The intestinal epithelium is a major barrier to the absorption of hydrophilic drugs. The presence of intercellular junctional complexes, particularly the tight junctions (zona occludens), renders the epithelium impervious to hydrophilic drugs, which cannot diffuse across the cells through the lipid bilayer of the cell membranes. There have been significant advances in understanding the structure and cellular regulation of tight junctions over the past decade. This article reviews current knowledge regarding the physiological regulation of tight junctions and paracellular permeability, and recent progress towards the rational design of agents that can effectively and safely increase paracellular permeability via modulation of tight junctions.
Over recent years, there has been a significant growth in the number of new drugs entering development with challenging pharmaceutical (e.g. solubility) and biopharmaceutical (e.g. permeability) properties. As a consequence, there is an increasing number of pharmaceutical companies using human absorption studies to provide a 'route map' for development. These projects are typically undertaken early in clinical development and utilize engineering-based capsules to provide non-invasive drug delivery to the selected sites of the human gut. The Enterion capsule has recently been developed to provide for the delivery of a wide range of different drug formulations, for example, solution, powder and granulate, into any region of the gut, both easily and efficiently.
The pharmaceutical industry relies on appropriate in vitro models for the evaluation of drug absorption and metabolism. Despite increasing interest in drug delivery via the lung, there is currently no widely accepted cell culture model of the airway epithelium. This review considers the airway epithelium, the culture of airway epithelial cells and the need for cell lines which can model the airway epithelium. Three of the most promising human bronchial cell lines, 16HBE14o-, Calu-3 and BEAS-2B, are reviewed, with emphasis on their recent application for the study of drug transport, drug metabolism and gene delivery. Current limitations and future directions for the development of these cell lines as models of the airway epithelium are discussed.
The mucosal epithelium of the upper respiratory tract constitutes an effective physical barrier to many pathogens. Its mucosal-associated lymphoid tissue is of particular importance for the protection and integrity of mucosal surfaces and the body's interior. Understanding the factors that influence the induction and regulation of mucosal immune responses will facilitate the design of vaccines capable of eliciting the appropriate type of protective immune response.
Drug metabolism determines several pharmacological and toxicological properties of pharmaceuticals and is catalysed by drug metabolizing enzymes. Prediction of drug metabolism in humans based on animal experiments is complicated by species differences in the catalytic properties of these enzymes. This review describes and evaluates the use of recombinant models that contain human drug metabolizing enzymes to facilitate the prediction of pharmacokinetic properties of candidate drugs in humans.
"The barriers between 'silos' in pharmaceutical R&D workflows are slowly eroding and this is driving a wider exchange of information across the various R&D disciplines."
In the veterinary field, the development of new routes of administration or new delivery systems capable of controlling the release of drugs are of considerable interest. Because of the large number of food-producing animals and the unique problems associated with the administration of drugs to these animals, the potential markets are huge and will only be fully realized if improvements to old dosage forms lead to practical and effective formulations. This review intends to summarize the state of the art in the field of veterinary controlled and/or prolonged release systems.
Colloidal drug carriers such as liposomes and nanoparticles can be used to improve the therapeutic index of both established and new drugs by modifying their distribution, and thus increasing their efficacy and/or reducing their toxicity. This is because the drug distribution then follows that of the carrier, rather than depending on the physicochemical properties of the drug itself. If these delivery systems are carefully designed with respect to the target and the route of administration, they may provide one solution to some of the delivery problems posed by new classes of active molecules, such as peptides and proteins, genes and oligonucleotides. They may also offer alternative modes for more conventional drugs, such as highly hydrophobic small molecules. This review discusses the use of colloidal, particulate carrier systems (25 nm to 1 µm in diameter) in such applications.
Polyamidoamine (PAMAM) dendrimers have steadily grown in popularity in the past decade in a variety of disciplines, ranging from materials science to biomedicine. This can be attributed in part to their use in applications that range from computer toners to medical diagnostics. PAMAM dendrimers are safe and nonimmunogenic, and can function as highly efficient cationic polymer vectors for delivering genetic material into cells. They have been shown to be as efficient or more efficient than either cationic liposomes or other cationic polymers (e.g. polyethylenimine, polylysine) for in vitro gene transfer. This article will focus on the application of PAMAM dendrimers as a nonviral gene delivery vector from the initial discovery of this capacity to the most recent experimental findings.
Interest in transdermal drug delivery has increased in recent years owing to its many advantages over other routes of administration. In order to evaluate a transdermal product effectively, three main issues need to be addressed: (1) the kind of skin model that will be used to evaluate the drug permeation; (2) the mathematical model that will be used to characterize the permeation of the drug across the skin; and (3) the diffusion apparatus that will be used to conduct the permeation study.
Antibody internalization is required for the success of many targeted therapeutics, such as immunotoxins, immunoliposomes, antibody-drug conjugates and for the targeted delivery of genes or viral DNA into cells. Recently, it has become possible to directly select antibody fragments from phage display libraries for internalization into mammalian cells. Here we review the therapeutic applications of internalized antibodies and describe how phage display enables the isolation of internalizing antibodies to novel or known targets.
Biopharmaceutical products represent a diverse group of products that includes proteins, peptides, nucleic acids, whole cells, viral particles and vaccines. The conformation of the macromolecule or cell must be maintained to retain biological activity, and animal models for biological activity and characterization assays are often developed in tandem with initial formulation studies. This presents the formulation scientist with a unique set of challenges when compared to those for small molecules. This review focuses on approaches to the formulation of macromolecules into biopharmaceutical products, and provides examples of studies that have been undertaken within the authors' laboratories.
The stratum corneum, poses a formidable challenge to formulators of drug delivery systems. Several approaches have been utilized to facilitate entry of drugs into the lower skin layers. Traditionally, permeation enhancers were designed to deliver high drug concentrations across the skin into the systemic circulation. The use of many of these agents resulted in unpleasant or toxic side effects. However, in recent years there has been a search for compounds that exhibit low toxicity, and maintain their enhancing activity. More recently, there has been interest in agents that may be used in topical formulations to prevent the passage of active ingredients or excipients into the lower skin layers. These so-called skin retardants have potential uses in many over-the-counter (OTC) skin formulations, such as sunscreens and pesticides, where the site of action is restricted to the skin surface or upper skin layers. Research in the area of permeation enhancement or retardation is yielding valuable insights into the structure–activity relationships of enhancers as well as retardants.
