Technische Universität Braunschweig, Institut für Pharmazeutische Technologie und Biopharmazie, Mendelssohnstr. 1, 38106 Braunschweig, Germany; Technische Universität Braunschweig, Zentrum für Pharmaverfahrenstechnik - PVZ, Franz-Liszt-Str. 35a, 38106 Braunschweig, Germany.
Technische Universität Braunschweig, Zentrum für Pharmaverfahrenstechnik - PVZ, Franz-Liszt-Str. 35a, 38106 Braunschweig, Germany; Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstr. 55, 38106 Braunschweig, Germany.
J Control Release. 2024 Oct;374:478-488. doi: 10.1016/j.jconrel.2024.08.021. Epub 2024 Aug 28.
In addition to the solubilization of poorly water-soluble, highly lipophilic drugs, lipid nanoemulsions bear potential for drug targeting approaches. This requires that the drug remains within the emulsion droplets until they reach the site of action. Since drug release is rather controlled by the lipophilicity of the drug than by the formulation, this study systematically investigated the influence of drug lipophilicity on the course of drug transfer in (physiological) acceptor media. An increase in drug lipophilicity, according to ClogD/P values, was achieved by the formation of lipophilic prodrugs of 5-phenylanthranilic acid - a potential pathoblocker. The range of substances was supplemented by orlistat, lumefantrine and cholesteryl acetate as model drugs. Drug transfer from supercooled trimyristin nanodroplets was determined via differential scanning calorimetry by monitoring their onset crystallization temperature, which decreases linearly with increasing drug content. Release of the model (pro)drugs ranged from burst to hardly any release in the order of the ClogD/P values. Except for cholesteryl acetate, the results were in line with the lipophilicity of the model (pro)drugs estimated by their retention times on a reversed-phase HPLC column under isocratic conditions. An approximate prediction of drug release kinetics was, thus, possible by logP calculations and, to a limited extent, also by reversed-phase HPLC. A further finding was the increased drug loading capacity of the lipid nanoemulsion for lipophilic prodrugs, if the structural changes of the parent compound were accompanied by a lower melting point.
除了增溶脂溶性差、亲脂性高的药物外，脂质纳米乳还具有药物靶向的潜力。这要求药物在到达作用部位之前保持在乳液滴中。由于药物释放主要受药物的亲脂性控制，而不是制剂，因此本研究系统地研究了药物亲脂性对（生理）接受介质中药物传递过程的影响。通过形成 5-苯丙氨酸的亲脂性前药，可提高药物的亲脂性，根据 ClogD/P 值，5-苯丙氨酸是一种潜在的病理阻断剂。该物质范围由奥利司他、盐酸左旋咪唑和醋酸胆固醇补充。通过监测过冷三硬脂酸纳米液滴的起始结晶温度，用差示扫描量热法确定药物从超冷三硬脂酸纳米液滴中的转移情况，起始结晶温度随药物含量的增加呈线性下降。模型（前）药物的释放范围从突释到几乎没有释放，按照 ClogD/P 值的顺序。除了醋酸胆固醇外，结果与模型（前）药物的亲脂性一致，这是根据它们在等度条件下反相 HPLC 柱上的保留时间估计的。因此，通过 logP 计算和在一定程度上通过反相 HPLC 可以对药物释放动力学进行近似预测。进一步的发现是，如果母体化合物的结构变化伴随着更低的熔点，脂质纳米乳对亲脂性前药的药物载药量增加。
