Quality by Design(QbD) : Development and Optimization of Sustained-Release Formulation of Tamsulosin Hydrochloride by Fluid-Bed Coating

국문 초록 (Abstract)

본 연구의 목적은 탐스로신 염산염의 부작용을 줄이기 위해 유동층 코팅 기술과 QbD 원리를 적용시켜 최적의 tamsulosin hydrochloride sustained-release pellets (TSP) 제형을 개발하는 것이다. 사전 지식과 예비 위험 분석을 기반으로 품질 특성 (QA)을 설정하였으며, 주요 품질 특성 (CQAs)는 위해 분석을 통해 정의되었다. Failure Mode effect critical analysis (FMEA)의 분석 결과로 위험도가 큰 변수들이 결정되었다. 그 결과, 방출 2 시간, 2.5 시간, 3 시간, 6 시간의 변수가 탐스로신 염산염 서방화 제형의 주요 품질 특성으로 정해졌다. 또한, 주요 물질 특성 (Ethylcellulose, Eudragit S100, Bead size)과 주요 공정 특성 (Atomizing air pressure)으로 총 4가지 주요 변수가 정해졌다. 반응 표면 분석법을 통한 박스-벤켄법을 사용하여 주요 변수들을 최적화하였고, 설계 공간을 확정하였다. 그 결과, CQA에 대한 최적 모델은 각각 R2이 80 이상, lack of fit도 p > 0.05으로 적합하였다. 최적화된 모델을 통해 예측된 다항식과 설계 공간으로 밸리데이션 실험을 진행한 결과, 실제 값과 예측 값 사이에 90% 이상의 정확도를 얻었으며 매우 좋은 상관 관계가 확립되었다. 설계 공간 내에서 선택된 조건에 의해 제조된 탐스로신 염산염 서방화 제형은 시판 제제인 Harunal®-D의 방출 프로파일과 유사하게 나타났다. 결론적으로, 본 연구에서는 탐스로신 염산염과 유사한 성질을 가진 다른 저용량 약물에도 QbD 원리가 적용될 수 있음을 입증하였다.

다국어 초록 (Multilingual Abstract)

The purpose of this study was to development and optimization of material and process of tamsulosin hydrochloride sustained-release pellets (TSP) to control release and decrease side effects by applying QbD principles and fluid-bed coating. Quality attributes (QAs) were set based on prior knowledge and by preliminary risk analysis, and critical quality attributes (CQAs) were selected by failure mode and effect analysis (FMEA) based on preliminary experiment. Summary of these results, release at 2.0 hours, 2.5 hours, 3.0 hours and 6.0 hours were chosen as CQAs of TSP. The resultant critical material attributes (Ethylcellulose, Eudragit S100, Bead size) and process parameter (Atomizing air pressure) were selected. Box-behnken design through response surface methodology was performed to optimize key variables and design space was determined. As a result, the optimal model on CQAs respectively provide the most appropriate fit (R2>80) and has no significant lack of fit (p > 0.05). The prediction equations and design spaces were established from the selected optimal models, it was confirmed by validation that the very good correlation with accuracy over 90% was obtained between the actual and predicted values. The optimal models exhibited similarly release profiles with Harunal®-D tablets. In conclusion, the methodologies based on QbD principles in this study may be applicable to other low dose drugs with similar properties to tamsulosin hydrochloride.

목차 (Table of Contents)

• Ⅰ. Introduction 1
• Ⅱ. Purpose 4
• Ⅲ. Materials & Methods 5
• 1. Materials 5
• 2. Preparation of TSP 6
• 3. Characterization of TSP 7
• 3.1 In vitro drug release tests 7
• 3.2 Drug loading amounts (%) 8
• 3.3 Content uniformity study 8
• 3.4 Morphology 9
• 3.5 Powder rheology 9
• 4. Screening by risk analysis 10
• 5. Optimization study by Box-behnken design 10
• 6. Stability Studies 12
• Ⅳ. Results and Discussion 13
• 1. Identification of CQAs for TSP by criticality assessment 13
• 2. Optimization of materials and process variables 15
• 3. Establishment and validation of design space 25
• 4. Post-optimization 29
• 5. Content uniformity study of optimized TSP 30
• 6. Morphology and Powder rheology tests of optimized TSP 31
• 7. Stability studies of optimized TSP 33
• 8. Release tests of optimized TSP 34
• Ⅴ. Conclusion 35
• Ⅵ. References 36