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Provides pharmaceutical development scientists with a detailed reference guide for the development of MR formulations
Oral Drug Delivery for Modified Release Formulations is an up-to-date review of the key aspects of oral absorption from modified-release (MR) dosage forms. This edited volume provides in-depth coverage of the physiological factors that influence drug release and of the design and evaluation of MR formulations.
Divided into three sections, the book begins by describing the gastrointestinal tract (GIT) and detailing the conditions and absorption processes occurring in the GIT that determine a formulation's oral bioavailability. The second section explores the design of modified release formulations, covering early drug substance testing, the biopharmaceutics classification system, an array of formulation technologies that can be used for MR dosage forms, and more. The final section focuses on in vitro, in silico, and in vivo evaluation and regulatory considerations for MR formulations. Topics include biorelevant dissolution testing, preclinical evaluation, and physiologically-based pharmacokinetic modelling (PBPK) of in vivo behaviour. Featuring contributions from leading researchers with expertise in the different aspects of MR formulations, this volume:
Oral Drug Delivery for Modified Release Formulations is an invaluable reference and guide for researchers, industrial scientists, and graduate students in general areas of drug delivery including pharmaceutics, pharmaceutical sciences, biomedical engineering, polymer and materials science, and chemical and biochemical engineering.
Edmund S. Kostewicz, PhD is at the Fraunhofer Institute for Translational Medicine and Pharmacology in Frankfurt, Germany.
Maria Vertzoni, PhD is an Assistant Professor of Pharmaceutical Technology and Biopharmaceutics at National and Kapodistrian University of Athens, Greece.
Heather A.E. Benson, PhD is an adjunct Associate Professor at the Curtin Medical School, Curtin University, Australia, where she leads the Skin Delivery Research Group.
Michael S. Roberts, PhD is a Professor of Therapeutics & Pharmaceutical Science at the University of South Australia, and a Professor of Clinical Pharmacology & Therapeutics at the University of Queensland, Australia.
Preface xvii
List of Contributors xix
Part I Understanding of Physiology and Anatomy - Factors Influencing Drug Release and Absorption from MR Formulations 1
1a Composition of Gastric Fluids Under Fasting and Fed Conditions 3Jens Van Den Abeele and Patrick Augustijns
1a.1 Gastric Volume 3
1a.2 Gastric Acid 3
1a.3 Buffer Capacity 4
1a.4 Mucus/Viscosity 5
1a.5 Enzymes 5
1a.6 Surface Tension 6
1a.7 Osmolality 6
1a.8 Duodenogastric Reflux 7
1b Composition of the Small Intestinal Contents Under Fasting and Fed Conditions 11Edmund S. Kostewicz
1b.1 Small Intestinal Volume 11
1b.2 pH Profile Along the Small Intestine 12
1b.3 Composition of the Luminal Contents 12
1b.4 Other Characteristics of Small Intestinal Fluids 14
1b.5 Influence of Age, Gender, and Disease on the Small Intestinal Composition 15
1c The Luminal Environment in the Proximal Colon 19Maria Vertzoni and Christos Reppas
1c.1 Volume of Luminal Contents 19
1c.2 Luminal pH Values 20
1c.3 Buffer Capacity 22
1c.4 Characteristics of Liquid Fraction of Contents 22
1c.5 Concluding Remarks 22
2 Gastrointestinal Transit and Hydrodynamics Under Fasting and Fed Conditions 25Mirko Koziolek
2.1 Introduction 25
2.2 Imaging Techniques Used for Assessment of Transit Times and Hydrodynamics 25
2.3 Oral Cavity and Esophagus 25
2.4 Stomach 26
2.5 Small Intestine 29
2.6 Large Intestine 31
2.7 Whole Gut Transit Time 32
2.8 Therapy- Related Effects on GI Transit 33
2.9 Motility Disorders Affecting the GI Transit of Oral Dosage Forms 33
2.10 Patient- Related Effects on GI Transit 34
2.11 Conclusion 36
3 Intestinal Epithelium and Drug Transporters 39Karelle Ménochet, Hugues Chanteux, Jamie Henshall, Jean- Marie Nicolas, Sara Wright, Judith van Asperen, and Anna-Lena Ungell
3.1 Introduction: Oral Drug Absorption General Mechanisms and Influencing Factors 39
3.2 Expression of Drug Transporters in the Intestinal Epithelium 40
3.3 Uptake Transporters Present at the Intestinal Level 40
3.4 Regional Distribution of Uptake Transporters 42
3.5 Efflux Transporters at the Intestinal Level 42
3.6 Regional Distribution of Efflux Transporters 43
3.7 Impact of the Regional Distribution of Enzymes and Transporters in the Intestine on the Enzyme/Transporter Interplay 43
3.8 Species Differences in Regional Expression of Uptake and Efflux Transporters 44
3.9 Models for Regional Assessment of Intestinal Permeability 45
3.10 Use of PBPK to Integrate Formulation and Permeation Knowledge 46
3.11 Impact of Regional Solubility and Permeability Along the Intestine 47
3.12 Formulation Excipients and Their Potential Modulatory Effects on Transporters 48
3.13 Other Confounding Factors Affecting Drug Intestinal Absorption 51
3.14 Drug-Drug Interactions 52
3.15 Conclusion and Future Challenges 53
4 The Interplay Between Drug Release and Intestinal Gut- Wall Metabolism 65Adam S. Darwich, Oliver J. Hatley, Andrés Olivares- Morales, Farzaneh Salem, Alison Margolskee, and Amin Rostami- Hodjegan
4.1 The Role of Gut Wall Metabolism in Determining Oral Bioavailability 65
4.2 Factors Affecting Gut Wall Metabolism 69
4.3 Preclinical and Clinical In Vivo and In Situ Models for Studying Intestinal Metabolism 71
4.4 In Vitro Assays for Studying Intestinal Metabolism 72
4.5 Models for Studying Bacterial Degradation 74
4.6 In Vitro-In Vivo Extrapolation of Metabolic Clearance and In Silico Models for Predicting In Vivo Gut Wall Metabolism 75
4.7 Oral Extended- Release Formulations and Gut Wall Metabolism 76
4.8 Excipient Effects on Gut Wall Metabolism 77
4.9 Considerations for Intestinal Metabolism in Special Populations 77
4.10 Summary 79
Part II Design of MR Formulations - Considerations, Mechanisms and Technologies 87
5 Preformulation Considerations for Design of Oral Modified- Release Products 89Christel A. S. Bergström and René Holm
5.1 Introduction 89
5.2 Purpose of MR Formulations 90
5.3 Means to Obtain MR Drug Products 91
5.4 Ionization Constant - pK a 93
5.5 Lipophilicity 93
5.6 Solubility 93
5.7 Chemical Stability 93
5.8 Solid State Characterization 94
5.9 Compatibility with Excipients 94
5.10 Permeability and Metabolism 94
5.11 Regional Absorption 95
5.12 Microbial Stability 96
5.13 Quality by Design (QbD) for MR formulations 97
5.14 Conclusions 98
6 The Application of Biopharmaceutics Classification Systems to Modified- Release Formulations 103James M. Butler
6.1 Introduction 103
6.2 The Use of Biopharmaceutics Classification Systems in Oral Drug Development 103
6.3 The Application of Classification Systems to MR Drug Product Development - An Evidence- Based Approach 104
6.4 Summary 114
7 Technologies and Mechanisms for Oral Modified Release by Monolithic and Multiparticulate Delivery Systems 119Gaia Colombo, Stavros Politis, and Alessandra Rossi
7.1 Introduction 119
7.2 Mechanism of Drug Release 121
7.3 Manufacturing Processes 124
7.4 Formulation Screening and Characterization 128
7.5 Conclusions and Perspectives 131
8 Lipid- based Formulations 137Joseph P. O'Shea, Caitriona M. O'Driscoll, and Brendan T. Griffin
8.1 Introduction 137
8.2 Mechanisms of Lipid- mediated Improvements in Bioavailability 138
8.3 Lipid- based Formulations for Controlled Release 142
8.4 Design of Lipid- based Formulations 144
8.5 Formulation Screening and Characterization 146
8.6 Industrial Considerations on LBF 154
8.7 Emerging Applications of Lipid- based Formulations 154
8.8 Conclusions 155
9 Strategies for MR Formulation Development: Mesoporous Silica 161Georgios K. Eleftheriadis, Eleni Kontogiannidou, Christina Karavasili, and Dimitrios G. Fatouros
9.1 Introduction 161
9.2 Technologies 161
9.3 Characterization 163
9.4 Stability of Drug Carrier 165
9.5 Silica- based Materials for the Modified Release of Poorly Soluble Drugs - In Vitro/In Vivo Applications 166
9.6 Toxicological Assessment 171
9.7 Conclusions and Future Directions 173
10 Hot- Melt Extrusion Technology for Modified- Release (MR) Formulation Development 181Harpreet Sandhu, Siva Ram Kiran Vaka, Dipen Desai, Paras Jariwala, Aruna Railkar, Wantanee Phuapradit, and Navnit Shah
10.1 Introduction 181
10.2 HME Technology Overview 182
10.3 General Considerations in Developing MR Dosage Forms Using HME Processing 185
10.4 Material Considerations for MR- HME Application 187
10.5 Dosage Form Design and Case Studies 189
10.6 Characterization of HME Products 195
10.7 Summary 200
11 Gattefosse: Strategies for MR Formulation Development - Lipids 205Yvonne Rosiaux, Vincent Jannin, and Cécile Morin
11.1 Introduction 205
11.2 Lipids Used in SR Matrix 205
11.3 Processing Lipid SR Matrix 206
11.4 Understanding Drug Release from Lipid Matrix 208
11.5 Characterizing Lipid SR Matrix 210
11.6 Conclusions 211
12 Polymethacrylates for Modified- Release Formulations 215Miriam Robota, Felix Hofmann, and Meike Pistner
12.1 Introduction 215
12.2 Polymethacrylate Polymers and Their Application in Modified- Release Dosage Forms 215
12.3 Protective Coatings 218
12.4 Gastro- Resistant Coatings 221
12.5 EUDRACAP Functional Ready-To-Fill Capsules for Fast Track Development of Sensitive Drugs 224
12.6 Modified- Release Technology 224
12.7 Modified- Release Formulations for Gastrointestinal Targeting 228
12.8 Matrix Tablets as an Alternative to Modified- Release Multiparticulate Dosage Forms 231
12.9 Alcohol- Resistant Formulation Concepts with EUDRAGIT® Polymers 232
12.10 Conclusion 232
13 Strategies for Modified Release Oral Formulation Development 235Aurélien Sivert, Randy Wald, Chris Craig, and Hassan Benameur
13.1 Introduction 235
13.2 Controlled- Release Drug Delivery Systems 235
13.3 Dual- Release Drug Delivery Systems and Fixed- Dose Combination 242
13.4 Site- Specific Drug Delivery Systems 243
13.5 Conclusion/Future Perspectives 249
Part III Evaluation of MR Formulations 253
14 Dissolution Equipment and Hydrodynamic Considerations for Evaluating Modified- Release Behavior 255Sandra Klein
14.1 Introduction 255
14.2 Compendial Dissolution Equipment 255
14.3 USP Apparatus 7 - Reciprocating Holder 263
14.4 Noncompendial Dissolution Equipment 264
14.5 Summary and Conclusion 268
15 The Role and Applications of Dissolution Media for the Investigation of Modified-Release Formulations 273Cord J. Andreas and Edmund S. Kostewicz
15.1 Introduction 273
15.2 Compendial Media 274
15.3 Biorelevant Media 275
15.4 Biphasic Dissolution Media 282
15.5 Summary and Outlook 283
16 Biorelevant Dissolution Testing to Forecast the In Vivo Performance of Modified- Release Formulations 289Mirko Koziolek
16.1 Introduction 289
16.2 Factors Affecting the In Vivo Performance of MR Products 289
16.3 Drug- Related Aspects 290
16.4 Formulation- Related Aspects 290
16.5 Biorelevant In Vitro Dissolution Test Methods 290
16.6 General Remarks on Dissolution Media 290
16.7 General Remarks on Dissolution Test Devices 291
16.8 Dissolution Test Methods for the Simulation of Regional Transit Conditions 292
16.9 Criteria for the Selection of a Suitable Biorelevant In Vitro Dissolution Method 299
16.10 Conclusion 300
17 In Vitro and Ex Vivo Dissolution Tests for Considering Dissolution in the Lower Intestine 305Constantinos Markopoulos and Maria Vertzoni
17.1 Introduction 305
17.2 Dissolution Tests for pH- responsive Delivery Systems 306
17.3 Dissolution Tests for Enzyme- triggered Delivery Systems 313
17.4 Conclusion 319
18 Preclinical Evaluation - Animal Models to Evaluate MR Formulations 325René Holm
18.1 Introduction 325
18.2 When to Use Nonclinical Models in the Development of Modified-release Formulations 325
18.3 Physiological Factors in Animals Used to Investigate Modified- release Formulations 326
18.4 Intestinal Site- specific Administration in Animals 330
18.5 Evaluation of Modified- release Formulations in Animal Models 330
18.6 Conclusions 334
19 In Vitro-In Vivo Correlations for Modified Release Formulations 341Ivana Tomic and Jean- Michel Cardot
19.1 Introduction 341
19.2 Definitions of IVIVC 341
19.3 Correlation Levels 341
19.4 Considerations in IVIVC Development 342
19.5 IVIVC Models 344
19.6 Predictability of IVIVC 348
19.7 Use of IVIVC 350
19.8 Limitations of an IVIVC 352
19.9 Conclusion 352
Acknowledgment 353
References 353
20 Application of the Simcyp Population- based PBPK Simulator to the Modelling of MR Formulations 355Nikunjkumar Patel, Shriram M. Pathak, and David B. Turner
20.1 Introduction 355
20.2 The ADAM Oral Absorption Model 357
20.3 Handling of Modified Release Formulations 358
20.4 System Information 361
20.5 MR Case Studies/Examples 363
20.6 Conclusion 370
21 PK- Sim for Modeling Oral Drug Delivery of Modified- Release Formulations 375Donato Teutonico, Michael Block, Lars Kuepfer, Juri Solodenko, Thomas Eissing, and Katrin Coboeken
21.1 General Introduction on PK- Sim® and MoBi® 375
21.2 Gastrointestinal Transit and Absorption Model 376
21.3 Formulations Available in PK- Sim® 380
21.4 Dissolved Form 380
21.5 Zero and First- order Release and Lint80 Release 381
21.6 Weibull 381
21.7 Particle Dissolution 382
21.8 Dissolution Media and Transit Times 383
21.9 Case Studies 384
21.10 Outlook 386
22 Clinical Evaluation - In Vivo Bioequivalence Assessment of MR Formulations 391Konstantina Soulele and Panos Macheras
22.1 Introduction/Historical Background 391
22.2 Clinical Evaluation of New and Generic Modified- Release Formulations 392
22.3 Summary 403
23 US Regulatory Considerations for Modified Release Products 409Hao Zhu, Ramana S. Uppoor, and Mehul Mehta
23.1 Introduction 409
23.2 Clinical Development Programs for Nongeneric MR Dosage Forms 410
23.3 Considerations for Clinical Development Programs for Generic MR Products 417
23.4 Studies to Support Postapproval Changes for MR Products 418
23.5 Summary 421
Disclaimer 421
References 422
24 Regulatory Assessment, European Perspective 425Malin Filler and Anders Lindahl
24.1 Introduction 425
24.2 Quality of Oral Extended- Release Products 425
24.3 Quality by Design in Pharmaceutical Development 429
24.4 Pharmacokinetic and Clinical Evaluation of Modified Release Dosage Forms 431
24.5 Concluding Remarks 436
25 Industry Perspectives for the Evaluation of MR Formulations 439Irena Tomaszewska and Mark McAllister
25.1 Introduction 439
25.2 Commercially Marketed MR Products - Historical Trends and Emerging Themes 439
25.3 Early- stage MR Product Development 440
25.4 Current Themes for Industrial MR Product Evaluation: (1) Dissolution Acceleration 444
25.5 Current Themes for Industrial MR Product Evaluation: (2) Hydro- ethanolic Studies 447
25.6 Conclusion 449
References 449
Index 455
Jens Van Den Abeele and Patrick Augustijns
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Gastric fluids consist of numerous components either secreted by the stomach (gastric acid, enzymes, electrolytes, mucus), swallowed/ingested (saliva, food, liquids), or refluxed from the duodenum in the stomach (bile constituents). When discussing stomach volume, distinction is often made between gastric content volume (GCV) and total gastric volume (TGV). GCV can be described as the resultant volume in the stomach of ingested material (e.g. food, liquids), swallowed saliva, gastric secretions, and the emptying of gastric content in the small intestine, whereas TGV also takes into account parts of the stomach void of liquid or solid material (i.e. GCV + air volume). In fasted state, gastric secretion occurs at a rate of approximately 1?ml/min [1-3]. In 1977, Dubois et al. reported a mean resting GCV (±SEM) of 24?±?5?ml in fasted subjects [3]. In more recent studies, magnetic resonance imaging (MRI) has been used to assess GCV. Using this technique, Goetze et al. [4] and Koziolek et al. [5] calculated mean baseline GCVs (± SD) of 35?±?22?ml (N =?48) and 31.4?±?19.7?ml (N = 12), respectively. Similar mean fasted GCV (35?±?7?ml; N = 12) was reported by Mudie et al. [6]. In addition, the authors investigated gastric volume changes after administration of 240?ml of water, in agreement with the guidelines for bioavailability (BA)/bioequivalence (BE) testing under fasting conditions [7, 8]. Immediately after water administration, GCV increased to a mean volume (±SEM) of 242?±?9?ml which returned to baseline levels within 45?minutes (t1/2, emptying = 13?±?1?min) [6].
After meal intake, the stomach is capable of significantly increasing its volume to accommodate ingested food [4, 5, 9, 10]. This expansion was visualized by Di Ciaula et al. [11] using functional ultrasonography. Mean antral surface area (±SEM) after a 200?ml liquid meal increased approximately four-fold in adults (basal area = 3.5?±?0.1?cm2, postprandial area = 12.0?±?0.3?cm2; N = 67). The extent to which the stomach expands depends on both meal volume and the interplay between (stimulated) gastric secretion, reported by Malagelada et al. [12] to increase to ~10?ml/min in the first hour after a solid-liquid meal, and emptying in response to food ingestion. TGVs of 800-900?ml have been reported [13]. Kwiatek et al. [13] observed that TGV increased with increasing meal volume (200, 400, 600, and 800?ml combinations of Ensure® TwoCal with iso-osmolar saline). However, TGV/meal volume ratio decreased with increasing meal volume, which has been suggested by the authors to be due to the rapid emptying of larger portions in case of large meal volumes compared to smaller meal volumes. Depending on meal volume and caloric content of the meal, it may take several hours for GCV to return to fasted state levels [5, 13].
Under normal fasted state conditions, gastric content is typically acidic due to the secretion of hydrochloric acid, commonly referred to as "gastric acid". Gastric acidity is crucial for several of the stomach's functions [14]. Multiple gastric enzymes, for instance, require acidity to display optimal activity [1, 15-17]. Furthermore, an unfavorable environment for the survival of micro-organisms is created, preventing bacterial overgrowth [15, 18]. Secretion is mediated by parietal cells of the oxyntic gastric mucosa, mainly located in the corpus and fundus region of the stomach [14, 18, 19]. Intraluminal potassium ions are exchanged for intracellular protons, a process regulated by the K+/H+ ATPase or "proton pump," while chloride ions are simultaneously transported to the gastric lumen to ensure isoelectricity. At rest, K+/H+ ATPases are stored in cytoplasmatic tubulovesicles [14, 19]. Upon stimulation, these proton pumps translocate from the cytoplasm to the apical membrane and gastric acid is subsequently secreted. Neural (acetylcholine) as well as endocrine (histamine, gastrin) stimuli promote acid secretion, whereas somatostatin, mainly secreted by D cells of the pyloric mucosa located in the antrum region of the stomach, is the main inhibitor of acid secretion [14, 18].
Gastric acid secretion rates ranging from 0.03 to 0.07?meq?H+?min-1 have been reported for fasted subjects [3, 20]. In a study by Lindahl et al. [21], a total of 36 gastric fluid samples were aspirated in 24 healthy human volunteers. Subjects were not allowed to consume water for the entire duration of the study. Measured pH values ranged from 1.4 to 7.5, with seven samples exceeding pH 5. Comparable ranges have been reported in similar studies with healthy human volunteers [17, 22-24]. High pH values in the fasted stomach may be due to (i) swallowing of saliva and/or nasal secretions and/or (ii) duodenogastric reflux [24, 25]. As a result, mean pH values (±SD) reported by Lindahl et al. [21] (2.9?±?1.97; N =?36) and Pedersen et al. [17] (2.5?±?1.4, N = 19) may be skewed toward higher values. Median values may therefore better reflect "normal" gastric acidity in fasted subjects. In literature, median gastric pH values between 1.55 and 1.94 have been reported [17, 21, 22, 26, 27].
Several studies have investigated acidity of gastric content after intake of water. As mentioned earlier (cfr. 1. Section 1a.1), this condition is of interest in the context of BA/BE studies. After water administration (>?200?ml), initial gastric pH exhibited large inter-individual differences with values ranging from pH 1-8 [25, 28, 29]. These differences can most probably be attributed to differences in residual gastric volume and inhomogeneous mixing of the administered water with gastric content.
After meal ingestion, meal volume and composition will be the main determinants of initial postprandial pH due to the generally large meal volume compared to residual gastric volume [2, 25, 27]. Kalantzi et al. [25], for instance, investigated changes in gastric pH after intake of a liquid meal (i.e. 500?ml Ensure® Plus). Thirty minutes after meal intake, gastric pH was found to be 6.4 (N =?15), similar to the pH of the administered meal (pH 6.6). As meal intake provokes the secretion of gastric acid, gastric contents will re-acidify as a function of time [2, 20]. The timeframe for this re-acidification to occur will mainly depend on the buffer capacity of the administered meal as well as the rate at which the meal is emptied from the stomach [25, 27, 30]. Dressman et al. [27] reported a timeframe of less than two hours to reach pH 2 in the postprandial stomach after ingestion of a solid meal (1000?kcal), whereas Kalantzi et al. [25] still observed a considerable effect of a liquid meal (i.e. Ensure® Plus) on the acidity of gastric content after several hours (median postprandial pH = 2.7 after 210?minutes).
Due to site-specific differences in expression of parietal cells in the stomach, acidic secretions have furthermore been found to be inhomogeneously distributed throughout the postprandial stomach. In this context, multiple studies confirmed the presence of a so-called "acid pocket," a layer of acidic gastric secretions near the gastro-esophageal junction in the fed stomach [4, 30, 31]. Steingoetter et al. [31] found that in patients suffering from gastro-esophageal reflux disease (GERD), contact time of this acidic layer with the gastro-esophageal junction was prolonged, increasing the risk of esophageal mucosa being harmed due to acid reflux.
With no water ingested, Pedersen et al. [17] reported a mean buffer capacity of 14.3?±?9.5?mmol/l??pH in gastric aspirates of fasted subjects (N = 19). Ingestion of water prior to the start of the experiment will dilute gastric content, resulting in a decrease in measured buffer capacity. Several authors reported lower buffer capacity of gastric aspirates right after administration of water compared to later time-points. After ingestion of 250?ml of water, median buffer capacity was found to increase from 7 to 18?mmol/ l??pH within a one-hour sampling period [25]. Litou et al. [32] observed a similar rise in buffer capacity as a function of time. Mean (±SD) values measured ranged from 4.7?±?4.6?mmol/l??pH 10?minutes...
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