拉米地坦片制备及体内外评价

Preparation and in vitro-in vivo evaluation of lasmiditan tablets

摘要

目的: 调研文献并设计自研制剂处方组成,对其处方组成以及制备工艺进行优化,制备拉米地坦片,同时对其体外溶出、药动学进行研究。方法: 基于湿法制粒制备工艺,通过 Box-Behnken 实验法,以Reyow^®作为参比制剂,筛选出预胶化淀粉、交联羧甲基纤维素钠、硬脂酸镁最佳辅料配比;通过单因素实验法确定制粒前原料药粒径和压片硬度;进一步研究自研制剂和参比制剂在体外平行人工膜（parallel artificial membrane permeability assay,PAMPA）中相关渗透参数及在 Beagle 犬体内的药动学特征。结果: 经实验确定原料药的最优粒径为 220μm,压片硬度为80 N;预胶化淀粉含量为8.77％,交联羧甲基钠含量为4.58％,硬脂酸镁含量为2.67%。自研制剂与参比制剂的膜渗透性分别为 1.125×10^-4 和 1.117×10^-4cm⋅s^-1,渗透速率分别为 0.846804 和 0.847113μg⋅min^-1⋅cm^-2。体内试验表明,自研制剂和 Reyow^®的 C_max分别为 189和 188ng⋅L^-1,T_max为 3 h。自研制剂的口服相对生物利用度为93.32%。结论: 自研制剂与参比制剂,在体外PAMPA 渗透和 Beagle 犬体内释放行为基本一致,自研制剂与原研片剂体内生物初步等效,该工艺适用于拉米地坦片的制备。

Abstract

Objective: To prepare lasmiditan tablets and study the in vitro dissolution and pharmacokinetics. Methods: Literature and patents were investigated for designing and optimizing the formulation composition and preparation process.Based on the wet granulation preparation process,taking Reyow ® as the reference preparation, the optimal excipient ratios of pregelatinized starch,croscarmellose sodium and magnesium stearate were screened out by Box-Behnken experiment.The particle size and tableting hardness of the API before granulation were determined by single factor experiment.The relevant permeation parameters and pharmacokinetic characteristics of the self-developed tablets and reference preparation in the PAMPA（parallel artificial membrane permeability assay）and the pharmacokinetic characteristics in Beagle dogs were further studied. Results: The particle size of the API was determined to be 220μm,and the hardness of the tablet was 80 N.The content of pregelatinized starch was 8.77％,and the content of croscarmelase sodium was 4.58％.The magnesium stearate content was 2.67％.The membrane permeability of the self-developed tablets and the reference preparation were 1.125×10^-4 and 1.117×10^-4cm⋅s^-1,respectively,and the permeability rates were 0.846804 and 0.847113μg⋅min^-1⋅cm^-2,respectively. The in vivo experiments showed that the C_max of the self-made tablets and Reyow^® were 189 and 188ng⋅L^-1,the T_max was 3 h.The oral relative bioavailability of homemade tablets was 93.32％. Conclusion: The PAMPA permeation and release behavior in Beagle dogs were basically the same between the self-developed tablets and the reference tablets.The self-developed preparation is preliminary bioequivalent to the original product.The process is suitable for the preparation of lasmiditan tablets.

关键词

拉米地坦 / 处方开发 / 体内外生物等效性评价 / Box-Behnken 实验法 / PAMPA 模型

Key words

lasmiditan / prescription development / evaluation of bioequivalence in vivo and in vitro / Box-Behnken experiment; / PAMPA model

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基金资助

泰山产业领军人才项目（tscx202306086）