Novel Formulation Technology to Enhance Oral Absorption of Water-insoluble Drugs

增强水不溶性药物口服吸收的新型制剂技术

• 批准号: 10433965
• 负责人: Xiaowei Dong
• 金额: $ 36.64万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10433965
• 关键词: Address; Amphotericin B; BAY 54-9085; Biodistribution; Biological Availability; Cytoplasmic Granules; Development; Dosage Forms; Drug Delivery Systems; Drug Formulations; Drug Modelings; Enhancement Technology; Excipients; Formulation; Foundations; Future; Gelatin; Goals; In Situ; Individual; Knowledge; Laboratories; Lead; Libraries; Lipids; Liquid substance; Oral; Patients; Pharmaceutical Preparations; Research; Resources; Route; Solid; Solubility; Structure; System; Technology; Tissues; Water; Work; absorption; base; capsule; drug candidate; drug development; drug market; improved; innovation; liquid formulation; nanoparticle; new technology; novel; novel therapeutics; olmesartan; particle; programs; self assembly; surfactant

Project Summary/Abstract Bioavailability enhancement technologies for insoluble drugs represent incremental progress, but no breakthrough oral drug technologies have been identified in the past three decades. Lipid-based drug delivery systems (LBDDS) are considered as a well-established, very important strategy for insoluble compounds. According to the previous knowledge, a stable binary lipid system (BLS) composed of one lipid and one water- soluble surfactant seems impossible. Another key tenet of LDBBS is that a drug must completely dissolve in a LBDDS to increase its dissolution and oral bioavailability. While co-excipients are added to increase drug solubility, drug loading in the final LBDDS is decreased. The stability of liquid formulations, compatibility of liquid excipients and capsule shell, and manufacturing liquid-filed soft gelatin capsules are also limiting the applications of LBDDS. Nanoparticles are the other alternatives for insoluble drugs. However, the liquid forms of nanoparticles lead to particle instability during storage. To address these limitations, incorporation of liquid LBDDS or NPs into a solid dosage form is highly desirable. However, low drug loading is the major issue for this conversion strategy. In addition, although lipids and surfactants in colloidal particles alter the biodistribution, the influence of individual excipient on biodistribution is unclear. The long-term goal of our research program is to advance formulation technologies for insoluble drugs. Our laboratory has recently developed novel in situ self-assembly nanoparticle (ISNP) granules that in contact with water produce drug-loaded ISNPs. Drug ISNP granules not only improved oral absorption but also showed the potential for tissue-targeted oral solid formulations. More importantly, we recently discovered that our ISNPs, composed of one lipid and one water-soluble surfactant, create a new stable BLS. Our results further demonstrated that completely dissolving the drug in our formulations and the formation of ISNPs are not mandatory for absorption enhancement. Building on these recent breakthrough findings, the goal of this proposal is to develop a novel formulation technology by bringing our unique findings of new colloidal binary lipid system into solid dosage forms to improve oral absorption of insoluble drugs. We propose to identify the relationship of excipients’ structure and the formation of BLS and build a library of BLS. The library will provide guidance for selecting appropriate compositions when formulators use the BLS. We will develop new BLS-based formulations for two model drugs, Olmesartan medoxomil and Amphotericin B, in order to establish a new technology of oral solid dosage forms for absorption enhancement. We will use sorafenib to prepare drug granules to dissect the influence of lipid or surfactant on biodistribution as well as identify the mechanism of absorption enhancement. Our studies will provide a strong foundational resource for BLS and represent a possibly game-changing approach for the use of lipids and surfactants in formulations. We expect these contributions will positively impact oral drug development and will lead to a breakthrough in oral drug delivery technologies. This work also can be extended to future studies of other drugs in other administration routes.

项目概要/摘要 不溶性药物的生物利用度增强技术代表了渐进的进步，但还没有 过去三十年中已经发现了突破性的口服药物技术。 系统（LBDDS）被认为是针对不溶性化合物的成熟且非常重要的策略。 根据先前的知识，由一种脂质和一种水组成的稳定的二元脂质系统（BLS） LDBBS 的另一个关键原则是药物必须完全溶解在可溶性表面活性剂中。 LBDDS 可增加其溶出度和生物口服利用度，同时添加辅助赋形剂可增加药物。 溶解度、最终LBDDS中的载药量降低，液体制剂的稳定性、液体的相容性。 赋形剂和胶囊壳以及液体填充软明胶胶囊的制造也限制了其应用 LBDDS 是不溶性药物的其他替代品。 为了解决这些限制，将液体 LBDDS 或 NP 掺入其中。 固体剂型是非常理想的，然而，低载药量是这种转换策略的主要问题。 此外，虽然胶体颗粒中的脂质和表面活性剂改变了生物分布，但个体的影响 赋形剂对生物分布的影响尚不清楚。我们研究计划的长期目标是推进制剂。 我们的实验室最近开发了新型原位自组装纳米颗粒技术。 (ISNP) 颗粒与水接触产生载药 ISNP 药物 ISNP 颗粒不仅改善了效果。 口服吸收，但也显示了组织靶向口服固体制剂的潜力。 最近发现我们的 ISNP 由一种脂质和一种水溶性表面活性剂组成，创造了一种新的稳定 BLS 我们的结果进一步证明药物完全溶解在我们的制剂中并形成。 ISNP 对于增强吸收不是强制性的。基于这些最近的突破性发现， 该提案的目标是通过利用我们对新胶体的独特发现来开发一种新颖的配方技术 我们建议鉴定二元脂质系统进入固体剂型以改善不溶性药物的口服吸收。 探讨辅料结构与BLS形成的关系并建立BLS库。 当配方设计师使用 BLS 时选择合适的组合物的指南我们将开发新的基于 BLS 的产品。 奥美沙坦酯和两性霉素 B 两种模型药物的配方，以建立新的 我们将使用索拉非尼来制备药物的口服固体剂型技术。 颗粒来剖析脂质或表面活性剂对生物分布的影响并确定其机制 我们的研究将为 BLS 提供强大的基础资源，并代表了一种增强吸收的方法。 我们期待在配方中使用脂质和表面活性剂的方法可能会改变游戏规则。 贡献将对口服药物的开发产生积极影响，并将带来口服药物输送的突破 这项工作还可以扩展到其他给药途径中其他药物的未来研究。