FAILURE MODES OF PEO BASED ABUSE DETERRENT OPIOIDS AND PROMETHAZINE HYDROCHLORIDE TABLETS
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 euphoria.
PEO 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. Moreover, it provided an overview of the societal impacts of the opioid crisis in the state of Indiana.
Investigations of the failure modes of the PEO-based prescription opioids and PMZ HCL tablets showed that physical manipulation techniques via chopping or grinding are much more effective in the destruction of the PEO matrix than thermal manipulation via the application of heat thus promoting the fast release. The factor with the most significant effect on the failure modes of PMZ HCL tablets was the application of physical manipulation, while the one with the lowest impact was the polymer grade. Moreover, producing PEO-based matrix tablets via Direct Compression DC significantly affected dose dumping behavior of the API from the drug products. The production of the PEO-based matrix tablets via DC was found to be favored over the usage of the melt extrusion method and molding techniques. It was clear that DC kept the integrity of the polymer, allowed for slow and controlled release fashion of the API, and rendered the extraction process relatively hard compared to the Hot Melt Extrusion HME and Molding techniques.
Furthermore, the release profile of the investigated PMZ HCL products consisted of various phases of polymer swelling and API release. Thermal manipulations via the application of heat were found to accelerate the dose dumping behavior (90% release) of the APIs from the compressed, extruded, and molded PEO-based matrix formulations similarly. On the other hand, heating was much more effective in the extraction of APIs than chopping or grinding thus promoting the ability to draw a solution containing the API into a syringe for injection relatively easy and facilitate higher % API recovery.
Among the formulation components that might have an impact on the AD properties of the PEO-based drug products are; the choice of the antioxidant, the use of complexing agents, chelating agents, and plasticizers. On the other hand, manufacturing process variables that might have a critical impact on AD properties of the PEO-based drug products include but are not limited to; processing temperature compared to the melting point of the polymer and time of exposure
PMZ HCl was used as a model drug for Oxycodone in dissolution and extractability studies, while Caffeine and L-Nicotine were used as model drugs in smoking simulation experiments. The combination of the propane torch and Kugelrohr apparatus mimic the real-world scenario for smoking Opioids; however, this experimental setup caused thermal degradation rather than vaporization of some model drugs.
According to the National Center for Health Statistics; a statistically significant increase in drug overdose death rates was reported in 2016 in the state of Indiana among other states. The number of deaths related to opioid pain relievers increased by 3732 folds in 2017 compared to the number of deaths in 2014. Moreover, Males were more affected by the opioid crisis than females. On the other hand, the age group 25-44 years, and white people were the most affected by the opioid crisis in Indiana.