Bakhteyar Hamid, Cassone Clayton, Kohan Hamed Gilzad, Sani Shabnam N
Carolina Compounding Pharmacy & Health Center, Cary, North Carolina.
Western New England University, College of Pharmacy, Department of Pharmaceutical & Administrative Sciences, Springfield, Massachusetts.
Int J Pharm Compd. 2017 Sep-Oct;21(5):418-425.
The purpose of this study was to formulate extemporaneously compounded Liothyronine Sodium (T3) slow-release capsules and to evaluate their in vitro drug release performance. Twenty-one formulations containing T3 (7.5 µg) with various compositions of two different grades of Methocel E4M and K100M premium (30% to 90%), and/or SimpleCap/Lactose (10% to 70%) were examined. Quality assessment of the capsules was conducted by standard quality control criteria of the United States Pharmacopeia (i.e., weight variation, content uniformity) to ensure their compliance. The dissolution release profile of the formulations was evaluated using United States Pharmacopeia Apparatus type II (paddle method) at a speed of 50 rpm and temperature of 37°C in phosphate buffered saline media ( pH = 7.2 to 7.4). Aliquots from the media were taken periodically up to 24 hours and analyzed using a validated enzyme-linked immunosorbent assay method. The cumulative percentage of drug release for each formulation was fitted to eleven major release kinetic equations to determine the best-fit model of drug release, as well as the mechanism of release. Assay sensitivity was as low as 1 ng/mL and the optimal calibration range was found to be between 0 ng/mL and 7.5 ng/mL, which corresponded well with the average physiological plasma concentrations of T3. Liothyronine sodium with either SimpleCap (100%) or Methocel E4M (100%) exhibited slowrelease kinetic patterns of Peppas and Zero Order, respectively. The formulation with SimpleCap (100%) had a higher percentage of drug release (as compared to 100% Methocel E4M) within the first four hours; this formulation released 80% of the drug within 12 hours when the release was plateaued thereafter. The formulation with 30% Methocel E4M and 70% SimpleCap released 100% of the drug within the initial 12 hours and exhibited a Zero Order slow-release kinetic pattern. In general, the release kinetic rate of the formulations containing Methocel K100M appeared to be slower than Methocel E4M. This alteration may be due to a higher molecular weight and apparent viscosity of Methocel K100M. While most of the formulations were fitted to a slow-release kinetic pattern, several others including Methocel E4M 100%, 30% Methocel E4M+ 70% Simple Cap, 40% Methocel K100M+ 60% SimpleCap, 50% Methocel K100M+ 50% SimpleCap, 30% Methocel E4M+ 70% Lactose, 90% Methocel E4M+ 10% Lactose, 40% Methocel K100M+ 60% Lactose, and 50% Methocel K100M+ 50% Lactose followed an ideal slow-release kinetic pattern of Zero Order or Higuchi. The results of this study successfully demonstrated the optiomal composition of slow-release compounded capsules of T3. Future studies are warranted to evaluate the in vivo performance of the optimal formulations and to establish an in vitro-in vivo correlation.
本研究的目的是制备左甲状腺素钠（T3）临时复方缓释胶囊，并评估其体外药物释放性能。研究了21种含有T3（7.5µg）的制剂，这些制剂具有两种不同等级的甲基纤维素E4M和K100M优质品（30%至90%）的不同组成，和/或SimpleCap/乳糖（10%至70%）。通过美国药典的标准质量控制标准（即重量差异、含量均匀度）对胶囊进行质量评估，以确保其符合要求。使用美国药典II型装置（桨法），在转速为50 rpm、温度为37°C的磷酸盐缓冲盐水介质（pH = 7.2至7.4）中评估制剂的溶出释放曲线。每隔一定时间从介质中取出等分试样，直至24小时，并使用经过验证的酶联免疫吸附测定法进行分析。将每种制剂的药物释放累积百分比与11个主要释放动力学方程进行拟合，以确定最佳拟合药物释放模型以及释放机制。测定灵敏度低至1 ng/mL，发现最佳校准范围为0 ng/mL至7.5 ng/mL，这与T3的平均生理血浆浓度非常吻合。仅含SimpleCap（100%）或甲基纤维素E4M（100%）的左甲状腺素钠分别表现出Peppas和零级的缓释动力学模式。含SimpleCap（100%）的制剂在前四小时内的药物释放百分比更高（与100%甲基纤维素E4M相比）；当释放此后达到平稳时，该制剂在12小时内释放了80%的药物。含30%甲基纤维素E4M和70% SimpleCap的制剂在最初12小时内释放了100%的药物，并表现出零级缓释动力学模式。一般来说，含有甲基纤维素K100M的制剂的释放动力学速率似乎比甲基纤维素E4M慢。这种变化可能是由于甲基纤维素K100M的分子量和表观粘度较高。虽然大多数制剂符合缓释动力学模式，但其他几种制剂，包括100%甲基纤维素E4M、30%甲基纤维素E4M + 70% Simple Cap、40%甲基纤维素K100M + 60% SimpleCap、50%甲基纤维素K100M + 50% SimpleCap、30%甲基纤维素E4M + 70%乳糖、90%甲基纤维素E4M + 10%乳糖、40%甲基纤维素K100M + 60%乳糖和50%甲基纤维素K100M + 50%乳糖，遵循零级或Higuchi的理想缓释动力学模式。本研究结果成功证明了T3缓释复方胶囊的最佳组成。未来的研究有必要评估最佳制剂的体内性能，并建立体外-体内相关性。
