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.

摘要