Microneedle Delivery of Trospium Chloride Optimized for Improved Tolerance and Patient Outcomes in Overactive Bladder Disease

优化曲司氯铵微针输送，改善膀胱过度活动症的耐受性和患者预后

• 批准号: 10546933
• 负责人: Elke Lipka
• 金额: $ 29.96万
• 依托单位: TSRL, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546933
• 关键词: Adhesives; Affect; Age; Anti-Cholinergics; Anxiety; Area; Biological Assay; Biological Availability; Bladder Diseases; Blood Circulation; Cattle; Chlorides; Client satisfaction; Crystallization; Data; Disease; Dose; Drug Formulations; Drug Interactions; Drug Kinetics; Enhancers; Ensure; Evaluation; Eye; Failure; Food; Formulation; Freeze Drying; Human; Hydrogels; Impaired cognition; In Situ; In Vitro; Incontinence; Medical; Mental Depression; Metabolism; Methods; Muscarinic Antagonists; Oral; Overactive Bladder; Painless; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Plasticizers; Polymers; Population; Powder dose form; Prevalence; Quality of life; Rattus; Regimen; Research; Route; Safety; Self Administration; Skin; Technology; Therapeutic; Time; Toxic effect; Toxicology; Transdermal substance administration; Treatment outcome; Urinary Incontinence; Woman; Work; absorption; aging population; cholinergic; clinical development; compliance behavior; design; driving force; drug candidate; falls; flu; improved; irritation; men; monomer; novel; novel therapeutics; oxybutynin; pharmacokinetics and pharmacodynamics; preclinical development; preclinical safety; product development; prototype; side effect; skin irritation; zanamivir

Abstract Overactive bladder (OB) is a disease that afflicts both men and women and is driven by the aging population with a prevalence estimated as high as 39% in the US and 45% for all women over 65. OB is accompanied with a significant loss of quality of life with documented increases in falls, anxiety, and depression. The muscarinic antagonists (anticholinergics) are the primary drugs for treatment, but these agents are associated with numerous side effects and drug-drug interactions leading to discontinuation of therapy in over 50% of patients in 6-12 months. Furthermore, with age there is a growing concern for anticholinergic drug overload (especially due to drug-drug interactions) leading to additional effects such as cognition impairment and other CNS affects. Studies have shown that the pharmacodynamics efficacy of muscarinic antagonists in OB therapy is strongly associated with area under the concentration-time curve (AUC) and that the many side effects are related to maximum plasma concentrations (Cmax). Oxybutynin, one of the agents with the most side effects, was formulated as an adhesive patch, which greatly reduced cholinergic side effects due to a constant effective drug concentration. Unfortunately, the patch had its own significant side effects, mainly serious skin irritations due to the permeation enhancers needed for effective delivery. Given the very large population afflicted with OB, and the many OB drugs and formulations which fail to adequately treat the disease, there remains a desperate unmet medical need for new therapy options. Multiple advantages of microneedle transdermal delivery over other transdermal methods have been documented. More recently, swellable hydrogel microneedles (HMN) have been shown to be a highly efficient and painless method for increasing the skin permeation of drugs without additives, sharps, or polymeric monomers entering the circulation. We have selected Trospium Chloride (TC), the OB drug with the best efficacy and least side effects, yet plagued by poor bioavailability and high pharmacokinetic variability for delivery via HMN. The product will be a drug-free HMN array with a TC drug reservoir to enable a tightly controlled delivery of TC, providing efficacious AUCs with consistent plasma concentrations. This self-administered patch is designed to deliver TC over the course of a week, and will be the first OB treatment with both excellent efficacy, as well as high patient compliance and satisfaction. The end result of this work will be a novel, transdermal delivery approach for TC with readily translatable PK, efficacy and initial preclinical safety data, ready to complete preclinical development activities leading to the opening of an IND. We have assembled a team of expert advisors and collaborators to ensure successful completion of this research plan.

抽象的 膀胱过度活动症 (OB) 是一种男性和女性都患有的疾病，是由人口老龄化造成的 据估计，美国的患病率高达 39%，所有 65 岁以上女性的患病率高达 45%。OB 伴随着 生活质量显着下降，跌倒、焦虑和抑郁的情况有所增加。毒蕈碱的 拮抗剂（抗胆碱能药）是主要的治疗药物，但这些药物与 众多副作用和药物间相互作用导致超过 50% 的患者停止治疗 6-12 个月内。此外，随着年龄的增长，人们越来越担心抗胆碱能药物超负荷（尤其是 由于药物之间的相互作用）导致额外的影响，例如认知障碍和其他中枢神经系统影响。 研究表明毒蕈碱拮抗剂在 OB 治疗中的药效学效果很强 与浓度-时间曲线下面积（AUC）相关，并且许多副作用与 最大血浆浓度（Cmax）。奥昔布宁是副作用最多的药物之一 配制为贴剂，由于药物持续有效，大大减少了胆碱能副作用 专注。不幸的是，该贴片有其自身的显着副作用，主要是由于以下原因引起的严重皮肤刺激： 有效递送所需的渗透促进剂。鉴于患有 OB 的人口非常多，并且 许多 OB 药物和制剂未能充分治疗该疾病，仍然有一个令人绝望的未得到满足的问题 医疗需要新的治疗选择。 与其他透皮方法相比，微针透皮给药具有多种优势 记录在案。最近，可膨胀水凝胶微针（HMN）已被证明是一种高效的 以及无痛方法，用于增加药物的皮肤渗透性，无需添加剂、锐器或聚合物 单体进入循环。我们选择了效果最好的OB药物曲司氯铵（TC） 且副作用最少，但仍受到生物利用度差和药代动力学变异性高的困扰 HMN。该产品将是一种无药物 HMN 阵列，带有 TC 药物储库，可实现严格控制的输送 TC，提供有效的 AUC 和一致的血浆浓度。这个自我管理的补丁是 旨在在一周内提供 TC，并且将是第一个具有优异疗效的 OB 治疗， 以及患者的高依从性和满意度。 这项工作的最终结果将是一种新颖的、具有易于转化的 PK 的 TC 透皮给药方法， 功效和初始临床前安全性数据，准备完成临床前开发活动，从而实现 IND 的开放。我们组建了一支由专家顾问和合作者组成的团队，以确保成功 完成本研究计划。