Parenteral water/oil emulsions containing hydrophilic compounds with enhanced in vivo retention: formulation, rheological characterisation and study of in vivo fate using whole body gamma-scintigraphy.

The preparation and characterization of parenteral water-in-oil (w/o) emulsions with a potential for sustained release of hydrophilic drugs was described with emphasis on rheological behaviour and spreading phenomenon after intramuscular (i.m.) injection in rabbit thigh muscle. Both steady state and dynamic rheological parameters were investigated showing Newtonian behaviour at low fraction of disperse phase ratio as opposed to viscoelastic and pseudoplastic behaviour at high fraction of disperse phase. Disappearance and spreading behaviour of hydrophilic radioactive markers, aprotinin (6512 g/mol) and pertechnetate (193 g/mol) entrapped in w/o emulsions from an i.m. injection site was studied by whole body gamma-scintigraphy. The retention of entrapped aprotinin 24 h postinjection was 83 +/- 5% for a low spreading emulsion and 76 +/- 6% for a high spreading emulsion. The corresponding values for pertechnetate were 50 +/- 11 and 23 +/- 2%, respectively. The relatively long retention times were suggested to be related to the good physical stability properties of the present emulsions. It was concluded that the presented w/o emulsions are promising vehicles for sustained release of hydrophilic drugs from an i.m. injection site.

Sustained elevated plasma aprotinin concentration in mice following intraperitoneal injections of w/o emulsions incorporating aprotinin.

This study was initiated to test the feasibility of w/o emulsions as a sustained release system for aprotinin following intraperitoneal injection in mice. The emulsion was well tolerated in mice and sustained release was observed over a period of 96 h. The time for maximum plasma concentration of aprotinin was 10 min and 12 h after injection of a control solution and the emulsion dosage form, respectively. Furthermore, the hemolytic activity of the emulsion constituents was low indicating a low acute toxicological potential of the emulsion. The present study also showed that the lipolytic activity in peritoneal exudate from mice is important for the clearance of oily vehicles from the peritoneal cavity with lipolytic rate constants ranging from 50 to 130 nmol free fatty acid released/min/mg exudate protein at 37 degrees C, pH 8.5. It was concluded that the w/o emulsion was well suited to provide sustained elevated plasma aprotinin concentrations in mice.

Formulation and evaluation of release and swelling mechanism of a water-in-oil emulsion using factorial design.

Water-in-oil emulsions have a potential as a parenteral prolonged release system for hydrophilic drugs. A consistent challenge when developing an emulsion drug delivery system is to obtain a proper release characteristic of the entrapped drug. The aim of the present study was to study the release mechanism from water-in-oil emulsions. Secondly, to study the effects of droplet size, phase ratio and osmotic pressure on the release rate of glucose from water-in-oil emulsions in a factorial experimental design. The release mechanism of glucose was deduced from the release kinetics of two coentrapped marker molecules, glucose and inulin, with a molecule weight of 180 and 5000 g/mol, respectively. The results indicate that release of glucose was dominated by diffusion through the oily barrier as opposed to membrane rupture. Using statistical methodology, the release rate of glucose could be varied 8 fold in a controlled manner with osmotic pressure as the most important parameter. The osmotic behaviour of the emulsions was further studied in a dynamic swelling study. These results show that the release of entrapped hydrophilic drug can be controlled within certain limits using pharmaceutical formulation principles.

Cyclodextrin inclusion complexes of antimycotics intended to act in the oral cavity--drug supersaturation, toxicity on TR146 cells and release from a delivery system.

The dissolution rate, the toxicity and the release from chewing gum of miconazole and econazole cyclodextrin products and complexes were investigated. The dissolution rate studies showed that an amorphous miconazole hydroxypropyl-beta-cyclodextrin product gave drug supersaturation, whereas drug supersaturation was not present during dissolution rate testing of an econazole hydroxypropyl-beta-cyclodextrin product. The miconazole hydroxypropyl-beta-cyclodextrin product and genuine cyclodextrin inclusion complexes of miconazole, econazole and clotrimazole were toxic on a human TR146 buccal cell culture model. The toxicity was probably due to drug supersaturation, thereby increasing the bioavailability of the antimycotics. The econazole hydroxypropyl-beta-cyclodextrin product and physical mixtures of miconazole or econazole and beta-cyclodextrin did not give supersaturation and were not as toxic as the above-mentioned compounds. Neat econazole and miconazole, a genuine econazole beta-cyclodextrin complex and the miconazole hydroxypropyl-beta-cyclodextrin product were incorporated in chewing gum. The miconazole hydroxypropyl-beta-cyclodextrin gum had a much higher drug release in vitro than the neat miconazole gum. The genuine econazole beta-cyclodextrin complex only increased the drug release moderately when compared with the release from the neat econazole gum. The release studies were performed on a mastication device.

The effect of controlled osmotic stress on release and swelling properties of a water-in-oil emulsion.

The purpose of this study was to investigate the effect of osmotic gradients in a water-in-oil (w/o) emulsion on release properties in order to control the release of hydrophilic drugs. The magnitude and direction of the osmotic gradient was shown to have a pronounced effect on the apparent permeability of the hydrophilic marker, [3H]glucose. The apparent permeability coefficient of glucose could be varied between 1.0x10(-5) and 5.0x10(-8) cm s-1 using osmotic gradients. The release rate of glucose was related to the swelling properties. The larger the degree of swelling, the lower the release rate. Furthermore the present w/o emulsion has a low viscosity and a long-term physical stability. This makes the emulsion a promising parenteral drug delivery system in which the release of hydrophilic drugs such as peptides, can be controlled.