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首页> 美国卫生研究院文献>Pharmaceutics >Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution
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Physiologically Relevant In Vitro-In Vivo Correlation (IVIVC) Approach for Sildenafil with Site-Dependent Dissolution

机译：西地那非具有部位依赖性溶出的生理相关的离体体内相关（IVIVC）方法

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摘要

This study aimed to establish a physiologically relevant in vitro-in vivo correlation (IVIVC) model reflecting site-dependent dissolution kinetics for sildenafil based on population-pharmacokinetic (POP-PK) modeling. An immediate release (IR, 20 mg) and three sustained release (SR, 60 mg) sildenafil tablets were prepared by wet granulation method. In vitro dissolutions were determined by the paddle method at pH 1.2, 4.5, and 6.8 media. The in vivo pharmacokinetics were assessed after oral administration of the prepared IR and SR formulations to Beagle dogs (n = 12). The dissolution of sildenafil from SR formulations was incomplete at pH 6.8, which was not observed at pH 1.2 and pH 4.5. The relative bioavailability was reduced with the decrease of the dissolution rate. Moreover, secondary peaks were observed in the plasma concentration-time curves, which may result from site-dependent dissolution. Thus, a POP-PK model was developed to reflect the site-dependent dissolution by separately describing the dissolution and absorption processes, which allowed for estimation of the in vivo dissolution of sildenafil. Finally, an IVIVC was established and validated by correlating the in vitro and in vivo dissolution rates. The present approach may be applied to establish IVIVC for various drugs with complex dissolution kinetics for the development of new formulations.
机译：这项研究旨在建立一个生理相关的体外-体内相关性（IVIVC）模型，该模型反映基于西药碱的人口药代动力学（POP-PK）建模的部位依赖性溶出动力学。通过湿法制粒制备了速释（IR，20mg）和三种缓释（SR，60mg）西地那非片剂。通过桨式方法在pH 1.2、4.5和6.8介质中测定体外溶出度。口服制备的IR和SR配方给Beagle犬（n = 12）后，评估体内药代动力学。西地那非在SR制剂中的溶解在pH 6.8时是不完全的，在pH 1.2和pH 4.5时未观察到。相对生物利用度随溶出度的降低而降低。此外，在血浆浓度-时间曲线中观察到了次要峰，这可能是由于部位依赖性溶出所致。因此，开发了一种POP-PK模型来通过分别描述溶解和吸收过程来反映位点依赖性溶解，从而可以评估sildenafil的体内溶解。最后，通过关联体外和体内溶出速率建立并验证了IVIVC。本方法可用于建立具有复杂溶解动力学的各种药物的IVIVC，以开发新的制剂。

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