Next-Generation Parenteral Drug Delivery Systems for Controlling Pharmacokinetics

项目总结/摘要 据估计，每天有39亿人服用药物治疗急性或慢性疾病。但尽管 尽管目前药物的巨大效用，但它们受到几个因素的限制，这些因素阻止了它们的更多 有效和扩大使用。理想情况下，药物将在作用部位达到所需的浓度， 治疗所需的时间。在实践中，这是困难的，因为身体不断代谢， 排泄药物，这需要重新给药。根据药物的治疗窗口和生物学特性， 半衰期，可能需要频繁给药，这降低了患者对其给药方案的依从性。 这一问题普遍存在，慢性病的不依从率高达50%，导致增加 发病率和死亡率，仅在美国每年就增加高达2900亿美元的医疗保健费用。的 制药领域已经开发出降低给药频率的制剂方法，包括 由包埋在可生物降解材料中药物组成的可注射控释系统。不幸的是， 目前临床批准的系统在它们可以递送的分子类型和药物 释放动力学可以实现。该提案寻求开发肠胃外药物递送策略， 增强安全性和有效性，提高患者依从性，并使生物药物能够持续释放。 我们假设新兴的纳米制造方法（例如多光子3D打印）可以用于控制 含有药物的表面侵蚀颗粒的结构和行为。因为， 这些疏水性材料被限制在表面，药物均匀地分布在它们的整个体积中 将以与其侵蚀速率和暴露表面积成比例的速率释放。使用这些方法，我们 可以模拟和合理设计微粒结构， rates.虽然这一概念可以应用于实现广泛的释放动力学，我们最感兴趣的是， 在获得零级释放动力学（这对于大多数疾病是期望的）和顺序释放（这 可以用于动态条件。此外，由于表面侵蚀材料排斥水， 微环境将保持干燥和中性，从而促进包封的生物制剂在37°C下的稳定性。的 表面侵蚀微粒的特征与现有的FDA批准的微粒形成鲜明对比 由吸收水并产生酸性降解产物的本体降解聚合物组成， 不可能事先预测释放动力学，有助于包封生物制剂的降解， 防止连续释放。我们提出的战略现在才有可能，因为 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， 足以保持微粒可注射性。如果成功，这种方法有能力从根本上改变 如何管理药物并改善所有医学领域的患者结果。

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.