Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Department of Medical Laboratory Technology, University Polytechnic, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, 835215, India.
AAPS PharmSciTech. 2021 Mar 24;22(3):116. doi: 10.1208/s12249-021-01987-y.
We focused to explore a suitable solvent for rifampicin (RIF) recommended for subcutaneous (sub-Q) delivery [ethylene glycol (EG), propylene glycol (PG), tween 20, polyethylene glycol-400 (PEG400), oleic acid (OA), N-methyl-2-pyrrolidone (NMP), cremophor-EL (CEL), ethyl oleate (EO), methanol, and glycerol] followed by computational validations and in-silico prediction using GastroPlus. The experimental solubility was conducted over temperature ranges T = 298.2-318.2 K) and fixed pressure (p = 0.1 MPa) followed by validation employing computational models (Apelblat, and van't Hoff). Moreover, the HSPiP solubility software provided the Hansen solubility parameters. At T = 318.2K, the estimated maximum solubility (in term of mole fraction) values of the drug were in order of NMP (11.9 × 10) ˃ methanol (6.8 × 10) ˃ PEG400 (4.8 × 10) ˃ tween 20 (3.4 × 10). The drug dissolution was endothermic process and entropy driven as evident from "apparent thermodynamic analysis". The activity coefficients confirmed facilitated RIF-NMP interactions for increased solubility among them. Eventually, GastroPlus predicted the impact of critical input parameters on major pharmacokinetics responses after sub-Q delivery as compared to oral delivery. Thus, NMP may be the best solvent for sub-Q delivery of RIF to treat skin tuberculosis (local and systemic) and cutaneous related disease at explored concentration.
我们专注于探索一种适合皮下（sub-Q）给药的利福平（RIF）推荐溶剂[乙二醇（EG）、丙二醇（PG）、吐温 20、聚乙二醇-400（PEG400）、油酸（OA）、N-甲基-2-吡咯烷酮（NMP）、吐温-EL（CEL）、油酸乙酯（EO）、甲醇和甘油]，随后通过 GastroPlus 进行计算验证和计算机预测。实验溶解度在温度范围 T = 298.2-318.2 K 和固定压力（p = 0.1 MPa）下进行，然后使用计算模型（Apelblat 和 van't Hoff）进行验证。此外，HSPiP 溶解度软件提供了 Hansen 溶解度参数。在 T = 318.2 K 时，药物的估计最大溶解度（以摩尔分数表示）值的顺序为 NMP（11.9 × 10）>甲醇（6.8 × 10）>PEG400（4.8 × 10）>吐温 20（3.4 × 10）。药物溶解是吸热过程，从“明显的热力学分析”可以看出，熵驱动。活度系数证实了 RIF-NMP 相互作用有利于增加溶解度。最终，GastroPlus 预测了皮下给药相对于口服给药后关键输入参数对主要药代动力学反应的影响。因此，NMP 可能是 RIF 皮下给药治疗皮肤结核（局部和全身）和皮肤相关疾病的最佳溶剂，在探索的浓度下。
