Influence of drug lipophilicity on drug release from sclera after iontophoretic delivery of mixed micellar carrier system to human sclera.

Mixed micelles prepared using sodium taurocholate (TA) and egg lecithin (LE) were previously found to be an effective carrier for sustained release of a poorly water-soluble drug in transscleral iontophoretic delivery. The objectives of the present study were to investigate the effects of drug lipophilicity upon micellar carrier solubilization potential and drug release profiles from the sclera after iontophoretic delivery of model lipophilic drugs dexamethasone (DEX), triamcinolone acetonide (TRIAM), and ß-estradiol (E2ß) with a mixed micellar carrier system of TA-LE (1:1 mole ratio). In this study, the micellar carrier system was characterized for drug solubilization. The micelles encapsulating these drugs were evaluated for transscleral passive and 2-mA iontophoretic delivery (both cathodal and anodal) and drug release from excised human sclera in vitro. The results show that drug solubility enhancement of the micellar carrier system increased with increasing drug lipophilicity. The more lipophilic drugs E2ß and TRIAM displayed slower drug release from the sclera compared with the less lipophilic drug DEX after iontophoretic drug delivery with the mixed micelles. These results suggest that the combination of transscleral iontophoresis and micellar carriers is more effective in sustaining transscleral delivery of the more lipophilic drugs studied in this investigation.

Sustained release micellar carrier systems for iontophoretic transport of dexamethasone across human sclera.

A challenge in ocular drug delivery is to maintain the therapeutic concentration of a drug at the site of action in the eye. The objective of the present study was to investigate the feasibility of micellar carrier systems for sustained drug delivery in transscleral iontophoresis in vitro. Simple and mixed micelles prepared using sodium taurocholate (TA) alone or with egg lecithin (LE) were the carrier systems studied. Dexamethasone (DEX), a poorly water soluble corticosteroid, was the model drug. The micellar carrier systems were first characterized for their solubilization and encapsulation of the drug. Passive and 2-mA iontophoretic (both cathodal and anodal) transport experiments were conducted using these micellar carrier systems in side-by-side diffusion cells with excised human sclera in vitro. Drug release studies were performed after the transport experiments. Saturated DEX solution without the micellar carriers was used as a control. It was found that the solubilization capacity of the micellar carrier systems increased as the total lipid concentration of the systems increased. Drug release from the sclera was significantly prolonged with the micellar carrier systems as compared to the control after passive and iontophoretic delivery. Less than ~20% of DEX was released from the sclera in approximately 2h after cathodal iontophoretic delivery of the micellar carrier systems, whereas more than ~50% of DEX was released from the control in the same time period under the same condition. Micellar carrier systems can be a suitable transscleral drug delivery system for poorly water soluble drugs by enhancing their aqueous solubilities and providing sustained drug delivery. These micellar carrier systems can be efficiently delivered into and across the sclera by iontophoresis for drug delivery.

Iontophoretic transport of charged macromolecules across human sclera.

The mechanisms of transscleral iontophoresis have been investigated previously with small molecules in rabbit sclera. The objective of the present study was to examine transscleral iontophoretic transport of charged macromolecules across excised human sclera. Passive and 2mA iontophoretic transport experiments were conducted in side-by-side diffusion cells with human sclera. The effects of iontophoresis upon transscleral transport of model permeants bovine serum albumin (BSA) and polystyrene sulfonic acid (PSS) as well as a model drug bevacizumab (BEV) were determined. Passive and iontophoretic transport experiments of tetraethylammonium (TEA) and salicylic acid (SA) and passive transport experiments of the macromolecules served as the controls. The results of iontophoresis enhanced transport of TEA and SA across human sclera were consistent with those in a previous rabbit sclera study. For the iontophoretic transport of macromolecules BSA and BEV, higher iontophoretic fluxes were observed in anodal iontophoresis as compared to passive and cathodal iontophoresis. This suggests the importance of electroosmosis. For the polyelectrolyte PSS, higher iontophoretic flux was observed in cathodal iontophoresis compared to anodal iontophoresis. Both electroosmosis and electrophoresis affected iontophoretic fluxes of the macromolecules; the relative contributions of electroosmosis and electrophoresis were a function of molecular size and charge of the macromolecules.

Chemical stability of hydromorphone hydrochloride in patient-controlled analgesia injector.

The chemical stability of hydromorphone hydrochloride in patient-controlled analgesia injectors was studied for 34 weeks at different temperatures. The sterility of the solution was also monitored at the end of 16-week storage. For the determination of stability of hydromorphone, five groups of six patient-controlled analgesia injectors containing hydromorphone solutions of 0.2 mg/mL (6 mg of drug solution in 30 mL 0.9% normal saline) sealed with plastic tip caps were stored at 5 degrees Celsius in refrigerator, 20 degrees Celsius on bench top, 20 degrees Celsius in dark, 35 degrees Celsius in dark, and 50 degrees Celsius in dark. Chemical stability was determined throughout a storage period of 34 weeks using high performance liquid chromatography. Sterility test was also performed at 16 weeks. Hydromorphone solutions stored in different conditions up to 34 weeks remained clear and free of visible precipitation throughout the study. After 8 weeks of storage in the patient-controlled analgesia injectors in different temperature conditions, the concentrations of hydromorphone in all the samples remained over 95% of their original value. At 16 and 34 weeks, the concentration of hydromorphone in the injectors decreased to 92% to 96% and 86% to 88% of their original value, respectively. In the sterility test of bacterial contamination of the hydromorphone solutions in the patient-controlled analgesia injectors at 16 weeks, none of the injector solutions showed evidence of microbial growth after 14 days of incubation in fluid thioglycolate medium. This study demonstrates the stability and sterility of hydromorphone hydrochloride solution.