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

基本信息

批准号：
10890222
负责人：
Kevin James McHugh
金额：
$ 7.35万
依托单位：
RICE UNIVERSITY
依托单位国家：
美国
项目类别：
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/10890222
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

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

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项目摘要

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.

项目摘要/摘要每天，估计有39亿人服用药物治疗急性或慢性病。但是，需求当前药物的巨大效用，它们受到几个因素的限制，这些因素可以防止其更多有效和扩展的使用。理想情况下，药物将达到所需的浓度需要治疗的持续时间。实际上，这很困难，因为身体不断代谢，并且排泄药物，必要的重新管理。取决于药物的治疗窗口和生物学可能需要半衰期，通常需要给药，这降低了患者对剂量方案的依从性。这个问题普遍存在，慢性疾病的不遵守率高达50％，导致增加发病率和死亡率，仅在美国，每年每年增加2900亿美元的医疗保健费用。这药物领域已开发出制定方法，以降低给药频率，包括由可生物降解材料嵌入的药物组成的可注射控制释放系统。很遗憾，当前临床批准的系统在它们可以输送的两种类型的类型中都受到限制释放他们可以实现的动力学。该建议旨在制定父母的药物输送策略提高安全性和效率，提高患者的依从性，并能够持续释放生物药物。我们假设新兴的纳米制作方法（例如多光子3D打印）可用于控制含有药物的表面磨练的颗粒的结构以及因此行为。因为这些疏水材料局限于表面，在整个体积中均匀分布的药物将以与其侵蚀率和暴露表面积成正比的速度释放。使用这些方法，我们可以建模和合理设计的微粒结构，以可预测的几何定义释放药物速率。尽管可以应用此概念来实现各种各样的发行动力学，但我们最感兴趣在获得零级释放动力学时，对于大多数疾病都是理想的，以及顺序释放，可能对动态条件有用。此外，由于表面侵蚀材料排除了水，因此内部微环境将保持干燥和中性，从而在37°C下促进了封装的生物制剂的稳定性。与现有的FDA批准的微粒形成鲜明对比的是表面修饰的微粒的特征由吸收水并产生酸性降解产物的散装聚合物组成不可能先验地预测动力学，导致封装生物制剂的降解和防止顺序释放。我们提出的策略直到现在才有可能制造和化学的进步，使我们能够以较小的规模利用结构功能关系足以保留微粒注射性。如果成功，这种方法有能力从根本上改变如何给药并改善所有药物的患者预后。