Biopharmaceutics E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: Advances in Pharmaceutical Technology
• Sprache: Englisch

Seitenzahl: 631

Veröffentlichungsjahr: 2021

Beschreibung

Explore the latest research in biopharmaceutics from leading contributors in the field In Biopharmaceutics - From Fundamentals to Industrial Practice, distinguished Scientists from the UK's Academy of Pharmaceutical Sciences Biopharmaceutica Focus Group deliver a comprehensive examination of the tools used within the field of biopharmaceutics and their applications to drug development. This edited volume is an indispensable tool for anyone seeking to better understand the field of biopharmaceutics as it rapidly develops and evolves. Beginning with an expansive introduction to the basics of biopharmaceutics and the context that underpins the field, the included resources go on to discuss how biopharmaceutics are integrated into product development within the pharmaceutical industry. Explorations of how the regulatory aspects of biopharmaceutics function, as well as the impact of physiology and anatomy on the rate and extent of drug absorption, follow. Readers will find insightful discussions of physiologically based modeling as a valuable asset in the biopharmaceutics toolkit and how to apply the principles of the field to special populations. The book goes on to discuss: * Thorough introductions to biopharmaceutics, basic pharmacokinetics, and biopharmaceutics measures * Comprehensive explorations of solubility, permeability, and dissolution * Practical discussions of the use of biopharmaceutics to inform candidate drug selection and optimization, as well as biopharmaceutics tools for rational formulation design * In-depth examinations of biopharmaceutics classification systems and regulatory biopharmaceutics, as well as regulatory biopharmaceutics and the impact of anatomy and physiology Perfect for professionals working in the pharmaceutical and biopharmaceutical industries, Biopharmaceutics - From Fundamentals to Industrial Practice is an incisive and up-to-date resource on the practical, pharmaceutical applications of the field.

Leseprobe

ADVANCES IN PHARMACEUTICAL TECHNOLOGY

A Wiley Book Series

Series Editors:Dennis Douroumis, University of Greenwich, UKAlfred Fahr, Friedrich–Schiller University of Jena, GermanyJurgen Siepmann, University of Lille, FranceMartin Snowden, University of Greenwich, UKVladimir Torchilin, Northeastern University, USA

Titles in the Series

Hot‐Melt Extrusion: Pharmaceutical ApplicationsEdited by Dionysios Douroumis

Drug Delivery Strategies for Poorly Water‐Soluble DrugsEdited by Dionysios Douroumis and Alfred Fahr

Computational Pharmaceutics: Application of Molecular Modeling in Drug DeliveryEdited by Defang Ouyang and Sean C. Smith

Pulmonary Drug Delivery: Advances and ChallengesEdited by Ali Nokhodchi and Gary P. Martin

Novel Delivery Systems for Transdermal and Intradermal Drug DeliveryEdited by Ryan Donnelly and Raj Singh

Drug Delivery Systems for Tuberculosis Prevention and TreatmentEdited by Anthony J. Hickey

Continuous Manufacturing of PharmaceuticalsEdited by Peter Kleinebudde, Johannes Khinast, and Jukka Rantanen

Pharmaceutical Quality by DesignEdited by Walkiria S Schlindwein and Mark Gibson

In Vitro Drug Release Testing of Special Dosage FormsEdited by Nikoletta Fotaki and Sandra Klein

Characterization of Pharmaceutical Nano‐ and MicrosystemsEdited by Leena Peltonen

Biopharmaceutics: From Fundamentals to Industrial PracticeEdited by Hannah Batchelor

Forthcoming Titles:

Process Analytics for PharmaceuticalsEdited by Jukka Rantanen, Clare Strachan and Thomas De Beer

Mucosal Drug DeliveryEdited by Rene Holm

Biopharmaceutics

From Fundamentals to Industrial Practice

Edited by

HANNAH BATCHELOR

Strathclyde Institute of Pharmacy and Biomedical Sciences

University of Strathclyde Glasgow, United Kingdom

This edition first published 2022© 2022 John Wiley & Sons Ltd

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Library of Congress Cataloging‐in‐Publication Data

Names: Batchelor, Hannah, editor.Title: Biopharmaceutics : from fundamentals to industrial practice / edited by Hannah Batchelor.Other titles: Biopharmaceutics (Batchelor) | Advances in pharmaceutical technology.Description: First edition. | Chichester, UK ; Hoboken, NJ : John Wiley & Sons, 2022. | Series: Advances in pharmaceutical technology | Includes bibliographical references and index.Identifiers: LCCN 2021050446 (print) | LCCN 2021050447 (ebook) | ISBN 9781119678281 (cloth) | ISBN 9781119678274 (adobe pdf) | ISBN 9781119678373 (epub)Subjects: MESH: Biopharmaceutics–methods | Drug DesignClassification: LCC RM301.5 (print) | LCC RM301.5 (ebook) | NLM QV 35 | DDC 615.7–dc23/eng/20211101LC record available at https://lccn.loc.gov/2021050446LC ebook record available at https://lccn.loc.gov/2021050447

Cover Design: WileyCover Image: © SCIEPRO/Getty Images

List of Contributors

Precious Akhuemokhan Institute of Pharmaceutical Sciences, King’s College London, London, United Kingdom

Abdul W. Basit Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Hannah Batchelor Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

Shanoo Budhdeo Seda Pharmaceutical Development Services, Alderley Edge, Alderley Park, Cheshire, United Kingdom

James Butler Biopharmaceutics, Product Development and Supply, GlaxoSmithKline R&D, Ware, United Kingdom

Paul A. Dickinson Seda Pharmaceutical Development Services, Alderley Edge, Alderley Park, Cheshire, United Kingdom

Talia Flanagan UCB Pharma S.A., Avenue de l’industrie, 1420Braine l’Alleud, Belgium

Ben Forbes Institute of Pharmaceutical Sciences, King’s College London, London, United Kingdom

Nikoletta Fotaki Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom

Simon Gaisford Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Francesca K. H. Gavins Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Pavel Gershkovich School of Pharmacy, Centre for Biomolecular Sciences, The University of Nottingham, Nottingham, United Kingdom

Wang Wang Lee Seda Pharmaceutical Development Services, Alderley Edge, Alderley Park, Cheshire, United Kingdom

Christine M. Madla Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Mark McAllister Pfizer Drug Product Design, Sandwich, United Kingdom

Laura E. McCoubrey Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Hamid A. Merchant Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, United Kingdom

Mine Orlu Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Claire M. Patterson Seda Pharmaceutical Development Services, Alderley Edge, Alderley Park, Cheshire, United Kingdom

Chris Roe Quotient Sciences, Mere Way, Ruddington, Nottingham, United Kingdom

Linette Ruston Advanced Drug Delivery, Pharmaceutical Sciences, R&D AstraZeneca, Macclesfield, United Kingdom

Konstantinos Stamatopoulos Biopharmaceutics, Pharmaceutical Development. PDS, MST, RD Platform Technology and Science, GSK, Ware, Hertfordshire, United Kingdom

Magda Swedrowska Institute of Pharmaceutical Sciences, King’s College London, London, United Kingdom

Sarah J. Trenfield Department of Pharmaceutics, UCL School of Pharmacy, University College London, London, United Kingdom

Vanessa Zann Quotient Sciences, Mere Way, Ruddington, Nottingham, United Kingdom

Panagiota Zarmpi Department of Pharmacy and Pharmacology, University of Bath, Bath, United Kingdom

Foreword

The term biopharmaceutics causes confusion, particularly with the advent of biopharmaceutical drug products. However, the origins of the word come from the combination of the prefix ‘bio’ from the Greek, ‘relating to living organisms and tissues’ where the patient is the organism (or owns the tissues) and pharmaceutics defined as the science relating to the preparation of medicines. Biopharmaceutics encompasses the physical/chemical properties of the drug, the dosage form (drug product) in which the drug is given, and the route of administration to better understand the rate and extent of systemic drug absorption.

Since its introduction in 1970, biopharmaceutics knowledge and testing has enabled scientists to predict drug absorption using a range of in vitro and in silico tools ensuring that the development of new pharmaceutical products is efficient by refining or reducing the burden of clinical testing. Technological advances during this period have resulted in changes in testing based both on scale, where understanding is now sought at the molecular level and also by the use of dynamic testing systems rather than static apparatus.

The application of biopharmaceutics has reformed the pharmaceutical development process, most notably allowing for clinically relevant risk assessments against formulation and processes changes. Recent advances have witnessed the extension of biopharmaceutics tools towards the earliest and latest stages in product development. Most major pharmaceutical companies have dedicated biopharmaceutics team, invested in improving the predictive power of the suite of tools available to minimise risks of clinical impact of formulation‐based changes. As the pharmaceutical industry seeks to accelerate the timelines for drug discovery and development, there is a need for efficient and robust formulations and manufacturing processes to meet the needs of the clinical programme. The biopharmaceutics teams must therefore rise to the challenge of ensuring that formulations used in the clinical programme provide the necessary exposure of drug and are adequately risk assessed.

The Academy of Pharmaceutical Sciences (APS) is a UK‐based professional membership body for pharmaceutical scientists. The biopharmaceutics focus group within the APS has a mission to promote scientific education and training in the field of biopharmaceutics to meet the needs of scientists working in both industrial and academic sectors. This book arose as a result of this mission where the members of the focus group recognised the need to provide training for those wanting to better understand biopharmaceutics and serves as a handbook to introduce the tools used within biopharmaceutics as applied to drug development.

The first six chapters cover the basics of biopharmaceutics and provide the context that underpins the later chapters. Chapters 7 and 8 specifically deal with how biopharmaceutics is integrated into product development within the pharmaceutical industry. Chapters 9 and 10 provide information on the regulatory aspects of biopharmaceutics. Chapter 11 highlights the impact of physiology and anatomy and how this can affect the rate and extent of drug absorption. Physiologically based modelling is a valuable asset in the biopharmaceutics toolkit, and this is introduced in Chapter 12. Chapter 13 provides information on a more advanced topic, the application of biopharmaceutics to special populations. Although oral administration remains the mainstay of drug therapy, it is not the exclusive route of administration, Chapters 14–16 cover alternative routes of administration. A newly emerging topic that considers the impact of the microbiome on the rate and extent of drug absorption is included as the final chapter in this book.

The chapters are written by members of the APS Biopharmaceutics focus group and includes academic and industrial authors with a diverse range of experience from those currently undertaking a PhD to those with more than 20 years of experience in this field.

It has been a real joy and privilege to bring this book together, and I thank all of the authors and the editorial team for their dedication in producing this book. I truly hope that this book is useful for those who want to explore biopharmaceutics in the future.

Hannah BatchelorStrathclyde Institute of Pharmacy and Biomedical Sciences,Glasgow, United Kingdom

1An Introduction to Biopharmaceutics

Hannah Batchelor

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

1.1 Introduction

The aim of this chapter is to introduce biopharmaceutics and to define some key terms used within biopharmaceutics. It will also briefly introduce where biopharmaceutics sits in the drug development process.

1.2 History of Biopharmaceutics

The term biopharmaceutics was introduced in the 1960s by Levy [1]. The word originates from the combination of bio‐ from the Greek meaning relating to living organisms or tissue and pharmaceutics defined as the science of pharmaceutical formulations; in this case the living organism is the person (or animal being treated). In modern parlance, the term biopharmaceutics encompasses the science associated with the physical/chemical properties of the drug product (including all components therein) and the interactions of this product with parameters linked to the route of administration that affect the rate and extent of drug uptake or presence at the site for local action. It combines knowledge of materials science; physiology; anatomy and physical sciences.

In more simple terms it is everything that controls the availability of the drug: that is how the drug exits the dosage form and travels to the systemic circulation (for systemically acting drugs) or to the local site of action for locally acting agents. It provides a link between the formulation and the clinical performance of a drug; a mechanistic understanding of biopharmaceutics ensures that the formulation is optimised in terms of exposure. This is shown schematically in Figure 1.1 where biopharmaceutics is focussed on absorption.

Figure 1.1Schematic of the fate of drugs once administered orally; biopharmaceutics relates to the absorption aspect of this image.

The term biopharmaceutics can cause confusion; particularly with the advent of biopharmaceutical drug products. There is evidence in confusion in terminology back in the 1970s where efforts were made to standardise the terminology used [2]; these efforts defined biopharmaceutics in several ways according to the experts at the time of publication. The most widely used definition is, ‘The study of the influence of formulation on the therapeutic activity of a drug product. Alternatively, it may be defined as a study of the relationship of the physical and chemical properties of the drug and its dosage form to the biological effects observed following the administration of the drug in its various dosage forms’ [3].

An analysis of new drug approvals in 2019 (US, EU and Japan) showed that oral products represented the majority of approvals (50%) with tablets and capsules as the dominant oral dosage forms [4]. Thus biopharmaceutics has tended to focus on oral more than alternative routes of administration.

Historically biopharmaceutics was part of clinical pharmacology and pharmaceutical chemistry, only becoming its own scientific discipline in the 1970s. In scientific terms, the MeSH definition (MeSH [Medical Subject Headings] is the United States National Library of Medicine controlled vocabulary thesaurus used for indexing articles for PubMed) of biopharmaceutics (introduced in 1970) is, ‘The study of the physical and chemical properties of a drug and its dosage form as related to the onset, duration and intensity of its action’. The MeSH term ‘biopharmaceutics’ being introduced in the 1970s provides an insight into the history of the topic; the scientific discipline existed long before but was previously listed in scientific data based under a bigger heading of pharmacology as:

Figure 1.2Frequency of biopharmaceutics as a MESH terms in publications versus time.

Source: Data from Pubmed.gov, November 2020.

Chemistry, Pharmaceutical (1966–1969)

Drug Compounding (1966–1969)

Drugs (1966–1969)

Pharmacology (1966–1969)

A search in PubMed of ‘Biopharmaceutics’ [Mesh] conducted in November 2020 resulted in 2725 retrieved documents with a peak in the early 1970s as the science of biopharmaceutics developed. There has also been a general trend of increased use of the term biopharmaceutics since the year 2000. This is shown in Figure 1.2.

There have been a number of key events in the history of biopharmaceutics and these are highlighted in Figure 1.3.

1.3 Key Concepts and Definitions Used Within Biopharmaceutics

There is a strong link between biopharmaceutics and pharmacokinetics. Pharmacokinetics measures the concentration of drug at a site in the body versus time. Understanding the biopharmaceutics will influence the pharmacokinetic profile observed. In particular, biopharmaceutics has a focus on the absorption phase of a drug as this is the phase where the dosage form design has influence over the pharmacokinetic profile. The metabolism and subsequent elimination and excretion are driven by the drug properties rather than those of the formulation used to administer the drug.

Pharmacokinetic studies provide information on drug concentrations (typically in plasma or blood) versus time; these studies can be used to demonstrate safety and efficacy of a drug as well as compare the relative performance of alternative dosage forms (for further details see Chapter 2). This performance can be by design, for example, to develop a sustained release product to alter dosing frequency. Generation of statistically similar pharmacokinetic profiles for alternative drug products provides reassurance that these medicines can be interchanged with limited effects on clinical efficacy. These statistically similar pharmacokinetic profiles show bioequivalence between drug products, this bioequivalence is discussed more in the chapter on regulatory biopharmaceutics (Chapter 10). This is of great importance for generic medicine development to ensure that medicines can be interchanged with not clinical impact to the patient.

Figure 1.3Overview of the biopharmaceutics timeline of key events.

Pharmacokinetic data can be analysed to demonstrate what fraction of the drug administered orally was measured within the system; this fraction is termed the bioavailable dose. It is recognised that not all drug administered will reach the site of measurement as some will be lost due to: localised degradation; failure to permeate membranes to reach the site of measurement; metabolism between site of absorption and site of measurement. Calculation of the bioavailability of a drug is important in dosage form design as it will influence the dose to be administered as well as the likelihood of reaching the target concentration at the site of measurement (and site of action). This can also be termed the bioperformance of a product.

The processes that influence the bioavailable dose are key to the science of biopharmaceutics. There is emphasis on the fraction of drug absorbed as this relates to the inherent drug properties and how they link with the dosage form as well as the site where absorption occurs. Formulation scientists can design dosage forms for a range of sites for administration and understanding how the fraction absorbed varies by site of administration is important for systemically acting drugs. Absorption can be complex and is not a single‐step process; there are often several membranes or other barriers that lie between the site of administration and the site of measurement (or action) for a drug. The permeability (Chapter 5) of the drug across each of these barriers will dictate the fraction that can traverse the membrane. Measuring the fraction absorbed at each membrane is not possible and often there is a single point for administration and a single point for measurement which can complicate accurate determination of the fraction absorbed. This is exemplified in oral absorption of drugs. Drugs will enter the gastro‐intestinal system where some of the drug will be solubilised and will traverse the intestinal membrane; however, there may be some metabolism at the intestinal wall meaning that not all the drug absorbed reaches the systemic circulation. Furthermore, the portal vein drains from the intestine directly into the liver where further metabolism is likely to occur again reducing the quantity of drug present in the systemic circulation. The site of measurement; typically a blood or plasma sample taken peripherally will only show the drug that successfully traversed the intestinal wall AND was not metabolised within the liver; therefore this is lower than the actual fraction of drug absorbed.

First pass metabolism is the term used to describe the fraction of drug lost between entering the portal vein directly from the intestine and existing the liver. This describes the fraction of drug lost during the first pass through the liver, prior to reaching the sampling site.

The oral route is the most common route of drug administration and as such much of this book will focus on oral biopharmaceutics; however there are chapters on alternative routes of administration (Chapter 14: Inhaled Biopharmaceutics; Chapter 15: Biopharmaceutics of Injectable Formulations and Chapter 16: Topical Bioavailability).

A key factor that influences the absorption of drug from the gastro‐intestinal tract is the solubility (Chapter 4) of the drug within the intestinal fluids. The intestinal fluids are complex, affected by food and many other factors associated with ethnicity, disease and gender (Chapter 13: Special Populations). Understanding the composition of intestinal fluids and replication of this for in vitro models is of huge interest to those working within biopharmaceutics. Due to the transit time within the intestinal tract, it is not just the solubility that is important but the rate of drug dissolution (Chapter 6) within the fluids present that will influence the rate and extent of drug absorption.

The biopharmaceutics classification system (BCS) (Chapter 9), introduced in 1995 by Gordon Amidon [5], sought to classify drugs based on their dissolution and permeability as these factors are fundamental in controlling the rate and extent of oral absorption. This system is still in use in regulatory science and has been extended to also look at the developability of drugs [6]. The BCS can also justify a biowaiver; this is a situation where the in vitro solubility and permeability data can negate the need for a clinical study to demonstrate bioequivalence, resulting in a large cost saving for those involved in development.

The major emphasis of research in biopharmaceutics is the development of in vitro and in silico model that predict how a drug will be absorbed in vivo. Thus the use of biorelevant models that replicate the physiology, anatomy and local environment within the gastro‐intestinal tract (or other site of administration) are important. In particular, the use of physiologically based pharmacokinetic (PBPK) models (Chapter 12) that not only replicate the body but also provide indications on the population‐based variability in drug absorption.

1.4 The Role of Biopharmaceutics in Drug Development

Drug development is a complex process that involves many scientists, a lot of money and at least 10 years. The process starts with target identification where chemicals are manufactured to ‘fit’ the receptor of interest and they are typically ranked by potency for that receptor. At this stage, there is little biopharmaceutics input. The next step is to evaluate the lead chemicals using preclinical models; this can be cell lines or animal models to determine whether the chemical is as potent in vivo. At this stage, some biopharmaceutics input is crucial as the drug may need to be formulated for administration to the animal model and may even be administered orally so the fraction absorbed can be measured. This often relates to the ‘drugability’ of the lead candidates; defined as the technical evaluation of whether a compound will be a commercially successful drug. Drugability here relates to the likelihood for sufficient and non‐variable pharmacokinetic exposure.

Success in preclinical models will trigger clinical evaluation in humans. There are three phases of clinical trial prior to launch of a product: phase 1 will measure safety and efficacy of a compound in healthy volunteers where possible; at this stage the bioavailable dose will be assessed. Phase 2 studies explore the safety and efficacy of the drug in patients with the disease of interest. The product used for phases 1 and 2 is often different to the final commercial product as the dose is still to be defined. Thus there may be differences in the bioavailable fraction of each formulation administered that needs to be accounted for when interpreting the data and determining the dose. The term bridging is used to describe how any differences between formulations used in preclinical and clinical testing are managed during the clinical testing. Phase 3 studies evaluate the efficacy and safety in a large patient population. Where possible the final commercial formulation will be used in phase 3 studies as these are pivotal to underpinning the evidence to justify the introduction of a new product. Biopharmaceutics is integral to the phases of clinical testing as predictive models to understand absorption and consequences of bridging are critical to the success of the interpretation of clinical data.

In parallel to the clinical evaluation (phase 1, 2 and 3 studies) work will be ongoing to ensure that the chemistry manufacturing and controls (CMC) activities are on track. These CMC activities ensure that the product and manufacturing process meet the stringent regulatory requirements ensuring that a safe and high‐quality product is available to the patient population. Any changes to the product or manufacturing process need to be understood, particularly if there are likely to be consequences to the patient; thus biorelevant predictive tests are of value in de‐risking the development process. In addition to biorelevant tests, often discriminatory dissolution testing is required; this is a method that links to clinical data and shows where changes in the product (as a result of composition or manufacturing changes) are likely to have an effect on the clinical performance. These discriminatory dissolution tests are generated by links to in vivo clinical data; either using an in vitro in vivo relationship (IVIVR) or using the principles of quality by design (QbD).

Regulatory approval of new products is essential. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together the regulatory authorities and pharmaceutical industry to discuss scientific and technical aspects of drug registration. ICH guidelines include information on biopharmaceutics that are essential for the approval of medicines. Two guidelines are focussed on biopharmaceutics specifically: ICH M9 Biopharmaceutics classification system based biowaivers and M13 Bioequivalence for Immediate release solid oral dosage forms. Within the US the major regulatory agency is the FDA (Food and Drug Administration); the FDA have a Biopharmaceutics council within the centre for drug evaluation and research. This office is responsible for the generation, implementation and review of biopharmaceutics‐related guidance, policies and practices. There are several biopharmaceutics specific FDA regulatory guidance papers issues that are critical to the approval of new drugs. Similar to the USA there are many global regulatory bodies where biopharmaceutics guidance has been issued including the EMA (European Medicines Agency) and the Japanese Food and Drug Administration. Recently the ICH M9 guidance has sought to align these where possible for the BCS classification.

Biopharmaceutics interfaces with several other scientific disciplines, this book aims to provide a background to biopharmaceutics and to showcase how knowledge can be applied to the efficient development of drug products. The level of detail in terms of biopharmaceutics knowledge of a drug and a drug product will increase during the drug development process. This is shown schematically in Figure 1.4.

Biopharmaceutics is an important scientific discipline, particularly for those developing new drugs. An understanding of biopharmaceutics aids in the design of appropriate drug candidates (Chapter 7) as well as optimised drug products (Chapter 8) to ensure that the drug is well absorbed from the site of administration. Clinical testing of drugs, from phase 1 to phase 4 clinical trials is expensive and time‐consuming. Biopharmaceutics tests and knowledge are critical to de‐risk changes in the clinical performance as a result of minor changes in the product and process used to manufacture the drug product used within these clinical trials. There is a strong relationship between biopharmaceutics and regulatory science during the development of drug products.

Figure 1.4Overview of biopharmaceutics input in the drug development pathway.

1.5 Conclusions

Biopharmaceutics is a relatively new science that brings together knowledge on anatomy and physiology to understand the biological environment where drugs are absorbed with materials science to appreciate the drug and excipient related effects on these processes. This book brings together the knowledge required to better understand biopharmaceutics and to apply this knowledge in the development of drug products.

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