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Risk based in vitro performance assessment of extended release abuse deterrent formulations.

ABSTRACT: High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing novel abuse deterrent formulations (ADF), with properties that may be viewed as barriers to abuse of the product. However, unlike regular extended release formulations, assessment of ADF technologies are challenging, in part due to the great variety of formulation designs available to achieve deterrence of abuse by oral, parenteral, nasal and respiratory routes. With limited prior history or literature information, and lack of compendial standards, evaluation and regulatory approval of these novel drug products become increasingly difficult. The present article describes a risk-based standardized in-vitro approach that can be utilized in general evaluation of abuse deterrent features for all ADF products.

SUBMITTER: Xu X

PROVIDER: S-EPMC4755808 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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Risk based in vitro performance assessment of extended release abuse deterrent formulations.

Xu Xiaoming X Gupta Abhay A Al-Ghabeish Manar M Calderon Silvia N SN Khan Mansoor A MA

International journal of pharmaceutics 20160116 1-2

High strength extended release opioid products, which are indispensable tools in the management of pain, are associated with serious risks of unintentional and potentially fatal overdose, as well as of misuse and abuse that might lead to addiction. The issue of drug abuse becomes increasingly prominent when the dosage forms can be readily manipulated to release a high amount of opioid or to extract the drug in certain products or solvents. One approach to deter opioid drug abuse is by providing ...[more]

PMID: 26784976

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Project description:Parabens have been used for decades as preservatives in food, drugs and cosmetics. The majority however, were banned in 2009 and 2014 leaving only methyl-, ethyl-, propyl-, and butyl-derivates available for subsequent use. Methyl- and propylparaben have been extensively tested in vivo, with no resulting evidence for developmental and reproductive toxicity (DART). In contrast, ethylparaben has not yet been tested for DART in animal experiments, and it is currently debated if additional animal studies are warranted. In order to perform a comparison of the four currently-approved parabens, we used a previously established in vitro test based on human induced pluripotent stem cells (iPSC) that are exposed to test substances during their differentiation to neuroectodermal cells. EC50 values for cytotoxicity were 906 µM, 698 µM, 216 µM and 63 µM for methyl-, ethyl-, propyl- and butylparaben, respectively, demonstrating that cytotoxicity increases with increasing alkyl chain length. Genome-wide analysis demonstrated that FDR-adjusted significant gene expression changes occurred only at cytotoxic or close to cytotoxic concentrations, for example 1,720 differentially expressed genes (DEG) at 1,000 µM ethylparaben, 1 DEG at 316 µM, and no DEG at 100 µM or lower concentrations. The highest concentration of ethylparaben that did not induce any cytotoxicity nor DEG was 1670-fold above the highest published concentrations reported in biomonitoring studies (60 nM ethylparaben in cord blood). In conclusion, cytotoxicity and gene expression alterations of ethylparaben occurred at concentrations of approximately three orders of magnitude above human blood concentrations; moreover, the substance fitted well into a scenario where toxicity increases with the alkyl chain length, and gene expression changes only occur at cytotoxic or close to cytotoxic concentrations. Therefore, no evidence was obtained suggesting that in vivo DART with ethylparaben would lead to different results as the methyl- or propyl derivates.

Project description:BackgroundSignificant public health concerns exist regarding the misuse and abuse of prescription opioids. Abuse-deterrent formulation (ADF) opioids may be leveraged as an important tool for combating the current opioid crisis.ObjectivesTo evaluate the relationships between ADF opioid formulary coverage and the ADF utilization rate, the risk for opioid abuse or overdose, opioid abuse or overdose-related healthcare resource utilization, and medical costs within a calendar year.MethodsThis cross-sectional multiyear panel study included adults prescribed an opioid medication in 2015 or 2016. We analyzed the medical and pharmacy claims linked to health plan benefit design data. An ADF opioid-including reformulated oxycodone hydrochloride (HCl) controlled-release (CR; reformulated OxyContin), morphine sulfate and naltrexone HCl extended-release (ER; Embeda), and hydrocodone bitartrate ER (Hysingla ER)-was considered covered if it was listed on the health plan's formulary. Generalized linear models were used to assess the association between ADF opioid formulary coverage and the study outcomes.ResultsOf 1,350,607 eligible patients, those enrolled in health plans with coverage of ADF opioids were more likely to fill a prescription for an ADF opioid than those enrolled in plans that did not cover ADF opioids. The risk for opioid abuse or overdose was significantly lower among patients enrolled in plans with broader ADF coverage (adjusted odds ratio [OR], 0.91; 95% confidence interval [CI], 0.86-0.95 for oxycodone HCl CR only vs no ADF coverage; adjusted OR, 0.70; 95% CI, 0.67-0.73 for oxycodone HCl CR plus ≥1 ADF opiods vs no ADF; adjusted OR, 0.77; 95% CI, 0.73-0.81 for oxycodone HCl CR plus ≥1 ADF opiods vs oxycodone HCl CR only; all P <.0001). Approximately 15% and 25% reductions in the opioid abuse or overdose-related hospitalization rate and medical costs were observed for those in the oxycodone HCl CR plus ≥1 ADF opioids coverage group versus those without ADF opioid coverage.ConclusionsBroad formulary coverage of ADF opioids is associated with reduced rates of opioid abuse or overdose in real-world managed care populations. Health plan administrators and policymakers may consider improving the formulary coverage of ADF opioids as a strategy to ensure appropriate patient access to necessary pain medications while mitigating risk for opioid abuse or overdose.

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Risk based in vitro performance assessment of extended release abuse deterrent formulations.

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Risk based in vitro performance assessment of extended release abuse deterrent formulations.

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