慢性肾病相关性贫血新药德西杜司他二元载体固体分散体的研制及药动学评价

IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Dekai Banerjee, Sanjay Sharma, Bappaditya Chatterjee
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引用次数: 0

摘要

目的替司他是一种新的口服低氧诱导因子脯氨酰羟化酶抑制剂,适用于慢性肾病相关性肾性贫血的治疗。溶解度差限制了其溶解,导致口服生物利用度差。方法以PVP K30和poloxam188为二元载体体系,建立了一种简单的熔体猝灭法。聚合物的选择是基于与药物的混溶性研究。结果当药物与载体(pvpk30 - poloxam188)的比例为1:3 (w/w)时,脱硝司他在SD中的溶解度提高了8倍。DSC热分析表明,在固体分散体系中,脱石剂由结晶向非晶态转变。红外光谱分析发现了药物与聚合物之间的氢键。粉末x射线衍射显示SD中晶体药物峰的丢失,证实其由晶体转变为部分非晶态。体外释药研究表明,在碱性培养基(pH 6.8)中,6小时内释药率为96.8%。溶出度的增强与药载比有关。亲水性载体体系溶解度的提高和结晶度的丧失是溶解增强的两个主要原因。体内药代动力学研究表明,与原料药相比,德司他固体分散体的口服生物利用度提高了1.6倍。结论固体分散法可提高消司他的口服生物利用度。PVP K30和poloxam188可以作为有效的二元载体体系进行分散。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development and Pharmacokinetic Evaluation of Binary Carrier-Based Solid Dispersion of Desidustat, a New Drug for Chronic Kidney Disease-Associated Anemia

Purpose

Desidustat is a new oral hypoxia-inducible factor prolyl hydroxylase inhibitor indicated for the management of chronic kidney disease-related renal anemia. Poor aqueous solubility of desidustat restricts its dissolution and leads to poor oral bioavailability.

Methods

A simple melt quenching method has been developed for solid dispersions (SD) of desidustat using PVP K30 and poloxamer 188 as a binary carrier system. Polymer selection was done based on the miscibility study with the drug.

Results

The aqueous solubility of desidustat was increased up to 8 times in SD with a drug: carrier (PVPK30-poloxamer 188) ratio of 1:3 (w/w). Thermal analysis by DSC indicated conversion of crystalline desidustat to amorphous in solid dispersion. Hydrogen bonding between the drug and polymer was noticed by infrared (IR) spectroscopy. Powdered X-ray diffraction revealed the loss of crystalline drug peaks in SD, confirming its conversion from crystalline to partially amorphous. An in vitro drug release study showed 96.8% release from desidustat SD in 6 hours in a basic medium (pH 6.8). The enhancement of dissolution was dependent on the drug: carrier ratio. The increased solubility by the hydrophilic carrier system and the loss of crystallinity are two main reasons for enhanced dissolution. An in vivo pharmacokinetic study showed 1.6 times enhancement in oral bioavailability from desidustat solid dispersion compared to the raw drug.

Conclusion

The solid dispersion approach can improve desidustat oral bioavailability. PVP K30 and poloxamer 188 can serve as an effective binary carrier system for the dispersion.

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来源期刊
Journal of Pharmaceutical Innovation
Journal of Pharmaceutical Innovation PHARMACOLOGY & PHARMACY-
CiteScore
3.70
自引率
3.80%
发文量
90
审稿时长
>12 weeks
期刊介绍: The Journal of Pharmaceutical Innovation (JPI), is an international, multidisciplinary peer-reviewed scientific journal dedicated to publishing high quality papers emphasizing innovative research and applied technologies within the pharmaceutical and biotechnology industries. JPI''s goal is to be the premier communication vehicle for the critical body of knowledge that is needed for scientific evolution and technical innovation, from R&D to market. Topics will fall under the following categories: Materials science, Product design, Process design, optimization, automation and control, Facilities; Information management, Regulatory policy and strategy, Supply chain developments , Education and professional development, Journal of Pharmaceutical Innovation publishes four issues a year.
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