Quality by Design for Cost Effective Production of Pregabalin Extended-Release Tablets: in vitro and in vivo Study

IF 2.7 4区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of Pharmaceutical Innovation Pub Date : 2025-08-20 DOI:10.1007/s12247-025-10058-9

Mohamed Ebeed, Gehan F. Balata, Hanaa A. El-ghamry, Noura G. Eissa

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引用次数: 0

Abstract

Purpose

Pregabalin (LYRICA^®) is a centrally acting neuromodulating agent for the management of neuropathic pain and fibromyalgia. Owing to its short half-life, LYRICA^® controlled release (CR) tablets have been approved to be administrated once daily. However, the tablets are prepared by a multi-step process using a combination of release-controlling, wetting, pore-forming, and gelling agents. Hence, there is a need to develop a simple cost-effective environment-friendly methodology for the manufacturing of pregabalin extended release (ER) tablets.

Methods

Quality by design (QbD) was applied for simple manufacturing of pregabalin extended release tablets with comparable efficacy to the reference product LYRICA^® CR (82.5 mg) utilizing hydrophilic and lipid components and hot-melt granulation. The design of experiment (DoE) based on Taguchi model was utilized to investigate the effect of combination of various hydrophilic and lipophilic matrices, fillers and compression forces on the release of pregabalin ER tablets. Pre-compression blends were evaluated for micrometrics while tablets were evaluated for drug content, average weight, hardness, friability, thickness, dissolution and release kinetics. A pharmacokinetics study was performed to evaluate the pharmacokinetics profile of the optimized formulation as compared to the reference marketed product.

Results

Results, analyzed using Minitab software^® 18, determined significant and non-significant variables. The lipophilic meltable binder displayed significant effects on the pre-compression blend characters, yet not able to attain an extended release profile for pregabalin. Combination of hydrophilic and lipophilic matrices efficiently developed pregabalin tablets of extended-release pattern. The optimized formulation (composed of 80 mg of stearic acid, 100 mg of Methocel K15M and lactose with compression value of 10 KN) showed a comparable pharmacokinetics profile to the reference drug in terms of AUC (4.12 and 4.78 µg.h/mL, respectively) and C_max (0.31 and 0.36 µg/mL, respectively) using a pilot-scale bioequivalence study in albino rabbits.

Conclusion

QbD and DoE can be effectively applied for the design and development of a timesaving and eco-friendly methodology for the preparation of pregabalin ER tablets as an alternative to the marketed product.

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普瑞巴林缓释片成本效益的质量设计：体外和体内研究

目的普瑞巴林（LYRICA®）是一种中枢神经调节剂，用于神经性疼痛和纤维肌痛的治疗。由于其半衰期短，LYRICA®控释片（CR）已被批准每天给药一次。然而，片剂是通过使用释放控制剂、润湿剂、成孔剂和胶凝剂的组合的多步骤工艺制备的。因此，有必要开发一种简单、经济、环保的普瑞巴林缓释片生产方法。方法采用设计质量法（QbD），采用亲水、脂质组分和热融造粒法简易制备与对照品LYRICA®CR （82.5 mg）疗效相当的普瑞巴林缓释片。采用基于田口模型的实验设计（DoE），考察了不同亲水性和亲脂性基质、填料和压缩力组合对普瑞巴林ER片释放的影响。对预压缩共混物进行微量测定，对片剂进行药物含量、平均重量、硬度、脆度、厚度、溶出度和释放动力学测定。进行了一项药代动力学研究，以评估优化制剂与参考上市产品的药代动力学特征。结果：使用Minitab®18软件对结果进行分析，确定显著性和非显著性变量。亲脂性可溶黏合剂对预压缩混合特性有显著影响，但不能达到普瑞巴林的延长释放特性。亲水性和亲脂性基质结合有效地制备了普瑞巴林缓释片。优化后的配方（硬脂酸80 mg、Methocel K15M 100 mg和压缩值为10 KN的乳糖）在白化病兔体内的AUC（分别为4.12和4.78µg.h/mL）和Cmax（分别为0.31和0.36µg/mL）方面与参比药具有相当的药代动力学特征。结论qbd和DoE可有效地用于设计和开发一种省时环保的制备普瑞巴林ER片的方法，以替代上市产品。

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

Journal of Pharmaceutical Innovation PHARMACOLOGY & PHARMACY-

CiteScore

3.70

自引率

3.80%

发文量

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.