Towards complete sustained release nanoformulations of NRTI based regimens

描述：目前可获得的抗逆转录病毒（ARV）制剂需要终生每日给药，在长时间服药后，患者可能会出现药丸疲劳，并经常错过服药剂量。这可能对治疗的成功产生不利后果，增加病毒对所用药物产生耐药性的可能性。两家制药公司已经开发出了rilpivirine LA和S/GSK744缓释制剂，可以每月给药一次，甚至更少。然而，这两种配方的一个主要限制是它们不是为相互组合而优化设计的。此外，目前的护理标准是同时使用三种抗逆转录病毒药物。目前大多数抗逆转录病毒治疗方案包括一类被称为核苷逆转录酶抑制剂（NRTIs）的药物。开发长效可注射联合抗逆转录病毒药物的一个主要障碍是nrti与用于生产这些制剂的技术不兼容。利用我们在固体药物纳米颗粒（SDN）技术方面的最新进展，我们建议优化由nrti组成的缓释骨干方案，以匹配当前的护理标准，并在后期开发中补充缓释制剂。由于nrti本身是水溶性的，因此它们与用于制造rilpivirine LA和S/GSK744的纳米研磨方法不兼容。使用我们新的专有技术，我们将评估两种缓释NRTI制剂策略，并在较长时间内建立NRTI缓释实用程序，为水溶性药物定义新的平台技术。药理学和化学之间的迭代将确保稳定的纳米颗粒具有足够高的载药量，以确定可行的剂量大小，并通过可扩展和可重复的合成验证无菌性、稳定性和成本效益。

DESCRIPTION: Currently available antiretroviral (ARV) formulations necessitate lifelong, daily dosing, and after prolonged periods of time, patients can encounter pill fatigue and frequently miss doses of their medication. This can have detrimental consequences for the success of therapy, increasing likelihood of the virus developing resistance to the drugs used. Two pharmaceutical companies have developed sustained-release formulations, rilpivirine LA and S/GSK744, that can be administered once a month or even less frequently. However, a major limitation for these two formulations is that they are not optimally designed to be combined with each other. Additionally, the current standard of care is to administer three ARVs simultaneously. Most current ARV regimens include a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). A major obstacle to developing long-acting injectable combination ARVs is that NRTIs are not compatible with the technologies being utilized to produce these formulations. Using our recent developments in solid drug nanoparticle (SDN) technology, we propose to optimize a sustained-release backbone regimen consisting of NRTIs to match current standard of care and compliment sustained-release formulations in late stage development. Since NRTIs are inherently water soluble, they are not compatible with the nanomilling approaches used to create rilpivirine LA and S/GSK744. Using our new and proprietary technology we will assess two strategies for sustained-release NRTI-formulations and establish the utility for NRTI sustained- release over an extended period of time, defining a new platform technology for water soluble drugs. Iteration between pharmacology and chemistry will ensure stable nanoparticles with sufficiently high drug-loading to make viable dosage sizes with scalable and reproducible synthesis validated for sterility, stability and cost effectiveness. Nanoparticles will undergo a sequential and detailed preclinical evaluation of their pharmacology and safety, to enable optimization of favorable properties. Lead candidates will be selected for analysis in humanized mice by integrating laboratory data through mathematical modeling. We will assess candidate formulations for stability in biological fluids, release kinetic, delivery to cells and antiviral activity. This new platform for sustained-release NRTIs will benefi patients by increasing options for long-acting ARV's, thus simplifying therapy. Our collaboration combines the unique expertise of one of the world's leading centers for nanoformulation research, protected by 25 patent families, with one of the world's leading centers for ARV pharmacology research.