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...