Explore the vast range of titles available.

There has been increasing interest in recent years in the drug delivery applications of tocols and their derivatives. Their biocompatibility and potential to deliver both poorly soluble and water-soluble drugs make tocols attractive as drug delivery vehicles. This review article will focus primarily on topical, oral, and parenteral drug administration using tocols, although other routes of delivery such as pulmonary and nasal will also be discussed. After an overview of the tocol structures, physicochemical properties with emphasis on their solvent properties, functions, and metabolism, specific case studies will be discussed where tocols have been successfully used in topical, oral, and parenteral drug formulations and marketed drug products. Case studies will be extended to those where tocol-based formulations were administered pulmonarily and nasally. As more clinical data and marketed drug products emerge, the utility and therapeutic value of tocols will certainly increase.

Purpose The aim of this study was to investigate and quantify drug movement to the brain via the neuro-olfactory system after intranasal dosing of four model drugs; three glycine receptor antagonists and one angiotensin antagonist. Methods The drugs were dosed to rats via intranasal or intravenous administration, after which a quantitative method for tissue distribution was utilised to determine drug distribution to the olfactory lobes, brain sections and the blood over 30 min. Autoradiography was used to visualise and quantify drug distribution throughout the brain and in the CSF. Micro-autoradiography was used to examine drug distribution throughout the olfactory nerve apparatus. Results The three glycine receptor antagonist compounds were transported to the CNS to differing degrees although they had similar molecular structures and similar physicochemical characteristics. All three compounds were shown to exploit a direct route of transport from nose to brain with Direct Transport Percentages (DTP) of 99.99%, 96.71% and 51.95%, respectively, although for the last molecule a major part of the brain content originated from systemic transport across the BBB. Intranasal administration of GR138950 resulted in over 3.5 times more drug in the olfactory lobes at 1 min post-dose compared to intravenous administration; and 5 times more drug was delivered to the olfactory lobes over 30 min. Micro-autoradiography showed that GR138950 could be found throughout the olfactory nerve apparatus. Autoradiography illustrated drug distribution throughout the brain and CSF, with drug concentrations in the CSF being equal or higher than in the brain tissue. It was determined that approximately 0.8% of the administered dose moved into the brain and CSF via the olfactory pathway over 30 min. Conclusions Intranasal administration resulted in greater delivery of the model drugs to the olfactory lobes and brain as compared to intravenous dosing. It is proposed that the drug moved through the neuro-olfactory system, primarily via paracellular pathways.

Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. & Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (i) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (ii) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an α-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of α-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

The current formulation of paclitaxel contains ethanol and Cremophor EL and has been reported to cause serious adverse reactions. The purpose of the present work was to develop an improved emulsion vehicle for paclitaxel and to study the physicochemical properties of such a system. Emulsions were prepared by either microfluidization or sonication method and the droplet size characterized by dynamic light scattering and light microscopy. Stable emulsions could be made using mixtures of lecithin/sodium deoxycholate as the emulsifiers. The formulation was further improved by using a combination of free acid and the sodium salt. Paclitaxel could be loaded into the emulsions at 2.5 mg/ml without the formation of drug crystals. While these emulsions were stable on storage, they flocculated when mixed with plasma. Steric stabilization of the emulsion droplets with poloxamer 188 increased the stability of the emulsions in plasma but promoted the crystallization of paclitaxel. The crystallization tendency could be reduced by using PEG5000PE (1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[poly (ethylene glycol) 5000]), a less water-soluble stabilizer. Emulsions with good stability characteristics containing 2.5 mg/ml paclitaxel could be made using bile salt/acid and lecithin, and the excellent stability of these emulsions in plasma was achieved by steric stabilization using PEG5000PE.

It is important when developing new vaccine systems to give proper attention to the question of delivery. In some cases the judicious choice of a delivery system can provide a greatly enhanced immune response and avoid the need to use a vaccine adjuvant. Delivery systems that have been developed originally for the administration of challenging drug can be used with success for vaccines. Polymer microspheres and lamellar particle based on the biodegradable materials polylactide and polylactide co-glycolide can be employed for the improved parenteral and mucosal administration of antigens. Likewise soluble biopolymers such as chitosan can be used for the improved nasal delivery of various antigens as well as DNA. Results from animal studies and recent clinical trials are provided.

The development of new generation vaccines against diphtheria is dependent on the identification of antigens and routes of immunization that are capable of stimulating immune responses similar to, or greater than, those obtained with the parenterally-delivered toxoid vaccine, while reducing the adverse effects that have been associated with the traditional vaccine. In this study, we examined the cellular and humoral immune responses in mice generated after both parenteral and mucosal immunizations with cross-reacting material (CRM 197) of diphtheria toxin. We found that both native and mildly formaldehyde-treated CRM 197 and conventional diphtheria toxoid (DT) induced mixed Th1/Th2 responses and similar levels of anti-DT serum IgG following parenteral immunization. In contrast, CRM 197 preparations were poorly immunogenic when administered intranasally in solution. However, formulation of the antigens with chitosan significantly enhanced their immunogenicity, inducing high levels of antigen-specific IgG, secretory IgA, toxin-neutralizing antibodies and T cell responses, predominately of Th2 subtype. Furthermore, intranasal immunization with CRM 197 and chitosan induced protective antibodies against the toxin in a guinea pig passive challenge model. We also found that priming parenterally with DT in alum and boosting intranasally with CRM 197 was a very effective method of immunization in mice, capable of inducing high levels of anti-DT IgG and neutralizing antibodies in the serum and secretory IgA in the respiratory tract. Our findings suggest that boosting intranasally with CRM 197 antigen may be very effective in adolescents or adults who have previously been parenterally immunized with a conventional diphtheria toxoid vaccine.

Due to the importance of drug-polymer interactions in, inter alia, drug loading/release, supramolecular assemblies and DNA delivery for gene therapy, the aim of this study was therefore to establish the mechanism of interaction between a model polymer (Polyacrylic acid, PAA) and a model drug (procaine HCl). This was performed by studying the effect of salt (KCl) concentration on their heat released values using Isothermal Titration Microcalorimetry (ITM). The integrated released heat data were computer fitted to a one class binding model and the thermodynamic parameters (Kobs, deltaH, and N) were determined. As the KCl concentration was increased, Kobs decreased thus establishing the salt dependence of the interaction. The linear variation of deltaGobs with deltaSobs indicated that their interaction was entropically driven. The stoichiometry of the interaction was calculated to be one procaine molecule per monomer of PAA. Dissection of the total observed free energy at each KCI concentration indicated that the contribution of the non-electrostatic attractions to the interaction of PAA with procaine HCl was greater than those of the electrostatic attractions. We have shown that the interaction between PAA and procaine HCl is dependent upon the presence of counterions (monovalent ions) and is mainly entropically driven. The calculated stoichiometry indicated that one procaine HCl molecule neutralised one carboxylic acid group on PAA. Although electrostatic interactions were necessary for initiating complex formation, the non-electrostatic forces were dominant in stabilising the PAA-procaine HCl complex.

Nanospheres can be utilised for the targeting of drugs and diagnostic agents to the regional lymph nodes. The surface modification of model polystyrene, (PS), and poly(lactide-co-glycolide),(PLGA), nanospheres by poly(lactide)-poly(ethylene glycol), (PLA:PEG), copolymers has been assessed by in vitro characterisation and in vivo biodistribution studies following subcutaneous administration of the nanospheres to the rat. Three PLA:PEG copolymers were investigated, with PEG chain lengths of 750, 2000 and 5000 Da. The PLA:PEG copolymers were either coated onto the surface of PS and PLGA nanospheres or used as a co-precipitate in the formation of PLGA-PLA:PEG nanospheres. Coating of the nanospheres was confirmed by an increase in their particle size and a corresponding decrease in the surface potential. The kinetics of injection site drainage and lymph node retention was determined over a 24 hour time course for naked, coated and co-precipitated nanosphere systems. Dependent on the surface characteristics, the distribution of the nanospheres can be significantly modified and the lymph node localisation dramatically enhanced by coating their surfaces with PLA:PEG copolymers or by producing co-precipitate nanospheres of PLGA and PLA:PEG. A fully biodegradable nanosphere system has been developed with excellent lymph node targeting characteristics.

A human volunteer study was carried out to investigate whether activation of the ileal brake mechanism affects the transit of tablets through the small intestine. Oleic acid, which has previously been shown to activate the brake, was delivered to the small intestine in a modified release capsule at doses of 300 mg, 600 mg and 1200 mg. The effect of the oleic acid was determined by measuring the transit of two sets of radiolabelled tablets by gamma scintigraphy. One set of tablets was dosed with the capsule and the other one hour later. The results show that in the majority of the volunteers small intestinal residence time was greater with the oleic acid than control. The effect was most pronounced in the tablets given concomitantly with the capsule and with the higher doses of oleic acid. The ileal brake, activated by oleic acid, can slow the transit of tablets through the small intestine.

To investigate the effects of the modification of the copolymers poloxamer 407 and poloxamine 908 on the physical and biological properties surface modified polystyrene nanospheres. A method to modify poloxamer 407 and poloxamine 908, introducing a terminal amine group to each PEO chain has been developed. The aminated copolymers can be subsequently radiolabelled with Iodinated (I125) Bolton-Hunter reagent. The aminated copolymers were used to surface modify polystyrene nanospheres. The physical and biological properties of the coated nanospheres were studied using particle size, zeta potential, in vitro non-parenchymal cell uptake and in vivo biodistribution experiments. The presence of protonated amine groups in the modified copolymers significantly affected the physical and biological properties of the resulting nanospheres, although the effects were copolyme specific. The protonated surface amine groups in both copolymers reduced the negative zeta potential of the nanospheres. Acetylation of the copolymer's free amine groups resulted in the production of nanospheres with comparable physical properties to control unmodified copolymer coated nanospheres. In vivo, the protonated amine groups in the copolymers increased the removal of the nanospheres by the liver and spleen, although these effects were more pronounced with the modified poloxamer 407 coated nanospheres. Acetylation of the amine groups improved the blood circulation time of the nanospheres providing modified poloxamine 908 coated nanospheres with comparable biological properties to control poloxamine 908 coated nanospheres. Similarly, modified poloxamer 407 coated nanospheres had only slightly reduced circulation times in comparison to control nanospheres. The experiments have demonstrated the importance of copolymer structure on the biological properties of surface modified nanospheres. Modified copolymers, which possess comparable properties to their unmodified forms, could be used in nanosphere systems where antibody fragments can be attached to the copolymers, thereby producing nanospheres which target to specific body sites.