Development of a Phosphoric Acid-Mediated Hyaluronic Acid Gel Sheet for Efficient Transdermal Delivery of Alendronate for Anti-Osteoporotic Therapy.

For efficient transdermal delivery of alendronate (ALN) for anti-osteoporotic therapy, we developed a hyaluronic acid (HA) gel sheet that was prepared simply by enhancing HA noncovalent interactions using phosphoric acid and polyhydric alcohol (propanediol and glycerin). HA solution viscosity increased after addition of phosphoric acid, and the HA gel sheet formed after heated drying. The HA gel sheet could be converted to high viscosity state by addition of water. These results indicate that phosphoric acid enhances the noncovalent interactions of HA molecules. The HA gel sheet elicited no skin irritation over 7 days after a 24-h application. The permeation of ALN across rat and human skin was 109 and 7.17 µg/cm2, respectively, up to 24 h after application of the ALN-loaded HA gel sheet, which is sufficient for clinical treatment of osteoporosis. The bioavailability of ALN in rats was ~20% after application of the ALN-loaded HA gel sheet, and plasma calcium levels were effectively reduced 3 days after sheet application. Furthermore, in a rat osteoporosis model, the reduction in tibial bone density was suppressed by treatment with the ALN-loaded HA gel sheet. These results indicate that our phosphoric acid-mediated HA gel sheet is a promising transdermal formulation for efficient ALN delivery.

Pharmacokinetics and Preventive Effects of Sulfo-Albumin as a Novel Macromolecular Hydrogen Sulfide Prodrug on Carbon Tetrachloride-Induced Hepatic Injury.

Hydrogen sulfide (H2S) has been recently recognized as a gaseous signaling molecule that controls various biological activities. In the present study, we developed sulfo-albumin as a macromolecular H2S prodrug for therapeutic use, in which multisulfide groups (source of H2S) were conjugated with bovine serum albumin through a covalent linkage. In an in vitro study on H2S release in phosphate buffered saline solution, we found that H2S was released from sulfo-albumin in the presence of 5-mM glutathione but not in its absence. Furthermore, sulfo-albumin was taken up by RAW 264.7 cells, and it released H2S in cells but not in plasma. These results indicate that H2S can be selectively released from sulfo-albumin in cells. 111In-labeled sulfo-albumin predominantly accumulated in the liver, dependent upon the number of sulfide groups, after intravenous injection in mice. In a carbon tetrachloride-induced acute liver injury mouse model, sulfo-albumin significantly suppressed the increase in plasma aspartate aminotransferase and alanine aminotransferase activities, which are indicators of hepatocyte injury, after intravenous injection. These findings indicate that sulfo-albumin is a promising compound for the treatment of hepatic injuries.