Barrie C. Finnin

Efficacy of antimicrobial polymer coatings in an animal model of bacterial infection associated with foreign body implants

OBJECTIVESnTo assess support discs, comprising polyethylene terephthalate (PET), coated with different polymer/levofloxacin combinations for antimicrobial activity in an animal model of infection, in order to explore the use of specific polymer coatings incorporating levofloxacin as a means of reducing device-related infections.nnnMETHODSnAliphatic polyester-polyurethanes containing different ratios of poly(lactic acid) diol and poly(caprolactone) diol were prepared, blended with levofloxacin and then used to coat support discs. The in vitro levofloxacin release profiles from these discs were measured in aqueous solution. Mice were surgically implanted with the coated discs placed subcutaneously and infection was initiated by injection of 10(6) cfu of Staphylococcus aureus into the subcutaneous pocket containing the implant. After 5, 10, 20 and 30 days, the discs were removed, and the number of bacteria adhering to the implant and the residual antimicrobial activity of the discs were determined.nnnRESULTSnIn vitro, the release of levofloxacin from the coated discs occurred at a constant rate and then reached a plateau at different timepoints, depending on the polymer preparation used. In vivo, none of the discs coated with polymer blends containing levofloxacin was colonized by S. aureus, whereas 94% of the discs coated with polymer alone were infected. All discs coated with levofloxacin-blended polymers displayed residual antimicrobial activity for at least 20 days post-implantation.nnnCONCLUSIONSnBioerodable polyester-polyurethane polymer coatings containing levofloxacin can prevent bacterial colonization of implants in an intra-operative model of device-related infections.

The buccal mucosa as an alternative route for the systemic delivery of risperidone.

The purpose of this study was to investigate the potential of the buccal mucosa for the systemic delivery of risperidone (RISP), and to determine the impact of Azone® (AZ) on the transport of RISP via this route. The permeability of RISP through porcine buccal mucosa was assessed in modified Ussing chambers at various concentrations to determine the mechanisms involved in transport across the tissue. The effect of AZ was assessed by administering AZ 5% (w/w) to the tissue as a pretreatment or together with RISP in solution or in a mucoadhesive gel formulation. RISP permeated the buccal mucosa via a passive diffusion mechanism and pretreatment or coadministration of AZ 5% did not significantly modify the permeation of RISP. Application of a RISP mucoadhesive gel resulted in a steady state flux of 64.65 ± 8.0u2009µg/cm(2)/h, which when extrapolated to the in vivo setting, is predicted to result in RISP plasma concentrations of 11.2-56.1u2009µg/L for mucosal application areas between 2 and 10 cm(2). Given that these predicted concentrations are within the therapeutic range of RISP required in humans, delivery of RISP via the buccal mucosa has the potential to result in therapeutically relevant plasma concentrations for the treatment of schizophrenia.

Assessment of the Lateral Diffusion and Penetration of Topically Applied Drugs in Humans Using a Novel Concentric Tape Stripping Design

ABSTRACTPurposeTo determine the extent of lateral spread and stratum corneum (SC) penetration of caffeine (CAF), hydrocortisone (HC) and ibuprofen (IBU) using a novel concentric tape stripping technique.MethodEthanolic solutions of CAF, HC or IBU were applied to the forearm of 8 volunteers. At various time points, 10 successive layers of SC were removed by stripping with tapes perforated into concentric rings and analysed for drug concentration and mass of SC protein. In vitro permeation studies assessed the percutaneous absorption of these compounds across human skin.ResultsCAF and IBU showed significant lateral spreading across the SC while HC formed a drug depot at the site of application. Relative to the applied dose, the in vivo recovery of all compounds from the combined 10 strips at 3xa0mins ranged between 83.0 and 92.9xa0% and decreased to between 64.5 and 66.9xa0% at 3xa0h. IBU recovery further decreased to 47.7u2009±u20095.6xa0% at 6xa0h, correlating with greater in vitro penetration relative to CAF and HC.ConclusionDrug concentration decreased with increased lateral distance from the application site. The lower recovery of IBU in the upper tape strip regions compared to CAF and HC may be a consequence of greater penetration into the SC with time.

A novel flow through diffusion cell for assessing drug transport across the buccal mucosa in vitro.

A novel flow through (FT) diffusion cell for assessing the permeability of compounds across the buccal mucosa was designed. Porcine buccal mucosa was mounted between two chambers with flow through capacity in both the donor and receptor chambers. The permeability of caffeine (CAF), triamcinolone acetonide (TAC), and estradiol (E(2)) was determined over 4 h and flux values were compared to those obtained using a modified Ussing chamber (MUC). No significant differences in the flux of each probe compound were observed using either the MUC or the novel FT cell. The design of the FT cell allowed for monitoring appearance of receptor solution within the donor chamber during the initial equilibration period, allowing for visual inspection of tissue integrity. These permeability studies demonstrate that this FT cell is a suitable alternative model for assessing drug permeability across the buccal mucosa, without the limitations associated with the static MUC. This novel model was then utilized to determine whether salmeterol xinafoate (SX) could permeate the buccal mucosa at concentrations expected in the oral cavity following inhalation. Concentration-dependent studies demonstrated that SX permeates the buccal mucosa via passive diffusion and that oral mucosal absorption may contribute significantly to the overall systemic exposure of inhaled SX.

The effect of formulation excipients on the penetration and lateral diffusion of ibuprofen on and within the stratum corneum following topical application to humans.

Distribution profiles of topically applied drugs can be influenced by the presence of excipients. This study investigated the effect of common topical excipients on the simultaneous lateral diffusion and stratum corneum (SC) penetration of a model compound, ibuprofen (IBU) in humans. IBU solutions with and without propylene glycol (PG), polyethylene glycol 200 (PEG 200), and/or octisalate (OS) were dosed onto the forearm of participants. At various times, 10 tape-strippings were obtained with perforated concentric tapes and analyzed for IBU concentration and SC protein mass. Complimentary in vitro permeation studies assessed the effect of excipients on the percutaneous absorption of IBU across human skin. Following in vivo application, IBU displayed a greater tendency for lateral diffusion when applied with OS, whereas IBU resisted lateral diffusion when dosed with PG and PEG 200. After 24 h, 25.3 ± 8.0% and 55.5 ± 18.6% of IBU was recovered from the SC in vivo with and without excipients, respectively. There was a twofold-to threefold enhancement in IBU flux in vitro when applied with excipients. The lower IBU recovery from the SC when applied with excipients may be attributed to the permeation enhancement effects of these excipients. The ability of IBU to laterally diffuse appears to be dependent on formulation excipients.