Archive | 2019
FAILURE MODES OF PEO BASED ABUSE DETERRENT OPIOIDS AND PROMETHAZINE HYDROCHLORIDE TABLETS
Abstract
Opioid addiction\nhas become a global epidemic and a national health crisis in recent years. In\n2016, approximately 64,000 Americans under 50 years old were killed because of\nopioid overdoses. The aim of developing an abuse deterrent opioid is to render\nany form of manipulation that encourages abuse challenging and therefore,\nnon-profitable. With this goal, the Food and Drug Administration (FDA) is\nextensively supporting research into the development of abuse deterrent\ntechnologies and prioritizing their production as a public health\nnecessity. Abuse deterrent approaches include but are not limited to the\nfollowing: (1) using a physical\nbarrier (e.g., Polyethylene oxide PEO) that basically limit the release\nof the drugs in the blood or the digestive tract and prevent mechanical\nalteration of the drugs by crushing, grating, grinding, chewing etc, (2) using\nchemical barriers that employ gelling agents that prevent the aqueous or organic\nextraction of the drugs, and (3) combining\nthe drug with an antagonist that blocks\nthe post-abuse euphoria.\n\nPEO is a popular\npolymer used as a matrix in these complex opioid products. The polymer is\nresponsible for the abuse deterrent properties as well as extended release\nbehavior of opioid drugs. PEO hinders the extraction of Opioid drugs from Abuse\nDeterrent Formulations (ADF), makes it challenging to be injected, and resists\nmechanical stress and pulverization when crushed. PEO can be subjected to thermal processing such as thermal curing,\ncompression molding, melt extrusion, and injection molding owing to its\nthermoplasticity.\n\nAssessment of the\nimpact of using various manufacturing processes to develop ADFs and the effect\nof using various grades of this polymer is essential to improve upon the next\ngeneration of ADFs. There are three main\ncategories of premarket studies: Category 1 – laboratory based (in-vitro\nmanipulations and drug extractions), category 2 – pharmacokinetic and category\n3 –clinical. These studies are required by the FDA to demonstrate that a given\nformulation exhibit abuse deterrent properties before a drug product is\nreleased to the market. In vitro laboratory based manipulation and\nextraction studies which are used to assess AD properties of these\nproducts are challenging, but essential for product development and\ngeneric abuse deterrent product approvals. It is important to realize\nthat there is a great correlation between the laboratory based in vitro\nmanipulation and extraction studies and the expectations of potential abuse and\nmisuse of opioid drugs. The ability of these studies to mimic the manipulation\ntechniques applied by abusers to defeat the abuse deterrent properties of a given\nformulation optimizes predictions on post-market abuse and misuse potential of\nADFs. These studies should also correlate well with in-vivo studies since there is a direct correlation with the\nconcentration (mg/mL in water) and the “high” obtained by an abuser. \n\nThis research aimed\nto conduct laboratory based in vitro manipulation and extraction studies to investigate\nfailure modes of PEO-based\nprescription opioids and Promethazine Hydrochloride PMZ HCl tablets. It\nhighlighted the formulation\ncomponents and the manufacturing parameters that might affect the dose dumping of\nActive Pharmaceutical Ingredients (APIs). Furthermore, this research identified\nmodel compounds that can be used as surrogates for Oxycodone and the best\nexperimental setup that can be used to conduct smoking simulation experiments.\nMoreover, it provided an overview of the societal impacts of the opioid crisis\nin the state of Indiana.\n\nInvestigations of the\nfailure modes of the PEO-based prescription opioids and PMZ HCL tablets showed\nthat physical manipulation techniques via chopping or grinding are much more\neffective in the destruction of the PEO matrix than thermal manipulation via\nthe application of heat thus promoting the fast release. The factor with the most\nsignificant effect on the failure modes of PMZ HCL tablets was the application\nof physical manipulation, while the one with the lowest impact was the polymer\ngrade. Moreover, producing PEO-based matrix tablets\nvia Direct Compression DC significantly affected dose dumping behavior of the\nAPI from the drug products. The production of the PEO-based matrix tablets via DC\nwas found to be favored over the usage of the melt extrusion method and molding\ntechniques. It was clear that DC kept the integrity of the polymer, allowed for\nslow and controlled release fashion of the API, and rendered the extraction\nprocess relatively hard compared to the Hot Melt Extrusion HME and Molding\ntechniques.\n\nFurthermore, the\nrelease profile of the investigated PMZ HCL products consisted of various phases\nof polymer swelling and API release. Thermal manipulations via the application\nof heat were found to accelerate the dose dumping\nbehavior (90% release) of the APIs from the compressed, extruded, and molded\nPEO-based matrix formulations similarly. On the other hand, heating was\nmuch more effective in the extraction of APIs than chopping or grinding thus\npromoting the ability to draw a\nsolution containing the API into a syringe for injection relatively easy and\nfacilitate higher % API recovery.\n\nAmong the formulation components that might have an\nimpact on the AD properties of the PEO-based drug products are; the choice of\nthe antioxidant, the use of complexing agents, chelating agents, and\nplasticizers. On the other hand, manufacturing process variables that might\nhave a critical impact on AD properties of the PEO-based drug products include\nbut are not limited to; processing temperature compared to the melting point of\nthe polymer and time of exposure\n\nPMZ HCl was used\nas a model drug for Oxycodone in dissolution and extractability studies, while\nCaffeine and L-Nicotine were used as model drugs in smoking simulation\nexperiments. The combination of the propane torch and Kugelrohr apparatus mimic\nthe real-world scenario for smoking Opioids; however, this experimental setup\ncaused thermal degradation rather than vaporization of some model drugs.\n\nAccording to the National\nCenter for Health Statistics; a statistically significant increase in drug\noverdose death rates was reported in 2016 in the state of Indiana among other\nstates. The number of deaths related to opioid pain relievers increased by 3732\nfolds in 2017 compared to the number of deaths in 2014. Moreover, Males were\nmore affected by the opioid crisis than females. On the other hand, the age\ngroup 25-44 years, and white people were the most affected by the opioid crisis\nin Indiana.