Next-Generation Parenteral Drug Delivery Systems for Controlling Pharmacokinetics

用于控制药代动力学的下一代肠外给药系统

• 批准号: 10667652
• 负责人: Kevin James McHugh
• 金额: $ 38.42万
• 依托单位: RICE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667652
• 关键词: 3D Print; Acute; Area; Behavior; Biocompatible Materials; Biological; Biological Products; Chemistry; Chronic; Chronic Disease; Clinical; Complex; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Dryness; Encapsulated; Exclusion; Excretory function; Exhibits; FDA approved; Formulation; Frequencies; Geometry; Goals; Half-Life; Health Care Costs; Hydrophobicity; Injectable; Kinetics; Medicine; Methods; Morbidity - disease rate; Patient-Focused Outcomes; Patients; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Pharmacy (field); Polymers; Regimen; Route; Running; Safety; Site; Structure; Structure-Activity Relationship; Surface; System; Therapeutic; Water; absorption; compliance behavior; controlled release; drug release kinetics; fabrication; improved; interest; manufacture; model design; mortality; multi-photon; nanofabrication; next generation; particle; prevent; rational design; side effect; therapy duration; welfare

PROJECT SUMMARY/ABSTRACT Every day, an estimated 3.9 billion people take medication to treat acute or chronic conditions. However, despite the enormous utility of current pharmaceuticals, they are limited by several factors that prevent their more effective and expanded use. Ideally, drugs would reach the desired concentration at the site of action for the duration that the therapy is required. In practice, this is difficult because the body is constantly metabolizing and excreting drugs, which necessitates re-administration. Depending on a drug’s therapeutic window and biological half-life, frequent administration may be required, which lowers patients’ adherence to their dosing regimens. This issue is pervasive with non-adherence rates as high as 50% for chronic diseases, leading to increased morbidity and mortality and as much as $290 billion in added healthcare costs each year in the U.S. alone. The field of pharmaceutics has developed formulation methods that reduce administration frequency, including injectable controlled-release systems composed of drug embedded in biodegradable materials. Unfortunately, current clinically-approved systems are limited in both the types of molecules that they can deliver and the drug release kinetics they can achieve. This proposal seeks to develop parenteral drug delivery strategies that enhance safety and efficacy, improve patient adherence, and enable the sustained release of biological drugs. We hypothesize that emerging nanofabrication methods (e.g. multi-photon 3D printing) can be used to control the structure—and thus behavior—of surface-eroding particles containing drug. Because the degradation of these hydrophobic materials is confined to the surface, drug distributed homogeneously throughout their volume will be released at a rate proportional to their erosion rate and exposed surface area. Using these methods, we can model and rationally design microparticle structures that release drug at predictable, geometrically-defined rates. Although this concept could be applied to achieve a wide array of release kinetics, we are most interested in attaining zero-order release kinetics, which are desirable for most diseases, and sequential release, which may be useful for dynamic conditions. Further, because surface eroding materials exclude water, their interior microenvironment will remain dry and neutral, thus promoting the stability of encapsulated biologics at 37°C. The features of surface-eroding microparticles run in stark contrast with existing FDA-approved microparticles composed of bulk-degrading polymers that absorb water and produce acidic degradation products, which makes it impossible to predict release kinetics a priori, contributes to the degradation of encapsulated biologics, and prevents sequential release. The strategies we propose are only now possible due to the convergence of advances in manufacturing and chemistry that allow us to exploit structure-function relationships at a scale small enough to retain microparticle injectability. If successful, this approach has the ability to fundamentally change how drugs are administered and improve patient outcomes across all of medicine.

项目概要/摘要 尽管如此，每天仍有 39 亿人服用药物来治疗急性或慢性疾病。 尽管现有药物具有巨大的效用，但它们受到多种因素的限制，阻碍了它们的进一步发展。 理想情况下，药物将在作用部位达到所需的浓度。 在实践中，这很困难，因为身体不断新陈代谢。 排泄药物，这需要重新给药，具体取决于药物的治疗窗和生物学。 由于半衰期较长，可能需要频繁给药，这降低了患者对其给药方案的依从性。 这个问题很普遍，慢性病的不依从率高达 50%，导致 仅在美国，每年就增加发病率和死亡率以及高达 2900 亿美元的医疗费用。 制药领域已开发出减少给药频率的配方方法，包括 由嵌入可生物降解材料的药物组成的注射控释系统。 目前临床批准的系统在其可以输送的分子类型和药物方面都受到限制 该提案旨在开发能够实现的药物释放动力学。 增强安全性和有效性，提高患者依从性，实现生物药物的缓释。 我们发现新兴的纳米加工方法（例如多光子 3D 打印）可用于控制 含有药物的表面侵蚀颗粒的结构和行为。 这些疏水性材料被限制在表面，药物均匀分布在其整个体积中 使用这些方法，我们将以其侵蚀率和暴露表面积成正比的速度释放。 可以建模和合理设计微粒结构，以可预测的、几何定义的方式释放药物 尽管这个概念可以应用于实现广泛的释放动力学，但我们最感兴趣的是。 实现大多数疾病所需的零级释放动力学，以及连续释放 此外，由于表面侵蚀材料不含水，因此其内部可能有用。 微环境将保持干燥和中性，从而促进封装生物制剂在 37°C 下的稳定性。 表面侵蚀微粒的特征与 FDA 批准的现有微粒形成鲜明对比 由吸收水并产生酸性降解产物的本体降解聚合物组成，这使得 无法先验预测释放动力学，导致封装生物制剂的降解，并且 由于收敛，我们提出的策略现在才成为可能。 制造和化学的进步使我们能够在小规模上利用结构-功能关系 如果成功的话，这种方法有能力从根本上改变。 如何在所有医学领域给药并改善患者的治疗效果。