Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable
Saquinavir Loaded Acetalated Dextran Microconfetti - a Long Acting Protease Inhibitor Injectable
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DOI：
10.1007/s11095-016-1936-y
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发表时间：
2016-08-01
影响因子：
3.7
通讯作者：
Ainslie, Kristy M.
中科院分区：
文献类型：
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作者：
Collier, Michael A.;Gallovic, Matthew D.;Ainslie, Kristy M.
自从采用高效抗逆转录病毒疗法以来，艾滋病毒疾病的进展在世界各地都有所减缓;然而，患者经常需要通过口服途径每天服用多种生物利用度差的药物，导致胃肠道刺激。最近，长效抗逆转录病毒注射剂（一次给药数月）已进入后期临床试验阶段。不幸的是，这些固相晶体制剂在潜在的剂量倾倒方面具有固有的缺点，并且与聚合物制剂相比，药物突释的可能性更大。然后使用研磨技术将这些支架加工成注射剂，称为沙奎那韦微粒。Microconfetti的体外和体内释放动力学进行了分析。高沙奎那韦负载缩醛化葡聚糖电纺纤维能够形成和加工成沙奎那韦microconfetti，而其他聚合物，如聚乳酸-羟基乙酸和聚己内酯不能这样做。沙奎那韦微粒释放动力学能够通过载药量和聚合物降解速率来调节。在体内，单次皮下注射沙奎那韦microconfetti释放药物超过一周，具有大的组织保留。Microconfetti是一种独特的可调长效注射剂，可减少粘附相关的HIV耐药性的形成。我们的研究结果表明，可注射微粒给药系统可用于沙奎那韦和其他疏水性小分子药物的长效控制释放。
Since the adoption of highly active antiretroviral therapy, HIV disease progression has slowed across the world; however, patients are often required to take multiple medications daily of poorly bioavailable drugs via the oral route, leading to gastrointestinal irritation. Recently, long acting antiretroviral injectables that deliver drug for months at a time have moved into late phase clinical trials. Unfortunately, these solid phase crystal formulations have inherent drawbacks in potential dose dumping and a greater likelihood for burst release of drug compared to polymeric formulations.Using electrospinning, acetalated dextran scaffolds containing the protease inhibitor saquinavir were created. Grinding techniques were then used to process these scaffolds into injectables which are termed saquinavir microconfetti. Microconfetti was analyzed for in vitro and in vivo release kinetics.Highly saquinavir loaded acetalated dextran electrospun fibers were able to be formed and processed into saquinavir microconfetti while other polymers such as poly lactic-co-glycolic acid and polycaprolactone were unable to do so. Saquinavir microconfetti release kinetics were able to be tuned via drug loading and polymer degradation rates. In vivo, a single subcutaneous injection of saquinavir microconfetti released drug for greater than a week with large tissue retention.Microconfetti is a uniquely tunable long acting injectable that would reduce the formation of adherence related HIV resistance. Our findings suggest that the injectable microconfetti delivery system could be used for long acting controlled release of saquinavir and other hydrophobic small molecule drugs.