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R 03应用程序的重点是创建一个创新的微针贴片（MNP） 完全由聚合的17β-雌二醇（E2）组成，这是主要的女性性激素。的 大分子前药材料是固化的热固性材料， 聚酯链含有当量的E2。这些交联的聚酯树脂经历缓慢的 水解降解，在植入部位局部释放低剂量的雌激素， 非常长的时间（长达数年）。经皮微针贴片提供 微创无痛的雌激素给药这些递送方法增强了患者 相对于皮下注射针头重复注射的依从性， 由于避免了首过肝脏清除率，在所有先进的 虽然MNP技术已经发展，但仍然没有完全由聚（前药）组成的MNP的实例。我们 实验室已经开发出一类新的含有侧链烯烃的可聚合雌激素前药 组在本提案中，我们将在微针模具中将pro-E2单体包埋。一个关键 创新之处在于，我们计划调整聚合物网络的玻璃化转变， 在室温下是坚硬的玻璃状的，可以穿透皮肤，但随后它们会转变为 在平衡到生理温度时，软质/橡胶状材料。 该项目可能通过开发新的聚（前药） 基于微针的贴片，能够透皮释放低剂量的E2， 延长的时间尺度。这里使用的化学和工程方法将广泛地 在两个关键方面可概括：1）我们的聚合方案容易修改以适应 几乎任何具有两个或更多个反应性官能团柄的药物分子，和2） 聚（pro-E2）可应用于广泛的临床应用，其中长期低剂量 E2是理想的。我们未来工作的目标是将这些释放E2的MNP应用于临床前啮齿动物 模型，首先评估安全性和皮肤刺激性，然后探索贴剂对 从挫伤性脊髓损伤中恢复功能