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JOHN WILEY Innovative Dosage Forms Design And Development At Early Stage by Yogeshwar Bachhav
Teaches future and current drug developers the latest innovations in drug formulation design and optimizationThis highly accessible, practice-oriented book examines current approaches in the development of drug formulations for preclinical and clinical studies, including the use of functional excipients to enhance solubility and stability. It covers oral, intravenous, topical, and parenteral administration routes. The book also discusses safety aspects of drugs and excipients, as well as regulatory issues relevant to formulation.Innovative Dosage Forms: Design and Development at Early Stage starts with a look at the impact of the polymorphic form of drugs on the preformulation and formulation development. It then offers readers reliable strategies for the formulation development of poorly soluble drugs. The book also studies the role of reactive impurities from the excipients on the formulation shelf life; preclinical formulation assessment of new chemical entities; and regulatory aspects for formulation design. Other chapters cover innovative formulations for special indications, including oncology injectables, delayed release and depot formulations; accessing pharmacokinetics of various dosage forms; physical characterization techniques to assess amorphous nature; novel formulations for protein oral dosage; and more.-Provides information that is essential for the drug development effort -Presents the latest advances in the field and describes in detail innovative formulations, such as nanosuspensions, micelles, and cocrystals -Describes current approaches in early pre-formulation to achieve the best in vivo results-Addresses regulatory and safety aspects, which are key considerations for pharmaceutical companies -Includes case studies from recent drug development programs to illustrate the practical challenges of preformulation designInnovative Dosage Forms: Design and Development at Early Stage provides valuable benefits to interdisciplinary drug discovery teams working in industry and academia and will appeal to medicinal chemists, pharmaceutical chemists, and pharmacologists. Preface xvii1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development 1MHD Bashir Alsirawan and Anant Paradkar1.1 Introduction 11.1.1 Background 11.1.2 Types of Polymorphism 21.1.3 Thermodynamic-Based Classification of Polymorphism 41.1.4 Concomitant Polymorphism 61.1.5 Debatable Polymorphism Cases 71.2 Polymorphism Impact on Drug/Excipient Properties 91.2.1 Physicochemical Properties 101.2.2 Mechanical Properties 111.2.3 Impact of Polymorphism on In Vivo Performance 131.3 Critical Impact of Polymorphic Form of API on Processing and Formulation 221.3.1 Process-induced Transformation Types 231.3.1.1 Grinding-induced Transitions 231.4 Conclusion 37References 382 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route 49Sanket Shah, Abhijit Date, and Rene Holm2.1 Introduction 502.2 Quality by Testing (QbT) and Quality by Design (QbD) 502.3 Linking the Formulation to the Clinical Phase 522.4 Defining the Formulation Strategy 552.5 Nanosuspensions 582.5.1 Description 582.5.2 Method of Manufacturing 592.5.3 Characterization of Nanosuspensions 632.6 Solid Dispersion 642.6.1 Description 652.6.2 Method of Manufacturing 662.6.3 Characterization 682.7 Lipid-Based Drug Delivery Systems 692.7.1 Description 702.7.2 Method of Manufacture 712.7.3 Characterization 752.7.4 Role of API Property on Lipid-Based DDS 762.8 Micellar System 762.8.1 Description 762.8.2 Formulation Development and Optimization 802.8.3 Characterization 812.9 Mesoporous Silica Particles 812.9.1 Description 822.9.2 Method of Manufacturing and Characterization 832.9.3 Case Study on the in Vivo Efficacy of Mesoporous Silica Particles 842.10 Conclusion 84References 853 Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products 91Ankit Sharma3.1 Introduction 913.2 Reactive Impurities in the Excipients and Their Impact on Drug Stability 923.3 Impact of Reactive Impurities on Drug-Excipient Compatibility 933.3.1 Physical Interactions 933.3.2 Chemical Interactions 943.3.3 Oxidative Degradation 943.3.4 Peroxides 953.3.5 Transition Metal Impurities 963.3.6 Condensation Reactions 993.3.7 Aldehyde Impurities 993.3.8 Reducing Sugars 1023.3.9 Organic Acids 1033.3.10 Hydrolytic Degradation 1053.4 Risk Assessment for API Incompatibilities and Mitigation Strategies 1073.5 Assessment of Incompatibilities of API with Excipients 1083.6 Design and Selection of Drug Substance 1093.7 Formulation Strategies to Circumvent API Degradation 1103.8 Inhibition of Oxidative Degradation 1103.8.1 Initiation Inhibitors 1113.8.2 Propagation Inhibitors 1113.8.3 Selection of Antioxidant 1123.9 Super-Refined Excipients 1133.9.1 Polyethylene Glycols (PEG) 1143.9.2 Polysorbates 1143.9.3 Fatty Acids 1153.10 Packaging and Storage 1153.11 Concluding Remarks 116References 1164 Preclinical Formulation Assessment of NCEs 119Raju Saka, Priyadarshini Sathe,Wahid Khan, and Sachin Dubey4.1 Introduction 1204.2 Significance of Various Properties of NCEs in Early Drug Discovery 1224.2.1 Solubility 1234.2.2 Permeability 1244.2.3 Stability 1254.3 Formulation Strategies to Improve Properties of NCEs 1254.3.1 pH Modification 1274.3.2 Cosolvents 1274.3.3 Cyclodextrins 1284.3.4 Surfactants 1284.3.5 Suspensions and Nanosuspensions 1294.3.6 Emulsions and Microemulsions 1304.3.7 Solid Dispersions 1304.3.8 Liposomes 1314.4 Preclinical Formulation Assessment of Oral, Parenteral, and Topical Dosage Forms 1314.4.1 Oral Formulations 1314.4.2 Parenteral Formulations 1344.4.3 Topical Formulations 1354.4.4 Excipients 1384.4.5 Characterization and Stability of Preclinical Formulations 1404.4.6 Formulation Selection for Pharmacokinetic Studies 1414.4.7 Formulation Selection for Pharmacodynamic Studies 1424.4.8 Formulation Development for Toxicity Studies 1424.5 Case Studies 1434.5.1 Case 1: Use of Surfactant to Prevent Precipitation of API in Cosolvent-Based Formulations 1434.5.2 Case 2: Topical Gel Microemulsion Formulation of Lipophilic Drug WHI-07 1444.5.3 Case 3: Salt Approach to Improve the Bioavailability of the Poorly Soluble Drug 1444.5.4 Case 4: Use of SMEDDS Dosage Form to Improve Bioavailability 1454.5.5 Case 5: Micronized Suspension of Poorly Soluble Lead Compounds Using Wet Milling Technique 1454.5.6 Case 6: Polymer Addition in Cyclodextrin-Based Formulations and pH Adjustment 1464.5.7 Case 7: Cyclodextrin Complexation to Improve Topical Delivery of a Poorly Soluble Compound 1464.5.8 Case 8: Use of Solublizers and Their Effect on PK of Preclinical Lead Candidates 1474.5.9 Case 9: Self-nanoemulsifying Drug Delivery Systems (SNEDDS) to Improve Solubility and Bioavailability 1474.6 Conclusion and Future Perspectives 148References 1485 Regulatory Aspects for Formulation Design - with Focus on the Solid State 155Michael Gruss5.1 The Understanding of "Regulatory" 1565.2 Formulation Design 1575.3 An Extended Timescale 1585.4 Solubility Data 1585.5 Impact of Solubility and Dissolution Rate on Formulation Design 1625.6 Single and Multicomponent Systems 1635.6.1 Introduction 1635.6.2 Scientific Point of View 1645.6.3 Fate and Pathway of a Compound During Development 1665.6.4 Regulatory Point of View 1675.7 Analytical Techniques for the Characterization of the Solid State 1685.7.1 Scientific Literature 1685.7.2 Pharmacopeias 1695.8 Control of Solid-state Constitution 1715.8.1 The Process - from Synthesis to Patient 1715.8.2 Change of Properties and Constitution 1735.8.3 Need for Control of Solid-State Properties During the Process and Supply Chain 1735.9 Regulatory Consideration of Solid Compounds 1745.9.1 Definitions for Solid Compounds 1745.9.2 Common Technical Document (CTD) - M4Q 1755.9.3 Guideline on the Chemistry of Active Substances 1785.9.4 Guideline on Quality of Transdermal Patches 1805.9.5 Quality Guidelines 1815.9.6 EMA - Consideration and Perspective 1885.9.7 FDA - Consideration and Perspective 1905.9.8 Similarities and Differences Between the Regulative Systems in the EU and United States 1975.10 Conclusions and Recommendations 198Disclaimer 198References 1986 Insight into Innovative Applications of Parenteral Formulations 209Clara Fernandes6.1 Introduction 2096.2 Factors Affecting Development of Sustained-/Controlled-Release Formulations 2096.3 Overview of Sustained and Controlled Release Parenteral Formulations 2136.3.1 Suspension Based Formulations 2136.3.2 Particulate System Based Formulations 2156.4 Case Studies 2196.4.1 Nanosuspension Formulation of Paclitaxel - Abraxane (R) 2196.4.2 PLGA Depot Based Formulation of Triptorelin - Trelstar (R) 2196.4.3 Microemulsion Formulation of Propofol 2206.4.4 Inorganic Metal Nanoparticle Based Formulation for Parenteral Applications 2206.4.5 Polymeric Formulation of Glatiramer 2216.5 Conclusion 2226.6 Future Prospects 222References 2227 Assessing Pharmacokinetics of Various Dosage Forms at Early Stage 227Susanne Bonsmann and Joachim Ossig7.1 Introduction 2277.2 Definition of Pharmacokinetics 2297.2.1 ADME Parameters 2297.2.2 Pharmacokinetic Parameters 2317.2.3 PK Studies During Drug Development 2367.3 Case Studies 2417.3.1 Case Study 1 2417.3.2 Case Study 2 2417.3.3 Case Study 3 2427.3.4 Case Study 4 2437.4 Summary 243References 2438 Transdermal Medical Devices: Formulation Aspects 245Mayank Singhal, Cesar E. S. Jimenez, Maria Lapteva, and Yogeshvar N. Kalia8.1 Introduction 2468.2 Microneedles 2478.2.1 Delivery Using Solid Microneedles: Skin Pretreatment 2488.2.2 Delivery Using Coated Microneedles 252Challenges Related to the Formulation of Coated Microneedles - A Case Study 2528.2.3 Delivery Using Dissolvable Microneedles 2548.2.4 Delivery Using Hollow Microneedles 2558.2.5 Delivery of Vaccines 2578.2.6 Modalities of Microneedle Use 2598.2.7 Perspectives in Microneedle-Mediated Transdermal Delivery 2598.3 Laser-Assisted Ablation: Skin Pretreatment 2608.3.1 Laser-Skin Interaction 2618.3.2 Formulation Aspects 2628.3.3 Perspective 2638.4 Iontophoresis 2638.4.1 Clinical Benefits of Iontophoresis in Transdermal/Topical Delivery 2648.4.2 Selection of Drug Candidates 2658.4.3 Iontophoretic Device Formulation Characteristics: Compositions and Challenges 2658.4.4 Earlier Approved Commercial Devices 2668.4.5 Smart Ionto System Features 2688.4.6 Perspectives 269References 2699 Physical Characterization Techniques to Access Amorphous Nature 281Aniket Sabnis, Niten Jadav, TimGough, Adrian Kelly, and Anant Paradkar9.1 Introduction 2829.1.1 Limitations of the Amorphous Form 2859.1.2 Stabilization of the Amorphous Form 2859.1.3 Solid Dispersion 2859.1.4 Factors Affecting Solubility of API in the Form of Solid Dispersions 2879.1.5 Limitations 2899.1.6 Co-Amorphous 2899.2 Screening Techniques for Amorphization 2909.2.1 Amorphization: Solution-Based Techniques 2919.2.2 Amorphization: Solid-State Techniques 2949.3 Characterization of Amorphous Materials 2989.3.1 X-Ray Powder Diffraction (XRPD) 2999.3.2 Thermal Methods 3029.3.3 Perfusion/Solution Calorimetry 3079.3.4 Density Measurements 3109.3.5 Sorption Technique: Dynamic Vapor Sorption (DVS) 3109.3.6 Vibrational Spectroscopy 3129.4 Summary 3219.5 Future Prospects 322References 32310 Design and Development of Ocular Formulations for Preclinical and Clinical Trials 331Mathieu Schmitt10.1 Introduction 33110.2 Ocular Anatomy and Physiology 33210.3 Ocular Routes of Administration 33610.4 Drug Discovery in Ophthalmology 33710.4.1 Repositioning of Existing Drugs from Other Disease Area 33710.4.2 Optimization of Compound Class to Enhance Selectivity, Tolerance Profile, and Efficacy 33810.4.3 Specific Development 33910.5 Topical Drug Administration 34010.5.1 Ocular Bioavailability 34010.5.2 Drug Design 34010.5.3 Prodrugs 34210.5.4 Physiological Factors 34310.5.5 Formulation and Drug Delivery Systems 34410.5.6 Patient Compliance Through Packaging 35410.6 Posterior Segment Delivery 35610.6.1 In Situ Depot 35710.6.2 Prodrugs 35710.6.3 Intraocular Implants/Microparticles 35810.7 Conclusion 360References 36111 Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes 367Florian Engel11.1 Introduction 36811.2 General Considerations 36911.3 Undesired Side Effects of Excipients 37011.4 Novel Excipients 37111.4.1 Regulatory Requirements 37211.5 Rationale in Selecting an Excipient 37511.5.1 Data Sources 37611.5.2 Strategies to Determine "Estimated Safe Excipient Doses" 37811.5.3 Special Considerations for Oral Use 38111.5.4 Special Considerations for Intravenous Use 38111.5.5 Special Considerations for Topical Use 38511.6 Conclusions 386References 38712 Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations 391Saurabh Patil, Aditya Narvekar, Amita Puranik, Ratnesh Jain, and Prajakta Dandekar12.1 Introduction 39212.1.1 Use of Proteins for Different Therapeutic Indications 39212.1.2 Importance of Physicochemical Properties on Preformulation and Formulation Development of Protein Therapeutics 39412.1.3 Stability Constraints and Formulation Challenges 39512.1.4 Current Market Status and Opportunities of Therapeutic Proteins 39612.1.5 Current Technologies for Protein Formulation Development 39812.1.6 Current Approaches in Oral Delivery of Proteins for Enhanced GIT Absorption 40012.2 Types of Proteins Used in Therapeutic Indications 40012.3 Important Physicochemical Properties of Proteins for Formulation Development 40212.4 Existing Route of Administrations of Protein Formulations 40412.5 Developmental Aspects of Oral Protein Formulations 40512.5.1 Resource Requirements for Manufacturing of Protein-Based Formulations 40612.5.2 Stability Concerns of Proteins in the Gastrointestinal Tract (GIT) 40712.5.3 Physical Barriers to Delivering Proteins and Peptides 40712.5.4 Formulation Strategies for the Oral Delivery of Proteins and Peptides 40912.5.5 Modification of the Physicochemical Properties 41112.5.6 Use of Particulate Formulations 41212.5.7 Colon-Targeted Delivery Systems for Proteins and Peptides 41612.5.8 Mucoadhesive Polymeric Systems and Stimuli-Responsive Hydrogels 41712.5.9 Cell-Penetrating Peptides 41712.5.10 Prodrug Approach 41712.6 Clinical Application of Oral Protein Formulations 41812.7 Case Studies of Oral Protein Formulations 41812.7.1 Case Study I: Cyclosporine A 41812.7.2 Case Study II: Oral Insulin 42112.7.3 Case Study III: Prodrug Approach - Desmopressin 42212.8 Conclusion 422References 423Index 433show more