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
-
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.
-
Keywords:
- felodipine /
- solubilizing /
- promote absorption /
- nanosuspension /
- solid dispersion
-
-
[1] . Drug Eval Res（药物评价研究），2019，42（5）：1014-1019. [2] Lüscher TF，Cosentino F. The classification of calcium antagonists and their selection in the treatment of hypertension. areappraisal［J］. Drugs，1998，55（4）：509-517. [3] Zhou Z，Dunn C，Khadra I，et al. Influence of physiological gastrointestinal surfactant ratio on the equilibrium solubility of BCS Class II drugs investigated using a four component mixture design［J］. Mol Pharm，2017，14（12）：4132-4144. [4] ?těpánková M，Krasulová K，Do?i?áková A，et al. Optical isomers of dihydropyridine calcium channel blockers display enantiospecific effects on the expression and enzyme activities of human xenobiotics-metabolizing cytochromes P450［J］. Toxicol Lett，2016，262：173-186. [5] Jing BY，Wang ZY，Yang R，et al. Enhanced oral bioavailability of felodipine by novel solid self-microemulsifying tablets［J］. Drug Dev Ind Pharm，2016，42（3）：506-512. [6] Zhang CG，Yu ZY，Yu CC，et al. Research progress of gastroretentive drug delivery system and its application in traditional Chinese medicine［J］. Chin J Mod Appl Pharm（中国现代应用药学），2020，37（7）：877-885. [7] Jing BY，Wang ZY，Li Y，et al. Preparation and in vitro evaluation of felodipinesolid dispersions［J］. J Shenyang Pharm Univ（沈阳药科大学学报），2010，27（3）：185-190. [8] Mori D，Makwana J，Parmar R，et al. Formulation， evaluation and optimization of the felodipine nanosuspension to be used for direct compression to tablet for in vitro dissolution enhancement［J］. Pak J Pharm Sci，2016，29（6）：1927-1936. [9] Yang H，Zhai B，Fan Y，et al. Intestinal absorption mechanisms of araloside a in situ single-pass intestinal perfusion and in vitro caco-2 cell model［J］. Biomed Pharmacother. 2018，106：1563-1569. [10] Zawaneh AH，Khalil NN，Ibrahim SA，et al. Micelle-enhanced direct spectrofluorimetric method for the determination of linifanib： application to stability studies［J］. Luminescence，2017，32（7）：1162-1168. [11] He CH，Zhang ZH，Wang S，et al. Study on intestinal absorption kinetics of apigenin in rats［J］. Chin J Chin Mater Med（中国中药杂志），2013，38（9）：1416-1420. [12] Luo YF，Ren LX，Li XH，et al. Summary of research methods for drug intestinal absorption［J］. Drug Eval Res（药物评价研究），2017，40（5）：706-710. [13] Zhou YJ，Qin DP，Wang YD，et al. Amelioration of tripterygium wilfordii polycoride on TNBS/ethanolinduced ulcerative colitis via inhibiting lipid peroxidation and its downstream inflammatory meditors［J］. Chin Herb Med（中草药 英文版），2017，9（4）：344-352. [14] Over B，Matsson P，Tyrchan C，et al. Structural and conformational determinants of macrocycle cell permeability［J］. Nat Chem Biol，2016，12（12）：1065-1074. -
期刊类型引用(8)
1. 吴菊华，李俊锋，陶雷. 基于知识图谱嵌入与深度学习的药物不良反应预测. 广东工业大学学报. 2024(01): 19-26+40 . 
百度学术
2. 任韡，黄彦，朱枫，喻锦扬，王青. 智能化药品不良反应报告辅助评价工具研究. 中国食品药品监管. 2024(09): 122-129 . 百度学术
3. 荣丹琪，王倩，唐丽，司婉雨，赵鸿萍. 基于特征的深度学习预测化合物-蛋白质相互作用的研究进展. 中国药科大学学报. 2023(03): 305-313 . 本站查看
4. 由丽萍，王世钰，李朝翻. 基于框架语义分析的社交网络药品不良事件抽取. 医学信息学杂志. 2023(07): 57-62 . 百度学术
5. 卢恒，陈章杰，周知. 基于知识图谱的虚拟学术社区用户生成内容知识共聚框架研究. 情报理论与实践. 2023(12): 157-166+192 . 百度学术
6. 仲雨乐，马诗雯，陆豪杰，韩普. 基于机器学习的药品不良反应实体识别研究综述. 软件工程. 2022(08): 1-6 . 百度学术
7. 陈伟，吴云志，涂凌，刘航，余克健，乐毅. 基于多头自注意力机制的实体识别研究. 蚌埠学院学报. 2022(05): 54-60 . 百度学术
8. 潘文洁，尹泽宇，侯婉馨，Jawad Hussain，张远鹏，姚敏，王理. 基于医学科研与临床应用的药物知识库研究进展. 中华临床医师杂志(电子版). 2021(01): 72-78 . 百度学术
其他类型引用(3)
计量
- 文章访问数: 264
- HTML全文浏览量: 5
- PDF下载量: 723
- 被引次数: 11
下载:
