Chitosan-Based Systems for Biopharmaceuticals

Delivery, Targeting and Polymer Therapeutics

Bruno Sarmento, Jose das Neves, Bruno Sarmento, Jose das Neves

• Publisher: Wiley
• Year: 2012
• Print ISBN: 9780470978320
• eBook ISBN: 9781119964070
• Edition: 1
• Topic: Physical Sciences
• Subtopic: Organic Chemistry

Chitosan is a linear polysaccharide commercially produced by the deacetylation of chitin. It is non-toxic, biodegradable, biocompatible, and acts as a bioadhesive with otherwise unstable biomolecules - making it a valuable component in the formulation of biopharmaceutical drugs.

Chitosan-Based Systems for Biopharmaceuticals provides an extensive overview of the application of chitosan and its derivatives in the development and optimisation of biopharmaceuticals. The book is divided in four different parts. Part I discusses general aspects of chitosan and its derivatives, with particular emphasis on issues related to the development of biopharmaceutical chitosan-based systems. Part II deals with the use of chitosan and derivatives in the formulation and delivery of biopharmaceuticals, and focuses on the synergistic effects between chitosan and this particular subset of pharmaceuticals. Part III discusses specific applications of chitosan and its derivatives for biopharmaceutical use. Finally, Part IV presents diverse viewpoints on different issues such as regulatory, manufacturing and toxicological requirements of chitosan and its derivatives related to the development of biopharmaceutical products, as well as their patent status, and clinical application and potential.

Topics covered include:

• chemical and technological advances in chitins and chitosans useful for the formulation of biopharmaceuticals
• physical properties of chitosan and derivatives in sol and gel states
• absorption promotion properties of chitosan and derivatives
• biocompatibility and biodegradation of chitosan and derivatives
• biological and pharmacological activity of chitosan and derivatives
• biological, chemical and physical compatibility of chitosan and biopharmaceuticals
• approaches for functional modification or crosslinking of chitosan
• use of chitosan and derivatives in conventional biopharmaceutical dosage forms
• manufacture techniques of chitosan-based microparticles and nanoparticles for biopharmaceuticals
• chitosan and derivatives for biopharmaceutical use: mucoadhesive properties
• chitosan-based systems for mucosal delivery of biopharmaceuticals
• chitosan-based delivery systems for mucosal vaccination
• chitosan-based nanoparticulates for oral delivery of biopharmaceuticals
• chitosan-based systems for ocular delivery of biopharmaceuticals
• chemical modification of chitosan for delivery of DNA and siRNA
• target-specific chitosan-based nanoparticle systems for nucleic acid delivery
• functional PEGylated chitosan systems for biopharmaceuticals
• stimuli-sensitive chitosan-based systems for biopharmaceuticals
• chitosan copolymers for biopharmaceuticals
• application of chitosan for anti-cancer biopharmaceutical delivery
• chitosan-based biopharmaceuticals scaffolds in tissue engineering and regenerative medicine
• wound healing properties of chitosan and its use in wound dressing biopharmaceuticals
• toxicological properties of chitosan and derivatives for biopharmaceutical applications
• regulatory status of chitosan and derivatives
• patentability and intellectual property issues
• quality control and good manufacturing practice
• preclinical and clinical use of chitosan and derivatives for biopharmaceuticals

Chitosan-Based Systems for Biopharmaceuticals is an important compendium of fundamental concepts, practical tools and applications of chitosan-based biopharmaceuticals for researchers in academia and industry working in drug formulation and delivery, biopharmaceuticals, medicinal chemistry, pharmacy, bioengineering and new materials development.

Part One

General Aspects of Chitosan

Chapter 1

Chemical and Technological Advances in Chitins and Chitosans Useful for the Formulation of Biopharmaceuticals

Riccardo A. A. Muzzarelli

Professor Emeritus of Enzymology, University of Ancona, Ancona, Italy

1.1 Introduction

Chitin is the first polysaccharide discovered (1811): its bicentennial has been celebrated in a review article by Muzzarelli et al. [1] that traces the origin of the modern carbohydrate polymers science. In a more recent time, chitosans and their derivatives have been studied for formulations that enhance the absorption of macromolecular biotherapeutics (peptides, protein therapeutics and antigens, as well as plasmid DNA) and for the preparation of particulate drug-targeting systems. The number of yearly published papers dealing with this topic during the period 2000–2009 has been growing at the following impressive rate: 90, 110, 120, 150, 245, 320, 420, 470, 670, and 705. Some review articles are cited here for readers seeking complementary information. Kean and Thanou [2] published an overview about the biodegradation, biodistribution, and toxicity of chitosan-based delivery systems as well as the current status of chitosan drug formulations and underlined that, despite the high number of published studies, chitosan is not approved by the US Food and Drug Administration for any product in drug delivery. Nevertheless, chitosan is used as a generally regarded as safe (GRAS) material. It was explained that when a hydrophobic moiety is conjugated to a chitosan unit, the resulting amphiphile forms self-assembled as nanoparticles that encapsulate a quantity of drugs and deliver them to specific sites. Chemical attachment of drugs to chitosan throughout a functional linker may also produce useful prodrugs, exhibiting the appropriate biological activity at the target site.

The advanced development of chitosan hydrogels has led to new drug delivery systems that release drugs under varying environmental stimuli. The development of intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In their review article, Bhattarai et al. [3] reported on the developments in chitosan hydrogel preparation and defined the design parameters in the development of physically and chemically cross-linked hydrogels. Carreira et al. [4] addressed smart polymers derived from chitosan, including particulate carrier systems, hydrogels, and film-based materials that are responsive to stimuli such as temperature and pH, and summarized recent developments in graft modification of chitosan by living radical polymerization.

Recent developments of chitosan nanosystems for delivery of hydrophilic and lipophilic drugs and polynucleotides into the eye surface were reviewed by de la Fuente et al. [5], who took into consideration that nanoscience and nanotechnology promoted important breakthroughs. In particular, the application of nanotechnology in ophthalmology has led to the development of novel strategies for the treatment of ocular disorders. Indeed, the association of an active compound to a nanocarrier allows the compound to intimately interact with specific ocular structures, to overcome ocular barriers, and to prolong its residence in the target tissue. Chitosan nanosystems have been specifically adapted for the delivery of hydrophilic and lipophilic drugs and also polynucleotides onto the eye surface, but these still demand a full preclinical evaluation. Oyarzun-Ampuero et al. [6] reviewed chitosan structures as transmucosal delivery vehicles for complex macromolecules, and as carriers of anticancer drugs. In the core-coating nanostructures, the core consists of a lipid (Miglyol 812 liquid; or tripalmitin, solid) surrounded by a chitosan layer. These nanostructures display outstanding properties in relation to the favored transport of peptides and vaccines across the nasal and intestinal barriers, as well as the targeted intracellular delivery of anticancer drugs into tumor cells. Reviews on oral delivery topics have also been published by Bowman and Leong [7], Kim et al. [8], Chopra et al. [9], Werle et al. [10], and Muzzarelli and Muzzarelli [11]. Reviews on the repair of wounded human and animal tissues, on the chemistry of chitosan hydrogels, and on the cross-linking with a safe plant compound are those by Muzzarelli [12–14], who also published reviews on the regeneration of bone [15, 16] and on the enhanced biochemical efficacy of oligomeric and partially depolymerized chitosans [17]. Information of more general interest about the presence of chitin in the earliest forms of life can be found in reference [18].

Among additional review articles on chitins and chitosans, those most directly involving chemical approaches were coauthored by Jayakumar et al. [19], who focused on the preparation and applications of carboxymethyl and succinyl derivatives of chitin and chitosan with particular attention to their biomedical applications; by Liu et al. [20], who centered on the hydrophobic modifications of chitosans mainly for gene delivery in comparison with polyethyleneimine and polylysine; by Kristiansen et al. [21], who pointed out selected examples of periodate oxidation of alginates, chitosans, hyaluronan, scleroglucan and schizophyllan, and cellulose; and by Hamman [22], who focused on periodate oxidation of polysaccharides for modification of chemical and physical properties. More general treatments can be found in review articles by Kumari et al. [23], Jayakumar et al. [24], and Zhang et al. [25].

The scope of the present chapter is therefore to bring to the reader's attention certain chemical approaches that are being developed today, and that seem to be prone to offer further chances to chitins and chitosans to act as protagonists in the scenario of drug and gene delivery, as well as in related fields. More detailed knowledge about the chemical aspects of the upgrading, processing, and exploitation technologies will help researchers to understand the interdisciplinary aspects of the ongoing applied research.

1.2 Safety of Chitins and Chitosans

A large body of knowledge exists today on the use of chitosans as safe biomaterials, and more specifically as drug carriers for a variety of applications. Lack of interdisciplinarity and limited perception of the importance of the chemical and biochemical characteristics of the isolated chitins or chitosans for the replication of experiments and optimization of results, however, are recurring faults in recent literature dealing with the biomedical applications of chitosan.

Articles that assessed the safety and biocompatibility aspects never reported intolerance or allergy in individuals and animals (with very few exceptions; see below), even when the quantities of chitosan used in single experiments were quite large. Therefore, crab, shrimp, prawn, and lobster chitins, as well as chitosans of all grades, once purified, should not be considered as “crustacean derivatives,” because the isolation procedures have removed proteins, fats, and other contaminants to such an extent as to allow them to be classified as chemicals regardless of their origin.

Isolated purified chitins and chitosans are linear polysaccharides that, at the nano level, have highly associated structures, recently refined in terms of regularity, nature of bonds, degree of crystallinity, and unusual colloidal behavior [26, 27]. Chitins and modified chitins exert a number of beneficial actions, namely: (1) they stimulate macrophages by interacting with receptors on the macrophage surface that mediate the internalization of chitin particles to be degraded by lysozyme and N-acetyl-β-glucosaminidase (such as Nod-like, Toll-like, lectin, Dectin-1, leukotriene, and mannose receptors); (2) they stimulate macrophages to produce cytokines and other compounds that confer nonspecific host resistance against bacterial and viral infections, and antitumor activity; (3) chitin is a strong Th1 adjuvant that up-regulates Th1 immunity induced by heat-killed Mycobacterium bovis, while down-regulating Th2 immunity induced by mycobacterial protein; (4) direct intranasal administration of chitin microparticles into the lung was also able to significantly down-regulate allergic response to Dermatophagoids pteronyssinus and Aspergillus fumigatus in a murine model of allergy; (5) chitin microparticles had a beneficial effect in preventing and treating histopathologic changes in the airways of asthmatic mice; and (6) authors support the fact that chitin depresses the development of adaptive type 2 allergic responses [28]. Moreover, Da Silva et al. [29] explicitly recognized that chitin particles are multifaceted immune adjuvants.

Notwithstanding these amply accepted points, a small number of articles raised concern about the presumed allergenicity of chitosan, but a close scrutiny of those few papers dealing with chitin and...

Table of contents

• Cover
• Title Page
• Copyright
• List of Contributors
• Foreword
• Preface
• Acknowledgments
• Part 1: General Aspects of Chitosan
• Part 2: Biopharmaceuticals Formulation and Delivery Aspects Using Chitosan and Derivatives
• Part 3: Advanced Application of Chitosan and Derivatives for Biopharmaceuticals
• Part 4: Regulatory Status, Toxicological Issues, and Clinical Perspectives
• Index