Controlled simultaneous iontophoresis of buflomedil hydrochloride and dexamethasone sodium phosphate to the mucosa for oral submucous fibrosis.

A novel concentric experimental set-up was used to investigate short-duration topical co-iontophoresis of cationic buflomedil hydrochloride (BUF) and anionic dexamethasone phosphate (DEX-P) to the oral mucosa. A constant current of 3.0 mA (0.6 mA/cm2 for BUF and 1.95 mA/cm2 for DEX-P) was applied to porcine esophageal mucosa for 5, 10 and 20 min. Iontophoresis for only 5 min increased total delivery of BUF from 29.8 ± 5.1 nmol/cm2 to 194.3 ± 23.8 nmol/cm2 and DEX-P from 29.4 ± 1.2 nmol/cm2 to 193.3 ± 19.8 nmol/cm2 as compared to passive controls. Quantification of drug between the electrode compartments reported on lateral ion migration. In the absence of current, DEX-P did not migrate laterally; however, iontophoresis for 5 min increased DEX-P delivery >5-fold under the cathodal compartment (its application area) and >8-fold in the adjacent "inter-electrode" area. Similarly, delivery of BUF increased ~6.8-fold under the anodal compartment and ~12.8-fold under the cathode. The results showed that co-iontophoresis enabled the controlled simultaneous delivery of BUF and DEX-P achieving therapeutically relevant concentrations after current application for only 5 min. Short duration topical co-iontophoresis of single or multiple therapeutics to the mucosa increases local bioavailability and presents a patient-friendly treatment for diseases of the oral cavity.

Iontosomes: Electroresponsive Liposomes for Topical Iontophoretic Delivery of Chemotherapeutics to the Buccal Mucosa.

The targeted local delivery of anticancer therapeutics offers an alternative to systemic chemotherapy for oral cancers not amenable to surgical excision. However, epithelial barrier function can pose a challenge to their passive topical delivery. The charged, deformable liposomes-"iontosomes"-described here are able to overcome the buccal mucosal barrier via a combination of the electrical potential gradient imposed by iontophoresis and their shape-deforming characteristics. Two chemotherapeutic agents with very different physicochemical properties, cisplatin (CDDP) and docetaxel (DTX), were co-encapsulated in cationic iontosomes comprising 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and Lipoid-S75. The entrapment of CDDP was improved by formulating it in anionic reverse micelles of dipalmitoyl-sn-glycero-3-phospho-rac-glycerol sodium (DPPG) prior to loading in the iontosomes. Cryo-TEM imaging clearly demonstrated the iontosomes' electroresponsive shape-deformable properties. The in vitro transport study using porcine mucosa indicated that iontosomes did not enter the mucosa without an external driving force. However, anodal iontophoresis resulted in significant amounts of co-encapsulated CDDP and DTX being deposited in the buccal mucosa; e.g., after current application for 10 min, the deposition of CDDP and DTX was 13.54 ± 1.78 and 10.75 ± 1.75 µg/cm2 cf. 0.20 ± 0.07 and 0.19 ± 0.09 µg/cm2 for the passive controls-i.e., 67.7- and 56.6-fold increases-without any noticeable increase in their transmucosal permeation. Confocal microscopy confirmed that the iontosomes penetrated the mucosa through the intercellular spaces and that the penetration depth could be controlled by varying the duration of current application. Overall, the results suggest that the combination of topical iontophoresis with a suitable nanocarrier system can be used to deliver multiple "physicochemically incompatible" chemotherapeutics selectively to oral cancers while decreasing the extent of systemic absorption and the associated risk of side effects.

Topical iontophoresis of buflomedil hydrochloride increases drug bioavailability in the mucosa: A targeted approach to treat oral submucous fibrosis.

The aim was to investigate the effect of constant current iontophoresis on the delivery and biodistribution of buflomedil hydrochloride (BUF) in the buccal mucosa. Quantification was by UHPLC-MS/MS; in addition to total delivery, the amounts present in the epithelia and the lamina propria (the target tissue) were also determined. Two-compartment vertical diffusion cells were used to investigate the effect of current density (0.5, 1 and 2 mA/cm2), application time (5, 10 and 20 min) and concentration (5, 10 and 20 mM) on iontophoretic delivery of BUF from aqueous solutions. In contrast to passive delivery, iontophoresis for 10 min at 1 mA/cm2 resulted in statistically equivalent transport from a 20 mM solution and a 2% HEC hydrogel (with equivalent BUF loading; 20 µmol). BUF delivery from the hydrogel using diffusion cells and a new coplanar "side-by-side" set-up was statistically equivalent (304.2 ±â€¯28.9 and 278.2 ±â€¯40.3 µg/cm2) - passive delivery was also similar. Iontophoresis (10 min at 1 mA/cm2) using a thin film (20 µmol BUF) was superior to the passive control (323.3 ±â€¯5.9 and 24.8 ±â€¯5.9 µg/cm2). Concentrations in the LP were ~700-fold > IC50 to block collagen production, potentially providing a new therapeutic strategy for oral submucous fibrosis.

Steering surface topographies of electrospun fibers: understanding the mechanisms.

A profound understanding of how to tailor surface topographies of electrospun fibers is of great importance for surface sensitive applications including optical sensing, catalysis, drug delivery and tissue engineering. Hereby, a novel approach to comprehend the driving forces for fiber surface topography formation is introduced through inclusion of the dynamic solvent-polymer interaction during fiber formation. Thus, the interplay between polymer solubility as well as computed fiber jet surface temperature changes in function of time during solvent evaporation and the resultant phase separation behavior are studied. The correlation of experimental and theoretical results shows that the temperature difference between the polymer solution jet surface temperature and the dew point of the controlled electrospinning environment are the main influencing factors with respect to water condensation and thus phase separation leading to the final fiber surface topography. As polymer matrices with enhanced surface area are particularly appealing for sensing applications, we further functionalized our nanoporous fibrous membranes with a phosphorescent oxygen-sensitive dye. The hybrid membranes possess high brightness, stability in aqueous medium, linear response to oxygen and hence represent a promising scaffold for cell growth, contactless monitoring of oxygen and live fluorescence imaging in 3-D cell models.