The objective of this study was to develop and evaluate a hydrogel vehicle for sustained release of growth factors for wound healing applications. Hydrogels were fabricated using ultraviolet photo-crosslinking of acrylamide-functionalized nondegradable poly(vinyl alcohol) (PVA). Protein permeability was initially assessed using trypsin inhibitor (TI), a 21 000 MW model protein drug. TI permeability was altered by changing the solids content of the gel and by adding hydrophilic PVA fillers. As the PVA content increased from 10% to 20%, protein flux decreased, with no TI permeating through 20% PVA hydrogels. Further increase in model drug release was achieved by incorporating hydrophilic PVA fillers into the hydrogel. As filler molecular weight increased, TI flux increased. The mechanism for this is most likely an alteration in protein/gel interactions and transient variations in water content. The percent protein released was also altered by varying protein loading concentration. Release studies conducted using growth factor in vehicles with hydrophilic filler showed sustained release of platelet-derived growth factor (PDGF-beta,beta) for up to 3 days compared with less than 24 hours in the controls. In vitro bioactivity was demonstrated by doubling of normal human dermal fibroblast numbers when exposed to growth factor-loaded vehicle compared to control. The release vehicle developed in this study uses a rapid and simple fabrication method, and protein release can be tailored by modifying solid content, incorporating biocompatible hydrophilic fillers, and varying protein loading concentration.

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INTRODUCTIONBuspirone hydrochloride (BH) is an orally administered anxiolytic that is structurally and pharmacologically distinct from all other anxiolytics, including benzodiazepines and barbiturates. It differs from other anxiolytics in that it does not possess anticonvulsant or muscle relaxant properties, does not impair psychomotor function, and does not cause sedation or physical dependence. BH is used to treat generalized anxiety disorder and anxiety caused by alcohol craving or smoking cessation, as well as attention deficit hyperactivity disorder in children.Since 1984, BH has been used in children and adolescents with anxiety disorders, and researchers have reported significant improvement with its use.1 The reported side effects were very mild, and many clinical trials have shown the superiority of BH over other traditional stimulant-based treatments. 2,3The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm 2 resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel resulted in a synergistic effect when combined with iontophoresis. Menthol was the most active enhancer, and when combined with iontophoresis it was possible to deliver 10 mg/cm 2 /day of buspirone hydrochloride.Although BH is rapidly absorbed in humans, it undergoes extensive first-pass metabolism such that the unchanged compound accounts for only 1% of the radioactivity in the plasma after oral administration of a 20-mg single dose of BH. Moreover, the average elimination half-life of unchanged BH after single doses of 10 to 40 mg is about 2 to 3 hours. 4 Consequently, treatment with BH typically requires 3 daily doses of between 5 and 20 mg each. Because of the chronic nature of the treatment, a reduction in the number of daily doses would be advantageous, as it should radically improve patient compliance. Thus, an effective transdermal buspirone delivery system would be expected to have a great impact on therapy success.

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