Harnessing Bile for Drug Absorption through Rational Excipient Selection

IF 4.5 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Pharmaceutics Pub Date : 2023-07-05 DOI:10.1021/acs.molpharmaceut.2c01009

Jonas Schlauersbach, Dominic Werthmüller, Cornelius Harlacher*, Bruno Galli, Simon Hanio, Bettina Lenz, Sebastian Endres, Ann-Christin Pöppler, Oliver Scherf-Clavel and Lorenz Meinel,

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引用次数: 1

Abstract

Bile solubilization and apparent solubility at resorption sites critically affect the bioavailability of orally administered and poorly water-soluble drugs. Therefore, identification of drug-bile interaction may critically determine the overall formulation success. For the case of the drug candidate naporafenib, drug in solution at phase separation onset significantly improved with polyethylene glycol-40 hydrogenated castor oil (RH40) and amino methacrylate copolymer (Eudragit E) but not with hydroxypropyl cellulose (HPC) in both phosphate-buffered saline (PBS) and PBS supplemented with bile components. Naporafenib interacted with bile as determined by 1H and 2D 1H-1H nuclear magnetic resonance spectroscopy and so did Eudragit E and RH40 but not HPC. Flux across artificial membranes was reduced in the presence of Eudragit E. RH40 reduced the naporafenib supersaturation duration. HPC on the other side stabilized naporafenib's supersaturation and did not substantially impact flux. These insights on bile interaction correlated with pharmacokinetics (PK) in beagle dogs. HPC preserved naporafenib bile solubilization in contrast to Eudragit E and RH40, resulting in favorable PK.

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通过合理选择赋形剂，利用胆汁促进药物吸收

胆汁的增溶性和吸收部位的表观溶解度严重影响口服给药和水溶性差药物的生物利用度。因此，药物-胆汁相互作用的鉴定可能关键地决定整体配方的成功。对于候选药物naporafenib，在相分离开始时，聚乙二醇-40氢化蓖麻油(RH40)和氨基甲基丙烯酸酯共聚物(Eudragit E)显著改善了溶液中的药物，但在磷酸盐缓冲盐水(PBS)和添加胆汁成分的PBS中，羟丙基纤维素(HPC)没有改善。1H和2D 1H - 1H核磁共振波谱测定Naporafenib与胆汁有相互作用，Eudragit E和RH40有相互作用，但HPC无相互作用。通过人工膜的通量在Eudragit E. RH40的存在下降低了naporafenib过饱和持续时间。另一方面，HPC稳定了naporafenib的过饱和，并没有实质性地影响通量。这些胆汁相互作用的见解与比格犬的药代动力学(PK)相关。与Eudragit E和RH40相比，HPC保留了naporafenib的胆汁增溶作用，从而产生有利的PK。

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

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.