A novel lipid nanoemulsion system for improved permeation of granisetron.

A new lipid nanoemulsion (LNE) system containing granisetron (GRN) was developed and its in vitro permeation-enhancing effect was evaluated using Caco-2 cell monolayers. Particle size, polydispersity index (PI) and stability of the prepared GRN-loaded LNE systems were also characterized. The mean diameters of prepared LNEs were around 50 nm with PI<0.2. Developed LNEs were stable at 4°C in the dark place over a period of 12 weeks. In vitro drug dissolution and cytotoxicity studies of GRN-loaded LNEs were performed. GRN-loaded LNEs exhibited significantly higher drug dissolution than GRN suspension at pH 6.8 for 2h (P<0.05). In vitro permeation study in Caco-2 cell monolayers showed that the LNEs significantly enhanced the drug permeation compared to GRN powder. The in vivo toxicity study in the rat jejunum revealed that the prepared GRN-loaded LNE was as safe as the commercial formulation (Kytril). These results suggest that LNE could be used as a potential oral liquid formulation of GRN for anti-emetic treatment on the post-operative and chemotherapeutic patients.

Piceatannol, a hydroxystilbene natural product, stabilizes HIF-1α protein by inhibiting HIF prolyl hydroxylase.

To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1α protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1α resulted from HIF-1α protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1α. Moreover, PCT prevented hydroxylation of cellular HIF-1α and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1α over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1α protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product.

Skin permeation enhancement of diclofenac by fatty acids.

This study systematically investigated the enhancing effect of fatty acids on the skin permeation of diclofenac. The fatty acids were evaluated in terms of their carbon-chain length, the degree of unsaturation, and their functional groups. The rat-skin permeation rates of diclofenac, saturated in propylene glycol (PG) containing 1% (w/v) fatty acid, were determined using the Keshary-Chien diffusion cells at 37 degrees C. The effect of fatty acids on the saturated solubility of diclofenac in PG was also determined at 37 degrees C using high-performance liquid chromatography. Among the saturated fatty acids tested, palmitic acid (C16:0) showed the most potent skin permeation-enhancing effect. A parabolic correlation was observed between the enhancement effect and the fatty acid carbon-chain length among these saturated fatty acids of C12-C20 units. For the monounsaturated fatty acid series, an increase in permeation was observed as the carbon-chain length increased, and oleic acid (C18:1) showed the highest permeation-enhancing effect. Increasing the number of double bonds in the octadecanoic acids resulted in a parabolic effect in the permeation of diclofenac, revealing oleic acid as the most effective enhancer used in this study. When the carboxylic acid moiety of oleic acid was changed to an amide (oleamide) or hydroxyl (oleyl alcohol) group, a decrease in permeation activity was observed. These results, therefore, suggest that the cis-monounsaturated configuration and the carboxylic acid moiety of an 18-carbon unit fatty acid in PG are the optimum requirements for the effective skin permeation of diclofenac.

Ketorolac amide prodrugs for transdermal delivery: stability and in vitro rat skin permeation studies.

Various amide prodrugs of ketorolac were synthesized and their rat skin permeation characteristics were determined. The solubility of the prodrugs in propylene glycol (PG) was determined at 37 degrees C while lipophilicity was obtained as 1-octanol/water partition coefficient (logP) and capacity factor (k') using HPLC. Stability of the prodrugs in rat skin homogenate, plasma and liver homogenate was investigated to observe the enzymatic degradation. Rat skin permeation characteristics of the prodrugs saturated in PG were investigated using the Keshary-Chien permeation system at 37 degrees C. The logP value of the prodrugs increased up to 4.28 with the addition of various alkyl chain to ketorolac which has a logP of 1.04. Good linear relationship between logP and capacity factor was observed (r(2)=0.89). Amide prodrugs were converted to ketorolac only in rat liver homogenate. However, the skin permeation rate of amide prodrugs did not significantly increase, probably due to their low aqueous solubility. Chemical modification of the ketorolac amide prodrug and/or the selection of proper vehicle to increase aqueous solubility would be necessary for an effective transdermal delivery of ketorolac.

Synthesis and evaluation of Ketorolac ester prodrugs for transdermal delivery.

Alkyl esters of ketorolac were synthesized as potential prodrugs for transdermal delivery and evaluated to determine the relationship between their skin permeation characteristics and their physicochemical properties. Solubility of the prodrugs in various vehicles was determined at room temperature while lipophilicity was obtained as 1-octanol/water partition coefficients (logP) and capacity factors (k') using HPLC. Metabolism of the prodrugs to ketorolac was studied both in rat skin homogenate and in plasma. Rat skin permeation characteristics of the prodrugs saturated in propylene glycol were investigated using the Keshary-Chien permeation system at 37 degrees C. An increase in logP and capacity factor values of the prodrugs were observed in proportion to their alkyl chain length. Good linear relationship between the logP values and capacity factor was observed (r(2) = 0.92). Prodrugs were rapidly degraded to ketorolac both in the skin homogenate and in plasma following a first-order kinetics. To determine accurate amounts of prodrug permeated, both the prodrug and parent drug concentration in the receptor solution were determined in mole units. The skin permeation rate of the alkyl ester prodrugs was significantly higher with a shorter lag time than that of ketorolac. The permeation rate of ketorolac reached maximum in its 1-propyl ester form as 46.61 nmol/cm(2)/h, and a parabolic relationship was observed between the permeation rate and the logP values of the prodrugs. Alkyl ester prodrugs of ketorolac having optimum lipophilicity could improve the transdermal delivery of ketorolac.

In vitro evaluation of patch formulations for topical delivery of gentisic acid in rats.

Gentisic acid (GA) is used in cosmetics as a skin-whitening agent for the treatment of skin pigmentary disorders by influencing the synthesis of melanin through inhibition of melanosomal tyrosinase activity. In order to achieve effective topical delivery of GA to the active site in the skin, a matrix-type transdermal delivery system was developed. The in vitro skin permeation as well as skin deposition of GA was studied in rats. Among the five pressure-sensitive adhesives tested, DuroTak 87-2510 was the most effective to achieve the highest permeation rate of GA. Dodecylamine showed the most potent enhancement among the enhancers tested, and significantly increased the permeation rate of GA up to 112.99 (+/-30.12) microg/cm(2) per h at the concentration of 1%, when 6% GA was incorporated in DuroTak 87-2510. Moreover, a linear relationship was observed between the skin permeation rate of GA and the amount of the skin deposition after 12 h of permeation (r(2)=0.95). Thus, the in vitro skin permeation data may be useful to determine the amount of GA actually deposited in the skin.