Delivery of Biological Therapeutics: Using Engineered Particles and Novel Deliver

描述 摘要 以安全和有效的方式将有前途的生物疗法应用到人体所需的位置是医学上的关键挑战之一。许多不同的疾病状态现在都是生物药物治疗的目标，包括肿瘤、自身免疫、炎症、代谢、心血管、神经和眼科。此外，预计生物疗法将在治疗疼痛以及用于抗感染、抗细菌、抗病毒和抗真菌治疗方面发挥重要作用。然而，尽管有机会，但在实现生物疗法和疫苗的全部潜力方面仍存在重大障碍，包括：i)需要显著改善循环时间；ii)无法使用简单的注射或口服给药来调整药代动力学；iii)无法通过肺部途径输送生物制品；iv)许多生物制品无法进入细胞内靶点；v)无法将生物制品输送到血运不良的组织。在这里，我建议发展新兴的自上而下的粒子制造技术，以制造由几乎纯生物分子组成的形状特定的微米和纳米粒子的二维阵列和自由流动的粉末。使用基于图案化薄膜的冷冻干燥过程，具有非常高的热和质量传输率，将合成由生物分子组成的颗粒的“固态溶液”，以控制模制颗粒的溶解速度或颗粒中生物分子的释放速度。此外，我建议利用独特的二维阵列形式和形状可控生物疗法和疫苗的自由流动粉末的形成来开发三种新的剂型，包括：i)通过高浓度分散体(溶液的替代品)传递；ii)通过吸入传递；以及iii)新的内窥镜

DESCRIPTION Abstract Getting promising biological therapeutics to the desired location in the body in a safe and effective fashion is one of the key challenges in medicine. Many different disease states are now being targeted for treatment with biologicals including oncology, autoimmune, inflammatory, metabolic, cardiovascular, neurological, and ophthalmologic. In addition, it is anticipated that biological therapies will play a major role in the treatment of pain and for the use in anti-infective, anti-bacterial, anti-viral and anti-fungal treatments. However, despite the opportunity, there are significant road blocks that stand in the way to realizing the full potential of biological therapeutics and vaccines including: i) the need to dramatically improve circulation times; ii) the inability to tailor pharmacokinetics using simple injections or oral delivery; iii) the inability to deliver biologicals via pulmonary routes; iv) the inability of many biologicals to access intracellular targets; and v) the inability to deliver biologicals to poorly-vascularized tissues. Herein I propose to evolve emerging top-down particle fabrication technologies to make 2-dimensional arrays and free flowing powders of shape specific micro- and nano-particles that are comprised of almost pure biological molecules. Using patterned thin film based lyophilization processes that have very high rates of thermal and mass transport, "solid state solutions" of particles comprised of biological molecules will be synthesized to control how quickly the molded particles will dissolve or how quickly the biological molecules within the particles will be released. In addition, I propose to exploit the unique 2-dimensional array format and the formation of free flowing powders of shape controlled biological therapeutics and vaccines to develop three novel dosage forms including: i) delivery via highly concentrated dispersions (alternative to solutions); ii) pulmonary delivery via inhalation; and iii) novel endosco