Research Supplements for R35 to Promote Diversity in Health-Related Research, PA-21-071

两性霉素B(Amb)是治疗危及生命的侵袭性真菌感染的首选药物。然而，截至 现在AMB的给药仅限于静脉输注，因为它的溶解性和渗透性很差， 这严重影响了患者的可及性。尽管口服AMB药物是一种非常受欢迎的解决方案， 口服AMB制剂即使在商业化60年后仍未实现。我们的实验室有 发现了由一种脂类和一种水溶性表面活性剂组成的新型稳定的二元脂质体系(BLS)，以 提高水不溶性药物的口服生物利用度。2020年，我们获得了最大化调查人员奖 NIGMS颁发的研究奖(R35)，以进一步研究这一新配方技术。父级R35的目标是 格兰特将开发一种新的配方技术，将我们独特的新胶体BLS发现转化为固体 改善不溶性药物口服吸收的剂型。父母助学金中的一项研究是建造一座图书馆 使用脂类和传统表面活性剂进行稳定的BLS。AMB代表一种两亲性分子，具有 大的环状结构，既有疏水区域，也有亲水区域。传统的带有极性头的表面活性剂 非极性尾部共轭的基团不适合AMB。胆盐是理想的生物表面活性剂，因为它们 生物相容性和独特的结构与平面类固醇部分。一种商用的AMB注射剂是由胆汁制成的 盐胶束。然而，胆盐还没有用于口服固体制剂，因为它们是水溶性的。 而且通常不喜欢脂类。根据我们在BLS中的新发现，我们假设BLS含有胆汁 盐类是提高AMB口服吸收的一种有效的制剂策略。因此，这种多样性的目标是 补充剂是利用含有一种脂质和一种胆盐的BLS开发治疗AMB的新型口服颗粒 作为培养一名非裔美国博士生成为一名生物医学研究人员。我们将开发口服AMB颗粒 并评价药代动力学和组织分布。我们期待着《补编》的结果。 建立以胆盐为基础的BLS，将其纳入家长问卷，以扩大图书馆和 测试我们的新配方技术。这项拟议的多样性补充方案将支持一名非裔美国人博士 学生为他的论文研究。拟议的研究计划与候选人的长期职业生涯相一致 目标和个人发展计划(IDP)。首席调查员/导师有广泛的指导 经验，特别是对代表性不足的学生。这个项目是围绕着改善 候选人的技能，根据候选人的国内流离失所者，以及培训候选人能够采取下一步 沿着独立药剂学家的道路前进。拟议的培训计划和具体目标提纲 有组织地学习新的制药技术、概念学科特定知识、 实验设计、数据分析以及展示方面的巨大增长机会， 写作和领导能力。总而言之，这项计划的设计除了加强家长资助外，还包括 增强候选人的能力和技能，为未来的研究资助和职业发展做准备。

Amphotericin B (AmB) is a first option therapy against life-threatening invasive fungal infections. However, as of now administration of AmB is limited to intravenous infusions because of poor solubility and poor permeability, which severely impacts patient accessibility. Although oral AmB medication is a highly sought-after resolution, oral AmB formulations have yet not to be achieved even after 6 decades of commercialization. Our lab has discovered novel stable binary lipid systems (BLS) that consist of one lipid and one water-soluble surfactant to enhance oral bioavailability of water insoluble drugs. In 2020, we were awarded a Maximizing Investigators’ Research Award (R35) from NIGMS to further study this new formulation technology. The goal of the parent R35 grant is to develop a novel formulation technology by bringing our unique findings of new colloidal BLS into solid dosage forms to improve oral absorption of insoluble drugs. One of studies in the parent grant is to build a library of stable BLS using lipids and traditional surfactants. AmB represents a type of amphiphilic molecules that have big ring structure with both hydrophobic and hydrophilic regions. The traditional surfactants with a polar head group conjugated to non-polar tails are not suitable for AmB. Bile salts are desirable biosurfactants due to their biocompatibility and unique structure with planar steroidal moiety. A commercial AmB injection is made of bile salt micelles. However, bile salts have not been used in oral solid dosage forms because they are water-soluble and normally do not like lipids. With our novel findings in the BLS, we hypothesize that the BLS containing bile salts is an effective formulation strategy to enhance oral absorption of AmB. Thus, the goal of this Diversity Supplement is to develop novel oral granules for AmB by using BLS containing one lipid and one bile salt as well as train an African American PhD student to become a biomedical researcher. We will develop oral AmB granules and evaluate pharmacokinetics and tissue distribution. We anticipate the outcome of the Supplement will establish bile salt based BLS, which will be incorporated into the parent questionnaire to expand the library and test our new formulation technology. This proposed Diversity Supplement will support an African American PhD student for his dissertation research. The proposed research plan aligns with the candidate’s long-term career goals and individual development plan (IDP). The principal investigator/mentor has extensive mentoring experiences, especially for underrepresented students. This project has been designed around improving the candidate’s skills, as per the candidate’s IDP, as well as training the candidate to be able to take the next steps along the path of an independent pharmaceutical scientist. The proposed training plan and specific aims outline a path for structured learning of new pharmaceutical techniques, conceptual discipline specific knowledge, experimental design, data analysis and also account for great opportunities to grow in terms of presentation, writing and leadership skills. In all, this project is well designed to enhance the parent grant in addition to bolstering the candidate’s capability and skills in preparation for future research grant and career development.