QbD enabled Process Variable Study to Develop Sustained Release Chitosan-Alginate Embedded Delivery System for Improved Patient Compliance

Abstract The current investigation entail systematic Quality by Design (QbD)-enabled approach for the development of Sustained released embedded drug delivery systems of L-Arginine employing ionic gelation technique to attain improved patient compliance. Hence, in this QbD enabled systematic approach; quality target product profile (QTTP) was defined and critical quality attributes (CQAs) were identified. Further the risk assessment studies were undertaken through Ishikawa fish bone diagram to locate the critical material attributes (CMAs) and/or critical process parameters (CPPs) for the formulation of beads that may affect CQAs of drug product. A face centered central composite design (CCD) for two factors at three levels each with α =1 was employed for the optimization process to checkout the impact of concentration of sodium alginate and concentration of chitosan as CMAs which wereprior identified from risk assessment study and further evaluated for CQAs viz. bead size, swelling index and percent drug entrapment. The optimum formulation was embarked upon by using mathematical model being developed yielding desired CQAs. Thereby chitosan coated calcium-alginate delivery system was successfully developed by strategically employing QbD approach.In a nutshell, the presentinvestigation reports the successful development of optimized chitosan coated alginate beads employing QbD approach which can serve as a platform for other drugs too.

摘要 本研究采用基于质量源于设计（Quality by Design, QbD）的系统性方法，开发L-精氨酸的缓释包埋给药系统，采用离子凝胶法制备以提升患者依从性。在该基于QbD的系统性研究框架下，首先明确了质量目标产品概况（quality target product profile, QTTP）并鉴定了关键质量属性（critical quality attributes, CQAs）。随后通过石川鱼骨图开展风险评估研究，以定位影响药品关键质量属性的微丸处方关键物料属性（critical material attributes, CMAs）与/或关键工艺参数（critical process parameters, CPPs）。本优化过程采用二因素各三水平、α=1的面中心型中心复合设计（face centered central composite design, CCD），考察前期通过风险评估筛选出的关键物料属性——海藻酸钠浓度与壳聚糖浓度的影响，并对微丸粒径、溶胀度及药物包封率这几项关键质量属性进行评价。通过构建数学模型得到可实现预期关键质量属性的最优处方。最终，通过合理运用QbD方法，成功开发了壳聚糖包衣海藻酸钙给药系统。简言之，本研究成功通过QbD方法开发了优化的壳聚糖包衣海藻酸钙微丸，该系统亦可作为其他药物的开发平台。