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: 10205113
• 负责人: Xiaowei Dong
• 金额: $ 36.55万
• 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/10205113
• 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.

项目总结/摘要 不溶性药物的生物利用度增强技术代表了渐进式的进展，但 在过去三十年中，已经确定了突破性的口服药物技术。基于脂质的药物递送 LBDDS系统（LBDDS）被认为是一个完善的，非常重要的战略不溶性化合物。 根据以往的知识，由一种脂质和一种水组成的稳定的二元脂质体系（BLS）， 可溶性表面活性剂似乎不可能。LDBBS的另一个关键原则是药物必须完全溶解在 LBDDS以增加其溶出度和口服生物利用度。同时加入辅助赋形剂以增加药物 溶解度降低，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，以及制造液填充软胶囊也限制了应用 的LBDDS。纳米颗粒是不溶性药物的另一种替代品。然而，纳米颗粒的液体形式 导致储存期间颗粒不稳定。为了解决这些限制，将液体LBDDS或NP掺入到 固体剂型是非常需要的。然而，低载药量是这种转化策略的主要问题。 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，但个体的影响并不显著。 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配方 不溶性药物的技术。本实验室最近开发了一种新型的原位自组装纳米粒子 与水接触的ISNP颗粒产生载药的ISNP。药物ISNP颗粒不仅改善了 口服吸收，但也显示出组织靶向口服固体制剂的潜力。更重要的是我们 最近发现，我们的ISNPs，由一种脂质和一种水溶性表面活性剂组成， 劳工统计局。我们的结果进一步表明，完全溶解药物在我们的制剂和形成 的ISNP对于吸收增强不是强制性的。基于这些最新的突破性发现， 该提案的目标是通过将我们对新胶体的独特发现， 将二元脂质体系转化为固体剂型以改善不溶性药物的口服吸收。我们建议确定 辅料结构与BLS形成的关系，建立BLS文库。图书馆将提供 当配方设计师使用BLS时，选择适当成分的指导。我们将开发新的基于BLS的 两种模型药物奥美沙坦酯和两性霉素B的制剂，以建立一种新的 口服固体剂型的吸收增强技术。我们将使用索拉非尼来制备药物 颗粒，以剖析脂质或表面活性剂对生物分布的影响，以及确定的机制， 吸收增强我们的研究将为BLS提供强大的基础资源，并代表 这可能是在配方中使用脂质和表面活性剂的改变游戏规则的方法。我们预计这些 贡献将积极影响口服药物开发，并将导致口服药物递送的突破 技术.这项工作也可以扩展到其他药物在其他给药途径的未来研究。