Hansen Solubility Parameters, Computational, and Thermodynamic Models for Tofacitinib Citrate Solubility in Neat Mono Solvents, and GastroPlus Based Predicted In Vivo Performance of Subcutaneous Solution in Humans

IF 3.4 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Iman Ehsan, Mudassar Shahid, Subramanian Natesan, Abdul Faruk, Ashwani Kumar Sood, Tasneem Khan
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引用次数: 0

Abstract

We investigated the experimental solubility of tofacitinib citrate (TNF) in HSPiP predicted mono solvents at varied temperature points, followed by validation with various models (computational and thermodynamic) and GastroPlus based predicted in-vivo performance in individuals (adult humans). HSPiP (Hansen software) predicted five mono solvents (N-methyl-2-pyrrolidone as NMP, ethanol, polyethylene glycol 400 as PEG400, chloroform, and water). The thermally stable drug was solubilized in these solvents. Computational (Van't Hoff and Apelblat) models were applied to validate the experimental solubility data (mole fraction solubility, Xe). The selected solvent (NMP) was used as a vehicle for subcutaneous (sub-Q) formulation development and compared against conventional tablet for high effectiveness in terms of pharmacokinetic parameters (PK) in humans. Results showed that the drug solubility in NMP was “endothermic and entropy” driven as evidenced with the applied models (computational and thermodynamic). The optimized components for sub-Q delivery were NMP (21.5% v/v), PEG400 (10.0% v/v), and PBS (phosphate buffer solution at pH 7.4). GastroPlus predicted 0.036 µg/mL and 0.042 µg/mL values of Cmax (maximum drug reached in the blood) in the blood after sub-Q and oral delivery, respectively. In vivo access of the drug was maximally extended in sub-Q delivery as compared to tablets as predicted in GastroPlus considering humans (fast condition). Conclusively, the sub-Q administration of TNF can be a promising alternative to the conventional tablets.

Graphical Abstract

Hansen溶解度参数,Tofacitinib在纯单溶剂中的溶解度的计算和热力学模型,以及基于GastroPlus的预测人体皮下溶液的体内性能
我们研究了托法替尼(TNF)在不同温度点下在HSPiP预测的单溶剂中的实验溶解度,随后使用各种模型(计算和热力学)和基于GastroPlus的个体(成人)体内预测性能进行验证。HSPiP (Hansen软件)预测了五种单一溶剂(n -甲基-2-吡咯烷酮作为NMP,乙醇,聚乙二醇400作为PEG400,氯仿和水)。热稳定的药物溶解在这些溶剂中。应用计算(Van't Hoff和Apelblat)模型验证实验溶解度数据(摩尔分数溶解度,Xe)。选择溶剂(NMP)作为皮下(亚q)制剂开发的载体,并在人体药代动力学参数(PK)方面与常规片剂进行了比较。结果表明,药物在NMP中的溶解度是“吸热和熵”驱动的,应用模型(计算和热力学)证明了这一点。优化后的亚q递送组分为NMP (21.5% v/v)、PEG400 (10.0% v/v)和PBS (pH 7.4的磷酸盐缓冲液)。GastroPlus预测亚q和口服给药后血液中Cmax值分别为0.036µg/mL和0.042µg/mL。考虑到人类(快速条件),与GastroPlus预测的片剂相比,在亚q递送中最大限度地延长了药物的体内可及性。最后,TNF的亚q给药可能是传统片剂的一个有希望的替代方案。图形抽象
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
AAPS PharmSciTech
AAPS PharmSciTech 医学-药学
CiteScore
6.80
自引率
3.00%
发文量
264
审稿时长
2.4 months
期刊介绍: AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.
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