenging, but essential for product development and generic abuse deterrent product approvals. It is important to realize that there is a great correlation between the laboratory based in vitro manipulation and extraction studies and the expectations of potential abuse and misuse of opioid drugs. The ability of these studies to mimic the manipulation techniques applied by abusers to defeat the abuse deterrent properties of a given formulation optimizes predictions on post-market abuse and misuse potential of ADFs. These studies should also correlate well with in-vivo studies since there is a direct correlation with the concentration (mg/mL in water) and the “high” obtained by an abuser.This research aimed to conduct laboratory based in vitro manipulation and extraction studies to investigate failure modes of PEO-based prescription opioids and Promethazine Hydrochloride PMZ HCl tablets. It highlighted the formulation components and the manufacturing parameters that might affect the dose dumping of Active Pharmaceutical Ingredients (APIs). Furthermore, this research identified model compounds that can be used as surrogates for Oxycodone and the best experimental setup that can be used to conduct smoking simulation experiments.
Degree
Ph.D.
Advisors
Byrn, Purdue University.
Subject Area
Industrial engineering|Marketing|Pharmaceutical sciences
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