Hybrid insulin cocrystals for controlled release delivery
Hybrid insulin cocrystals for controlled release delivery
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DOI：
10.1038/nbt722
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发表时间：
2002-08-01
影响因子：
46.9
通讯作者：
Myers, SR
中科院分区：
文献类型：
--
作者：
Brader, ML;Sukumar, M;Myers, SR
通过操纵其制剂基质来定制药物释放曲线的能力提供了重要的治疗优势。我们在这里表明，人胰岛素可以与完全活性的亲脂修饰的胰岛素衍生物辛酰基-N-LysB 29-人胰岛素（C8-HI）以预选的比例共结晶。共晶体类似于与人胰岛素形成的NPH（中性鱼精蛋白哈格多恩）晶体复合物，人胰岛素通常用作糖尿病治疗的长效胰岛素组分。共晶体的体外和体内释放速率可以通过调节两种胰岛素组分的相对比例来控制。我们鉴定了包含75%C8-HI和25%人胰岛素的共晶组合物，其在生长抑素处理的比格犬中表现出接近理想的基础药效学。释放速率对共晶比例的依赖性为调节胰岛素药效学提供了一种稳健的机制。这些发现表明，晶体蛋白质基质可以容纳化学修饰，其以治疗上有用的方式改变晶体的溶解速率，但其结构上无害，足以保持原始微晶实体的药物完整性和母体分子的药理活性。
The ability to tailor the release profile of a drug by manipulating its formulation matrix offers important therapeutic advantages. We show here that human insulin can be cocrystallized at preselected ratios with the fully active lipophilically modified insulin derivative octanoyl-N-LysB29-human insulin (C8-HI). The cocrystal is analogous to the NPH (neutral protamine Hagedorn) crystalline complex formed with human insulin, which is commonly used as the long-acting insulin component of diabetes therapy. The in vitro and in vivo release rates of the cocrystal can be controlled by adjusting the relative proportions of the two insulin components. We identified a cocrystal composition comprising 75% C8-HI and 25% human insulin that exhibits near-ideal basal pharmacodynamics in somatostatin-treated beagle dogs. The dependence of release rate on cocrystal ratio provides a robust mechanism for modulating insulin pharmacodynamics. These findings show that a crystalline protein matrix may accommodate a chemical modification that alters the dissolution rate of the crystal in a therapeutically useful way, yet that is structurally innocuous enough to preserve the pharmaceutical integrity of the original microcrystalline entity and the pharmacological activity of the parent molecule.