Oral Drug Delivery for Modified Release Formulations

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
9.7 Conclusions and Future Directions
References
Chapter 10 Hot-Melt Extrusion Technology for Modified-Release (MR) Formulation Development
10.1 Introduction
10.2 HME Technology Overview
10.2.1 Feeding of Raw Materials
10.2.1.1 Single-screw Extruders: Flood Feeding
10.2.1.2 Twin-screw Extruders: Starve Feeding
10.2.2 Conveying and Melting
10.2.3 Mixing
10.2.3.1 Dispersive Mixing
10.2.3.2 Distributive Mixing
10.2.4 Venting
10.2.5 Die Pressurization
10.2.6 Pumping and Shaping
10.2.7 Postprocessing
10.2.8 Process Monitoring and Statistical Process Controls
10.3 General Considerations in Developing MR Dosage Forms Using HME Processing
10.4 Material Considerations for MR-HME Application
10.5 Dosage Form Design and Case Studies
10.5.1 Powder/Granules/Multiparticulates
10.5.2 Compressed Tablets
10.6 Characterization of HME Products
10.6.1 Rheological Techniques
10.6.2 Use of Diffraction-Based Methods
10.6.3 Spectroscopic Methods
10.6.4 Thermal Methods
10.6.5 Microscopic Techniques
10.6.6 Chemical Properties
10.6.7 In Vitro Dissolution/Release Properties
10.7 Summary
References
Chapter 11 Gattefosse: Strategies for MR Formulation Development – Lipids
11.1 Introduction
11.2 Lipids Used in SR Matrix
11.2.1 Names and Structures
11.2.2 Physicochemical Properties
11.2.3 Physiological Properties
11.3 Processing Lipid SR Matrix
11.3.1 Direct Compression (DC)
11.3.1.1 Impact of Dual Hydrophilic/Hydrophobic Matrix
11.3.1.2 Impact of Filler
11.3.1.3 Impact of Tablet Size
11.3.1.4 Comparison with Polymer Matrices
11.3.2 Granulation
11.3.3 Melt and Mix Methods
11.3.4 Hot Melt Coating
11.4 Understanding Drug Release from Lipid Matrix
11.4.1 Drug Release Mechanism
11.4.2 Optimizing Drug Release with Formulation and Process Parameter Adjustments
11.4.3 Drug Release Prediction
11.5 Characterizing Lipid SR Matrix
11.5.1 In Vitro Characterization
11.5.2 In Vivo–In Vitro Correlation (IVIVC)
11.5.3 Resistance and Alcohol
11.5.4 Stability
11.6 Conclusions
References
Chapter 12 Polymethacrylates for Modified-Release Formulations
12.1 Introduction
12.2 Polymethacrylate Polymers and Their Application in Modified-Release Dosage Forms
12.3 Protective Coatings
12.4 Gastro-Resistant Coatings
12.5 EUDRACAP™ Functional Ready-To-Fill Capsules for Fast Track Development of Sensitive Drugs
12.6 Modified-Release Technology
12.7 Modified-Release Formulations for Gastrointestinal Targeting
12.7.1 Duodenal Drug Release
12.7.2 Colonic Drug Release
12.7.3 Modulated Drug Release
12.8 Matrix Tablets as an Alternative to Modified-Release Multiparticulate Dosage Forms
12.9 Alcohol-Resistant Formulation Concepts with EUDRAGIT® Polymers
12.10 Conclusion
References
Chapter 13 Strategies for Modified Release Oral Formulation Development
13.1 Introduction
13.2 Controlled-Release Drug Delivery Systems
13.2.1 Osmotic Tablets
13.2.1.1 Formulation, Characterization, and Evaluation
13.2.1.2 Manufacturing and Process Considerations
13.2.2 Multiparticulate Systems
13.2.2.1 Formulation, Characterization, and Evaluation of Spray-Layered Multiparticulates
13.2.2.2 Manufacturing and Process Considerations of Spray-Layered Multiparticulates
13.2.2.3 Formulation, Characterization, and Evaluation of Lipid-Based Multiparticulates
13.2.2.4 Manufacturing and Process Considerations of Lipid-Based Multiparticulates
13.3 Dual-Release Drug Delivery Systems and Fixed-Dose Combination
13.3.1 DuoCap™ Capsule-in-Capsule Technology
13.3.1.1 Formulation, Characterization, and Evaluation
13.3.1.2 Manufacturing and Process Considerations
13.4 Site-Specific Drug Delivery Systems
13.4.1 Postgastric-Targeted Release
13.4.1.1 Delayed-Release Acid-Resistant Capsules (DRcaps®)
13.4.1.2 Enteric Drug Delivery Capsules (enTRinsic™)
13.4.2 Encode™ Colonic Drug Delivery System
13.4.2.1 Formulation, Characterization, and Evaluation
13.4.2.2 Manufacturing and Process Considerations
13.5 Conclusion/Future Perspectives
References
Part III Evaluation of MR Formulations
Chapter 14 Dissolution Equipment and Hydrodynamic Considerations for Evaluating Modified-Release Behavior
14.1 Introduction
14.2 Compendial Dissolution Equipment
14.2.1 USP Apparatus 1 – Basket Apparatus
14.2.2 USP Apparatus 2 – Paddle Apparatus
14.2.3 USP Apparatus 3 – Reciprocating Cylinder
14.2.4 USP Apparatus 4 – Flow-Through Cell
14.3 USP Apparatus 7 – Reciprocating Holder
14.4 Noncompendial Dissolution Equipment
14.4.1 Dynamic Monocompartmental Models
14.4.1.1 Rotating Beaker Apparatus
14.4.1.2 Apparatus for Simulating GI Forces Acting on a Dosage Form
14.4.1.3 Dynamic Gastric Model
14.4.1.4 Dynamic Colon Model
14.4.2 Dynamic Multicompartmental Models
14.4.2.1 Dissolution Stress Test Device
14.4.2.2 In Vitro Gastrointestinal Model (TIM)
14.5 Summary and Conclusion
References
Chapter 15 The Role and Applications of Dissolution Media for the Investigation of Modified-Release Formulations
15.1 Introduction
15.2 Compendial Media
15.3 Biorelevant Media
15.3.1 Concept of Different Levels of Complexity for Dissolution Media
15.3.2 Case Example Level I Media
15.3.3 Case Example Level II Media
15.3.4 Case Example Level III Media
15.3.5 Application of Levels Concept
15.3.6 Bicarbonate Buffer
15.4 Biphasic Dissolution Media
15.5 Summary and Outlook
References
Chapter 16 Biorelevant Dissolution Testing to Forecast the In Vivo Performance of Modified-Release Formulations
16.1 Introduction
16.2 Factors Affecting the In Vivo Performance of MR Products
16.2.1 Physiological Aspects
16.3 Drug-Related Aspects
16.4 Formulation-Related Aspects
16.5 Biorelevant In Vitro Dissolution Test Methods
16.6 General Remarks on Dissolution Media
16.7 General Remarks on Dissolution Test Devices
16.8 Dissolution Test Methods for the Simulation of Regional Transit Conditions
16.8.1 Simulation of Fasted State Administration of Oral MR Products
16.8.2 Simulation of Fed State Administration of Oral MR Products
16.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method
16.10 Conclusion
References
Chapter 17 In Vitro and Ex Vivo Dissolution Tests for Considering Dissolution in the Lower Intestine
17.1 Introduction
17.2 Dissolution Tests for pH-responsive Delivery Systems
17.2.1 Dissolution Tests Using Compendial Apparatuses
17.2.2 Dissolution Tests Using Noncompendial Apparatuses
17.3 Dissolution Tests for Enzyme-triggered Delivery Systems
17.3.1 Dissolution Tests Using Enzyme-supplemented Compendial Media
17.3.2 Dissolution Tests Using Rat Cecal Contents
17.3.3 Dissolution Tests Using Human Fecal Contents
17.3.4 Dissolution Tests Using Bacteria-containing Media
17.4 Conclusion
References
Chapter 18 Preclinical Evaluation – Animal Models to Evaluate MR Formulations
18.1 Introduction
18.2 When to Use Nonclinical Models in the Development of Modified-release Formulations
18.3 Physiological Factors in Animals Used to Investigate Modified-release Formulations
18.3.1 The Stomach
18.3.2 The Small Intestine
18.3.3 The Large Intestine
18.4 Intestinal Site-specific Administration in Animals
18.5 Evaluation of Modified-release Formulations in Animal Models
18.5.1 Rodents – Rats
18.5.2 Dogs
18.5.3 Pigs and Mini-Pigs
18.5.4 Monkeys
18.6 Conclusions
References
Chapter 19 In Vitro–In Vivo Correlations for Modified Release Formulations
19.1 Introduction
19.2 Definitions of IVIVC
19.3 Correlation Levels
19.4 Considerations in IVIVC Development
19.4.1 In Vivo Absorption
19.4.2 In Vitro Dissolution Methodology
19.5 IVIVC Models
19.6 Predictability of IVIVC
19.7 Use of IVIVC
19.7.1 Setting In Vitro Dissolution Limits
19.7.2 Optimization of Formulations
19.7.3 Dissolution and IVIVC as a Surrogate for In Vivo Data
19.8 Limitations of an IVIVC
19.9 Conclusion
Acknowledgment
References
Chapter 20 Application of the Simcyp Population-based PBPK Simulator to the Modelling of MR Formulations
20.1 Introduction
20.2 The ADAM Oral Absorption Model
20.3 Handling of Modified Release Formulations
20.4 System Information
20.5 MR Case Studies/Examples
20.5.1 Introduction
20.5.2 Bottom-up Methods
20.5.3 Virtual Bioequivalence, Biowaivers, and Setting Dissolution Specifications
20.5.4 Physiologically Based IVIVC
20.6 Conclusion
References
Chapter 21 PK-Sim® for Modeling Oral Drug Delivery of Modified-Release Formulations
21.1 General Introduction on PK-Sim® and MoBi®
21.2 Gastrointestinal Transit and Absorption Model
21.3 Formulations Available in PK-Sim®
21.4 Dissolved Form
21.5 Zero and First-order Release and Lint80 Release
21.6 Weibull
21.7 Particle Dissolution
21.7.1 Direct Use of MR In Vitro Release Profiles
21.8 Dissolution Media and Transit Times
21.9 Case Studies
21.9.1 Use of a Fitted In Vitro Dissolution Function as a Direct Drug Input
21.9.2 Prediction of Plasma Concentration After Administration of an Enteric-coated Tablet
21.10 Outlook
References
Chapter 22 Clinical Evaluation – In Vivo Bioequivalence Assessment of MR Formulations
22.1 Introduction/Historical Background
22.2 Clinical Evaluation of New and Generic Modified-Release Formulations
22.2.1 Pharmacokinetic Studies
22.2.2 The Modified-Release Formulations in the Milieu of the Gastrointestinal Tract
22.2.3 Influence of Drug Properties
22.2.4 Influence of Physiological Factors
22.2.5 Food Effect and Drug Interactions
22.2.6 The Use of In Vitro/In Vivo Correlations (IVIVC) in Clinical Evaluation of Controlled-Release Formulations
22.2.7 Bioequivalence of MR Products: An Ever-Evolving Field
22.2.8 Approaches and Metrics Associated with the Modified-Release Bioequivalence Assessment
22.2.9 Current Regulatory Requirements for the Demonstration of Bioequivalence of MR Formulations
22.3 Summary
References
Chapter 23 US Regulatory Considerations for Modified Release Products
23.1 Introduction
23.2 Clinical Development Programs for Nongeneric MR Dosage Forms
23.2.1 Clinical Development Programs for Obtaining Efficacy and Safety Information
23.2.1.1 Bioequivalence Trials
23.2.1.2 Bioavailability Trials in Combination with PK/PD Trials or with Clinical Efficacy and Safety Trials
23.2.2 Clinical Development Program for Product Characterization
23.2.2.1 In Vivo Evaluation of Multiple Strengths
23.2.2 Clinical Development Program for Product Characterization
23.2.2.3 Assessment of Alcohol Effect
23.2.2.4 Dosage Instructions in Patients with Changed Clearance
23.2.3 Modeling and Simulations to Support Product Development
23.3 Considerations for Clinical Development Programs for Generic MR Products
23.4 Studies to Support Postapproval Changes for MR Products
23.4.1 Different Levels of Postapproval Changes
23.4.2 Additional In Vitro Dissolution Evaluations
23.4.3 In vitro/In Vivo Correlations (IVIVC)
23.5 Summary
Disclaimer
References
Chapter 24 Regulatory Assessment, European Perspective
24.1 Introduction
24.2 Quality of Oral Extended-Release Products
24.2.1 Pharmaceutical Development
24.2.1.1 Quality Target Product Profile and Critical Quality Attributes
24.2.1.2 Manufacturing Process
24.2.1.3 Dissolution Method and Discriminatory Power
24.2.1.4 Bioavailability Studies
24.2.2 In Vitro–In Vivo Correlation
24.2.3 Setting Specifications
24.2.3.1 Case (A) Level A IVIVC is Established
24.2.3.2 Case (B) No IVIVC is Established
24.2.4 Control Strategy
24.3 Quality by Design in Pharmaceutical Development
24.3.1 Risk Assessment
24.3.2 Design Space
24.3.3 Control Strategy
24.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms
24.4.1 Rationale for Development
24.4.1.1 Pharmacokinetic Studies
24.4.1.2 Prolonged Residence Time in the Stomach
24.4.1.3 Clinical Studies
24.4.1.4 Generic Modified Release Formulations
24.5 Concluding Remarks
References
Chapter 25 Industry Perspectives for the Evaluation of MR Formulations
25.1 Introduction
25.2 Commercially Marketed MR Products – Historical Trends and Emerging Themes
25.3 Early-stage MR Product Development
25.4 Current Themes for Industrial MR Product Evaluation: (1) Dissolution Acceleration
25.5 Current Themes for Industrial MR Product Evaluation: (2) Hydro-ethanolic Studies
25.6 Conclusion
References
Index
EULA