Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen O, Denmark.
Pharm Res. 2013 Nov;30(11):2772-84. doi: 10.1007/s11095-013-1096-2. Epub 2013 Jun 22.
The purpose of this study was to identify and optimize spray drying parameters of importance for the design of an inhalable powder formulation of a cationic liposomal adjuvant composed of dimethyldioctadecylammonium (DDA) bromide and trehalose-6,6'-dibehenate (TDB).
A quality by design (QbD) approach was applied to identify and link critical process parameters (CPPs) of the spray drying process to critical quality attributes (CQAs) using risk assessment and design of experiments (DoE), followed by identification of an optimal operating space (OOS). A central composite face-centered design was carried out followed by multiple linear regression analysis.
Four CQAs were identified; the mass median aerodynamic diameter (MMAD), the liposome stability (size) during processing, the moisture content and the yield. Five CPPs (drying airflow, feed flow rate, feedstock concentration, atomizing airflow and outlet temperature) were identified and tested in a systematic way. The MMAD and the yield were successfully modeled. For the liposome size stability, the ratio between the size after and before spray drying was modeled successfully. The model for the residual moisture content was poor, although, the moisture content was below 3% in the entire design space. Finally, the OOS was drafted from the constructed models for the spray drying of trehalose stabilized DDA/TDB liposomes.
The QbD approach for the spray drying process should include a careful consideration of the quality target product profile. This approach implementing risk assessment and DoE was successfully applied to optimize the spray drying of an inhalable DDA/TDB liposomal adjuvant designed for pulmonary vaccination.
本研究旨在确定和优化喷雾干燥参数，以设计一种由二甲基双十八烷基溴化铵（DDA）和海藻糖-6,6'-二硬脂酸酯（TDB）组成的阳离子脂质体佐剂的可吸入粉末制剂。
采用质量源于设计（QbD）方法，通过风险评估和实验设计（DoE），将喷雾干燥过程的关键工艺参数（CPP）与关键质量属性（CQA）联系起来，然后确定最佳操作空间（OOS）。进行了中心复合面心设计，然后进行多元线性回归分析。
确定了 4 个 CQA；空气动力学质量中值直径（MMAD）、脂质体在加工过程中的稳定性（大小）、水分含量和收率。以系统的方式确定和测试了 5 个 CPP（干燥气流、进料流速、进料浓度、雾化气流和出口温度）。成功地对 MMAD 和收率进行了建模。对于脂质体粒径稳定性，成功地对喷雾干燥前后的粒径比进行了建模。残留水分含量的模型较差，尽管在整个设计空间中水分含量都低于 3%。最后，从构建的喷雾干燥海藻糖稳定的 DDA/TDB 脂质体模型中起草了 OOS。
喷雾干燥工艺的 QbD 方法应包括仔细考虑质量目标产品特性。这种实施风险评估和 DoE 的方法成功地应用于优化设计用于肺部接种的可吸入 DDA/TDB 脂质体佐剂的喷雾干燥。
