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 此R03应用程序专注于创建创新的微针贴片(MNP) 完全由聚合的17β-雌二醇(E_2)组成，E_2是女性的主要性激素。这个 大分子亲药材料是固化的热固性材料，其中每个重复单元 聚酯链中含有一种相当于E2的物质。这些交联型聚酯树脂经历了缓慢的 水解性降解，在植入部位局部释放低剂量雌激素，用于 超长的时间周期(长达数年)。经皮微针贴片提供 微创、无痛的雌激素注射。这些分娩方法提高了患者的 与重复皮下注射针头有关的依从性，它们需要较低的剂量 而不是口服，避免了肝脏的首过清除。在众多先进技术中 在MNP技术方面，目前还没有完全由多聚(前药物)组成的MNPs的例子。我们的 LAB已开发出一类含有侧链烯烃的新型可聚合雌激素前体药物 组。在这个方案中，我们将在微针模具中聚合Pro-E2单体。一把钥匙 创新之处在于，我们计划调整聚合物网络的玻璃化转变，使针头 在室温下坚硬而玻璃状，便于皮肤穿透，但随后它们会转变为 平衡到生理温度后的软/橡胶材料。 该项目可能通过开发新的多聚(前药物)做出重大贡献。 基于微针贴片能够释放低剂量的雌二醇经皮吸收 延长的时间尺度。这里使用的化学和工程方法将广泛地 可概括为两个关键方面：1)我们的聚合方案很容易修改，以适应 几乎任何具有两个或更多活性官能团手柄的药物分子，以及2)MNP Poly(PRO-E2)可广泛应用于延长低剂量的临床应用 所需的是E2。我们未来工作的目标是将这些释放E2的MNPs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，然后探索贴片对 脊髓挫伤后的功能恢复。