Dong Xiaowei, Zhang Tao, Moreno Sanchez Hellen L, Mans Jaylen C, Bae Sung Hun, Bian Liangqiao
Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
Department of Pharmaceutical Sciences, SUNY-Binghamton University, Binghamton, NY 13902, USA.
Pharmaceutics. 2025 Sep 17;17(9):1210. doi: 10.3390/pharmaceutics17091210.
: Prodrug strategies are a vital aspect of drug development, with ester prodrugs particularly notable for modifying parent drug properties through ester functional groups to enhance oral absorption. However, ester prodrugs are prone to hydrolysis by water and enzymes, making stability in the gastrointestinal (GI) tract prior to absorption a key challenge. Few formulation strategies effectively address this degradation issue. We recently introduced binary lipid systems (BLS), comprising a lipid and a water-soluble surfactant only that form stable microemulsions. This study aimed to explore the application of BLS for enhancing the oral absorption of ester prodrugs by coating drug crystals with BLS in solid granules and study the impact of the compositions of BLS on oral absorption. : Olmesartan medoxomil (OLM), a methyl ester prodrug of olmesartan (OL), was selected as a model drug. Various lipids were combined with TPGS to form BLS and used to prepare OLM solid granules containing OLM crystals. : Among the tested formulations, OLM MCM-TPGS granules significantly enhanced drug release and protected OLM from enzyme-mediated degradation in two-step dissolution studies with esterase. Pharmacokinetic and tissue distribution studies in rats confirmed that OLM MCM-TPGS granules improved oral absorption by 145% and increased tissue uptake compared to OLM powder. : This approach overcomes solubility limitations when using lipids and surfactants as excipients, enabling high drug loading in solid dosage forms and expanding the utility of lipids and surfactants for water-insoluble drugs. This novel formulation strategy holds great potential for enhancing oral absorption of ester prodrugs, representing a significant advancement in formulation technologies and offering more effective and versatile drug delivery solutions.
前体药物策略是药物开发的一个重要方面，酯前体药物尤其值得注意，它通过酯官能团改变母体药物性质以增强口服吸收。然而，酯前体药物容易被水和酶水解，使得在吸收前在胃肠道（GI）中的稳定性成为一个关键挑战。很少有制剂策略能有效解决这一降解问题。我们最近引入了二元脂质系统（BLS），它仅由一种脂质和一种水溶性表面活性剂组成，能形成稳定的微乳液。本研究旨在探索BLS在固体颗粒中通过将药物晶体用BLS包衣来增强酯前体药物口服吸收的应用，并研究BLS的组成对口服吸收的影响。：奥美沙坦酯（OLM），奥美沙坦（OL）的甲酯前体药物，被选为模型药物。将各种脂质与聚乙二醇维生素E琥珀酸酯（TPGS）组合形成BLS，并用于制备含有OLM晶体的OLM固体颗粒。：在测试的制剂中，OLM中链甘油三酯-TPGS颗粒在与酯酶的两步溶出研究中显著增强了药物释放，并保护OLM免受酶介导的降解。大鼠的药代动力学和组织分布研究证实，与OLM粉末相比，OLM中链甘油三酯-TPGS颗粒使口服吸收提高了145%，并增加了组织摄取。：这种方法克服了将脂质和表面活性剂用作辅料时的溶解度限制，能够在固体剂型中实现高载药量，并扩大了脂质和表面活性剂对水不溶性药物的应用范围。这种新型制剂策略在增强酯前体药物口服吸收方面具有巨大潜力，代表了制剂技术的重大进步，并提供了更有效和通用的药物递送解决方案。
