Cyclodextrin-Based Inclusion Complexes Improve the In Vitro Solubility and Pharmacokinetics of Ivacaftor Following Oral Administration in Mice

IF 3.4 4区医学 Q2 PHARMACOLOGY & PHARMACY

AAPS PharmSciTech Pub Date : 2025-05-16 DOI:10.1208/s12249-025-03131-6

David S. Nakhla, Youssef W. Naguib, Sanjib Saha, Dylan Gao, Nikesh Gupta, Walla Malkawi, Timothy M. Acri, Aliasger K. Salem

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Abstract

Cystic fibrosis is a serious life-threatening hereditary disease that occurs due to a mutation in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Ivacaftor (IVA) is a drug that targets the mutated CFTR protein. IVA is highly hydrophobic (log P = 5.6) with poor aqueous solubility (0.05 µg/mL) and is formulated as an amorphous solid dispersion tablet under the brand name Kalydeco^®. The recommended daily dose of Kalydeco^® is twice per day with a high fat meal to aid in IVA’s absorption. In this research, we studied the application of cyclodextrins (CDs) to improve the dissolution of IVA. Phase solubility studies between IVA and four different CDs (α-, β-, γ-, and hydroxypropyl-β-CD [HP-β-CD]) were conducted and a significant improvement in IVA’s aqueous solubility with HP-β-CD was observed. Solid state characterizations confirmed the formation of IVA/HP-β-CD inclusion complexes. In vitro dissolution studies were conducted at pH = 6.8 and showed improvement in IVA’s rate and extent of dissolution with IVA/HP-β-CD (1:2) complexes in comparison to uncomplexed IVA. In vivo pharmacokinetics in mice showed a 2-fold increase in area under the curve (AUC) after the oral administration of the IVA/HP-β-CD complex in comparison to Kalydeco tablets. In addition, HP-β-CD extended the release of IVA from the IVA/HP-β-CD complexes with a longer T_max of 7.05 h compared to 2.96 h with Kalydeco^® tablets. These results demonstrate that CD inclusion complexes of IVA using HP-β-CD can be a successful alternative approach to improving the solubility of IVA while extending its release.

Graphical Abstract

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环糊精包合物改善Ivacaftor体外溶解度及小鼠口服药代动力学

囊性纤维化是由于囊性纤维化跨膜传导调节基因（CFTR）突变而发生的一种严重危及生命的遗传性疾病。Ivacaftor （IVA）是一种靶向突变CFTR蛋白的药物。IVA是高度疏水性的（log P = 5.6），水溶性差（0.05µg/mL），是Kalydeco®品牌下的无定形固体分散片。Kalydeco®的推荐每日剂量是每天两次，高脂肪餐，以帮助IVA的吸收。在本研究中，我们研究了环糊精（CDs）在提高IVA溶出度方面的应用。研究了IVA与四种不同的cd （α-、β-、γ-和羟丙基-β- cd [HP-β- cd]）的相溶解度，发现IVA与HP-β- cd的水溶液溶解度显著提高。固态表征证实了IVA/HP-β-CD包合物的形成。体外溶出度研究在pH = 6.8时进行，结果显示与IVA/HP-β-CD（1:2）配合物相比，IVA的溶出率和程度有所改善。小鼠体内药代动力学显示，口服IVA/HP-β-CD复合物后，曲线下面积（AUC）比口服Kalydeco片增加2倍。此外，HP-β-CD延长了IVA/HP-β-CD复合物的IVA释放时间，最大释放时间为7.05 h，而Kalydeco®片的最大释放时间为2.96 h。这些结果表明，利用HP-β-CD包合IVA的CD包合物是一种成功的替代方法，可以提高IVA的溶解度，同时延长其释放。图形抽象

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来源期刊

AAPS PharmSciTech 医学-药学

CiteScore

6.80

自引率

3.00%

发文量

264

审稿时长

2.4 months

期刊介绍： AAPS PharmSciTech is a peer-reviewed, online-only journal committed to serving those pharmaceutical scientists and engineers interested in the research, development, and evaluation of pharmaceutical dosage forms and delivery systems, including drugs derived from biotechnology and the manufacturing science pertaining to the commercialization of such dosage forms. Because of its electronic nature, AAPS PharmSciTech aspires to utilize evolving electronic technology to enable faster and diverse mechanisms of information delivery to its readership. Submission of uninvited expert reviews and research articles are welcomed.