Current Drug Delivery - Volume 1, Issue 3, 2004

In the last decade, polymer based technologies have found wide biomedical applications. Polymers, whether synthetic (e.g. polylactide-co-glycolide or PLG) or natural (e.g. alginate, chitosan etc.), have the property of encapsulating a diverse range of molecules of biological interest and bear distinct therapeutic advantages such as controlled release of drugs, protection against the premature degradation of drugs and reduction in drug toxicity. These are important considerations in the long-duration treatment of chronic infectious diseases such as tuberculosis in which patient noncompliance is the major obstacle to successful chemotherapy. Antitubercular drugs, singly or in combination, have been encapsulated in polymers to provide controlled drug release and the system also offers the flexibility of selecting various routes of administration such as oral, subcutaneous and aerosol. The present review highlights the approaches towards the preparation of polymeric antitubercular drug delivery systems, emphasizing how the route of administration may influence drug bioavailability as well as the chemotherapeutic efficacy. In addition, the pros and cons of the various delivery systems are also discussed.

Variations in drug uptake and efflux, as well as changes in intracellular drug entrapment and distribution may represent important resistance mechanisms to cancer therapy. A variety of ATP binding cassette transporters (ABC) localised in multiple cell membranes is implied in those phenomena, representing a mechanism of protection of cells against xenobiotics. Many cancer cell lines over express some ABC transporters, especially p-glycoprotein, MRP1 and BCRP. This over expression is related to worse cancer treatment outcome and, in some cases, reduced overall survival of cancer patients. This paper reviews the location and physiological role of the three transporters mentioned and also describes the drugs that are substrates of these proteins. The usefulness of animal and cellular models to evaluate the role of these transporters on the uptake and efflux of anticancer drugs is discussed. Finally, the results of preclinical and clinical studies about the utility of some inhibitors of these pumps, as well as the implications of polymorphism of ABC transporters on the efficacy and safety of anticancer therapeutics are reported.

Passive transport properties of drug molecules are of utmost importance for their pharmacological and biopharmaceutical effectiveness. Diffusion in different media and through lipid bilayers is in many cases the ratedetermining step for the distribution in the body. In the present review an attempt is made to demonstrate the importance of solvation of drug molecules for the diffusion and partition / distribution in phases of different lipophilicity. Different approaches known in the literature to describe solvation of compounds with flexible conformation are discussed as well as the experimental methods to directly measure the energy of solvation. NSAIDs are chosen as an example of a class of drugs of different molecular structures that have already been studied thoroughly in many aspects, and a set of aliphatic alcohols can be used as a model for compartments of different lipophilic / hydrophilic properties. Thermodynamic characteristics of solvation of the drug molecules yielded by independent classical experimental methods (Gibbs energy, enthalpic and entropic terms of Gibbs energy) are studied in order to better understand diffusion and distribution properties. Correlations between in-vitro-data (partition coefficient, enthalpy of solvation) with biopharmaceutically relevant characteristics (plasma half-life) are also discussed.

A new route to obtain chitosan derivatives containing cyclodextrin moieties as pendant groups was developed. The chitosan microspheres, obtained through crosslinking with glutaraldehyde of an acetic acid solution of chitosan, in an organic suspension medium, were reacted with chloroacyl cyclodextrins in organic basic solvents. The acyl cyclodextrin moieties are linked to the chitosan microspheres through C-N bonds, with the elimination of HCl; higher amounts of acyl cyclodextrin are linked to the microspheres with a smaller crosslinking degree. The chitosan-cyclodextrin conjugates retain higher amounts of bioactive substances (nalidixic acid, piroxicam) or of p-nitrophenol (model substance) than their parent chitosan supports, both by ionic forces and by the formation of inclusion complexes in the cyclodextrin inner cavities. After these preliminary studies, one can appreciate that the cyclodextrin-chitosan conjugates could be used as supports for chromatographic separations or controlled release drug systems.

Many therapeutic agents have intracellular compartments as their site of action. Targeted delivery of these agents to their specific intracellular targets could result in enhanced therapeutic efficacy and reduced toxicity. Various carriers have been shown useful in targeted delivery of different classes of therapeutic agents. Among these carriers, biodegradable nanoparticles formulated from biocompatible polymers poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA) have shown the potential for sustained intracellular delivery of different therapeutic agents. In this review, we discuss different intracellular targets, barriers to intracellular delivery, mechanism and pathways of intracellular delivery, and various carriers and approaches that have been investigated for intracellular drug delivery.

In this review, the concepts of chronobiology, circadian rhythm, chronopharmacology, homeostasis and chronotherapy are taken into account to approach the optimal drug therapy, in which the timing of drug administration plays an important role. Based on these considerations, our laboratory has developed a thermo-responsive membrane by entrapping a single or binary liquid crystal to achieve an on-off switching drug delivery for transdermal application via the externally repeated cycle of temperature change, which may simulate the dosing time of therapeutic needs for human body.

Casein entrapped within gel microbeads using alginate, amidated LM pectin, gellan gum and a system containing a mixture of these polysaccharides (pectin:gellan:alginate, 1 / 3: 1 / 3: 1 / 3), were obtained by ionic gelation in a high-pressure capillary apparatus. Hydrogenated vegetable fat was also added to produce the gel microbeads and protein release in all the systems was measured, including from freeze-dried capsules containing protein and fat. Encapsulation efficiency, capsule size and morphology were evaluated as well as the protein release profile. Encapsulation efficiencies from 83.7 to 90.7% were obtained for the protein capsules and from 71.8 to 95.4% for those containing protein and fat. Greater release was observed from gel microbeads without fat where alginate presented the greatest diffusion (100%) and the system with a mixture of polyssacharides, the best barrier, with protein retention of 90% after 240 min in solution. The fat containing gel microbeads presented good percent retentions and both the gel microbeads and the dry microbeads showed similar percentages for release. The majority of the systems studied showed a burst effect on release. Gel microbeads size distribution was similar, both with and without fat, and independent of the matrix material, the mean size being 150mm. The morphological observations showed that the gel microbeads were spheroidal with a homogenous distribution of fat droplets in the microcapsules. Agglomeration occurred on drying but many particles maintained a partially spheroidal form, with a configuration of solid material.

The placenta has traditionally been considered as a highly permeable organ for a large variety of substances with diverse molecular structures that are readily able to cross it from the maternal blood to reach the foetus. This has recommended limiting the use of drugs during pregnancy as far as possible. However, our present knowledge points to the existence of different systems, including plasma membrane carriers, biotransforming enzymes, and export pumps, that determine the selectivity and efficacy of the so-called placental barrier. A good understanding of the molecular bases of these processes and their regulation is crucial: i) to predict interactions between drug-drug, drug-endogenous substances and drug-food components, ii) to analyse the relevance of polymorphisms in the inter-individual variability of conceptus sensitivity to drugs, and iii) to develop novel pharmacological strategies aimed at delivering medicinal drugs to pregnant women, simultaneously minimising the risk of foetal exposure to active agents, and to specifically target drugs to the placenta and / or foetus. The present review does not attempt to offer a complete list of the available medicinal compounds and their ability to cross the placenta but instead to provide the reader with an up-to-date overview of the mechanisms involved in carrying out or preventing the transfer of active drugs across the placenta.

Captive Asian elephants have been maintained in captivity by humans for over 4000 years. Despite this association, there is little published literature on the treatment of elephant diseases or methods of drug administration to these animals. Elephants in captivity are generally healthy and require few therapeutic interventions over the course of their lifetime. However, when they become acutely ill, treatment becomes a serious issue. The successful and consistent administration of therapeutics to elephants is formidable in an animal that presents significant limitations in drug delivery options. The single most important factor in administering drugs to an elephant is the animal's cooperation in accepting the medication. Working around elephants can be very dangerous and this is magnified when working around sick or injured animals where the elephant is subject to increased stress, pain, and unusual situations associated with treatment. The large body size of the Asian elephant produces a separate set of issues. In this paper, methods of drug administration and their associated limitations will be reviewed. Considerations of medicating such large animals can serve to highlight the problems and principles of treatment that are inherent in these species.

Liposomes sustain considerable interest to develop ways to fabricate drug delivery systems that would provide a good release without inducing any systemic reactions into the host. However, in many cases, liposomes injected into the blood stream are rapidly cleared from the system and only a fraction reaches the target site even when poly(ethylene glycol) (PEG)-coated liposomes are used. Composite drug delivery systems with liposomes i.e., liposomes linked to other substrates can be good candidates for certain type of drug release to achieve a localised treatment. This paper reviews the fundamental phenomena of the interactions between liposomes and solid substrates. Then, we address various techniques that have been used to immobilize intact liposomes onto and into different substrates. Finally, properties of liposomes used as drug delivery systems are briefly reviewed.