Penetration of Flurbiprofen from a Locally Applied Sore Throat Lozenge and Spray into Cadaveric Human Pharynx Tissue: A Novel ex vivo Model and Microautoradiography Method.

OBJECTIVE: Flurbiprofen 8.75 mg lozenge and spray are used for symptomatic relief of sore throat, with a rapid onset of analgesia suggesting a localized mechanism of action. Building on previous studies, this investigation aimed to use microautoradiography to visualize the depth penetration of radiolabeled flurbiprofen into human pharynx tissue using an ex vivo model. Quantification of flurbiprofen in the tissue was performed to provide a quantitative representation of flurbiprofen distribution through the tissue. METHODS: Cadaveric human pharynx tissue was mounted between the donor and receiver compartments of a Franz diffusion cell. After that 8.75 mg spray and dissolved lozenge formulations, containing radiolabeled flurbiprofen, were added to the donor compartment of a Franz diffusion cell. After incubation for one hour, the pharynx tissue was removed, processed, and sectioned both horizontally and vertically. The sections were placed within an imaging cassette to determine the penetration of radiolabeled flurbiprofen visually, before being solubilized to quantify the amount of flurbiprofen present in each section. RESULTS: In the horizontally sectioned samples, flurbiprofen was present in the top layers of all replicates and decreased in intensity throughout the tissue. Of the applied dose, 48.0-99.9% of flurbiprofen was detected in the top one-third of the pharynx tissue, closest to the dosing site, and 0-14.8% of flurbiprofen was detected within the deepest third of pharynx tissue, furthest from the dosing site. In the vertically sectioned tissue samples, radiolabeled flurbiprofen was found at a high intensity at the dosing site and reduced in intensity throughout the thickness of the tissue. Lateral penetration of flurbiprofen was also seen in tissue dosed with the spray. CONCLUSION: Our findings demonstrate that lozenge and spray formulations of flurbiprofen can penetrate throughout the layers of cadaveric human pharynx tissue in an ex vivo model, as visualized by microautoradiography.

Determination of the Permeation and Penetration of Flurbiprofen into Cadaveric Human Pharynx Tissue.

OBJECTIVE: Flurbiprofen 8.75 mg spray and lozenge have a rapid onset of action for sore throat relief, suggesting local action, although tissue penetration and the mechanism of local relief have not been determined. This investigation aimed to quantify the permeation and penetration of flurbiprofen, applied as local pharmaceutical forms, into full-thickness cadaveric human mucosal pharynx tissue, representing the clinical scenario as far as possible. METHODS: A validated high-performance liquid chromatography method quantified the permeation and penetration of flurbiprofen (spray and lozenge formulations) into human cadaveric pharynx tissue using a micro Franz cell model mimicking physiological and anatomical conditions. Full-thickness mucosal pharynx tissue, consisting of oral epithelium, basement membrane, and lamina propria, was utilized to imitate the in vivo setting. Flurbiprofen was analyzed on the surface of the pharynx tissue, within the pharynx tissue and in receiver fluid, over 60 mins. RESULTS: Flurbiprofen was detected in receiver fluid from 10 mins following spray application and was quantifiable from 20 mins. Flurbiprofen from lozenge was detected from 10 mins and was above the limit of quantitation in receiver fluid from 40 mins. Flurbiprofen recovered from the surface of the pharynx tissue was 24.45% and 8.48% of applied dose for spray and lozenge, respectively. Flurbiprofen recovered within pharynx tissue was 46.50% and 54.65% of applied dose for spray and lozenge, respectively. For flurbiprofen lozenge, recovery within pharynx tissue was 6-fold higher relative to recovery from the pharynx tissue surface. CONCLUSION: Flurbiprofen from spray and lozenge formulations penetrated human cadaveric pharynx tissue, indicating that flurbiprofen can reach all layers of the pharynx mucosal tissue, including the underlying lamina propria, which contains blood vessels and nerve fibers that contribute to pain during sore throat. This suggests that flurbiprofen may have a local mechanism of action for sore throat, although this has yet to be determined.

Validation of an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue.

The aim of this investigation was to develop receiver and extraction fluids, and subsequently validate an analytical method to quantify the permeation and penetration of flurbiprofen into human pharynx tissue using a Franz diffusion cell. The solubility and stability of flurbiprofen in a suitable receiver fluid, and a suitable extraction method and fluid to recover and quantitate flurbiprofen from human pharynx tissue, were investigated using high-performance liquid chromatography (HPLC). The potential interference of human pharynx tissue in the receiver fluid was also investigated. The HPLC analytical method was successfully validated according to current guidelines. The final receiver fluid demonstrated sufficient solubility and stability, and the extraction method and fluid resulted in >95% recovery of flurbiprofen following exposure to human pharynx tissue. The lower limit of quantitation of flurbiprofen was 0.045 µg/mL in both the receiver and extraction fluids. There was no interference of the human pharynx tissue with the HPLC method. This investigation validated an analytical method for quantitating flurbiprofen, and determined a suitable receiver fluid and extraction method and fluid, which can be used to investigate the permeation and penetration of flurbiprofen through human pharynx tissue using the Franz diffusion cell method.

Use of in vitro performance models in the assessment of drug delivery across the human nail for nail disorders.

INTRODUCTION: Onychomycosis is the most prevalent nail condition, affecting between 5% and 20% of the population in western countries. Oral therapies are not the treatment of choice due to poor patient compliance, high relapse rates, severe side effects, and contraindication. However, the difficultly in curing the condition using topical delivery is partly due to both the nail structure presenting a complex barrier and the lack of understanding of how best to achieve delivery of drug to the nail bed. AREAS COVERED: Several novel in vitro models incorporating human nails discussed in this article have been developed in recent years that allow for the study of the mechanisms of ungual drug absorption and formulation efficacy to be assessed. EXPERT OPINION: The TurChub zone of inhibition model is a high-throughput performance screen for prototype formulations during development, while the robustness of the ChubTur nail permeation, TurSh nail penetration, and RoMar antifungal efficacy models ensure these can be validated for in vitro bioequivalence testing of generic products to reference listed drugs. With clinical trials being a costly and high-risk approach to generic approval, the described novel in vitro screening and performance testing techniques offer a de-risked and less-expensive route to market.