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研究生： 沈文宗
Shen, Wen-Tsung
論文名稱： 體外溶離與體內表現評估作為口服藥品開發策略之研究
Assessment of In Vitro Dissolution and In Vivo Performance as a Strategy for Oral Drug Product Development
指導教授： 周辰熹
Chou, Chen-Hsi
學位類別： 博士
Doctor
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2026
畢業學年度： 114
語文別： 英文
論文頁數： 118
中文關鍵詞： 體外溶離 、體內表現 、體外－體內相關性 、生體相等性 、口服製劑
外文關鍵詞： In vitro dissolution, In vivo performance, In vitro–in vivo correlation (IVIVC), Oral drug products, Bioequivalence
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    • 本論文探討口服製劑之體外溶離行為與體內藥動學表現間之關聯性，並評估影響藥物吸收之關鍵因素。論文內容包含三項代表性研究：以 olmesartan medoxomil 探討主成分粒徑對溶離與吸收之影響並建立 Level A IVIVC 模型；以 olanzapine 口溶錠評估製程差異對體外溶離及生體相等性之影響；以 pantoprazole 腸溶錠分析空腹與進食條件下之藥動學表現及相關影響因素。研究結果顯示，對於低溶解度藥物（例如BCS Class II）或呈現溶離受限吸收特性之系統，適當設計且具鑑別力之體外溶離試驗可與體內表現建立良好關聯性，並透過 IVIVC 模型有效預測藥動學表現。此外，即使為 BCS Class II 藥物，當劑型設計可使藥物快速溶離時，製程差異對體內表現之影響可能相對有限。本研究建立體外溶離與體內表現之整合性評估架構，可作為口服藥品開發及生體相等性評估之重要參考。

    This dissertation investigates the relationship between in vitro dissolution behavior and in vivo pharmacokinetic performance of oral drug products and evaluates the key factors influencing drug absorption. The research comprises three representative studies. The first study examined the effect of active pharmaceutical ingredient (API) particle size on the dissolution and absorption of olmesartan medoxomil establishing a Level A in vitro–in vivo correlation (IVIVC). The second study evaluated the impact of manufacturing differences on the dissolution behavior and bioequivalence of olanzapine orally disintegrating tablets (ODTs). The third study investigated the pharmacokinetic performance of pantoprazole enteric-coated tablets under fasting and fed conditions and assessed factors affecting drug absorption.
    The results demonstrated that, for low-solubility drugs (such as BCS Class II) or systems exhibiting dissolution-limited absorption, appropriately designed and discriminatory dissolution methods can establish meaningful correlations with in vivo performance and enable reliable prediction of pharmacokinetic behavior through IVIVC modeling. Furthermore, even for BCS Class II drugs, the impact of manufacturing differences on in vivo performance may be limited when formulation design enables rapid drug dissolution. This dissertation establishes an integrated framework linking in vitro dissolution and in vivo performance and provides scientific support for oral drug product development and bioequivalence assessment.

    Certificate of Approval for Doctoral Dissertation I Abstract II Introduction III Material and Methods V Results and Discussion VI Conclusion VIII 中文摘要 IX Acknowledgments XV Chapter 1. General Introduction and Outline of the Dissertation 1 1.1 Background and Factors Influencing Oral Drug Absorption 1 1.2 Impact of Particle Size on Drug Dissolution and Absorption 3 1.3 Impact of Formulation Design and Manufacturing Processes on Drug Absorption 4 1.4 Impact of Dosage Form Design and Physiological Factors on Drug Absorption 5 1.5 Relationship Between In Vitro Dissolution and In Vivo Performance 6 1.6 Challenges in Predicting In Vivo Performance During Oral Drug Product Development 8 1.7 Integrated Assessment Across the Three Studies 9 1.8 Objectives of This Dissertation 11 Chapter 2. Influence of API Particle Size on In Vitro Dissolution and In Vivo Pharmacokinetics of Olmesartan: An Exploratory IVIVC Study 12 2.1 Abstract 12 2.2 Introduction 12 2.3 Materials and Methods 14 2.3.1 Materials 14 2.3.2 Preparation of Formulations 14 2.3.3 Particle Size Characterization 15 2.3.4 In Vitro Dissolution Study 15 2.3.5 In Vivo Pharmacokinetic Study 15 2.3.6 IVIVC Model Development and Validation 16 2.4 Results 20 2.4.1 API Particle Size Distribution 20 2.4.2 In Vitro Dissolution Profiles 21 2.4.3 Pharmacokinetic Profiles 23 2.4.4 Relationship Between Tmax and Cmax 24 2.4.5 In Vitro–In Vivo Correlation (IVIVC) 26 2.5 Discussion 28 2.5.1 Impact of API Particle Size on Dissolution Behavior 28 2.5.2 Impact of Dissolution on Pharmacokinetic Performance 29 2.5.3 Establishment and Significance of IVIVC 29 2.5.4 Role of Dissolution Media in Discriminatory Testing 30 2.5.5 Implications for Formulation Development and Regulatory Perspective 31 2.5.6 Study Limitations and Future Perspectives 31 2.6 Conclusion 32 Chapter 3. Assessment of Bioequivalence Between Generic and Branded Olanzapine ODTs Manufactured by Different Processes 33 3.1 Abstract 33 3.2 Introduction 33 3.3 Materials and Methods 35 3.3.1 Chemicals and Reagents 35 3.3.2 In Vitro Dissolution Test 35 3.3.3 In Vivo Bioequivalence Study 36 3.4 Results 38 3.4.1 Comparison of Formulation Composition and Dosage Form 38 3.4.2 In Vitro Relevant Comparison 39 3.4.3 Pharmacokinetic Analysis 40 3.5 Discussion 43 3.5.1 Biopharmaceutics Background 43 3.5.2 Formulation Design and Manufacturing Differences 44 3.5.3 In Vitro Dissolution Behavior 45 3.5.4 Pharmacokinetic Performance and Safety 45 3.5.5 Interpretation of Bioequivalence 45 3.5.6 Influence of Physiological and Genetic Factors 46 3.5.7 Individual Variability and Final Confirmation of Bioequivalence 47 3.6 Conclusion 49 Chapter 4. Influence of Food Effect and Inter-Subject Pharmacokinetic Variability on Pantoprazole Bioequivalence 50 4.1 Abstract 50 4.2 Introduction 50 4.3 Materials and Methods 52 4.3.1 Study Products 52 4.3.2 Chemicals and Reagents 52 4.3.3 In Vitro Disintegration Test 53 4.3.4 In Vitro Dissolution Test 53 4.3.5 In Vivo Bioequivalence Study 54 4.4 Results 58 4.4.1 Formulation Architecture Comparison 58 4.4.2 In Vitro Evaluation 59 4.4.3 In Vivo Pharmacokinetic Analysis 61 4.4.4 Identification of Exposure Subgroups 66 4.5 Discussion 67 4.5.1 Introduction to formulation challenges 67 4.5.2 In Vitro Performance of Test and Reference Formulations 68 4.5.3 Clinical Pharmacokinetics and Bioequivalence Outcomes 69 4.5.4 Effect of Food on Drug Absorption 69 4.5.5 Inter-Individual Variability and Exposure Subgroups 70 4.5.6 Clinical Implications 72 4.6 Conclusion 73 Chapter 5. General Conclusion and Future Perspectives 75 5.1 General Conclusion 75 5.2 Future Perspectives 78 References 79 Appendix 84 Appendix A: Ethics Approval (IRB Documents) 84 Appendix B: Product Appearance (Test vs. Reference). 89 Appendix C. Supplementary Pharmacokinetic Analysis 93

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