Delivery of Biological Therapeutics: Using Engineered Particles and Novel Deliver

描述 摘要 以安全有效的方式将有前途的生物治疗剂送到体内所需的位置是医学的关键挑战之一。许多不同的疾病状态现在被靶向用于生物制剂治疗，包括肿瘤学、自身免疫性、炎症、代谢、心血管、神经学和眼科。此外，预计生物疗法将在疼痛治疗和用于抗感染、抗细菌、抗病毒和抗真菌治疗中发挥重要作用。然而，尽管有机会，但在实现生物治疗剂和疫苗的全部潜力的道路上存在重大障碍，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递送来调整药代动力学; iii）无法通过肺部途径递送生物制剂; iv）许多生物制剂无法接近细胞内靶标;和v）不能将生物制品递送到血管化不良的组织。在这里，我建议发展新兴的自上而下的颗粒制造技术，以制造由几乎纯的生物分子组成的特定形状的微米和纳米颗粒的二维阵列和自由流动的粉末。使用具有非常高的热传递和质量传递速率的基于图案化薄膜的冻干工艺，将合成由生物分子组成的颗粒的“固态溶液”，以控制模制颗粒溶解的速度或颗粒内的生物分子释放的速度。此外，我建议利用独特的二维阵列形式和形状控制的生物治疗剂和疫苗的自由流动粉末的形成来开发三种新剂型，包括：i）通过高度浓缩的分散体（替代溶液）递送; ii）通过吸入的肺部递送;和iii）新的内分泌途径。

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