Ex vivo evaluation of bioadhesive films for buccal delivery of fentanyl.

The goals of this work were (i) to develop bioadhesive films for the buccal delivery of fentanyl, and (ii) to evaluate their performance in vitro using the pig esophageal model. Films were made with polyvinylpyrrolidone (PVP) of two different molecular weights: PVP K30 and PVP K90. Delivery of fentanyl was determined across full-thickness mucosa and across heat-separated epithelium (where the permeability barrier was shown to be located). The influence of film pH was investigated, and it was found that fentanyl permeation increased with increasing pH (i.e., when a higher percentage of the unionized fraction of drug was present). However, at the pH values studied, fentanyl was predominantly ionized suggesting that transport pathways offering a hydrophilic, or polar, environment across the mucosa were available. The transport rates achieved from the PVP films providing the highest delivery suggest that a buccal system of only 1-2 cm(2) in surface area could achieve a therapeutic effect equivalent to a 10 cm(2) transdermal patch, with a much shorter lag-time.

Evaluation of pig esophageal mucosa as a permeability barrier model for buccal tissue.

Porcine buccal mucosa is frequently used for in vitro drug absorption studies as its structure and permeability characteristics are close to those of human tissue. However, this tissue model suffers from practical disadvantages, including a limited surface area, damage caused by mastication, and a fastidious and time-consuming excision procedure. It has been hypothesized that such limitations may be overcome by replacing the buccal tissue with the pig esophageal mucosa. The latter has a very similar structure and is easier to separate from the underlying tissue; furthermore, its surface area is greater and is generally intact. The aims of this work, therefore, were (i) to perform histological studies on the two membranes; (ii) to compare the transport of fentanyl citrate across buccal and esophageal mucosae; and (iii) to evaluate the effects of freezing on the tissue permeability. The results show that their histology is comparable, that the permeability of fentanyl citrate across the two epithelial barriers is similar, and that freezing the tissues did not alter their permeability.

Transport of fentanyl through pig buccal and esophageal epithelia in vitro: influence of concentration and vehicle pH.

PURPOSE: To validate pig esophageal epithelium as a model for the permeability barrier of the buccal mucosa, the transport of fentanyl across the two tissues was compared in vivo. METHODS: The epithelia were separated by immersing the excised mucosae into an isotonic saline solution at 60--65 degrees C. Fentanyl was delivered as the citrate salt at a concentration of 1 or 2 mg/mL buffered at one of four pH values (between 6.0 and 7.4). RESULTS: Across both barriers, drug transport increased proportionally with concentration as expected. However, drug flux was not linearly related to the unionized fraction of the drug; indeed, fentanyl delivery was significant even when 98.5% of the drug was in the ionized form. CONCLUSIONS: Buccal and esophageal fluxes were very similar under all conditions suggesting that the esophageal epithelium is a representative tool for buccal transport studies in vitro.

Comparison of the lipid composition of porcine buccal and esophageal permeability barriers.

Pig esophageal mucosa has been shown to be a useful and practical substitute for buccal mucosa in in vitro permeability studies in that it offers a larger surface area and it is much easier to prepare. Further, the tissues demonstrate similar histological characteristics. The objectives of this work were to characterize the lipid composition of the esophageal mucosa, to compare it to that of the buccal tissue, and to correlate lipid composition with the membranes' permeability to fentanyl. The major lipid classes of buccal and esophageal epithelia were separated and analysed by automated multiple development high-performance thin-layer chromatography (AMD-HPTLC). The two epithelia presented a very similar lipid pattern. In general, there were more polar lipids than non-polar; glycosylceramides were relatively abundant whereas the amount of ceramides present was very small. The flux of fentanyl applied as the citrate in aqueous solution was comparable across the buccal and esophageal barriers. Lipid extraction provoked a significant increase in permeability. In conclusion, this research confirms the suitability of the esophageal mucosa as a model for buccal permeability studies.