A 3D in-vitro biomimicking Caco-2 intestinal permeability model-based assessment of physically modified telmisartan towards an alkalizer-free formulation development

IF 4.4 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Sunil Kumar Sah , Kamare Alam , Mamta Kumari , R. Malootty , Subham Nath , Velayutham Ravichandiran , Subhadeep Roy , Santanu Kaity
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Abstract

Efficient telmisartan delivery for hypertension management requires the incorporation of meglumine and/or sodium hydroxide as an alkalizer in the formulation. Long-term use of powerful alkalis with formulation as part of chronic therapy can cause metabolic alkalosis, ulcers, diarrhea, and body pain. Here, we aimed to design a telmisartan formulation without alkalizers. Telmisartan properties were tailor-made by microfluidizer-based physical modification. After microfluidization, telmisartan nanosuspension was lyophilized to obtain telmisartan premix powder. The optimized telmisartan nanosuspension had an average particle size of 579.85 ± 32.14 nm. The lyophilized premix was characterized by FT-IR, DSC, and PXRD analysis to ensure its physicochemical characteristics. The solubility analysis of premix showed 2.2 times, 2.3 times, and 6 times solubility improvement in 0.1 N HCl, phosphate buffer pH 7.5, and pH 6.8 compared to pure telmisartan. A 3D in-vitro Caco-2 model was developed to compare apparent permeability of API and powder premix. It showed that the powder premix was more permeable than pure API. The tablet formulation prepared from the telmisartan premix showed a dissolution profile comparable to that of the marketed formulation. The technique present herein can be used as a platform technology for solubility and permeability improvement of similar classes of molecules.

Abstract Image

基于三维体外生物模拟 Caco-2 肠道渗透性模型的物理修饰替米沙坦评估,以开发无碱制剂。
要高效地将替米沙坦用于高血压治疗,就必须在制剂中加入麦格鲁明和/或氢氧化钠作为碱化剂。作为慢性疗法的一部分,长期使用强碱制剂会导致代谢性碱中毒、溃疡、腹泻和身体疼痛。在此,我们旨在设计一种不含碱化剂的替米沙坦制剂。通过微流控物理改性,量身定制了替米沙坦的特性。经过微流化后,将替米沙坦纳米悬浮液冻干,得到替米沙坦预混粉。优化后的替米沙坦纳米悬浮液的平均粒径为 579.85 ± 32.14 nm。冻干预混剂通过傅立叶变换红外光谱(FT-IR)、电离辐射光谱(DSC)和射线衍射(PXRD)分析进行表征,以确保其理化特性。预混物的溶解度分析表明,在 0.1 N HCl、pH 值为 7.5 的磷酸盐缓冲液和 pH 值为 6.8 的缓冲液中,其溶解度分别是纯替米沙坦的 2.2 倍、2.3 倍和 6 倍。为了比较原料药和预混粉的表观渗透性,我们建立了一个三维体外 Caco-2 模型。结果表明,预混粉的渗透性高于纯原料药。用替米沙坦预混粉制备的片剂显示出与市售制剂相当的溶解曲线。本文介绍的技术可作为一种平台技术,用于改善类似类别分子的溶解性和渗透性。
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
CiteScore
8.80
自引率
4.10%
发文量
211
审稿时长
36 days
期刊介绍: The European Journal of Pharmaceutics and Biopharmaceutics provides a medium for the publication of novel, innovative and hypothesis-driven research from the areas of Pharmaceutics and Biopharmaceutics. Topics covered include for example: Design and development of drug delivery systems for pharmaceuticals and biopharmaceuticals (small molecules, proteins, nucleic acids) Aspects of manufacturing process design Biomedical aspects of drug product design Strategies and formulations for controlled drug transport across biological barriers Physicochemical aspects of drug product development Novel excipients for drug product design Drug delivery and controlled release systems for systemic and local applications Nanomaterials for therapeutic and diagnostic purposes Advanced therapy medicinal products Medical devices supporting a distinct pharmacological effect.
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