Polymers in Drug Delivery

Ijeoma F. Uchegbu, Andreas G. Schatzlein

• Publisher: CRC Press
• Year: 2006
• eBook ISBN: 9781000611243
• Topic: Medicine
• Subtopic: Medical Theory, Practice & Reference

Together, the nano explosion and the genomic revolution are ushering in a new frontier in drug delivery. In recent years we've seen how polymers can play a crucial role in controlling the rate of drug release, enhancing solubility and uptake, and limiting degradation and toxicity. In the very near future, they may well be used to deliver gene thera

1 Introduction

Ijeoma F. Uchegbu

CONTENTS

1.1 Drug Delivery

1.2 Polymers in Drug Delivery

1.3 This Volume

1.4 The Future

References

1.1 DRUG DELIVERY

The science of drug delivery may be described as the application of chemical and biological principles to control the in vivo temporal and spatial location of drug molecules for clinical benefit. When drugs are administered, only a very small fraction of the dose actually hits the relevant receptors or sites of action, and most of the dose is actually wasted either by being taken up into the “wrong” tissue, removed from the “right” tissue too quickly, or destroyed en route before arrival. Scientists researching drug delivery seek to address these issues in order to (1) maximize drug activity and (2) minimize side effects [1].

Drug delivery is becoming an extremely demanding science. The reasons are essentially threefold: (1) the emergence of the more challenging low-molecular-weight molecules and biomacromolecules with either poor aqueous solubility, poor tissue permeation, or both, (2) the increased use of biological materials with poorly understood physical properties or questionable shelf life issues, and (3) the realization that if the portion of the dose responsible for adverse events could be directed away from sites where they originate, toxic side effects would become less frequent, thus benefiting the therapeutic index. Today’s world requires that drug delivery systems be precise in their control of drug distribution and, preferably, respond directly to the local environment of the pathology in order to achieve a dynamic and beneficial interaction with the host pathology or physiology.

1.2 POLYMERS IN DRUG DELIVERY

Whether the control of oral absorption is desired [2] or the delivery of genes to the interior of specific cells is sought [3,4], the drug delivery macromolecule has emerged the most ubiquitous entity. In the current volume, macromolecules and their “younger (and sometimes smaller) cousins,” dendrimers, are presented as components extraordinaire of a variety of drug delivery systems. Scientific reports are peppered with polymer- or dendrimer-containing systems that:

• Prolong drug action by entrapping the drug within matrices [5]

• Shift drug distribution in the direction of tumors [6]

• Shunt therapeutic genes [4] or oligonucleotides [7] into cells

• Enable drug absorption at optimum gastrointestinal tract absorptive sites, [8]

• Make the drug available only when there is a defined change in temperature [9,10] or pH [10] or when activated by an enzyme (as described in Chapter 10 of this volume)

In fact, recent reports show that polymers and dendrimers themselves demonstrate intrinsic bioactivity [3,11]. The drug delivery macromolecule is alive and well, and now has both drug and drug carrier properties [3].

The beauty of this discipline, polymers in drug delivery, is its longevity and self-transforming quality. Polymers have, for decades, performed a valuable function as excipients in tablet and capsule formulations [12,13,14], moved steadily into the parenteral arena as blood circulation time enhancers [1,15], and are now capable of offering advanced and sophisticated functions (such as drug targeting) [16] to medicines. Polymers have unique cooperative properties that are not found with low-molecular-weight compounds, and therein lies the root of their success. The chemical influence of one molecule may extend not to a few angstroms but to tens of angstroms, enabling it to control events over a comparatively wide three-dimensional (or four-dimensional, including time) continuum. With the intermolecular cooperativity enjoyed by some polymers, the spatial influence of polymers extends even further. A simple example of this capability is the ability of polymers to restrict the diffusion of low-molecular-weight compounds in matrix or nanomedicine arrangements.

Simple manipulation of the water solubility of polymers, by increasing their chain length through cross-linking or by hydrophobising or hydrophilizing them with copolymers and other groups, yields a wealth of materials with a wide spectrum of possible applications. The resulting materials are capable of a variety of drug-enhancing functions. Polymers are able to:

• Prolong drug availability if medicines are formulated as hydrogels [17,18] or micro-particles [19]

• Favorably alter biodistribution if formulated into dense nanoparticles [20]

• Enable hydrophobic drug administration if formulated as micelles [21]

• Transport a drug to its usually inaccessible site of action if formulated as gene medicines [3]

• Make drugs available in response to stimuli [9]

With these wonderful systems comes the inevitable task of polymer characterization. Efficient and thorough characterization will advance our understanding of these materials. In each vial of a “homogenous” polymer there may reside a number of different molecules each of which have roughly the same monomer type, but not necessarily in the same order (if a random copolymer) or connected in the same chain length. To overcome what would otherwise be a major limitation, statistical definitions are used to characterize the mixtures: the mean molecular weight, average level of copolymer A in relation to that of copolymer B, the average number of drug substituents, and so on. This strategy has allowed the advancement of drug delivery polymers because it has been acknowledged that the precise control of atomic composition and molecular weight, applied to low-molecular-weight drug delivery agents or low-molecular-weight drugs, need not be applied to polymeric excipients. However, as scientists endeavor to imitate nature, it must be appreciated that the future will most likely belong to the macromolecules that closely resemble nature’s tools, i.e., the proteins and glycoproteins, with a definite polymer sequence and defined and precisely controlled polymer lengths.

What about tolerability? Are these molecules safe? Safety is a concept that is easy to understand but a little difficult to define. A variety of polymers such as the cellulose derivatives and poly(ethylene oxide) derivatives are already routinely used in medicine and appear to pose no identifiable hazard. However, with the new tailored molecules having targeting ability and cell-based activity, there is much to understand with respect to safety, and if we are to exploit the huge potential of the many polymeric materials that science has to offer, the issue of safety will have to be addressed for these new molecules and presumably on a case-by-case basis. Well-designed tests that are relevant to their final purpose will be needed for these new polymer-containing systems.

1.3 THIS VOLUME

This volume is primarily aimed at the nonspecialist reader, but the wide spectrum of opinion contained herein should also offer food for thought to the specialist. An eminent group of international experts have contributed to the volume, and it is hoped that the reader will judge this effort to be a richly sourced, informative, and ultimately rewarding read.

The aim of Chapter 1 is to introduce the subject matter in as jargon-free a manner as possible. Chapters 2 outlines the issues that must be considered when selecting a polymer for biomedical applications: i.e., for fabricating a drug delivery agent, surgical suture, prosthetic implant, or medical device. A number of exemplar polymers and their critical properties are discussed. It is important to understand that these biomaterials may be fabricated into biomedical entities that serve a dual purpose. The use of biomaterials to produce a combined prosthetic device and drug delivery system has been recently demonstrated by the emergence of a new therapeutic entity — the drug-eluting stent [22]. Chapter 3 focuses on polymer characterization and outlines the methods by which polymers may be characterized prior to use. It is impossible to detail all possible characterization techniques, and so only the more commonly used techniques are presented, e.g., methods to measure molecular weight and thermally controlled transitions.

Chapter 4, Chapter 5 and Chapter 6 profile polymer matrices that have been used in the formulation of solid oral dosage forms, tissue-engineering drug delivery scaffolds, and hydrogels. These matrix systems effectively retard the diffusion of drug molecules, trapping them within a three-dimensional network of polymer chains. Polymers form the basis of technologies, such as tablet matrices and tablet coatings, aimed at modifying drug release in the gastrointestinal tract. A deeper understanding of the effect of diseases of nongastrointestinal origin on gastrointestinal physiology and pathology is required for the advancement of polymers and other oral drug delivery agents. The emerging areas of tissue engineering and tissue reconstruction (Chapter 6) have harnessed the polymer matrix and made it do more than just regulate the release of drug. The mechanical properties of th...

Table of contents

• Cover
• Half Title
• Title Page
• Copyright Page
• Preface
• About the Editors
• Contributors
• Table of Contents
• Chapter 1 Introduction
• Chapter 2 Selecting the Right Polymer for Biomaterial Applications
• Chapter 3 Polymer Characterization Techniques
• Chapter 4 The Role of Polymers in Solid Oral Dosage Forms
• Chapter 5 Hydrogel Drug Delivery Systems
• Chapter 6 An Assessment of the Role of Polymers for Drug Delivery in Tissue Engineering
• Chapter 7 Poly(lactic-co-glycolic acid) Microspheres
• Chapter 8 Polymeric Nanoparticles as Drug Carriers
• Chapter 9 Polymeric Micelles as Pharmaceutical Carriers
• Chapter 10 Polymeric Vesicles
• Chapter 11 Polymer-Drug Conjugates
• Chapter 12 Polymers Used for the Delivery of Genes in Gene Therapy
• Chapter 13 Dendrimers in Drug and Gene Delivery
• Glossary
• Index