Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1139

Veröffentlichungsjahr: 2011

Beschreibung

Cyclodextrins in Pharmaceutics, Cosmetics, and Biomedicine covers a wide range of knowledge on cyclodextrins, from an overview of molecular and supramolecular aspects of cyclodextrin physicochemistry, to the latest outcomes in cyclodextrin use and future possibilities in the employment of these systems. This book focuses on the derivatives and physicochemical and biological properties of cyclodextrins, and considers drug delivery through topical, mucosal, and oral via cyclodextrin complexes.

Leseprobe

Contents

Cover

Title Page

Copyright

Contributors

Preface

Part I: Cyclodextrins: History, Properties, Applications, and Current Status

Chapter 1: Cyclodextrins and Their Inclusion Complexes

1. Introduction

2. Main CDs and Their Ability to Include Guest Molecules

3. Preparation of Inclusion Complexes

4. Physical Studies of Inclusion Complexes

5. Conclusions

References

Chapter 2: Cyclodextrins as Potential Excipients in Pharmaceutical Formulations: Solubilizing and Stabilizing Effects

1. Introduction

2. Uses

3. Effects of CDs on Important Drug Properties in Formulation

4. Conclusions

References

Chapter 3: Cyclodextrins as Bioavailability Enhancers

1. Introduction

2. Increasing Oral Bioavailability of Drugs with CDs

3. Biopharmaceutics Classification System and CDs

4. Evaluation of Bioequivalency of Generic Drugs containing CD Complexes

5. Conclusions

Acknowledgment

References

Chapter 4: Cyclodextrins as Smart Excipients in Polymeric Drug Delivery Systems

1. Introduction

2. Basic Concepts of Drug Diffusion in Polymeric Systems

3. CD Addition in Polymeric Drug Delivery Systems: the State of the Art

4. Conclusions

References

Chapter 5: Recent Findings on Safety Profiles of Cyclodextrins, Cyclodextrin Conjugates, and Polypseudorotaxanes

1. Introduction

2. Safety profiles of CDs in vitro

3. In Vivo Safety Profile of CDs

4. Safety Profile of CD Conjugates

5. Safety Profile of Polypseudorotaxanes

6. Perspective

References

Chapter 6: Regulatory Status of Cyclodextrins in Pharmaceutical Products

1. Introduction

2. Regulatory Status of Excipients in Formulations

3. Future Perspectives on the Regulatory Status of CDs

4. Conclusions

References

Chapter 7: Cyclodextrins in the Cosmetic Field

1. Introduction

2. CDs and the Skin

3. CDs as a Delivery System

4. Application of CDs in Cosmetic Formulations

5. Conclusions and Future Outlook

References

Chapter 8: Cyclodextrin-Enhanced Drug Delivery Through Mucous Membranes

1. Introduction

2. Mucous Membranes

3. Mathematical Model

4. Mucosal Drug Delivery

5. Conclusions

References

Chapter 9: Applications of Cyclodextrins for Skin Formulation and Delivery

1. Introduction

2. Safety of CDs for the skin

3. Potential of CDs in Drug Stabilization and Drug Tolerance

4. Skin Formulations Containing CDs

5. Skin Delivery of Drugs with CDs [3, 4, 6, 8–11]

6. Biological Effect of CDs

7. Conclusions

References

Chapter 10: Oral Drug Delivery with Cyclodextrins

1. Introduction

2. Biopharmaceuticals Classification System

3. CDs and Drug Permeability Through Biological Membranes

4. Strategies to Improve CD Complexation Efficiency

5. CDs in Oral Dosage Forms

6. CDs in Buccal and Sublingual Administrations

7. Conclusions

8. Future Trends

References

Part II: Novel and Specialized Applications of Cyclodextrins

Chapter 11: Amphiphilic Cyclodextrins: Synthesis and Characterization

1. Introduction

2. Synthesis of Amphiphilic CDs: General Approaches

3. Nonionic Amphiphilic CDs

4. Ionic Amphiphilic CDs

5. Conclusions

References

Chapter 12: Gene Delivery with Cyclodextrins

1. Introduction

2. Systems Based on CD Derivatives

3. Systems Based on Polypseudorotaxanes and Polyrotaxanes

4. Systems Based on CD Oligomers and Polymers

5. Conclusions

References

Chapter 13: Targeted Cyclodextrins

1. Introduction

2. Tumor Targeting

3. Gastrointestinal Targeting

4. Targeting the Liver

5. Rotaxanes: Multivalent Binding to Biological Targets

6. Other Targeting Approaches

References

Chapter 14: Cyclodextrins and Biotechnological Applications

1. Introduction

2. Application of CDs in Biotechnology

3. CDs in Separation Techniques

4. Conclusions and Future Prospects

References

Chapter 15: Cyclodextrins and Cellular Interactions

1. Introduction

2. Cell Membrane Cholesterol Efflux

3. Cellular Adhesion

4. Membrane Proteins and Receptors

5. Viral Infections

6. Bacterial Infections

7. Organelles and Intracellular Transport

8. Lectins

9. Immune System

10. Nervous System

11. Endocrine System

12. Fertilization and Embryogenesis

13. Cardiovascular System

14. Muscle

15. Conclusions

Acknowledgments

References

Chapter 16: Cyclodextrin-Based Hydrogels

1. Hydrogels in Drug Delivery

2. Synthesis and Applications of Hydrogels with CDs

3. Conclusions and Perspectives

Acknowledgments

References

Chapter 17: Cyclodextrin Nanosponges and Their Applications

1. Introduction

2. CD-Based Carbamate Nanosponges

3. CD-Based Carbonate Nanosponges

4. CD-Based Ester Nanosponges

5. Polyamidoamine Nanosponges

6. Modified Nanosponges

7. Concluding Remarks

References

Chapter 18: Photodynamic Tumor Therapy with Cyclodextrin Nanoassemblies

1. Overview on the Photodynamic Therapy of Tumors: State of the art and Perspectives

2. Physicochemical Properties and Mechanism of Photosensitizers in Nano- and Microenvironments

3. Passive and Active PDT with Colloidal Nanoassemblies

4. PDT with Photosensitizers Encapsulated in CD Nanoassemblies

5. Cellular Internalization and Phototoxicity

Acknowledgments

References

Chapter 19: Sugammadex: A Cyclodextrin-Based Novel Formulation and Marketing Story

1. Introduction

2. The Problem

3. The Proposed Solution: Specific Binding

4. Preclinical Pharmacology

5. Mechanism of Action in Humans

6. The future of Sugammadex in Clinical Practice

7. Conclusions

References

Chapter 20: Cyclodextrins and Polymer Nanoparticles

1. Introduction

2. CDs in polymer nanoparticles

3. CD systems for gene delivery

4. Conclusions

References

Color Plates

Index

Copyright © 2011 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

Cyclodextrins in pharmaceutics, cosmetics, and biomedicine : current and future industrial applications / edited by Erem Bilensoy.

p.; cm.

Includes bibliographical references and index.

ISBN 978-0-470-47422-8 (cloth)

1. Cyclodextrins. I. Bilensoy, Erem.

[DNLM: 1. Cyclodextrins–chemistry. 2. Technology, Pharmaceutical. 3. Biomedical Technology. QU 83]

TP248.65.C92C93 2011

660.6'3–dc22

2010036222

oBook ISBN: 9780470926819

ePDF ISBN: 9780470926802

ePub ISBN: 9780470934616

Contributors

Füsun Acartürk, Gazi University, Etiler-Ankara, Turkey

Alka Ahuja, Oman Medical College, Muscat, Oman

Javed Ali, Hamdard University, New Delhi, India

Carmen Alvarez-Lorenzo, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

Catherine Amiel, Institut de Chimie et Matériaux Paris Est, Thiais, France

Hidetoshi Arima, Kumamoto University, Kumamoto, Japan

Sanjula Baboota, Hamdard University, New Delhi, India

Uttam C. Banerjee, National Institute of Pharmaceutical Education and Research, SAS Nagar, India

Erem Bilensoy, Hacettepe University, Ankara, Turkey

Amélie Bochot, Université Paris–Sud, Paris, France

Marcus E. Brewster, Johnson & Johnson Pharmaceutical Research and Development, Beerse, Belgium

Nevin Çelebi, Gazi University, Etiler-Ankara, Turkey

Angel Concheiro, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

François Donati, Université de Montréal, Montréal, Québec, Canada

Justin M. Dreyfuss, California State University–Northridge, Northridge, California

Dominique Duchêne, Université Paris–Sud, Châtenay Malabry, France

Hakan Erolu, Hacettepe University, Ankara, Turkey

Ana Rita Figueiras, University of Coimbra, Coimbra, Portugal; University of Beira Interior, Covilhã, Portugal

Ruxandra Gref, Université Paris–Sud, Châtenay, Malabry, France

A. Atilla Hincal, Education, Consultancy Ltd. Co. and Hacettepe University, Ankara, Turkey

Tetsumi Irie, Kumamoto University, Kumamoto, Japan

Phatsawee Jansook, University of Iceland, Reykjavik, Iceland

Abhishek Kaler, National Institute of Pharmaceutical Education and Research, SAS Nagar, India

Thorsteinn Loftsson, University of Iceland, Reykjavik, Iceland

Antonino Mazzaglia, Università di Messina, Messina, Italy

Agnese Miro, University of Naples, Naples, Italy

Keiichi Motoyama, Kumamoto University, Kumamoto, Japan

Maria D. Moya-Ortega, University of Iceland, Reykjavik, Iceland

Gulam Mustafa, Hamdard University, New Delhi, India

Steven B. Oppenheimer, California State University–Northridge, Northridge, California

Rachit Patil, National Institute of Pharmaceutical Education and Research, SAS Nagar, India

Hélène Parrot-Lopez, Université de Lyon, Lyon, France

Florent Perret, Université de Lyon, Lyon, France

Géraldine Piel, University of Liège, Liège, Belgium

Fabiana Quaglia, University of Naples, Naples, Italy

Stefano Salmaso, University of Padua, Padua, Italy

Amit Singh, National Institute of Pharmaceutical Education and Research, SAS Nagar, India

Vachan Singh, National Institute of Pharmaceutical Education and Research, SAS Nagar, India

Fabio Sonvico, University of Parma, Parma, Italy

Nilüfer Tarimci, Ankara University, Ankara, Turkey

Juan J. Torres-Labandeira, Universidad de Santiago de Compostela, Santiago de Compostela, Spain

Francesco Trotta, Università di Torino, Torino, Italy

Francesca Ungaro, University of Naples, Naples, Italy

Francisco Veiga, University of Coimbra, Coimbra, Portugal

Amelia Vieira, University of Coimbra, Coimbra, Portugal

Véronique Wintgens, Institut de Chimie et Matériaux Paris Est, Thiais, France

Preface

Discovered toward the end of the nineteenth century, cyclodextrins have attracted the interest of scientists and industries in a variety of sectors. The main reason for this growing interest is the unique structure of the natural cyclodextrins, which enables inclusion of guest molecules in their apolar cavity and masking of the physicochemical properties of the included molecule. The included molecules, mostly hydrophobic, enter a cyclodextrin cavity totally or partially, depending on the size and configuration of the molecule. This book is limited to applications of natural and chemically modified cyclodextrins in the pharmaceutical, biomedical, and cosmetic fields. However, cyclodextrins find use in textile, food, agricultural, and environmental technologies, owing to their unique inclusion complex–forming capability. The relatively low cost of cyclodextrins, being enzymatic degradation products of starch, contributes to their largescale production as pharmaceutical and cosmetic excipients and resulted recently in the use of a cyclodextrin derivative as an active ingredient in a pharmaceutical product.

Although they were discovered more than a century ago, these “100-year-old spinsters,” as Prof. Dominique Duchene had called them at the 1998 CRS Workshop on Cyclodextrins, have been characterized by an ever-increasing number of publications and patents in the literature, which suggests that cyclodextrins continue to offer new horizons to scientists, with a wide range of possible modifications for adding novel properties to the natural cyclodextrins.

When one reviews the literature on cyclodextrins, the major characteristic of these ying-yang molecules seems to be their solubility enhancement and stability improvement effects on hydrophobic and/or labile active therapeutic or cosmetic ingredients. This effect causes a significant bioavailability enhancement of drug molecules with reduced efficacy due to lower drug absorption and plasma profiles as a result of their low solubility and stability problems, arising from hydrolysis, pH, and photodegradation.

Cyclodextrins produced on a large scale as industrial excipients are used primarily for their solubilizing effect, incorporated in the formulation of analgesic or anesthetic drugs with expected rapid onset. On the other hand, new groups of cyclodextrins are introduced in the pharmaceutical and biomedical fields every day. These exhibit a wide range of properties, including self-assembly, polymerization/condensation, gene delivery, swelling and gelling properties, encapsulation of perfumes and ingredients, and nano- and microencapsulation, which allows cyclodextrins to be actively researched as promising excipients in the nanomedicine, drug delivery, cosmetics, and biomedical fields.

This book consists of two main sections. Part I focuses on the general physicochemical properties of cyclodextrins, such as complexation, as well as drug solubilization and stabilization, which made them come into use in the first place, followed by specific chapters dedicated to various routes of administration, such as oral, mucosal, and skin. This part also covers the most recent findings on the toxicological overview and safety profiles of cyclodextrin derivatives and the regulatory status of cyclodextrins as excipients in the pharmaceutical industry, including the views and applications of regulatory authorities in different parts of the world and corresponding to different markets. The effects of cyclodextrins on the drug release properties of polymeric systems of different types are also discussed in this section, with examples from current literature.

Part II consists of novel and specialized applications of cyclodextrins based on the diversity of modified cyclodextrins. A major group of novel cyclodextrin derivatives are amphiphilic cyclodextrins with different surface charges. Anionic, nonionic, and cationic amphiphilic cyclodextrins have been reported by research groups, and the self-assembly properties of these new cyclodextrin derivatives give them the capability to form nanoparticles spontaneously in addition to complex-forming properties. Applications of cyclodextrin polymers in gene delivery, peptide and protein delivery, biotechnological applications of cyclodextrins, and novel targeted cyclodextrins destined to carry their load to tumor cells or specific sites such as the colon in complex or conjugated form are also reviewed extensively in this part. Cyclodextrins and their incorporation into polymeric nanoparticles forming new drug delivery systems, cyclodextrin hydrogels, cellular interactions of cyclodextrins, and their relevance in the pharmaceutical and medical fields are discussed as well as the development and marketing story of sugammadex, a pharmaceutical product containing a cyclodextrin derivative as an active molecule. The emergence of cyclodextrins as active molecules rather than smart excipients in therapeutic or cosmetic products seems to be the next step in the discovery and development of cyclodextrin technology.

The goal of this book is to introduce readers of academic or industrial backgrounds to the diverse properties of cyclodextrins, different natural and modified cyclodextrins, and their applications and trends in cyclodextrin research which may be applicable to a variety of industries, such as the pharmaceutical, cosmetic, textile, environmental, and food industries.

Acknowledgments

I would like to express my sincere thanks to my Ph.D. thesis supervisors, Professor Atilla Hincal and Professor Dominique Duchêne, who have opened for me the gates of the everpromising cyclodextrin world. They kindly contributed to this book with significant chapters explaining properties, applications, and the regulatory status of cyclodextrins. The valuable contributions of all chapter authors have made this book possible, and I would like to thank all authors for their effort, time, and support. I owe special thanks to Dr. Hakan Erolu for his assistance in the preparation of the book, and I would also like to thank my editor at Wiley, Jonathan Rose, for encouragement, brilliant ideas, and support throughout the preparation and publication process.

Last but not least, I am indebted to my family—my husband, Tamer, and my daughter, Deniz—for their love and support during realization of this book.

Erem Bilensoy

Part I

Cyclodextrins: History, Properties, Applications, and Current Status

Chapter 1

Cyclodextrins and Their Inclusion Complexes

Dominique Duchêne

UMR CNRS 8612, Physico-Chimie–Pharmacotechnie–Biopharmacie, Université Paris–Sud, Châtenay, Malabry, France

1. Introduction

Cyclodextrins (CDs) are molecules of natural origin discovered in 1891 by Villiers. Studied by Schardinger at the beginning of the twentieth century, they became the topic of prominent scientific interest only in the late 1970s, early 1980s [1]. The main value of these oligosaccharides resides in their ring structure and their consequent ability to include guest molecules inside their internal cavity. This is at the origin of many applications: modification of the physicochemical properties of the included molecule (i.e., physical state, stability, solubility, and bioavailability), preparation of conjugates, and linking to various polymers. This results in the use of CDs in many industries, such as agro-food, cosmetology, pharmacy, and chemistry. Presently, the annual average number of articles, book chapters, lectures, and scientific contributions is between 1500 and 2000.

Presented briefly in this chapter are the main cyclodextrins available on the market, and their major characteristics, focusing on their ability to yield inclusion complexes. Also described is the manner in which complexes can be obtained and studied.

2. Main CDs and Their Ability to Include Guest Molecules

2.1 Main CDs

2.1.1 Natural CDs

CDs result from starch degradation by cycloglycosyl transferase amylases (CGTases) produced by various bacilli, among them Bacillus macerans and B. circulans [2]. Depending on the exact reaction conditions, three main CDs can be obtained: α-, β-, and γ-cyclodextrin, comprising six, seven, or eight α(1,4)-linked D(+)-glucopyranose units, respectively [3]. CDs are ring molecules, but due to the lack of free rotation at the level of bonds between glucopyranose units, they are not cylindrical but, rather, toroidal or cone shaped [4]. The primary hydroxyl groups are located on the narrow side; the secondary groups, on the wider side (Fig. 1).

Figure 1 Schematic representation of α-CD.

Due to steric factors and tensions in the ring, CDs with fewer than six glucopyranose units cannot exist. On the other hand, although cyclodextrins with 9, 10, 11, 12, or 13 glucopyranose units (δ-, ε-, ζ-, η-, or θ-CD, respectively) have been described, only δ-CD has been well characterized [4]. The largest CDs, those with a helicoidal conformation, are rapidly reduced to smaller products.

The aqueous solubility of CDs is much lower than that of similar acyclic saccharides. This is the consequence of strong binding of CD molecules inside the crystal lattice. Furthermore, for β-CD, with its odd number of glucopyranose units, intramolecular hydrogen bonds appear between hydroxyl groups, preventing hydrogen bond formation with surrounding water molecules and resulting in poor water solubility [4] (Table 1).

Table 1. Main Natural CDs and Their Characteristics.

The central cavity of CDs, which is composed of glucose residues, is hydrophobic when the external part is hydrophilic because of the presence of hydroxyl groups. In aqueous solution, water molecules inside the CD cavity can easily be replaced by apolar molecules or apolar parts of molecules, leading (reversibly) to an inclusion host–guest complex [5] which can be isolated.

When compared with its free molecular state, the included guest molecule has (apparent) new physicochemical properties, among which is higher apparent water solubility. This increase in water solubility depends on the CD water solubility, but this parameter is limited compared with linear oligosaccharides. This is one reason that highly water-soluble CD derivatives have been synthesized.

2.1.2 CD Derivatives

CDs' low aqueous solubility results from hydrogen bonds between hydroxyl groups. Any substitution on the hydroxyl groups, even by hydrophobic moieties, leads to a dramatic increase in water solubility [4]. The different CD derivatives still have the ability to include molecules inside their cavity, but with a different affinity than that of the parent CD. Among the water-soluble CD derivatives most often employed are three classes of modified CDs: methylated, hydroxypropylated (both neutral), and sulfobutylated (negatively charged).

Theoretically, methylation of CDs can occur on either two or three hydroxyl groups per glucopyranose unit. In the first case [dimethyl-cyclodextrins (DM-CDs)] the methylation takes place on all the primary hydroxyl groups (position C6) and all the secondary hydroxyl groups in position C2, the secondary hydroxyl groups in position C3 remaining free. In the second case [trimethyl-cyclodextrins (TM-CDs)] all the hydroxyl groups are substituted, including those in C3.

Most often, and in the case of β-CD, it is a randomly substituted CD that is used with an average substitution degree (number of substitutions per glucopyranose unit) of 1.8 (e.g., RAMEB, which is an amorphous product). There also exists a very slightly substituted β-CD: Crysmeb, with a substitution degree of 0.5.