College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
Int J Pharm. 2021 Aug 10;605:120726. doi: 10.1016/j.ijpharm.2021.120726. Epub 2021 May 23.
In the design of abuse-deterrent formulations (ADFs), pharmaceutical strategies that do not modify the physical and chemical properties of opioid dosage forms should be investigated. Among these, four major drug abusing factors, including particle size by physical modification, swellability, dissolution rate, and solvent extraction, were mainly characterized for evaluating abuse deterrence of narcotics. Tramadol hydrochloride (TMD) was chosen as a model drug. In this study, the frequently used eight generally recognized as safe (GRAS)-listed pharmaceutical excipients, including polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC 4,000, HPMC 100,000), xanthan gum (XG), cellulose acetate (CA), polyethylene oxide (PEO), carbomer 940 NF, and Compritol® 888 ATO, were selected as abuse deterring agents and used to prepare TMD-loaded tablet. A new abuse-deterrent index (ADI) for compressed TMD-loaded tablets was originally defined and considered as an index of drug abuse deterrence, based on the assumption that it was proportional to particle size and swellability but inversely proportional to dissolution and solvent extraction rates after assigning the categorized five scale scores (one to five) to the four experimental data. The resulting ADI of the selected eight abuse deterring agents in deionized water was given in decreasing order: HPMC 4000 > carbomer 940 > Compritol® 888 ATO > XG > PVA > HPMC 100,000 > PEO, and CA while in 40% hydro-alcoholic solution in the decreasing order: carbomer 940 > HPMC 4,000 ≒ XG > PVA > HPMC 100,000 > PEO > Compritol® 888 ATO > CA. Interestingly, the HPMC 4,000 and carbomer 940 showed the highest ADI and gave drug abuse deterrent potential. This study could provide a pharmaceutical strategy that utilizes a variety of abuse-deterring agents and resist to extraction solvents in designing drug abuse-deterrent formulations and establishing their standard guidelines for regulatory authorities.
在设计滥用障碍配方（ADF）时，应研究不改变阿片类药物剂型物理和化学性质的药物策略。其中，通过物理修饰、溶胀性、溶解速率和溶剂萃取来主要表征四大滥用因素，以评估麻醉品的滥用障碍。盐酸曲马多（TMD）被选为模型药物。在这项研究中，选择了八种常用的被普遍认为安全（GRAS）的药物辅料，包括聚乙烯醇（PVA）、羟丙基甲基纤维素（HPMC 4,000、HPMC 100,000）、黄原胶（XG）、醋酸纤维素（CA）、聚氧化乙烯（PEO）、卡波姆 940 NF 和 Compritol® 888 ATO，作为滥用障碍剂，用于制备载有 TMD 的片剂。根据假设，新的用于压缩 TMD 载片剂的滥用障碍指数（ADI）被定义为药物滥用障碍的指标，因为它与颗粒大小和溶胀性成正比，但与溶解和溶剂萃取率成反比，在对四个实验数据进行分类后（一到五分）。在去离子水中，所选八种滥用障碍剂的 ADI 依次降低：HPMC 4000 > 卡波姆 940 > Compritol® 888 ATO > XG > PVA > HPMC 100,000 > PEO，而在 40%的水醇溶液中，顺序依次为：卡波姆 940 > HPMC 4000 ≒ XG > PVA > HPMC 100,000 > PEO > Compritol® 888 ATO > CA。有趣的是，HPMC 4000 和卡波姆 940 表现出最高的 ADI，并具有阻止滥用的潜力。这项研究为利用多种滥用障碍剂和抵抗设计药物滥用障碍配方中的提取溶剂的药物策略提供了参考，并为监管机构建立了其标准指南。
