增溶策略促非洛地平口服吸收的作用研究
Effect of solubilizing strategies on oral absorption of felodipine
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摘要: 基于非洛地平低溶解、高渗透的典型生物药剂学分类系统（BCS） Ⅱ类药性质，考察不同增溶策略对其口服吸收的影响。首先，制备原料药粒径为（200、150、25 μm）的非洛地平普通片；同时采用增溶手段制备非洛地平固体分散体和平均粒径（168.90 ± 6.22）nm，多分散指数PDI 0.11 ± 0.06的非洛地平纳米混悬剂。考察上述不同非洛地平制剂在大鼠十二指肠、空肠、回肠、结肠的吸收速率、表观渗透系数Papp、累积吸收量及体内药代动力学特性。大鼠在体单向肠灌流结果表明，不同制剂的非洛地平在十二指肠、空肠、回肠的吸收均优于结肠，非洛地平在小肠有广泛的吸收窗，最佳吸收部位在小肠，且不同制剂的非洛地平Papp均大于2.0 × 10-5 cm/s，低溶解性是限制其吸收的主要因素。体内药代动力学实验表明，增溶策略可显著提高生物利用度，原料药粒径为150 μm和25 μm的非洛地平普通片、纳米混悬剂、固体分散体生物利用度分别为原料药粒径为200 μm的非洛地平普通片的138.75%、173.01%、208.65%和314.53%。增溶策略可显著提高非洛地平胃肠道吸收速率和吸收量，从而提高生物利用度，为BCS Ⅱ类药提高口服吸收效果提供理论参考。Abstract: As a typical BCS Ⅱ drug, felodipine exhibits low solubility and high permeability. We herein investigated the effects of different solubilization strategies on the oral absorption of felodipine. Firstly felodipine tablets based on 200 μm, 150 μm and 25 μm particle size of bulk drug were prepared. Meanwhile, felodipine solid dispersion and felodipine nanosuspension with average particle size of (168.90 ± 6.22) nm, PDI of 0.11 ± 0.06 were prepared. The absorption rate, apparent permeability coefficient (Papp), absorption quality in duodenum, jejunum, ileum and colon of rats and in vivo pharmacokinetics of the above different felodipine preparations were investigated. The results of rat single-pass intestinal perfusion showed that the absorption of felodipine preparations in duodenum, jejunum and ileum was better than in colon. Felodipine had a wide absorption window in the small intestine, with the best absorption site in the small intestine. Papp of different felodipine preparations was greater than 2.0 × 10-5 cm/s. Thus, the low solubility was the main factor limiting the absorption. In vivo pharmacokinetic experiments demonstrated the solubilization strategies significantly improved the bioavailability. The bioavailabilities of felodipine tablets with particle sizes of 150 and 25 μm, as well as nanosuspension, and solid dispersion were 138.75%, 173.01%, 208.65% and 314.53% that of the tablets with particle size of 200 μm, respectively. Solubilization strategies can significantly improve the gastrointestinal absorption rate and absorption quality of felodipine, and thus improve its bioavailability, which provides some reference for the research on the improvement of oral absorption of BCS II drugs.
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Keywords:
- felodipine /
- solubilizing /
- promote absorption /
- nanosuspension /
- solid dispersion
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