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可调节长效给药的高度亲脂性抗逆转录病毒药物的肠外给药平台。

Parenteral platforms for tunable, long-acting administration of a highly hydrophobic antiretroviral drug.

机构信息

ViiV Healthcare, Five Moore Drive, Research Triangle Park, NC, 27709, USA.

Department of Chemistry, Oak Crest Institute of Science, 128‑132 W. Chestnut Ave., Monrovia, CA, 91016, USA.

出版信息

Sci Rep. 2024 May 21;14(1):11573. doi: 10.1038/s41598-024-58583-w.

Abstract

GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound's physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.

摘要

GSK2838232(GSK8232)是一种第二代成熟抑制剂(MI),专为治疗 HIV 而开发,具有出色的广谱病毒学特征。该化合物作为一种口服制剂,已显示出有前途的临床效果。此外,该化合物的物理和药理学特性为长效注射制剂的开发提供了机会。尽管存在溶解度和 GSK8232 剂量等独特的设计限制,但我们报告了三种有效的可调药物输送策略:原料药(API)混悬剂、离子液体和皮下植入物。这三种方法都在大鼠中实现了有前途的持续药物释放曲线。此外,我们还能够通过结合被动和主动策略来调节药物释放速率,从而拓宽了这些制剂方法的适用性,超越了 GSK8232。总的来说,本报告是推进不适合传统长效候选药物的关键 HIV 药物长效制剂开发的重要第一步。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f2d2/11109207/e08bcc455a72/41598_2024_58583_Fig1_HTML.jpg

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