Ramos Yacasi Gladys Rosario, Calpena Campmany Ana Cristina, Egea Gras María Antonia, Espina García Marta, García López María Luisa
a Department of Pharmacy and Pharmaceutical Technology and Physical Chemistry , Universitat de Barcelona Facultat de Farmacia y Ciencias de la Alimentación , Barcelona , Spain.
Drug Dev Ind Pharm. 2017 Apr;43(4):637-651. doi: 10.1080/03639045.2016.1275669. Epub 2017 Jan 22.
The stabilization of flurbiprofen loaded poly-ɛ-caprolactone nanoparticles (FB-PɛCL-NPs) for ocular delivery under accurate freeze-drying (FD) process provides the basis for a large-scale production and its commercial development.
Optimization of the FD to improve long-term stability of ocular administration's FB-PɛCL-NPs.
FB-PɛCL-NPs were prepared by solvent displacement method with poloxamer 188 (P188) as stabilizer. Freezing and primary drying (PD) were studied and optimized through freeze-thawing test and FD microscopy. Design of experiments was used to accurate secondary drying (SD) conditions and components concentration. Formulations were selected according to desired physicochemical properties. Furthermore, differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to study interactions components.
Optimized FB-PɛCL-NPs, stabilized with 3.5% (w/w) P188 and protected with 8% (w/w) poly(ethylene glycol), was submitted to precooling at +10 °C for 1 h, freezing at -50 °C for 4 h, PD at +5 °C and 0.140 mbar for 24 h and a SD at +45 °C during 10 h. These conditions showed 188.4 ± 1.3 nm, 0.087 ± 0.014, 85.5 ± 1.4%, 0.61 ± 0.12%, -16.4 ± 0.1 mV and 325 ± 7 mOsm/kg of average size, polydispersity index, entrapment efficiency, residual moisture, surface charge and osmolality, respectively. It performed a long-term stability >12 months. DSC and XRD spectra confirmed adequate chemical interaction between formulation components and showed a semi-crystalline state after FD.
An optimal freeze dried ocular formulation was achieved. Evidently, the successful design of this promising colloidal system resulted from rational cooperation between a good formulation and the right conditions in the FD process.
在精确冷冻干燥（FD）过程中稳定负载氟比洛芬的聚-ε-己内酯纳米颗粒（FB-PɛCL-NPs）用于眼部给药，为大规模生产及其商业开发提供了基础。
优化冷冻干燥工艺以提高眼部给药的FB-PɛCL-NPs的长期稳定性。
采用溶剂置换法，以泊洛沙姆188（P188）为稳定剂制备FB-PɛCL-NPs。通过冻融试验和FD显微镜对冷冻和一次干燥（PD）进行研究和优化。采用实验设计确定二次干燥（SD）条件和组分浓度。根据所需的物理化学性质选择制剂。此外，采用差示扫描量热法（DSC）和X射线衍射法（XRD）研究组分间的相互作用。
优化后的FB-PɛCL-NPs用3.5%（w/w）P188稳定，并用8%（w/w）聚乙二醇保护，在+10℃预冷1小时，在-50℃冷冻4小时，在+5℃和0.140毫巴下进行24小时的一次干燥，在+45℃下进行10小时的二次干燥。这些条件下，平均粒径、多分散指数、包封率、残留水分、表面电荷和渗透压分别为188.4±1.3nm、0.087±0.014、85.5±1.4%、0.61±0.12%、-16.4±0.1mV和325±7mOsm/kg。其长期稳定性大于12个月。DSC和XRD光谱证实制剂组分之间有充分的化学相互作用，并显示冷冻干燥后为半结晶状态。
获得了一种优化的冻干眼部制剂。显然，这种有前景的胶体系统的成功设计源于良好的制剂与冷冻干燥过程中合适条件之间的合理配合。
