Hussain Md Saddam, Faisal Khandokar Sadique, Clulow Andrew J, Albrecht Hugo, Krasowska Marta, Blencowe Anton
Applied Chemistry and Translational Biomaterials (ACTB) Group, Centre for Pharmaceutical Innovation (CPI), UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.
Australian Synchrotron, Australian Nuclear Science and Technology Organisation (ANSTO), 800 Blackburn Road, Clayton, Melbourne, VIC 3168, Australia.
Polymers (Basel). 2023 Apr 21;15(8):1974. doi: 10.3390/polym15081974.
Polymeric micelles are promising carriers for the delivery of poorly water-soluble drugs, providing enhanced drug solubility, blood circulation times, and bioavailability. Nevertheless, the storage and long-term stability of micelles in solution present challenges requiring the lyophilization and storage of formulations in the solid state, with reconstitution immediately prior to application. Therefore, it is important to understand the effects of lyophilization/reconstitution on micelles, particularly their drug-loaded counterparts. Herein, we investigated the use of β-cyclodextrin (β-CD) as a cryoprotectant for the lyophilization/reconstitution of a library of poly(ethylene glycol--ε-caprolactone) (PEG--PCL) copolymer micelles and their drug-loaded counterparts, as well as the effect of the physiochemical properties of different drugs (phloretin and gossypol). The critical aggregation concentration (CAC) of the copolymers decreased with increasing weight fraction of the PCL block (), plateauing at ~1 mg/L when the was >0.45. The blank (empty) and drug-loaded micelles were lyophilized/reconstituted in the absence and presence of β-CD (9% /) and analyzed via dynamic light scattering (DLS) and synchrotron small-angle X-ray scattering (SAXS) to assess for changes in aggregate size (hydrodynamic diameter, ) and morphology, respectively. Regardless of the PEG--PCL copolymer or the use of β-CD, the blank micelles displayed poor redispersibility (<10% relative to the initial concentration), while the fraction that redispersed displayed similar to the as-prepared micelles, increasing in as the of the PEG--PCL copolymer increased. While most blank micelles displayed discrete morphologies, the addition of β-CD or lyophilization/reconstitution generally resulted in the formation of poorly defined aggregates. Similar results were also obtained for drug-loaded micelles, with the exception of several that retained their primary morphology following lyophilization/reconstitution, although no obvious trends were noted between the microstructure of the copolymers or the physicochemical properties of the drugs and their successful redispersion.
聚合物胶束是用于递送难溶性药物的有前景的载体，可提高药物的溶解度、血液循环时间和生物利用度。然而，胶束在溶液中的储存和长期稳定性存在挑战，这需要将制剂冻干并以固态储存，并在使用前立即复溶。因此，了解冻干/复溶对胶束的影响，特别是对载药胶束的影响非常重要。在此，我们研究了使用β-环糊精（β-CD）作为冷冻保护剂，用于聚（乙二醇-ε-己内酯）（PEG-PCL）共聚物胶束库及其载药对应物的冻干/复溶，以及不同药物（根皮素和棉酚）的物理化学性质的影响。共聚物的临界聚集浓度（CAC）随着PCL嵌段重量分数（）的增加而降低，当>0.45时，在~1 mg/L处达到平稳。空白（空的）和载药胶束在不存在和存在β-CD（9% /）的情况下进行冻干/复溶，并通过动态光散射（DLS）和同步加速器小角X射线散射（SAXS）分别分析聚集体尺寸（流体动力学直径，）和形态的变化。无论PEG-PCL共聚物如何或是否使用β-CD，空白胶束的再分散性都很差（相对于初始浓度<10%），而重新分散的部分显示出与制备的胶束相似的，随着PEG-PCL共聚物的增加而增加。虽然大多数空白胶束呈现离散形态，但添加β-CD或冻干/复溶通常会导致形成定义不明确的聚集体。载药胶束也获得了类似的结果，除了少数在冻干/复溶后保留其原始形态的胶束外，尽管在共聚物的微观结构或药物的物理化学性质与其成功再分散之间没有明显的趋势。
