Novel Perspectives on the Design and Development of a Long-Acting Subcutaneous Raltegravir Injection for Treatment of HIV—In Vitro and In Vivo Evaluation

Author:

Abd-Ellah Heba S.12ORCID,Mudududdla Ramesh1ORCID,Carter Glen P.3,Baell Jonathan B.14

Affiliation:

1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052, Australia

2. Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt

3. Microbiology and Immunology Department, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Parkville, VIC 3001, Australia

4. School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, China

Abstract

Antiretrovirals (ARVs) are a highly effective therapy for treatment and prevention of HIV infection, when administered as prescribed. However, adherence to lifelong ARV regimens poses a considerable challenge and places HIV patients at risk. Long-acting ARV injections may improve patient adherence as well as maintaining long-term continuous drug exposure, resulting in improved pharmacodynamics. In the present work, we explored the aminoalkoxycarbonyloxymethyl (amino-AOCOM) ether prodrug concept as a potential approach to long-acting ARV injections. As a proof of concept, we synthesised model compounds containing the 4-carboxy-2-methyl Tokyo Green (CTG) fluorophore and assessed their stability under pH and temperature conditions that mimic those found in the subcutaneous (SC) tissue. Among them, probe 21 displayed very slow fluorophore release under SC-like conditions (98% of the fluorophore released over 15 d). Compound 25, a prodrug of the ARV agent raltegravir (RAL), was subsequently prepared and evaluated using the same conditions. This compound showed an excellent in vitro release profile, with a half-life (t½) of 19.3 d and 82% of RAL released over 45 d. In mice, 25 extended the half-life of unmodified RAL by 4.2-fold (t½ = 3.18 h), providing initial proof of concept of the ability of amino-AOCOM prodrugs to extend drug lifetimes in vivo. Although this effect was not as pronounced as seen in vitro—presumably due to enzymatic degradation and rapid clearance of the prodrug in vivo—the present results nevertheless pave the way for development of more metabolically stable prodrugs, to facilitate long-acting delivery of ARVs.

Funder

Monash University

Publisher

MDPI AG

Subject

Pharmaceutical Science

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3