Poly(pro-Estrogen) Microneedle Patches

聚（雌激素原）微针贴片

• 批准号: 10647375
• 负责人: Edmund Francis Palermo
• 金额: $ 7.8万
• 依托单位: RENSSELAER POLYTECHNIC INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647375
• 关键词: Alkenes; Applications Grants; Biocompatible Materials; Biological Availability; Body Temperature; Buffers; Chemistry; Clinical; Curcumin; Dermal; Development; Dexamethasone; Dose; Drug Compounding; Drug Delivery Systems; Elastomers; Emerging Technologies; Engineering; Estradiol; Estrogens; Exhibits; Failure; Fibroblasts; Foundations; Future; Gel Chromatography; Glass; Goals; Hepatic; Human; Hydrolysis; Hydrophobicity; Hypogonadism; Immersion; In Vitro; Individual; Injections; Kinetics; Laboratories; Length; Libraries; Malignant Neoplasms; Mechanics; Menopause; Methods; Molds; Needles; Oral Administration; Organic solvent product; Pain; Painless; Penetration; Pharmaceutical Preparations; Physiological; Plant Resins; Polyesters; Polymers; Probucol; Procedures; Prodrugs; Property; Puncture procedure; Recovery of Function; Reproducibility; Resistance; Resveratrol; Rodent Model; Sampling; Scanning Electron Microscopy; Scheme; Site; Skin; Skin Temperature; Solvents; Spinal cord injury; Stratum corneum; Stress; Sulfhydryl Compounds; Technology; Temperature; Time; Transition Temperature; Work; biomaterial compatibility; birth control; clinical application; compliance behavior; controlled release; crosslink; drug release kinetics; elastomeric; fabrication; female sex hormone; flexibility; functional group; gabapentin; hypodermic needle; implantation; innovation; liquid chromatography mass spectroscopy; macromolecule; mechanical properties; minimally invasive; monomer; nanoindentation; nanomolar; new technology; perfluoropolyether; pharmacokinetics and pharmacodynamics; polymerization; pre-clinical; safety assessment; scaffold; skin irritation; transgender

Project Summary This R03 application is focused on creation of an innovative microneedle patch (MNP) composed entirely of a polymerized 17β-estradiol (E2), the major female sex hormone. The macromolecular pro-drug materials are cured thermosets in which every repeating unit in the polyester chains contains an equivalent of E2. These crosslinked polyester resins undergo slow hydrolytic degradation to release low doses of estrogen, locally at the site of implantation, for exceptionally long time periods (up to many years). Transdermal microneedle patches offer minimally invasive, painless administration of estrogen. These delivery methods enhance patient compliance relative to repeated injections with hypodermic needles and they require lower doses than oral administration due by avoiding first-pass hepatic clearance. Of all the many advanced MNP technologies, there are still no examples of MNPs composed entirely of poly(pro-drug). Our lab has developed a new class of polymerizable estrogen pro-drugs containing pendant alkene groups. In this proposal, we will polymerize the pro-E2 monomers in a microneedle mold. A key innovation is that we plan to tune the glass transition of the polymer network such that the needles are hard and glassy at room temperature for skin penetration, but then they transition into a soft/rubbery material upon equilibration to physiological temperature. This project is likely to make significant contributions by developing new poly(pro-drug) based microneedle patches capable of releasing low doses of E2 transdermally for exceptionally prolonged timescales. The chemistry and engineering approaches used here will be broadly generalizable in two key ways: 1) our polymerization scheme is easily modified to accommodate nearly any drug molecule with two or more reactive functional group handles, and 2) the MNP of poly(pro-E2) can be applied to a broad range of clinical applications where prolonged low-dose E2 is desired. Our goal for future work is to apply these E2-releasing MNPs in a preclinical rodent model to first assess safety and skin irritation and later to explore the impact of the patch on functional recovery from contusive spinal cord injury.

项目摘要 该R03应用的重点是创建创新的微针贴片（MNP） 完全由主要女性性激素的聚合17β-雌二醇（E2）组成。 大分子促毒物材料是固化的热固体，其中每个重复单元中的每个重复单元 聚酯链含有相当于E2。这些交联的聚酯树脂经历慢 水解降解以释放低剂量的雌激素，在植入部位局部 非常长的时间（长达多年）。透皮微针斑块提供 微创，无痛的雌激素给药。这些分娩方法增强了患者 相对于反复注射皮下注射针的依从性，它们需要较低的剂量 通过避免初次肝清除率应得的口服给药。在所有高级 MNP技术，仍然没有完全由聚（Pro-Pro-drug）组成的MNP的例子。我们的 实验室已经开发了一类新的可聚合雌激素前药，其中含有吊坠烯烃 组。在此提案中，我们将在微针霉菌中聚合pro-E2单体。钥匙 创新是我们计划调整聚合物网络的玻璃过渡，以使针头 在室温下硬度硬化，以使皮肤穿透，但随后它们过渡到 平衡到物理温度后，软/橡胶材料。 该项目可能通过开发新的Poly（Pro-Drug）做出重大贡献 基于微针斑块，能够释放低剂量的E2透射剂 长时间的时间尺度。这里使用的化学和工程方法将广泛 可推广的两个关键方法：1）我们的聚合方案很容易修改以适应 几乎所有具有两个或多个反应性功能组手柄的药物分子，以及2） 聚（Pro-E2）可以应用于延长低剂量的广泛临床应用 需要E2。我们未来工作的目标是在临床前啮齿动物中应用这些E2释放的MNP 模型以首次评估安全性和皮肤刺激，然后探索贴片对 脊髓损伤中的功能恢复。