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Chemical Aspects of Drug Delivery Systems
By D. R. Karsa, R. A. Stephenson The Royal Society of Chemistry
Copyright © 1996 The Royal Society of Chemistry
All rights reserved.
ISBN: 978-0-85404-706-2
CHAPTER 1
New Materials and Systems for Drug Delivery and Targeting
P. York
POSTGRADUATE STUDIES IN PHARMACEUTICAL TECHNOLOGY, SCHOOL OF PHARMACY, UNIVERSITY OF BRADFORD, BRADFORD BD7 1DP, UK
1 NTRODUCTION
The range of bioactive substances emerging as potential drug candidates, together with those currently under research and development, continue to provide major challenges for efficient drug delivery and targeting. Various strategies for formulation design using diverse chemicals as formulation excipients are available, and numerous materials are being considered and developed to provide specific functionalities in the design of medicines. A number of approaches to formulation and drug delivery will be discussed at this symposium and this lecture, serving as a general introduction, highlights the need and value of these approaches coupled with the related issues of excipient properties and design.
It has been a constant ambition of formulation scientists to optimise drug delivery systems which provide a defined dose, at a chosen rate, at a selected time, to a targeted biological site. Whilst improvements in drug delivery over recent years are impressive, there is still some way to go in filly achieving these objectives. Key issues requiring continuing research and study range from fundamental understanding of the biosystems and targets and basic characterisation of novel classes of bioactive agents, to the development of 'designer' or 'smart' materials which provide required excipient or carrier properties to achieve modulated and targeted drug delivery. Coupled with these activities is the necessary realism of the practical constraints imposed in designing drug delivery systems. These include the necessity of using materials which will achieve regulatory approval and clearance, and the constraints imposed by the nature of the various routes of administration available for drug delivery.
2 ROUTES OF ADMINISTRATION AND CLASSIFICATION OF DRUG DELIVERY SYSTEMS
The principal routes of administration for medicinal products are listed in Table 1, together with a general classification of the main groups of traditional dosage forms. The choice of an appropriate route of administration for a specific bioactive will be influenced by many factors, such as required time of onset of action or drug targeting issues. Similarly, selection of drug delivery class is based on these and other numerous factors, as well as features related to the properties of the bioactive material itself, such as solubility and stability.
The explosion of synthetic and semi-synthetic bioactive substances in the 1950's and 1960's, which continues to the present day, led to the development of a range of the conventional dosage forms which dominate the range of medicines available today. However, newer trends and strategies in drug discovery with the advent of highly potent compounds or those requiring location at specific biological tissues or sites has led to the development of alternative drug delivery systems, which attempt to address the requirements of rate and extent of drug release, and thereby absorption. Delivery systems include oral sustained release formulations (e.g. multiple unit disintegrating particles or beads, single unit non-disintegrating system), controlled release preparations (e.g. oral osmotic pump) and bioadhesives and liposomes. The products of biotechnology research in the 1980's and 1990's have imposed even greater demands on drug delivery formulations and drug targeting with the emergence of peptides, problems, oligonucleotides and elements of DNA as potential drug candidates, since specific challenging features of such bioactives in terms of efficient and safe drug delivery need to be addressed from the points of view of administration route and suitable excipient and carrier materials.
Table 2 highlights the various groups of chemicals that are used as vehicles, carriers and excipients in both conventional and more recent approaches to formulating medicines. Much research activity is focused on the development and testing of new carrier systems, such as biodegradable polymers, such as the polylactides, and composite materials like low density lipoproteins.
3 DRUG DELIVERY AND TARGETING
A diagramatic illustration of the inter-relationship between the components controlling the processes of drug delivery and targeting is presented in Figure 1. In the diagram, the drug is delivered via a carrier system and four situations are identified. In A, leakage of the drug occurs as the drug-carrier system moves down the route of administration, whilst in B the drug is lost via the walls of the delivery route to non-target sites. In C and D, successful drug delivery to the target sites is achieved although drug loss to surrounding tissues can occur. Careful attention must thus be given to the characteristics of the targets, including access and location, as well as the characteristics of any carrier materials incorporated into drug delivery systems.
4 CARRIER SYSTEMS
In many cases, carrier materials are used in particulate forms, and Table 3 lists various types of microparticle colloidal carrier systems, together with ranges of particle diameters in nanometers. Microspheres and nanoparticles have continuous matrices containing dispersed or dissolved drug whilst microcapsules and nanocapsules are composed of a drug core surrounded by a layer acting as a coating or barrier to drug diffusion or dissolution. Vesicles are made up of single or multi-lamellar bilayer spherical particles containing drug within their lipid or aqueous regions. Emulsion and microemulsions are composed of oil or aqueous droplets dispersed in a continuous phase of the other liquid, or multiple emulsions (ie, oil-in-water-in-oil and water-in-oil -in-water), with drug dissolved in either or both oil and aqueous phases. Low-density lipoproteins have the benefit of being natural materials and drug can, for example, be adsorbed onto the protein or phospholipid head groups, solubilised in the lipid containing core, or attached to the surface. The range in particle sizes available for the various carrier systems provides potential regarding choice of administration route allowing smaller particles to be administered by parenteral routes for intravenous, subcutaneous and intramuscular drug delivery.
The types of carrier materials used, the drug substance and the biological environment for drug delivery all influence the mechanisms of drug release. Table 4 highlights the principal release mechanisms and drug, particle and environmental factors influencing drug release. The complex matrix of variables and interactions which influence and ultimately control drug release will clearly continue to provide major challenges for pharmaceutical scientists working in drug delivery and targeting.
5 FORMULATION STRATEGIES FOR CONTROLLED DRUG RELEASE AND DRUG TARGETING
A variety of approaches to formulation design are available and are being developed, some of which incorporate the newer excipients and materials with specific and directed functionality in terms of drug release. Tables 5 A and 5B list a number of formulation systems used by the oral, parenteral and pulmonary routes. Strategies range from chemical modification of the drug substance to provide a lower solubility salt, to more complex drug delivery systems involving enzymatic breakdown of a formulation component or particle coating to effect drug release, to the delivery of drugs containing liposomes to the lungs by nebulisation.
Recent developments have further extended opportunities with the advent of externally activated drug delivery systems (see Table 6). Activating sources based on heat, sound, light, electrical pulses and magnetic fields are coupled with advanced materials incorporated into dosage forms to achieve controlled, pulsed and/or modulated drug release. Whilst many of these systems are in their infancy the potential of these approaches will continue to be explored, undoubtedly leading to advanced drug delivery systems.
6 DRUG PARTICLE ENGINEERING
Drug particle engineering, or crystal engineering, provides an additional dimension to drug delivery and targeting. Traditional methods of particle formation, crystallisation and precipitation from solvents, do not generally provide the preferred properties required for formulation and processing of drugs into drug delivery systems, and it is common for additional processing to be carried out, such as milling and classification. However whilst such extra processing provides desired characteristics (eg, particle size and size distributions), changes in other properties can take place in an uncontrolled manner leading to batch inconsistency and thereby lack of precise control of performance in formulated products. Physicochemical changes observed include solid state phase transitions and surface crystallisation. In this respect the non-equivalency of particles resulting from conventional crystallisation, harvesting and drying operation can be added to by further processing. Understanding of these changes has been facilitated by recent developments in high resolution analytical techniques, such as microcalorimetry inverse phase gas chromatography and x-ray powder diffraction. The concept of optimising particulate formulations in terms of surface properties, such as surface energy requirements for powder inhalation drug delivery systems, is becoming a practical reality.
The attractive alternative approach of producing drug particles and crystals with desired properties, such as particle size, shape, surface-free energy and crystallinity has been realised through the use of super-critical fluid technology. In the SEDS process (Solution Enhanced Dispersion by Supercritical Fluids), two streams with one composed of a liquid solution containing the drug and a second containing supercritical carbon dioxide are introduced simultaneously using a coaxial nozzle arrangement into a particle formation vessel held at constant temperature and pressure supercritical conditions. The process involves virtually instantaneous dispersion, mixing and extraction of the solution solvent by the supercritical fluid leading to very high supersaturation ratios. These factors, together with precise control of relative flow rates of the two streams in the nozzle, provide uniform conditions for nucleation and particle formation, and the pure, solvent-free product is retained in the particle formation vessel. By varying the working conditions and changing the drug solution solvent, it has been shown possible to provide directed control over particle size, shape morphology, purity and polymorphic form. This capacity provides benefits over other reported techniques for particle formation using supercritical fluids and clearly such precise manipulation of critically important properties of drug and carrier particles, coupled to consistency within and between batch, provides vast opportunities for drug delivery and targeted systems.
7 CONCLUDING REMARKS
Whilst conventional dosage forms, such as tablets and hard gelatin capsules, composed of drugs with traditional excipients, continue today as the vast majority of formulations available for drug administration, major progress has been achieved over recent years in the fields of controlled drug delivery and targeting. Success in these areas is important both to improve the bioperformance and efficiency of drug delivery systems and to deal with recent trends in drug discovery. The range of materials used as functional excipients and carriers continues to grow, as does the novelty of alternative approaches in drug targeting. Nevertheless, the therapeutic agents emerging from studies in biotechnology, such as proteins and gene constructs, demand further research and creativity due to their particular properties and targeting requirements. All these developments need to be paralleled by research and inventiveness in pharmaceutical material science and control of particles during their formation. Recent advances in applying supercritical fluid technologies do, however, provide opportunities for future developments in these areas.
CHAPTER 2
The Use of Bioadhesive Polymers as a Means of Improving Drug Delivery
Slobodanka Tamburic and Duncan Q. M. Craig
CENTRE FOR MATERIALS SCIENCE, SCHOOL OF PHARMACY, UNIVERSITY OF LONDON, 29–39 BRUNSWICK SQUARE, LONDON WC1N 1AX, UK
1 INTRODUCTION
Bioadhesion is a complex phenomenon related to the ability of some natural and synthetic macromolecules to adhere to biological tissues. In medical applications, bioadhesion has been employed in surgery and dentistry for many years through the use of "super glues", particularly the esters of α-anoacrylates, polyurethanes, epoxy resins, acrylates and polystyrene. The mechanism of bonding in these cases usually involves the formation of covalent bonds with the target tissue (bond or tooth), providing a permanent linkage.
If the biological substrate is a mucus membrane, bioadhesive interactions occur primarily with the mucus layer and this process is referred to as mucoadhesion. The bonds involved are more likely to be of secondary chemical nature, combined with physical entanglement of polymer chains. The process is a reversible one, where the detachment of the mucoadhesive is caused either by the breakage of low energy bonds or by the physiological process of mucus turnover.
Pharmaceutical applications of bio(muco)adhesion have been the subject of great interest and intensive research during the last decade. Bioadhesive polymers fulfil the following desirable features of a controlled release system. a) localisation in specified regions to improve and enhance bioavailability of drugs b) optimum contact with the absorbing dace to permit modification of tissue permeability, which is especially important in the case of peptides/proteins and ionised species, and c) prolonged residence time to permit once-daily dosing, thus improving patient compliance. To date, the use of mucoadhesion in prolonging and controlling drug delivery has been employed with respect to a number of mucus membranes, i.e. gastrointestinal, ocular, nasal, oral, vaginal and rectal. Theoretically, mucoadhesion could resolve several problems of controlled release drug delivery systems, particularly the low availability of some drugs, short residence time, first-pass metabolism and insufficient patient compliance. Both topical and systemic administration of active agents has been studied using a wide variety of dosage forms, including tablets, patches, films, discs, ointments, gels, powders, beads, microcapsules, liposomes and plasters.
This paper will describe some aspects of bioadhesion, such as mucus structure, stages of adhesion and the theories proposed to explain the phenomenon. A range of bioadhesive polymers have been examined so far, and these will be reviewed, along with the factors that affect the bioadhesive strength, the testing techniques used and the dosage forms studied. In addition, some results of our work, focused on the use of poly(acry1ic acid) polymers, will be presented.
2 THE MUCUS LAYER
Mucus is a continuous layer covering all the internal tracts of the body and having both a protective and lubricating role. It is a gel-like structure that adheres firmly to the epithelial cell surface. In most cases, the adhesive interaction would initially be between the bioadhesive polymer and the mucus layer, and would not directly involve the epithelial surface. Since an understanding of the target tissue is essential in considering the interactions with mucoadhesive polymers, a brief review on mucus structure and properties will be given.
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Excerpted from Chemical Aspects of Drug Delivery Systems by D. R. Karsa, R. A. Stephenson. Copyright © 1996 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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