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.

项目摘要/摘要 不溶性药物的生物利用度增强技术代表着渐进的进步，但没有 在过去的三十年里，已经确定了突破性的口服药物技术。脂类给药 系统(LBDDS)被认为是处理不溶性化合物的一种成熟的、非常重要的策略。 根据已有的知识，一个稳定的二元脂质体系(BLS)是由一个脂质和一个水组成的。 可溶性表面活性剂似乎是不可能的。LDBBS的另一个关键原则是药物必须完全溶解在 LBDDS可提高其溶出度和口服生物利用度。同时添加辅料以增加药物 溶解度、载药量在最终的LBDDS中降低。液体制剂的稳定性，液体的配伍 辅料和胶囊壳以及液体软胶胶囊的制造也限制了这种技术的应用 LBDDS。纳米粒子是不溶性药物的另一种替代品。然而，液体形式的纳米颗粒 导致颗粒在储存过程中不稳定。为了解决这些限制，将液态LBDDS或NPs加入到 固体剂型是非常可取的。然而，低载药量是这一转换策略的主要问题。 此外，尽管胶体颗粒中的脂类和表面活性剂改变了生物分布，但个体的影响 赋形剂的生物分布尚不清楚。我们研究计划的长期目标是推进 不溶性药物的技术。我们实验室最近开发了一种新型的原位自组装纳米颗粒 与水接触的(ISNP)颗粒会产生载药的ISNP。药物ISNP颗粒不仅改善了 口服吸收，但也显示了潜在的组织靶向口服固体制剂。更重要的是，我们 最近发现，我们的ISNPs由一种脂类和一种水溶性表面活性剂组成，创造了一种新的稳定的 劳工统计局。我们的结果进一步证明，在我们的制剂中完全溶解药物并形成 ISNPs不是促进吸收的强制性条件。基于这些最新的突破性发现， 这项提议的目标是通过带来我们独特的新胶体发现来开发一种新的配方技术 将二元脂质体系制成固体剂型，提高不溶性药物的口服吸收。我们建议确定 研究赋形剂结构与BLS形成的关系，建立BLS文库。图书馆将提供 配方师使用BLS时选择适当成分的指南。我们将开发新的基于BLS的 奥美沙坦美多昔米和两性霉素B两种模型药物的处方研究 口服固体制剂促进吸收的技术。我们将使用索拉非尼来制备药物 剖析脂质或表面活性物质对生物分布的影响以及确定其作用机制 吸收增强。我们的研究将为劳工统计局提供强大的基础资源，并代表着 可能改变游戏规则的方法是在配方中使用脂类和表面活性剂。我们期待着这些 贡献将对口腔药物开发产生积极影响，并将导致口腔药物输送方面的突破 技术。这项工作也可以扩展到其他给药途径的其他药物的未来研究。