PK-PD Tox & Formulation Section, Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu, 180001, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
AAPS J. 2024 Apr 22;26(3):52. doi: 10.1208/s12248-024-00922-w.
The long treatment period and development of drug resistance in tuberculosis (TB) necessitates the discovery of new anti-tubercular agents. The drug discovery program of the institute leads to the development of an anti-tubercular lead (IIIM-019), which is an analogue of nitrodihydroimidazooxazole and exhibited promising anti-tubercular action. However, IIIM-019 displays poor aqueous solubility (1.2 µg/mL), which demands suitable dosage form for its efficient oral administration. In the present study, third generation solid dispersion-based formulation was developed to increase the solubility and dissolution of IIIM-019. The solubility profile of IIIM-019 using various polymeric carriers was determined and subsequently, PVP K-30 and P-407 were selected for preparation of binary and ternary solid dispersion. The third-generation ternary solid dispersion comprising PVP K-30 and P-407 revealed a remarkable enhancement in the aqueous solubility of IIIM-019. Physicochemical characterization of the developed formulations was done by employing FTIR spectroscopy, scanning electron microscopy, X-ray diffraction analysis, differential scanning calorimetry, and dynamic light scattering analysis. The dissolution study indicated an impressive release profile with the optimized formulation. The optimized formulation was further examined for cytotoxicity, cellular uptake, and hemolytic activity. The results indicated that the formulation had no apparent cytotoxicity on Caco-2 cells and was non-hemolytic in nature. Moreover, the optimized formulation showed significantly improved anti-tubercular activity compared to the native molecule. These findings showed that the developed third generation ternary solid dispersion could be a promising option for the oral delivery of investigated anti-tubercular molecule.
结核病（TB）的治疗周期长且易产生耐药性，因此需要开发新的抗结核药物。本研究所的药物发现计划导致了一种抗结核先导化合物（IIIM-019）的开发，它是硝基二氢咪唑恶唑的类似物，表现出有前景的抗结核作用。然而，IIIM-019 的水溶性较差（1.2µg/mL），这要求其口服给药时使用合适的剂型。在本研究中，开发了基于第三代固体分散体的制剂，以提高 IIIM-019 的溶解度和溶解速率。使用各种聚合物载体确定了 IIIM-019 的溶解度谱，随后选择 PVP K-30 和 P-407 用于制备二元和三元固体分散体。由 PVP K-30 和 P-407 组成的第三代三元固体分散体显著提高了 IIIM-019 的水溶解度。采用傅里叶变换红外光谱、扫描电子显微镜、X 射线衍射分析、差示扫描量热法和动态光散射分析对所开发制剂进行了物理化学特性表征。溶解研究表明，优化的制剂具有令人印象深刻的释放特性。进一步对优化的制剂进行了细胞毒性、细胞摄取和溶血活性研究。结果表明，该制剂对 Caco-2 细胞没有明显的细胞毒性，且性质上是非溶血的。此外，与天然分子相比，优化的制剂显示出明显改善的抗结核活性。这些发现表明，所开发的第三代三元固体分散体可能是一种有前途的口服递药选择，用于研究的抗结核分子。
