Ramesh Panchagnula

Polymers in drug delivery

Advances in polymer science have led to the development of several novel drug-delivery systems. A proper consideration of surface and bulk properties can aid in the designing of polymers for various drug-delivery applications. Biodegradable polymers find widespread use in drug delivery as they can be degraded to non-toxic monomers inside the body. Novel supramolecular structures based on polyethylene oxide copolymers and dendrimers are being intensively researched for delivery of genes and macromolecules. Hydrogels that can respond to a variety of physical, chemical and biological stimuli hold enormous potential for design of closed-loop drug-delivery systems. Design and synthesis of novel combinations of polymers will expand the scope of new drug-delivery systems in the future.

P-glycoprotein inhibitors and their screening: a perspective from bioavailability enhancement

Drug efflux pumps like P-glycoprotein (P-gp) and multidrug resistance (MDR) proteins were recognized to possess functional role in determining the pharmacokinetics of drugs administered by peroral as well as parenteral route. Advancements in molecular biology, to some extent, had revealed the structure, localization and functional role of P-glycoprotein and its mechanism of drug efflux. Broad substrate recognition by this protein and clinical implications of its inhibition has revolutionized cancer chemotherapy leading to design and development of novel P-glycoprotein inhibitors. In the recent times, the application of these inhibitors in improving peroral drug delivery has gained special interest. Inhibition of P-glycoprotein improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Eventually, various screening methodologies have been developed for determining the activity of P-glycoprotein, kinetics of drug transport and identification of substrates and inhibitors. In the present review, techniques used for screening P-glycoprotein inhibitors and the scope of these inhibitors in optimizing peroral drug absorption and pharmacokinetics are discussed along with a brief introduction to P-glycoprotein, its physiological function and active role in extrusion of drugs.

Transdermal drug delivery of imipramine hydrochloride. I. Effect of terpenes.

The objective of this investigation was to study the effect of different terpenes on IMH permeation in EtOH:W (2:1) system. Permeation studies of IMH were carried out with unjacketed Franz diffusion cells through rat skin. The flux of IMH with terpenes was found to be significantly higher than that in control (EtOH:W, 2:1) (P<0.05). Amongst all studied terpenes, menthol, terpineol, cineole and menthone were found to be effective permeation enhancers for IMH. It was found that the contribution of diffusivity in enhanced permeation of IMH was much higher in comparison to partitioning of IMH in skin with terpene treatment. Results of this study were explained with the help of H-bond breaking potential and self-association of terpenes. In order to elucidate the effect of terpenes on stratum corneum barrier FT-IR was used.

Localized paclitaxel delivery.

While the search for new antineoplastic agents is in progress, optimization of delivery for existing drugs will remarkably improve the current scenario in the management of cancer. Paclitaxel, a new antineoplastic agent, is one such drug deserving attention in the field of regional drug delivery, offering immense pharmacokinetic as well as therapeutic advantage via localized delivery. The antiangiogenic activity of paclitaxel has been demonstrated using the chick chorioallantoic membrane model (CAM). This review focuses on the antiangiogenic activity of paclitaxel supported by the evidence that angiogenesis inhibitors display potential synergism with cytotoxic agents in the treatment of primary and metastatic cancers. Preclinical trials have confirmed that the biological and cytotoxic effects of paclitaxel on several tumor cell lines are enhanced by the increase in both the drug concentration and the duration of exposure. Sufficient experimental evidence has accumulated to state that localized delivery will exploit the multiple pharmacological effects of paclitaxel in the treatment of refractory and metastatic cancerous diseases. The drug delivery systems, namely, microspheres, surgical pastes and implants, fabricated for localized paclitaxel delivery are reviewed explaining the concept of increased tumor burden alleviating body burden as a consequence of such delivery systems. Some of the preclinical trials are very encouraging and speculate a promising future for these devices in the battle against solid tumors. Finally, the review briefs on the possibilities for better paclitaxel delivery and the future drug delivery systems for localized cancer chemotherapy.

Biopharmaceutics and pharmacokinetics in drug research.

With the synergistic and multiplicative interactions of rational drug design, recombinant biotechnology, combinatorial chemistry and high-throughput screening, millions of compounds are being synthesized by chemists. However, development of these drug candidates has often been impeded, if not terminated, due to biopharmaceutic and/or pharmacokinetic constraints. This has resulted in delays in development time and escalation of cost in the drug research programmes. So, the present emphasis is to reduce development time and cost, which is analogous to added patent life besides the enormous reduction in human suffering. In this compilation the important biopharmaceutic and pharmacokinetic approaches are discussed, which will help in the development of safe and more efficacious drugs with reduced development time and cost.

Transdermal delivery of insulin from poloxamer gel: ex vivo and in vivo skin permeation studies in rat using iontophoresis and chemical enhancers.

Gels are considered to be the most suitable delivery vehicle for iontophoresis, as they can be easily amalgamated with the iontophoretic delivery system and can also match the contours of the skin. Insulin was used as a model peptide for large peptides in the molecular weight range of 3-7 kDa. A gel formulation of insulin was formulated using poloxamer 407 and was evaluated by ex vivo and in vivo skin permeation studies in rat with chemical enhancer and/or iontophoresis. The poloxamer gel was physically and chemically stable during the storage period. In ex vivo studies, both linoleic acid and menthone in combination with iontophoresis showed a synergistic enhancement of insulin permeation. The plasma insulin concentration (PIC) was highest with linoleic acid pre-treatment, in agreement with ex vivo permeation studies, but the reduction in plasma glucose levels (PGL) was comparable to iontophoresis. Menthone pre-treatment resulted in rapid attainment of peak PIC, but the reduction in PGL was less than other treatment groups. There was no direct relation between PIC and PGL and is attributed to the fact that the action of insulin in mediated by a cascade of cellular mechanisms, before a reduction in PGL is observed. However, iontophoresis either alone or in combination with linoleic acid produced a reduction in PGL to the extent of 36-40%. A combination of chemical enhancers and iontophoresis caused greater skin irritation than when either of them was used alone.

Development and characterization of biodegradable chitosan films for local delivery of paclitaxel

Intratumoral and local drug delivery strategies have gained momentum recently as a promising modality in cancer therapy. In order to deliver paclitaxel at the tumor site in therapeutically relevant concentrations, chitosan films were fabricated. Paclitaxel could be loaded at 31% wt/wt in films, which were translucent and flexible. Physicochemical characterization of paclitaxel via thermal, spectroscopic, x-ray diffraction, and electron microscopy techniques revealed information on solid-state properties of paclitaxel as well as chitosan in films. While chitosan was in amorphous form, paclitaxel seemed to be present in both amorphous and crystalline forms in film. The polymeric dispersion of paclitaxel in poloxamer formed fibrous structures generating discontinuities in the film matrix, thereby leading to the introduction of perturbations in the packing arrangement of polymer chains. These films released only 10% to 15% of loaded paclitaxel by a burst effect under in vitro testing conditions, with lysozyme having no effect on the release. However, films softened after implantation in mice and lost integrity over time. The implantable delivery system is not only biodegradable but also well tolerated in vivo and hence, biocompatible as revealed by histological studies. The lack of formulation-induced local inflammatory responses of paclitaxel chitosan films suggests a new paradigm for localized chemotherapy based on implantable systems.

Transdermal delivery of naloxone: effect of water, propylene glycol, ethanol and their binary combinations on permeation through rat skin

The effect of the solvent systems water, ethanol (EtOH), propylene glycol (PG) and their binary combinations was studied on the ex vivo permeation profile of the opioid receptor antagonist, naloxone, through rat skin. Fourier transform-infrared (FT-IR) spectroscopic studies were done to investigate the effect of enhancers on the biophysical properties of the stratum corneum (SC), in order to understand the mechanism of permeation enhancement of naloxone by the solvent systems used. The flux of naloxone was found to increase with increasing concentrations of EtOH, upto 66% in water, and PG upto 50% in water. The maximum flux of 32.85 microg cm(-2) h(-1) was found with 33% PG in EtOH. The FT-IR spectra of SC treated with EtOH showed peak broadening at 2920 cm(-1) at all concentrations of EtOH studied indicating that EtOH increases the translational freedom (mobility) of lipid acyl chains. Theoretical blood levels well above the therapeutic concentration of naloxone can be achieved with the solvent system comprising 33% PG in EtOH and hence, provides flexibility in choice of patch size depending on the addiction status of the patient to be treated.

Insulin therapies - past, present and future

The discovery of insulin is one of the greatest milestones in medical history. This discovery revolutionized the use of peptides and proteins as therapeutic agents. For more than six decades, insulin from different animal sources was used, until the breakthrough in biotechnology made it possible to produce human insulin in sufficient amounts. The evolution of the biotechnological era gave rise to modified insulins to solve some of the bottlenecks in insulin therapy. Efforts are currently focused towards developing non-invasive insulin delivery systems, and there are several competing technologies in different stages of development. The next few years will see several novel approaches to mimic the endogenous release and kinetics of insulin, and also many improved analogues designed to achieve better control and effective treatment of diabetes.

Transdermal delivery of zidovudine: effect of vehicles on permeation across rat skin and their mechanism of action

The purpose of this study was to investigate the effects of various solvent systems containing water, ethanol, propylene glycol (PG), and their binary combinations on the ex vivo permeation of zidovudine (AZT) across Sprague-Dawley rat skin using Franz diffusion cells at 37 degrees C. Further, saturation solubility and epidermis/vehicle partition coefficient of AZT in the solvent systems, and their effect on percentage hydration of epidermis using thermogravimetric analysis were determined to understand the mechanisms by which these solvent systems change drug permeability properties. All binary combinations of PG, ethanol and water significantly increased saturation solubility of AZT. Maximum AZT flux was observed with 66.6% ethanol among ethanol-water solvents, with 33.3% PG in PG-water solvents and with 100% ethanol among PG-ethanol combinations. PG-water and PG-ethanol solvents neither reduced the lag time nor increased AZT flux across rat skin. In addition, high concentrations of PG in both water and ethanol reduced steady state flux of AZT. Further, thermogravimetric studies revealed that solvents containing high PG concentrations dehydrate epidermis. Among all the solvent combinations, highest flux and short lag time were achieved with ethanol at 66.6% in water and hence is a suitable vehicle for transdermal delivery of AZT.