Cover -- Title Page -- Copyright Page -- Contents -- Preface -- List of Contributors -- Part I Understanding of Physiology and Anatomy - Factors Influencing Drug Release and Absorption from MR Formulations -- Chapter 1a Composition of Gastric Fluids Under Fasting and Fed Conditions -- 1a.1 Gastric Volume -- 1a.2 Gastric Acid -- 1a.3 Buffer Capacity -- 1a.4 Mucus/Viscosity -- 1a.5 Enzymes -- 1a.6 Surface Tension -- 1a.7 Osmolality -- 1a.8 Duodenogastric Reflux -- References -- Chapter 1b Composition of the Small Intestinal Contents Under Fasting and Fed Conditions -- 1b.1 Small Intestinal Volume -- 1b.2 pH Profile Along the Small Intestine -- 1b.3 Composition of the Luminal Contents -- 1b.3.1 Bile -- 1b.3.2 Phospholipids -- 1b.3.3 Monoglycerides and Free Fatty Acids -- 1b.4 Other Characteristics of Small Intestinal Fluids -- 1b.4.1 Buffer Capacity -- 1b.4.2 Osmolality -- 1b.4.3 Surface Tension -- 1b.4.4 Ionic Strength -- 1b.4.5 Viscosity -- 1b.5 Influence of Age, Gender, and Disease on the Small Intestinal Composition -- References -- Chapter 1c The Luminal Environment in the Proximal Colon -- 1c.1 Volume of Luminal Contents -- 1c.1.1 Liquid Contents -- 1c.1.2 Aspirated Contents and Liquid Fractions -- 1c.2 Luminal pH Values -- 1c.2.1 Data Collected with Telemetric Capsules -- 1c.2.2 Data Collected with Aspirated Samples -- 1c.3 Buffer Capacity -- 1c.4 Characteristics of Liquid Fraction of Contents -- 1c.5 Concluding Remarks -- References -- Chapter 2 Gastrointestinal Transit and Hydrodynamics Under Fasting and Fed Conditions -- 2.1 Introduction -- 2.2 Imaging Techniques Used for Assessment of Transit Times and Hydrodynamics -- 2.3 Oral Cavity and Esophagus -- 2.4 Stomach -- 2.5 Small Intestine -- 2.6 Large Intestine -- 2.7 Whole Gut Transit Time -- 2.8 Therapy-Related Effects on GI Transit.

2.9 Motility Disorders Affecting the GI Transit of Oral Dosage Forms -- 2.10 Patient-Related Effects on GI Transit -- 2.10.1 Age -- 2.10.2 Gender -- 2.10.3 Dietary and Smoking Habits -- 2.11 Conclusion -- References -- Chapter 3 Intestinal Epithelium and Drug Transporters -- 3.1 Introduction: Oral Drug Absorption General Mechanisms and Influencing Factors -- 3.2 Expression of Drug Transporters in the Intestinal Epithelium -- 3.3 Uptake Transporters Present at the Intestinal Level -- 3.4 Regional Distribution of Uptake Transporters -- 3.5 Efflux Transporters at the Intestinal Level -- 3.6 Regional Distribution of Efflux Transporters -- 3.7 Impact of the Regional Distribution of Enzymes and Transporters in the Intestine on the Enzyme/Transporter Interplay -- 3.8 Species Differences in Regional Expression of Uptake and Efflux Transporters -- 3.9 Models for Regional Assessment of Intestinal Permeability -- 3.10 Use of PBPK to Integrate Formulation and Permeation Knowledge -- 3.11 Impact of Regional Solubility and Permeability Along the Intestine -- 3.12 Formulation Excipients and Their Potential Modulatory Effects on Transporters -- 3.13 Other Confounding Factors Affecting Drug Intestinal Absorption -- 3.14 Drug-Drug Interactions -- 3.15 Conclusion and Future Challenges -- References -- Chapter 4 The Interplay Between Drug Release and Intestinal Gut-Wall Metabolism -- 4.1 The Role of Gut Wall Metabolism in Determining Oral Bioavailability -- 4.1.1 Cytochrome P450's (CYPs) -- 4.1.2 Uridine 5-Diphosphate Glucuronosyltransferases (UGTs) -- 4.1.3 Sulfotransferases (SULTs) -- 4.1.4 Other Drug-Metabolizing Enzymes in the Gut-Wall -- 4.1.5 Luminal Degradation in the Gut -- 4.2 Factors Affecting Gut Wall Metabolism -- 4.2.1 Absorption -- 4.2.2 Mucosal Blood Flow -- 4.2.3 Protein Binding -- 4.2.4 Metabolic Drug-Drug Interactions.

4.2.5 Intestinal Transporter-Metabolism Interplay -- 4.3 Preclinical and Clinical In Vivo and In Situ Models for Studying Intestinal Metabolism -- 4.4 In Vitro Assays for Studying Intestinal Metabolism -- 4.5 Models for Studying Bacterial Degradation -- 4.6 In Vitro-In Vivo Extrapolation of Metabolic Clearance and In Silico Models for Predicting In Vivo Gut Wall Metabolism -- 4.7 Oral Extended-Release Formulations and Gut Wall Metabolism -- 4.8 Excipient Effects on Gut Wall Metabolism -- 4.9 Considerations for Intestinal Metabolism in Special Populations -- 4.10 Summary -- References -- Part II Design of MR Formulations - Considerations, Mechanisms and Technologies -- Chapter 5 Preformulation Considerations for Design of Oral Modified-Release Products -- 5.1 Introduction -- 5.2 Purpose of MR Formulations -- 5.3 Means to Obtain MR Drug Products -- 5.3.1 Physicochemical Characterization of the Drug Substance and its Impact on the Design of Modified-release Dosage Forms -- 5.4 Ionization Constant - pKa -- 5.5 Lipophilicity -- 5.6 Solubility -- 5.7 Chemical Stability -- 5.8 Solid State Characterization -- 5.9 Compatibility with Excipients -- 5.10 Permeability and Metabolism -- 5.10.1 Additional Early Drug Substance Testing -- 5.11 Regional Absorption -- 5.12 Microbial Stability -- 5.12.1 Early Performance Testing of Formulations -- 5.13 Quality by Design (QbD) for MR formulations -- 5.14 Conclusions -- References -- Chapter 6 The Application of Biopharmaceutics Classification Systems to Modified-Release Formulations -- 6.1 Introduction -- 6.2 The Use of Biopharmaceutics Classification Systems in Oral Drug Development -- 6.3 The Application of Classification Systems to MR Drug Product Development - An Evidence-Based Approach -- 6.3.1 Test Sets Used.

6.3.2 Where Do Successfully Marketed Modified-Release Products Fit in Solubility/Permeability Classification Systems? -- 6.3.3 Classification System Categorization and Relative Colonic Bioavailability Data -- 6.3.4 The Significance of Dissolution Rate and Solubility in the Colon -- 6.3.5 Does Ionization State Matter? -- 6.3.6 Managing Low Solubility (DCS IIA/IIB) -- 6.3.7 Managing Low Permeability (DCS III/IV) -- 6.3.8 Beyond Permeability and Solubility: Other Factors Affecting MR Feasibility -- 6.3.8.1 Time-period for Drug Release and Absorption -- 6.3.8.2 Bacterial Metabolism in the Colon -- 6.3.8.3 Uptake Transporters -- 6.3.8.4 Gut Wall First-Pass Metabolism -- 6.3.8.5 Efflux Transporters -- 6.3.9 Relative Bioavailability in the Colon (FrelColon) as a Guide to Extended-Release Formulation Feasibility -- 6.3.10 The Properties of Drugs for Delayed-Release (Gastro Protection) -- 6.3.11 The Properties of Drugs for Targeting Local Release in the Lower GI Tract -- 6.4 Summary -- References -- Chapter 7 Technologies and Mechanisms for Oral Modified Release by Monolithic and Multiparticulate Delivery Systems -- 7.1 Introduction -- 7.2 Mechanism of Drug Release -- 7.3 Manufacturing Processes -- 7.3.1 Pelletization Processes -- 7.3.1.1 Extrusion-spheronization -- 7.3.1.2 Layering Techniques -- 7.3.1.3 Direct Pelletization from Powders (Wet Granulation) -- 7.3.2 Particulate Production from Liquid Systems (Globulation Methods) -- 7.3.2.1 Pelletization Methods Utilizing Melts -- 7.3.2.2 Spray Drying and Spray Congealing -- 7.3.2.3 Jet Cutting (Prilling) -- 7.3.3 Compression Methods -- 7.4 Formulation Screening and Characterization -- 7.5 Conclusions and Perspectives -- References -- Chapter 8 Lipid-based Formulations -- 8.1 Introduction -- 8.2 Mechanisms of Lipid-mediated Improvements in Bioavailability.

8.2.1 Increased Drug Solubilization and Dissolution in the GIT -- 8.2.2 Increased Intestinal Permeability, Reduced First-pass Metabolism, and Intestinal Efflux -- 8.2.3 Promotion of Intestinal Lipid Absorption and Lymphatic Uptake -- 8.3 Lipid-based Formulations for Controlled Release -- 8.3.1 Solid Lipid Excipient Matrices -- 8.3.2 Solid Lipid Nanoparticles -- 8.4 Design of Lipid-based Formulations -- 8.4.1 Excipient Type and Selection -- 8.4.2 Drug Loading -- 8.4.3 Formulation Types and the Lipid Formulation Classification System -- 8.5 Formulation Screening and Characterization -- 8.5.1 Drug Solubility in Lipid-based Formulations -- 8.5.2 Self-emulsification and the Effect of Dispersion -- 8.5.3 Impact of Digestion -- 8.5.4 Assessing Supersaturation and Precipitation -- 8.5.5 Identifying Formulation Limiting Factors and the Lipid Formulation Performance Classification System (LF-PCS) -- 8.5.6 Characterization of Nanoparticulate Lipid-based Formulations -- 8.5.7 Preclinical to Clinical Dose Scaling and Developing In Vitro and In Vivo Correlations -- 8.6 Industrial Considerations on LBF -- 8.7 Emerging Applications of Lipid-based Formulations -- 8.8 Conclusions -- References -- Chapter 9 Strategies for MR Formulation Development: Mesoporous Silica -- 9.1 Introduction -- 9.2 Technologies -- 9.2.1 The Template Method in Synthesis of Mesoporous Silica -- 9.2.1.1 M41S Mesoporous Materials -- 9.2.1.2 SBA Mesoporous Materials -- 9.2.2 Factors Affecting Drug Loading -- 9.3 Characterization -- 9.4 Stability of Drug Carrier -- 9.5 Silica-based Materials for the Modified Release of Poorly Soluble Drugs - In Vitro/In Vivo Applications -- 9.5.1 pH-sensitive Silica-based Systems -- 9.5.2 Surface-modification of Silica-based Materials -- 9.5.3 Lipid Formulations of Silica-based Materials -- 9.6 Toxicological Assessment -- 9.6.1 In vitro Toxicity.