Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy.
Strengths, weaknesses, opportunities and challenges for long acting injectable therapies: Insights for applications in HIV therapy.
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DOI：
10.1016/j.addr.2016.02.003
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发表时间：
2016-08-01
影响因子：
16.1
通讯作者：
Rannard S
中科院分区：
文献类型：
--
作者：
Owen A;Rannard S
固体药物纳米颗粒技术的进步已经产生了许多长效（LA）制剂，具有每月一次或更长时间给药的潜力。此类制剂对慢性疾病提供了巨大的效用，特别是当缺乏药物依从性可能对治疗反应有害时。两种这样的制剂正在用于HIV的临床开发中，但是LA递送的概念起源于诸如精神分裂症和避孕的适应症。许多术语被用来描述LA方法，标准化将是有益的。最终，定义将取决于具体的适应症和交付途径，但对于艾滋病毒，我们提出的基准，反映了感知的临床效益和现有的数据，病人的态度。具体而言，我们建议口服、注射或植入策略的给药间隔分别为≥ 1周、≥ 1个月或≥ 6个月。本次审查的重点是在实现注射制剂的LA结果的效力的至关重要性，并探讨了已采用的跨适应症的既定和新兴技术。关键的技术挑战，如需要一致性和易于管理的药物组合，也进行了讨论。最后，审查探讨了知识的差距，从颗粒为基础的LA注射悬浮液的药物释放的药理学。一些假说进行了讨论，根据现有的数据有关的局部药物代谢，主动运输系统，的药物，巨噬细胞和患者的具体因素。更多地了解药物释放和长期暴露的机制将有助于进一步开发这种策略，以实现有希望的临床获益。
Advances in solid drug nanoparticle technologies have resulted in a number of long-acting (LA) formulations with the potential for once monthly or longer administration. Such formulations offer great utility for chronic diseases, particularly when a lack of medication compliance may be detrimental to treatment response. Two such formulations are in clinical development for HIV but the concept of LA delivery has its origins in indications such as schizophrenia and contraception. Many terms have been utilised to describe the LA approach and standardisation would be beneficial. Ultimately, definitions will depend upon specific indications and routes of delivery, but for HIV we propose benchmarks that reflect perceived clinical benefits and available data on patient attitudes. Specifically, we propose dosing intervals of ≥ 1 week, ≥ 1 month or ≥ 6 months, for oral, injectable or implantable strategies, respectively. This review focuses upon the critical importance of potency in achieving the LA outcome for injectable formulations and explores established and emerging technologies that have been employed across indications. Key technological challenges such as the need for consistency and ease of administration for drug combinations, are also discussed. Finally, the review explores the gaps in knowledge regarding the pharmacology of drug release from particulate-based LA injectable suspensions. A number of hypotheses are discussed based upon available data relating to local drug metabolism, active transport systems, the lymphatics, macrophages and patient-specific factors. Greater knowledge of the mechanisms that underpin drug release and protracted exposure will help facilitate further development of this strategy to achieve the promising clinical benefits.