Haider Mohamed, Elsayed Ibrahim, Ahmed Iman S, Fares Ahmed R
Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, University of Sharjah, Sharjah 27272, UAE.
Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah 27272, UAE.
Pharmaceuticals (Basel). 2021 Jan 14;14(1):66. doi: 10.3390/ph14010066.
In this work, sucrose acetate isobutyrate (SAIB) and polylactic co-glycolic acid (PLGA) were used alone or in combination as a matrix-former (MF) to prepare long-acting injectable rivastigmine (RV) in situforming microparticles (ISM). RV-ISM were prepared by the emulsification of an internal phase, containing the drug and the matrix former(s), into an external oily phase containing a stabilizer. The statistical design, Central Composite Design (CCD), was adopted as a quality by design (QbD) approach to optimize the formulation of RV-ISM systems. The fabricated RV-ISM systems was designed to minimize the initial burst drug release and maximize the sustainment of RV release from the ISM and ease of injection. The influence of critical formulation variables such as the matrix-former to drug (MF/D) ratio and SAIB to PLGA (S/P) ratio in the internal phase with respect to critical quality attributes (CQAs), such as the percentage drug release within the first day (Q), the time required for 50% drug release (T) and the rate of injection, were studied using the CCD. The optimal RV-ISM system with the highest desirability value (0.74) was predicted to have an MF/D ratio of 11.7:1 (/) and an S/P ratio of 1.64:1 (/). The optimal RV-ISM system was assessed for its release profile, injectability, rheological properties, morphology, effect on cell viability, tolerance to γ-sterilization and in vivo performance in male albino rabbits. In vitro release studies revealed that the optimal RV-ISM system released 100% of its drug content throughout a release period of 30 days with only 15.5% drug release within the first day (Q) and T of 13.09 days. Moreover, the optimal system showed a high injection rate of 1.012 mL/min, pseudoplastic flow, uniform spherical globules with homogenous particle size, minimal cytotoxicity and high tolerability to γ-sterilization. In vivo pharmacokinetic (PK) studies revealed that the rate of absorption of RV from the optimal RV-ISM system was controlled compared to a drug solution following either intramuscular (IM) or subcutaneous (SC) injection. Furthermore, the optimal RV-ISM was found to follow flip-flop PK with poor correlation between in vitro release and in vivo findings. These findings suggest that the optimal RV-ISM is a promising tool to achieve a sustained release therapy for RV; however, further investigation is still required to optimize the in vivo performance of RV-ISM.
在本研究中，单独或联合使用醋酸蔗糖异丁酸酯（SAIB）和聚乳酸 - 乙醇酸共聚物（PLGA）作为基质形成剂（MF），制备长效注射用卡巴拉汀（RV）原位形成微粒（ISM）。通过将含有药物和基质形成剂的内相乳化到含有稳定剂的外油相中制备RV - ISM。采用统计设计中心复合设计（CCD）作为质量源于设计（QbD）方法，优化RV - ISM系统的配方。所制备的RV - ISM系统旨在最小化药物的初始突释，最大化RV从ISM中的释放维持时间，并便于注射。使用CCD研究了关键配方变量，如内相中基质形成剂与药物（MF/D）的比例和SAIB与PLGA（S/P）的比例，对关键质量属性（CQA）的影响，如第一天内的药物释放百分比（Q）、50%药物释放所需时间（T）和注射速率。预测具有最高合意性值（0.74）的最佳RV - ISM系统的MF/D比例为11.7:1（/），S/P比例为1.64:1（/）。对最佳RV - ISM系统进行了释放曲线、可注射性、流变学性质、形态、对细胞活力的影响、对γ - 灭菌的耐受性以及在雄性白化兔体内的性能评估。体外释放研究表明，最佳RV - ISM系统在30天的释放期内释放了100%的药物含量，第一天内的药物释放量仅为15.5%（Q），T为13.09天。此外，最佳系统显示出1.012 mL/min的高注射速率、假塑性流动、粒径均匀的均匀球形颗粒、最小的细胞毒性以及对γ - 灭菌的高耐受性。体内药代动力学（PK）研究表明，与肌肉注射（IM）或皮下注射（SC）后的药物溶液相比，最佳RV - ISM系统中RV的吸收速率得到了控制。此外，发现最佳RV - ISM呈现出翻转PK，体外释放与体内结果之间的相关性较差。这些发现表明，最佳RV - ISM是实现RV缓释治疗的一种有前途的工具；然而，仍需要进一步研究以优化RV - ISM的体内性能。
