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: 10029438
• 负责人: Xiaowei Dong
• 金额: $ 36.15万
• 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/10029438
• 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增量进度，但没有 在过去的三十年中，已经确定了突破性的口服药物技术。基于脂质的药物输送 系统（LBDD）被认为是建立良好的，非常重要的不溶性化合物策略。 根据先前的知识，由一个脂质和一个水组成的稳定二元脂质系统（BLS） 可溶性表面活性剂似乎不可能。 LDBB的另一个关键宗旨是，药物必须完全溶解在 LBDD可以增加其溶解和口服生物利用度。同时添加共同剥削以增加药物 溶解度，最终LBDD中的药物载荷减少。液体配方的稳定性，液体的兼容性 赋形剂和胶囊外壳，以及制造液体文件软明胶胶囊也限制了应用 LBDD。纳米颗粒是不溶性药物的其他替代方法。但是，纳米颗粒的液体形式 导致存储期间的粒子不稳定。为了解决这些限制，将LBDD或NP纳入 固体剂型非常可取。但是，低药物负荷是这种转换策略的主要问题。 另外，尽管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 生物分布的赋形剂尚不清楚。我们的研究计划的长期目标是提高公式 不溶性药物的技术。我们的实验室最近开发了原位自组装纳米颗粒的小说 （ISNP）与水产生的吸毒ISNP接触的颗粒。药物ISNP颗粒不仅改善了 口服滥用，但也显示出靶向组织的口服固体公式的潜力。更重要的是，我们 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，创建了一种新的稳定 BLS。我们的结果进一步表明，将药物完全溶于我们的配方和形成 ISNP的增强不是强制性的。以这些最近的突破性发现为基础 该提案的目标是通过带来我们独特的新胶体的发现来开发一种新颖的公式技术 二元脂质系统成固体剂型，以改善对无法溶的药物的口服滥用。我们建议确定 赋形剂结构与BLS的形成并建立BLS库的关系。图书馆将提供 当配方器使用BLS时，选择适当的组成的指南。我们将开发新的基于BLS的 两种模型药物Olmesartan Medoxomil和两性霉素B的配方，以建立一个新的 口服固体剂型的技术，用于滥用滥用。我们将使用索拉非尼准备毒品 颗粒剖析脂质或表面活性剂对生物分布的影响，并确定 吸收增强。我们的研究将为BLS提供强大的基础资源，并代表 在配方中使用脂质和表面活性剂的改变游戏的方法。我们期望这些 贡献将对口服药物开发产生积极影响，并会导致口服药物的突破 技术。这项工作还可以扩展到其他行政途径中其他药物的未来研究。