通过 QbD 方法配制和评估来地帕韦纳米悬浮剂

Md Rezowanur Rahman, Diponkor Kumar Shill, U. Kumar, Asm Monjur Al Hossain, S. C. Bachar, A. S. Rouf
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引用次数: 0

摘要

来地帕韦属于 BCS II 类药物,是一种直接作用的抗病毒药物,用于治疗丙型肝炎病毒感染。由于水溶性和口服生物利用度较差,为这种药物开发有效的给药系统一直是配方设计师面临的巨大挑战。此外,适合儿童和老年患者以及吞咽困难患者的剂型也是一个额外的负担。因此,本研究旨在采用质量源于设计(QbD)的方法,通过固体分散技术,在口服液悬浮剂的基础上配制纳米悬浮剂。首先,使用傅立叶变换红外光谱(FT-IR)和电热恒温(DSC)对与莱迪帕韦相容的聚合物进行了筛选,最后,考虑到聚合物--poloxamer 188、poloxamer 407、HPC 和 HMPC--在固体分散体中能将原料药变成无定形状态的能力,选择了这些聚合物。配方设计和使用 Design Expert® 软件进行的 D-Optimal 设计分析表明,莱迪帕韦与聚合物的比例为 0.3:0.7 时,poloxamer 188 和 poloxamer 407 可制成优化的纳米悬浮配方,其数学模型具有显著的统计学意义。随后,以黄原胶(gm)、avicel® RC-591(gm)和一水柠檬酸(gm)的用量为自变量,以粘度(cp)和ZETA电位(mv)为响应变量,通过Box-Behnken设计优化悬浮载体,稳定制剂。溶解曲线显示,制备的莱迪帕韦悬浮剂比市场上的片剂产品溶解速度快得多。使用 PKSolver® 进行的体内模拟研究表明,配制的混悬液在单剂量水平(90 毫克)的药物吸收率与市售产品相当,而在三剂量水平(270 毫克)的药物吸收率则高于市售产品。通过加速稳定性研究发现,配制的混悬液在三个月和六个月的时间内都很稳定。有趣的是,稳定悬浮液在六个月后的溶解情况与初始悬浮液相似。Dhaka Univ.22(2):173-188,2023 年(12 月)
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Formulation and Evaluation of Ledipasvir Nano-suspension Through QbD Approach
Ledipasvir, belonging to the BCS class II, is a directly acting anti-viral agent used to treat Hepatitis C virus infections. Due to poor water solubility and oral bioavailability, developing an effective delivery system for this drug has been an enormously challenging issue for the formulators. Moreover, suitable dosage forms for pediatric and geriatric patients and patients having difficulty in swallowing as well pose an added burden. Therefore, the present study aims to formulate a nanosuspension, via a solid dispersion technique, based on liquid oral suspension using the Quality by Design (QbD) method. Primarily, the compatible polymers for Ledipasvir were screened using FT-IR and DSC, and finally, the polymers- poloxamer 188, poloxamer 407, HPC and HMPC were selected, considering their ability to turn the API into amorphous state in solid dispersions. The design of formulation and analysis with the D-Optimal design using Design Expert® Software revealed that poloxamer 188 and poloxamer 407 at 0.3:0.7 ratio of Ledipasvir:Polymer produced the optimized nanosuspension formulations with a statistically significant mathematical model. Subsequently, the formulations were stabilized using a suspension vehicle optimized via Box-Behnken design using the amount of xanthan gum (gm), avicel® RC-591 (gm) and citric acid monohydrate (gm) as independent variables, and viscosity (cp) and zeta potential (mv) as responses. The dissolution profiles revealed that the prepared suspensions of Ledipasvir had much faster dissolution than the market products available as the tablet dosage form. In-vivo simulation studies using PKSolver® suggested that the absorption of the drug from the formulated suspensions was comparable to that of market product up to a single dose level (90 mg) and superseded in triplicate dose level (270 mg). The formulated suspensions were found to be stable over three- and six-month periods, as identified via accelerated stability studies. Interestingly, the dissolution profile of the stabilized suspensions was found to be similar after six months to that of the initial. Dhaka Univ. J. Pharm. Sci. 22(2): 173-188, 2023 (December)
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