从多囊脂质体中探测布比卡因药物释放的机制。
Probing the mechanism of bupivacaine drug release from multivesicular liposomes.
机构信息
Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA; Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, USA.
Division of Biology, Chemistry and Materials Science, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, Food and Drug Administration, Silver Spring, MD 20993, USA.
出版信息
J Control Release. 2019 Jan 28;294:279-287. doi: 10.1016/j.jconrel.2018.12.029. Epub 2018 Dec 18.
The mechanism of drug release from complex dosage forms, such as multivesicular liposomes (MVLs), is complex and oftentimes sensitive to the release environment. This challenges the design and development of an appropriate in vitro release test (IVRT) method. In this study, a commercial bupivacaine MVL product was selected as a model product and an IVRT method was developed using a modified USP 2 apparatus in conjunction with reverse-dialysis membranes. This setup allowed the use of in situ UV-Vis probes to continuously monitor the drug concentration during release. In comparison to the traditional sample-and-separate methods, the new method allowed for better control of the release conditions allowing for study of the drug release mechanism. Bupivacaine (BPV) MVLs exhibited distinct tri-phasic release characteristics comprising of an initial burst release, lag phase and a secondary release. Temperature, pH, agitation speed and release media composition were observed to impact the mechanism and rate of BPV release from MVLs. The size and morphology of the MVLs as well as their inner vesicle compartments were analyzed using cryogenic-scanning electron microscopy (cryo-SEM), confocal laser scanning microscopy and laser diffraction, where the mean diameters of the MVLs and their inner "polyhedral" vesicles were found to be 23.6 ± 11.5 μm and 1.52 ± 0.44 μm, respectively. Cryo-SEM results further showed a decrease in particle size and loss of internal "polyhedral" structure of the MVLs over the duration of release, indicating erosion and rearrangement of the lipid layers. Based on these results a potential MVL drug release mechanism was proposed, which may assist with the future development of more biorelevant IVRT method for similar formulations.
复杂剂型（如多泡脂质体（MVL））的药物释放机制复杂，且通常对释放环境敏感。这给适当的体外释放测试（IVRT）方法的设计和开发带来了挑战。在本研究中，选择了一种商业布比卡因 MVL 产品作为模型产品，并使用改良的 USP 2 装置结合反向透析膜开发了一种 IVRT 方法。该设置允许使用原位 UV-Vis 探头在释放过程中连续监测药物浓度。与传统的取样和分离方法相比，新方法可以更好地控制释放条件，从而可以研究药物释放机制。布比卡因（BPV）MVL 表现出明显的三相释放特征，包括初始突释、迟滞期和二次释放。温度、pH 值、搅拌速度和释放介质组成被观察到会影响 MVL 中 BPV 的释放机制和速率。使用低温扫描电子显微镜（cryo-SEM）、共聚焦激光扫描显微镜和激光衍射分析了 MVL 的大小和形态及其内部囊泡隔室，发现 MVL 的平均直径及其内部“多面体形”囊泡分别为 23.6±11.5μm 和 1.52±0.44μm。cryo-SEM 结果进一步表明，在释放过程中，MVL 的粒径减小且内部“多面体形”结构丢失，表明脂质层的侵蚀和重排。基于这些结果，提出了一种潜在的 MVL 药物释放机制，这可能有助于未来开发更具生物学相关性的类似制剂的 IVRT 方法。
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