Controlled Drug Delivery Systems

Emmanuel Opara

• Publisher: CRC Press
• Year: 2020
• Print ISBN: 9781032653921
• eBook ISBN: 9780429582752
• Topic: Medicine
• Subtopic: Pharmacology

This book will describe current research on drug delivery systems that encompass four broad categories, namely: routes of delivery, delivery vehicles, payload, and targeting strategies. Where appropriate delivery vehicles and relevant release of specific agents in any of these categories in clinical application will be discussed. All chapters will highlight the translational aspects of the various technologies discussed and will provide insights into the advantages of such delivery systems over current ones in clinical or research use. Each technology reviewed in this book will have significant potential to improve patients' lives by enhancing the therapeutic efficacy of drugs.

This book:

Discusses the various factors that mitigate effective oral insulin delivery and the current status of research efforts to overcome these barriers along with recent clinical projections

Examines the advantages and disadvantages of each drug delivery system

Examines the standard method of accomplishing controlled drug release through the incorporation of the drugs within polymeric biomaterials such as capsules and microcapsules as well as other vehicles such as liposomes

Discusses various controlled drug delivery systems, including sustained release delivery systems and pulse or delayed release, e.g. to target different regions of the gastrointestinal tract.

In view of these wide-ranging technological areas, and the up-to-date discussions of opportunities and challenges associated with these applications, the book should provide readers from technology, materials science, pharmacology and clinical disciplines with very valuable information.

1     Introduction – Approaches to Controlled Drug Delivery

Katie Hogan and Antonios G. Mikos

Rice University

Professor Emmanuel Opara is a leading researcher in drug delivery technologies. This textbook, Controlled Drug Delivery Systems, stems from this expertise and seeks to enlighten readers on topics and techniques of interest within the field of drug delivery. The goal of controlled drug delivery systems is to provide a means for predictable in vivo release of therapeutics over a desired timeframe. This design objective allows for more targeted therapeutic responses that reduce the need for high dosing frequency and large systemic doses. As may be seen throughout this book, the specific criteria for controlled drug delivery vary widely based on the drug of interest and its intended target, and these requirements have led to the development of diverse types of drug delivery systems. Here, the role of biomaterials in drug delivery for a variety of applications (direct therapeutic response, tissue regeneration, etc.) will be discussed as well as delivery systems designed to interact with specific tissues.

The first portion of this book describes the formulation and modification of hydrogel systems for drug delivery. In Chapter 2 the use of alginates and their chemical modification via covalent bond-forming reactions for drug delivery and regenerative medicine applications are detailed. These modifications are explored via the type of modifying reaction used and the intended function of the resulting alginate material. Chapter 3 looks into the tunability of hydrogel systems for specific applications involving the long-term release of cell-secreted products with therapeutic potential. Chapter 4 similarly deals with potential methods for hydrogel modification, looking specifically at thermoresponsive hydrogels such as those based on N-isopropylacrylamide. Methods using gluthatione to address one of the key disadvantages of hydrogels composed of linear polymer chains, poor in vivo degradation, are discussed in detail.

Subsequent chapters discuss specific applications of controlled drug delivery systems and unique challenges encountered with tissue- and organ-specific targeting. In Chapter 5, for instance, the use of biodegradable particles as single-injection vaccine systems is discussed as an alternative to traditional multidose vaccine regimens. The authors describe the many factors that must be considered for controlled-release vaccine development, including device formulation strategies and large-scale clinical distribution considerations.

Tissue engineering and regenerative medicine is a key application for controlled drug delivery systems. Thus, the next several chapters describe general and specific applications of drug delivery systems for tissue engineering. Endocrine pathways are far-reaching and often have systemic side effects which are not immediately obvious. Chapter 6 discusses general hormone delivery and controlled release methods, introducing the concept of hormone pellet implants. Chapter 7 describes an application of hormone delivery and targeting that clearly demonstrates this concept – delivery of ovarian hormones for the preservation of bone health. The challenges and benefits of this strategy are explored within the context of tissue engineering and regenerative medicine approaches that seek to harness cellular production and delivery of these hormones. In Chapter 8, the use of controlled molecular delivery for tissue engineering and biofabrication is more generally discussed. Growth factors and other bioactive molecules are frequently introduced into tissue engineered constructs to induce processes such as cellular differentiation and angiogenesis. Here, the authors discuss methods of delivery and release of these molecules alongside current techniques used in tissue regeneration. Looking deeper at a specific integral component of engineering tissue, Chapter 9 delves into the importance and intricacies of stimulating vasculogenesis via the delivery of angiogenic proteins. Vascularization is an important component in the solution to issues with tissue engineered construct scalability, survival, and integration with native tissue. Within this chapter, strategies including polymer delivery systems are discussed, which seek to produce closely controlled and timely release of growth factors to provide greater therapeutic efficacy and angiogenesis compared with single growth factor administration. Chapter 10 describes advances in tissue engineering for wound healing and the role of drug delivery in skin regeneration technologies. Specifically, the importance of hydrogel-based biomaterials is examined as a vehicle for biological elements such as stem cells and cytokines as well as essential proteins for skin regeneration like collagen. The chapter discusses patient successes in skin regeneration and the use of technologies like 3D printing to improve cell and growth factor delivery for improved therapeutic effects.

The next three chapters explore the development of different approaches to controlled drug delivery for a single application: insulin regulation. Diabetic patients often need exogenous insulin to regulate glucose levels. However, the need for multiple daily injections often leads to inconsistent patient compliance. Chapter 11 explores how an adaptive model predictive control algorithm may be used in conjunction with a multivariable artificial pancreas to characterize glucose concentration dynamics. This information may then be used to calculate exogenous insulin dosing from an insulin pump in simulated case studies. Focusing on an alternative strategy, Chapter 12 reviews research related to the development of an oral insulin formulation. Specifically, this survey reveals advances in addressing key challenges related to an oral formulation, namely enzymatic degradation of and mucosal transport of polypeptide insulin, and discusses challenges that must be mitigated before clinical translation. Next, Chapter 13 offers yet another prospective solution for insulin delivery which harnesses tissue engineering strategies for the creation of a bioartificial pancreas. It details limitations of previously developed artificial pancreas strategies, including pancreatic tissue transplantation, and describes strategies for biomaterial-based devices that provide structural support for cell-based systems and employ selective permeability.

The next section of this book explores additional routes of controlled drug delivery in greater depth. For instance, Chapter 14 offers a description of transdermal delivery systems. The chapter addresses unique advantages that make this technique desirable for local or systemic drug delivery as well as challenges. Additionally, basic components of transdermal delivery systems, common architectures, material evaluation, and novel formulation strategies are discussed. In Chapter 15, oral drug delivery systems are once again examined, this time regarding specific new technologies which seek to address inherent issues with this delivery route. This chapter investigates in depth the mucoadhesive properties of chitosan and the application of its derivatives to create nanoparticle delivery systems for oral drug delivery. Similarly, Chapter 16 describes liposomes as a means of targeted therapy delivery for applications including pain management, treating infections, and cancer therapeutics. The various materials which can be used to create liposomes and increase their tissue specificity and the unique systems which may be generated using these concepts are described in detail. Further, focusing on the clinical translatability of these technologies, those liposomal formulations which have been tested in clinical trials or reached market and their clinical applications are discussed. Finally, in Chapter 17, emerging technologies are reviewed which allow for oral delivery of probiotics with increased efficacy. Therapeutic bacteria operate via a symbiotic relationship with gut bacteria, and this chapter illustrates ways in which cell encapsulation strategies have provided orally delivered cells from acidic destruction and demonstrates how engineered polymers have provided new routes for targeted bacterial delivery to the intestine.

Taken together, this textbook provides a comprehensive overview of topics relevant to controlled drug delivery systems in a wide array of formulations and applications. We hope that readers enjoy the excellent tour of systems for targeted therapeutic release provided by Professor Opara’s textbook and are inspired to create new solutions to clinical challenges in drug delivery.

2 Chemical Modifications of Alginates for Use in Drug Delivery and Regenerative Medicine Applications

Mark E. Welker

Wake Forest University

CONTENTS

2.1 Introduction

2.2 Common Chemical Reactions of Alginates

2.2.1 Simple Monosaccharide Modification Reactions

2.2.1.1 Hydroxyl Modification

2.2.1.2 Carboxylic Acid Modification

2.2.2 Chemical Modifications for In Situ Covalently Crosslinking Alginates

2.2.3 Chemical Modifications That Are Subsequently Used for Crosslinking

2.2.3.1 Modifications That Are Followed by Photochemical Crosslinking

2.2.3.2 Modifications That Are Followed by Nucleophile–Electrophile or Cycloaddition Reaction Crosslinking

2.2.4 Chemical Modifications to Add Ligands to the Polysaccharide

2.2.5 Chemical Modifications That Add Both Crosslinking Capability and Ligands

2.3 Review of Recent Alginate Covalent Bond Forming Reaction Chemistry

2.3.1 Modifications That Begin with Periodate Oxidation

2.3.1.1 Modifications That Begin with Periodate Oxidation Where the Alginate Application Is Cell Growth or Survival

2.3.1.2 Modifications That Begin with Periodate Oxidation Where the Alginate Application Is Drug Delivery

2.3.2 Modifications That Begin with Amidation

2.3.2.1 Modifications That Begin with Amidation and Any Crosslinking Is Nucleophile–Electrophile or Cycloaddition Chemistry Where the Alginate Application Is Enhanced Cell Growth or Survival

2.3.2.2 Modifications That Begin with Amidation and Any Crosslinking Is Nucleophile–Electrophile or Cycloaddition Chemistry Where the Alginate Application Is Drug Delivery

2.3.3 Modifications That Involve Radical Chemistry

2.3.4 Modifications That Begin with Reactions Other Than Periodate Oxidation, Amidation, or Radical Chemistry

2.4 Conclusions

References

2.1 Introduction

This chapter covers covalent bond forming chemical modification of alginates that are subsequently used for drug delivery and regenerative medicine applications. Many mixtures of alginates with other polysaccharides and other additives have been used in drug delivery and regenerative medicine, but that work will not be covered here since that type of work does not involve planned covalent bond modification of alginates. A book chapter that has good coverage of the structures of alginates and a chronological history of chemical modifications of its hydroxyl and carboxylic acid functional groups appeared in 2017 [1]. Review articles on the chemical modifications of alginates for use in biomedical applications have appeared in 2010–2014, so this chapter will largely cover this topic for the last 5 years (2014–2018) [2–7]. The articles reviewed here came from one of the three topical searches within the Science Citation Index. A search using keywords alginate and regenerative medicine yielded 285 references which were subsequently checked for reported organic chemistry. A second search using keywords alginate and drug delivery yielded 2,191 references with 146 of them within the subtopic of organic chemistry and those were also checked for reported chemical functionalization of alginates. Last, a search using keywords alginate derivative yielded 267 references with 40 of them within the subtopic of organic chemistry which were also checked for chemical modification of alginates and had possible uses in drug delivery or regenerative medicine. Two nice reviews of chemical functionali...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Table of Contents
• Foreword
• Preface
• Editor
• Contributors
• Chapter 1 Introduction – Approaches to Controlled Drug Delivery
• Chapter 2 Chemical Modifications of Alginates for Use in Drug Delivery and Regenerative Medicine Applications
• Chapter 3 Tunable Hydrogel Systems for Delivery and Release of Cell-Secreted and Synthetic Therapeutic Products
• Chapter 4 The Effect of Glutathione Incorporated as Chain Transfer Agent in Thermosensitive Hydrogels for Controlled Release of Therapeutic Proteins
• Chapter 5 Controlled Vaccine Delivery
• Chapter 6 Controlled Release of Hormones by Pellet Implants
• Chapter 7 Delivery of Ovarian Hormones for Bone Health
• Chapter 8 Controlled Delivery Models of Bioactive Factors for the Maturation of Engineered Tissues
• Chapter 9 Controlled Delivery of Angiogenic Proteins
• Chapter 10 Controlled Therapeutic Delivery in Wound Healing
• Chapter 11 Leveraging Plasma Insulin Estimates and Wearable Technologies to Develop an Automated Insulin Delivery System in Type 1 Diabetes
• Chapter 12 New Developments in Oral Insulin Delivery
• Chapter 13 Insulin Delivery by a Bioartificial Pancreas
• Chapter 14 Transdermal Drug Delivery
• Chapter 15 Mucoadhesive Chitosan-Based Nanoparticles for Oral Drug Delivery
• Chapter 16 Liposome-Based Delivery of Therapeutic Agents
• Chapter 17 Targeted Intestinal Delivery of Probiotics
• Index