The Future of Pharmaceuticals: A Nonlinear Analysis

 

Description:

 

 

Before now, biological systems could only be expressed in terms of linear relationships, however, as knowledge grows and new techniques of analysis on biological systems is made available, we are realizing the non-linearity of these systems. The concepts and techniques of nonlinear analysis allow for more realistic and accurate models in science. The Future of Pharmaceuticals: A Nonlinear Analysis provides an opportunity to understand the non-linearity of biological systems and its application in various areas of science, primarily pharmaceutical sciences. This book will benefit professionals in pharmaceutical industries, academia, and policy who are interested in an entirely new approach to how we will treat disease in the future. Key Features: Addresses a new approach of nonlinear analysis. Applies a theory of projection to chalk out the future, instead of basing on linear evolution. Provides an opportunity to better understand the non-linearity in biological systems and its applications in various areas of science, primarily pharmaceutical sciences. Helps change the thought process for those looking for answers to their questions which they do not find in the linear relationship approach. Encourages a broader perspective for the creative process of drug development.

 

Table of Contents:

 

1 Understanding Nonlinearity

1.1 Background

1.2 Predictions

1.2.1 Examples

1.3 Modeling Systems

1.3.1 Bayes’ Theorem

1.3.1.1 Phases of Paradigm Shift

1.3.2 Future Shifts

1.4 Conclusion

Additional Reading

2 The Evolution of Pharmaceuticals

2.1 Background

2.2 The Pre-Historical Era

2.3 The New World Era

2.4 The Regulatory Era

2.5 The Legal Era

2.6 The Gene Era

2.6.1 The Biological Medicine Era

2.6.2 Nobel Prizes

2.7 The Future Era

2.8 New Entities

2.8.1 A Special Case

2.9 Conclusion

2.10 Appendix: New Molecular Entities Approved by the FDA 2011–2020

Additional Reading

3 Artificial Intelligence

3.1 Background

3.2 Bioinformatics

3.3 Artificial Intelligence

3.4 Deep Learning Architecture

3.4.1 Graph Representation Learning

3.5 Repurposing

3.6 Data and Model Harmonization

3.7 Drug Discovery and Development

3.7.1 Stepwise Approach

3.7.2 Application Types

3.7.3 An Example of AI Application

3.8 AI Tools

3.9 Conclusion

Additional Reading

4 Drug Discovery Trends

4.1 Background

4.2 High-Throughput Screening (HTS)

4.2.1 Phenotypic Screening

4.2.2 Modeling

4.2.3 Screening Using Fragments (FBS)

4.2.4 Ligandomics

4.2.5 Gene-Based Testing

4.2.6 Target Identification

4.2.6.1 Hit Identification

4.2.6.2 Hit to Lead

4.2.6.3 Target Validation and Efficacy

4.2.6.4 Cell-Based Models

4.2.6.5 In Vivo Testing

4.3 Structural Biology

4.4 Hit Optimization

4.4.1 PK–PD Relationship

4.5 Chemistry and Formulation

4.5.1 Lipinski’s Rule of Five (RO5)

4.6 Safety Testing

4.6.1 Animal Models

4.6.2 Replacing Animal Testing

4.7 Synthetic Biology

4.8 Libraries

4.8.1 DNA Libraries

4.9 Microphysiometry

4.9.1 Microfluidics

4.9.2 Organs-on-a-Chip (OOC)

4.9.3 Brain-on-a-Chip

4.9.4 Lung-on-a-Chip

4.9.5 Heart-on-a-Chip

4.9.6 Kidney-on-a-Chip

4.9.7 Nephron-on-a-Chip

4.9.8 Vessel-on-a-Chip

4.9.9 Skin-on-a-Chip

4.9.10 Human-on-a-Chip

4.10 Clinical Trials

4.10.1 Biomarkers

4.10.1.1 BEST

4.11 Exploratory IND

4.12 Repurposing

4.13 Orphan Drugs

4.14 Conclusion

Additional Reading

5 Drug Development Assays

5.1 Background

5.1.1 Assay Optimization

5.2 Assay Development and Validation

5.2.1 Pre-Study Validation

5.2.2 In-Study Validation

5.2.3 Cross-Validation

5.2.4 Critical Path

5.3 Receptor Binding Assays in HTS

5.3.1 Scintillation Proximity Assays (SPA)

5.3.2 Filtration Assays

5.4 In Vitro Biochemical Assays

5.4.1 Definitions

5.4.2 Signs of Enzymatic Contamination

5.4.3 Solutions for Enzymatic Contamination

5.4.4 Batch Testing

5.4.4.1 Identity and Mass Purity

5.4.4.2 Methods for Confirming Identity and Mass Purity

5.4.4.3 Protein Stain of SDS-PAGE

5.4.4.4 Western Blot with the Specific Antibody

5.4.4.5 Analytical Gel Filtration

5.4.4.6 Reversed-Phase HPLC

5.4.4.7 Mass Spectrometry

5.4.4.8 Whole Mass for Protein

5.4.4.9 Peptide Mass Finger Printing

5.4.4.10 Edman Sequencing

5.4.4.11 Crude Enzyme Preparations

5.4.4.12 Commercial Enzymes

5.4.4.13 Co-Purification of Contaminating Enzymes

5.4.4.14 Mock Parallel Purification

5.4.4.15 Reversal of Enzyme Activity

5.4.5 Detecting Enzyme Impurities

5.4.5.1 Consequences of Substrate Selectivity

5.4.5.2 Substrate Km

5.4.5.3 Enzyme Concentration

5.4.5.4 Format Selection

5.4.6 Validating Enzymatic Purity

5.4.6.1 Inhibitor-Based Studies

5.4.6.2 IC50 Value

5.4.6.3 Hill slope

5.4.7 Substrate-Based Studies

5.4.7.1 Substrate Km Determination

5.4.7.2 Substrate Selectivity Studies

5.4.7.3 Comparison Studies

5.4.7.4 Enzyme Source

5.4.7.5 Format Comparison

5.5 Enzymatic Assays for HTS

5.5.1 Basic Concept

5.5.1.1 Initial Velocity

5.5.2 Reagents and Method Development

5.5.2.1 Detection System Linearity

5.5.2.2 Enzyme Reaction Progress Curve

5.5.2.3 Measuring the Initial Velocity of an Enzyme Reaction

5.5.2.4 Measurement of Km and Vmax

5.5.2.5 What Does the Km Mean?

5.5.2.6 How to Measure Km

5.5.2.7 Determination of IC50 for Inhibitors

5.5.2.8 Optimization Experiments

5.6 ELISA-Type Assays

5.6.1 Basic Concept

5.6.2 General Considerations

5.6.2.1 Assay Design and Development

5.6.3 Fluorescence Polarization/Anisotropy

5.6.3.1 Assay Design

5.6.4 Fluorescent/Förster Resonance Energy Transfer and Time-Resolved (TR) FRET

5.6.5 AlphaScreen Format

5.6.5.1 Optical Biosensors

5.6.5.2 Nuclear Magnetic Resonance (NMR)

5.6.5.3 Isothermal Calorimetry (ITC)

5.6.5.4 Sedimentation Analysis (SA; Analytical Ultracentrifugation)

5.6.5.5 X-Ray Crystallography

5.7 In Vitro Toxicity and Drug Efficacy Testing

5.8 In Vivo Assay Validation

5.8.1 General Concepts

5.8.1.1 Pre-Study Validation

5.8.1.2 In-Study Validation

5.8.1.3 Cross-Validation

5.8.1.4 Resources

5.8.2 Assay Validation Procedures

5.8.2.1 Pre-Study Validation

5.9 Pharmacokinetics and Drug Metabolism

5.9.1 In Vitro Analysis

5.9.1.1 Lipophilicity

5.9.1.2 Solubility

5.9.1.3 Hepatic Microsome Stability

5.9.1.4 Plasma Stability

5.9.1.5 Plasma Protein Binding

5.9.1.6 Screening Cytotoxicity and Hepatotoxicity Test

5.9.1.7 CYP450 Inhibition Profiling

5.9.1.8 Permeability

5.10 Conclusion

Additional Reading

6 Nanomedicine

6.1 Background

6.2 Delivery Routes

6.3 Liposomes

6.4 Dendrimers

6.5 Polymers

6.6 Metal Particles

6.7 Quantum Dots

6.8 Fullerenes

6.9 Theranostics

6.10 Diagnostics

6.11 Specific Diseases

6.11.1 IBD

6.11.2 Diabetes

6.11.3 Cancer

6.12 Regulatory

Additional Reading

7 Antimicrobials

7.1 Background

7.2 Eradicable Diseases

7.2.1 Polio

7.2.2 Guinea Worm Disease (Dracunculiasis)

7.2.3 Lymphatic Filariasis

7.2.4 Measles, Mumps, and Rubella

7.2.5 Cysticercosis

7.2.6 Yaws

7.2.7 Trachoma

7.2.8 Onchocerciasis

7.2.9 Malaria

7.3 Vaccines

7.3.1 Live-Attenuated Vaccines

7.3.2 Inactivated Vaccines

7.3.3 Subunit, Recombinant, Polysaccharide, and Conjugate Vaccines

7.3.4 Toxoid Vaccines

7.3.5 Nucleic Acid Vaccines

7.4 Antibiotics

7.4.1 Antibiotic Discovery

7.4.1.1 Semi-Synthetic

7.4.1.2 Synthetic

7.4.1.3 Genomic Approaches

7.4.2 Reverse Genomics: Revival of Cell-Based Screening

7.4.3 Post-Genomics

7.4.3.1 Transcriptomics, Proteomics, and Lipidomics

7.4.3.2 Metabolomics to Meta-Omics

7.5 Phage Therapy

7.6 Microbiome

7.6.1 Impact on Health

7.6.2 Drug Metabolism

7.6.3 Drug Toxicity

7.6.4 Biomarkers

7.7 Conclusion

Additional Reading

8 Therapeutic Proteins

8.1 Background

8.2 Protein Structure and Properties

8.2.1 Primary Structure

8.2.2 Secondary Structure

8.2.2.1 Alpha Helix

8.2.2.2 Beta-Sheet

8.2.3 Tertiary Structure

8.2.4 Quaternary Structure

8.2.5 Post-Translational Modification (PTM)

8.2.6 Association and Aggregation

8.3 Non-Antibody Therapeutic Proteins

8.3.1 Hormone Peptide Drugs

8.3.2 Human Hematopoietic Factor

8.3.3 Human Cytokines

8.3.4 Human Plasma Protein Factor

8.3.5 Human Bone Formation Protein

8.3.6 Enzymes

8.4 Antibody Therapeutic Proteins

8.4.1 Mode of Action

8.4.2 Types of Antibodies

8.4.2.1 Recombinant Antibodies

8.4.2.2 Synthetic Antibodies

8.4.2.3 Affimer Proteins

8.4.2.4 Structural Protein Scaffolds

8.4.2.5 Bispecific Antibodies (BsAbs)

8.4.2.6 Multi-Specific Antibodies (MsAbs)

8.4.2.7 Fab Fragments and Single-Chain Antibodies

8.4.2.8 Humanized and Chimeric mAbs

8.4.2.9 Affinity Maturation

8.4.2.10 Antigenized Antibodies

8.4.2.11 IgG1 Fusion Proteins

8.4.2.12 Drug or Toxin Conjugation

8.4.2.13 Future Antibodies

8.4.3 Development of Antibodies

8.4.4 Exogenous Methods

8.4.4.1 Mouse Hybridoma

8.4.4.2 Transgenic Mice

8.4.5 Surface Display Libraries

8.4.5.1 Phage Display

8.4.5.2 Yeast Display

8.4.5.3 Ribosome Display

8.4.5.4 mRNA Display

8.4.6 Recombinant Expression

8.5 Immunogenicity

8.5.1 Protein Immunogenicity

8.5.2 Immunogenicity Testing

8.5.3 Innate System

8.5.4 Adaptive System

8.6 Pharmacokinetics of Therapeutic Proteins

8.6.1 Absorption

8.6.2 Distribution

8.6.3 Elimination

8.6.4 Pharmacokinetic Manipulations

8.6.4.1 Protein Modification to Increase Duration of Action

8.6.4.2 Protein Pegylation

8.6.4.3 Unnatural Construction

8.7 Conclusion

Additional Reading

9 Manufacturing Trends

9.1 Background

9.2 Process Optimizations

9.2.1 Cell Line Development

9.2.2 Media

9.2.3 High Cell Density Cryopreservation

9.2.4 Cell Culture Operations

9.2.5 Bioreactor Cycle

9.3 Single-Use Technology (SUT)

9.3.1 Containers and Mixing Systems

9.3.2 Drums, Containers, and Tank Liners

9.3.2.1 2D Bags

9.3.2.2 3D Bags

9.3.3 Advantages

9.3.4 Single-Use Bioreactors (SUBS)

9.3.5 Other Components

9.3.5.1 Optical Sensors

9.3.5.2 Biomass Sensors

9.3.5.3 Electrochemical Sensors

9.3.5.4 Pressure Sensors

9.3.5.5 Sampling Systems

9.3.5.6 Connectors

9.3.5.7 Tubing

9.3.5.8 Pumps

9.3.5.9 Tube Welder and Sealers

9.3.6 Sampling

9.3.7 Downstream Processing

9.3.7.1 Cell Harvest

9.3.7.2 Purification

9.3.7.3 Virus Removal

9.3.7.4 Filtration—UF/DF and TFF

9.3.7.5 General Filtration Applications

9.3.8 Fill Finish Operations

9.3.9 Safety

9.3.9.1 Polymers and Additives

9.3.9.2 Material Selection

9.3.9.3 Testing

9.3.9.4 Regulatory

9.4 Online Monitoring

9.5 Continuous Manufacturing

9.5.1 Continuous Chromatography Operations

9.5.1.1 Straight Through Processing (STP)

9.5.1.2 Periodic Countercurrent Chromatography (PCC)

9.5.1.3 Simulated Moving Bed (SMB) Chromatography

9.6 Conclusion

Appendix: Databases Relevant to Antibodies

Additional Reading

10 Therapeutic Protein Delivery Systems

10.1 Background

10.2 Route Selection

10.2.1 Selection

10.2.2 Excipients and Properties

10.2.2.1 pH

10.2.2.2 Surface Tension

10.2.2.3 Tonicity

10.2.2.4 Protectants

10.2.2.5 Stabilizers

10.2.3 Liquid Formulations

10.2.4 Lyophilized Formulations

10.3 Delivery Routes

10.3.1 Intravenous

10.3.2 Subcutaneous

10.3.3 Oral

10.3.4 Nasal

10.3.5 Transdermal

10.3.6 Pulmonary

10.3.7 Ocular

10.3.8 Rectal

10.4 Formulation Technologies

10.4.1 Hydrogels and In Situ Forming Gels

10.4.2 Nanoparticles

10.4.3 Liposome

10.4.4 Higher Concentration Formulations

10.5 Examples of Formulation

10.5.1 Oprelvekin Injection (Interleukin IL-11)

10.5.2 Interleukin Injection (IL-2)

10.5.3 Interferon Alfa-2a Injection

10.5.4 Interferon Beta-1b

10.5.5 Interferon Beta-1a Injection

10.5.6 Interferon Alfa-n3 Injection

10.5.7 Interferon Alfacon-1 Injection

10.5.8 Interferon Gamma-1b Injection

10.5.9 Infliximab for Injection

10.5.10 Daclizumab for Injection

10.5.11 Coagulation Factor VIIa (Recombinant) Injection

10.5.12 Reteplase Recombinant for Injection

10.5.13 Alteplase Recombinant Injection

10.6 Conclusion

Appendix 10.1: Physicochemical Properties of Proteins and Peptides Approved by the FDA

Additional Reading

11 Gene and Cell Therapy

11.1 Background

11.2 Gene Therapy

11.2.1 Viral Vector Manufacturing

11.2.2 Downstream Manufacturing

11.2.3 Risks of Gene Therapy

11.2.4 Gene Editing

11.2.5 Techniques

11.2.6 Gene Editing Technologies

11.2.7 CRISPR

11.2.8 DNA-Based Therapeutics

11.2.9 Gene Transfer Technologies

11.2.9.1 Mechanical and Electrical Techniques

11.2.9.2 Vector-Assisted Delivery Systems

11.2.10 Approved Products

11.3 Cell Therapy

11.3.1 Types of Cell Therapies

11.3.2 CAR-T Therapy

11.3.3 Allogenic Cell Therapy

11.4 Regulatory Considerations

11.4.1 Development and Characterization of Cell Populations for Administration (https://www.fda.gov/media/72402/download)

11.4.1.1 Collection of Cells

11.4.1.2 Tissue Typing

11.4.1.3 Procedures

11.4.2 Characterization and Release Testing of Cellular Gene Therapy Products

11.4.2.1 Cell Identity

11.4.2.2 Potency

11.4.2.3 Viability

11.4.2.4 Adventitious Agent Testing

11.4.2.5 Purity

11.4.2.6 General Safety Test

11.4.2.7 Frozen Cell Banks

11.4.3 Additional Applications: Addition of Radioisotopes or Toxins to Cell Preparations

11.4.4 Production, Characterization, and Release Testing of Vectors for Gene Therapy

11.4.4.1 Vector Construction and Characterization

11.4.4.2 Vector Production System

11.4.4.3 Master Viral Banks

11.4.4.4 Lot-to-Lot Release Testing and Specifications for Vectors

11.4.4.5 Adventitious Agents

11.4.5 Issues Related to Particular Classes of Vectors for Gene Therapy

11.4.5.1 Additional Considerations for the Use of Plasmid Vector Products

11.4.5.2 Additional Considerations for the Use of Retroviral Vector Products

11.4.5.3 Additional Considerations for the Use of Adenoviral Vectors

11.4.6 Modifications in Vector Preparations

11.4.7 Preclinical Evaluation of Cellular and Gene Therapies

11.4.7.1 General Principles

11.4.7.2 Animal Species Selection and Use of Alternative Animal Models

11.4.7.3 Somatic Cell and Gene-Modified Cellular Therapies

11.4.7.4 Direct Administration of Vectors In Vivo

11.4.7.5 Expression of Gene Product and Induction of Immune Responses

11.4.7.6 Vector Localization to Reproductive Organs

11.5 Conclusion

Additional Reading

12 Nucleic Acid Vaccines

12.1 Background

12.2 mRNA Vaccine

12.2.1 Development Cycle

12.2.2 Formulation and Delivery

12.2.3 COVID-19 Vaccine

12.3 DNA Vaccine

12.3.1 Delivery

12.3.2 Antibody Response

Additional Reading

13 Botanical Products

13.1 Overview

13.2 Complimentary Medicines

13.2.1 History

13.2.2 Development Innovations

13.2.3 Technologies

13.2.4 Genomics and Biomarkers

13.2.5 Proteomics

13.2.6 Target Identification of Label-Free Botanical Products

13.2.7 Metabolomics and Metabonomics

13.3 Regulatory Plan

13.3.1 Background

13.3.2 Chemistry

13.3.3 Specifications

13.3.4 Standardization

13.3.5 Efficacy and Safety

13.3.6 Prior Human Use

13.3.7 CMC

13.3.7.1 Starting Material

13.3.7.2 Control of Botanical Substances and Preparations

13.3.7.3 Control of Vitamins and Minerals (If Applicable)

13.3.7.4 Control of Excipients

13.3.7.5 Stability Testing

13.3.7.6 Testing Criteria

13.3.7.7 Botanical Substances

13.3.7.8 Botanical Product

13.4 Conclusion

Additional Reading

14 Regulatory Optimization

14.1 Background

14.2 Scope

14.2.1 Assumptions

14.2.2 Definitions

14.3 New Chemical Entities

14.3.1 Decision Stage #1—Target Identification

14.3.2 Decision Stage #2—Target Validation

14.3.3 Decision Stage #3—Identification of Actives

14.3.4 Decision Stage #4—Confirmation of Hits

14.3.5 Decision Stage #5—Identification of Chemical Lead

14.3.6 Decision Stage #6—Selection of Optimized Chemical Lead

14.3.7 Decision Stage #7—Selection of a Development Candidate

14.3.8 Decision Stage #8—Pre-IND Meeting with the FDA

14.3.9 Decision Stage #9—Preparation and Submission of an IND Application

14.3.10 Decision Stage #10—Human Proof of Concept

14.3.11 Decision Stage #11—Clinical Proof of Concept

14.4 Repurposing of Marketed Drugs

14.4.1 Decision Stage #1: Identification of Actives

14.4.2 Decision Stage #2: Confirmation of Hits

14.4.3 Decision Stage #3: Gap Analysis/Development Plan

14.4.4 Decision Stage #4: Clinical Formulation Development

14.4.5 Decision Stage #5: Preclinical Safety Data Package

14.4.6 Decision Stage #6: Clinical Supplies Manufacture

14.4.7 Decision Stage #7: IND Preparation and Submission

14.4.8 Decision Stage #8: Human Proof of Concept

14.5 Drug Delivery Platform Technology

14.5.1 Decision Stage #1: Clinical Formulation Development

14.5.2 Decision Stage #2: Development Plan

14.5.3 Decision Stage #3: Clinical Supplies Manufacture

14.5.4 Decision Stage #4: Preclinical Safety Package

14.5.5 Decision Stage #5: IND Preparation and Submission

14.5.6 Decision Stage #6: Human Proof of Concept

14.5.7 Decision Stage #7: Clinical Proof of Concept

14.6 Biological Products

14.6.1 Batch

14.6.2 Upstream

14.6.3 Downstream

14.6.4 Facility

14.6.5 Equipment

14.6.6 Validation

14.6.7 Testing

14.6.8 Quality

14.6.9 Fill

14.6.10 Water

14.6.11 Facility Design

14.6.12 Cleaning

14.6.13 Filling and Finishing

14.7 Testing

14.8 Documentation Process

14.8.1 Process Analytical Technology (PAT)

14.8.2 Automation

14.9 Predictions

14.10 Conclusion

Additional Reading

15 Intellectual Property

15.1 Background

15.2 About Patents

15.3 Patent Landscape

15.4 Patent Laws

15.4.1 Pharmaceutical Patenting Practices

15.5 Types of Patents

15.5.1 Utility Model in the EU

15.5.2 Provisional Application

15.6 Nonobviousness

15.7 Patent Management

15.7.1 Broad Coverage

15.7.2 Submarine Patents

15.7.3 System Expression Patents

15.7.4 Process Patents of Originator

15.7.5 Third-Party Process Patents

15.7.6 Formulation Composition

15.7.7 Lifecycle Formulation Projections

15.7.8 Alternate Offering

15.7.9 Delivery Devices

15.7.10 Unpatentable Inventions

15.7.11 Software Patents

15.7.12 Medical Method Patents

15.8 Patent Classification

15.8.1 Class 435

15.8.2 Class 424

15.8.3 Class 801

15.9 Biological Patents

15.9.1 Biological Products

15.9.2 Monoclonal Antibody Technology

15.9.3 Antisense Technology

15.9.4 Transgenic Plants

15.10 Freedom to Operate

15.11 Conclusion

Additional Reading

Index

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An aparitie	1 Mar. 2022
Autor	Sarfaraz K. Niazi
Dimensiuni	253 x 176 x 43 mm
Editura	CRC Press
Format	Paperback
ISBN	9780367701390
Limba	Engleza
Nr pag	568