title: Permeation studies and histological examination of sheep nasal mucosa following administration of different nasal formulations with or without absorption enhancers.
abstract: This study was designed to investigate the possible histological effects of different intranasal (IN) formulations of indomethacin (IND) on nasal mucosa in sheep. For this purpose, oil-in-water (O/W) emulsion (E) and solution (S) formulations including 3 mg/mL of IND were prepared. Penetration enhancers such as polyvinylpyrolidone (PVP), citric acid (CA) and sodium taurocholate (NaT) were added to emulsion (1%) at the final step into the formulations. First, the effect of penetration enhancers on permeation of IND was evaluated by in vitro permeation studies in which sheep nasal mucosa was used. According to the permeation studies PVP showed the highest enhancing effect on the permeation rate of IND from sheep nasal mucosa. Furthermore, the IND permeation from E containing PVP (1.624 +/- 0.045 mg) was significantly higher than that obtained from E (0.234 +/- 0.012 mg) (p < 0.05). For the histological studies, white Karaman sheep of approximately 20 +/- 5 kg, aged 4 to 8 months were used. They were randomly divided into eight groups, each including three sheep. Five experimental groups received different formulations of IND emulsion without/ with penetration enhancers (E-PVP, E-CA, E-NaT, E) and IND solution (S), respectively. Parallel controls were composed of either untreated groups and were given blank emulsion or isotonic sodium chloride solution (0.31 mg/kg). 2 mL of each experimental formulation was applied to both nostrils of sheep, and 1/3 central and lower regions of the nose were dissected and prepared for light microscopy. Specimens stained with hematoxylin and eosin and Gomori's trichrome were examined by light microscopy. No signs of inflammation or erosion were noticed in the nasal mucosa of the control groups. Widened epithelial intercellular spaces were noticed in E-CA, E-NaT, and E-PVP groups as well with the E-PVP group showing the largest intraepithelial separations. E-CA and E-NaT groups showed significant decrease in the amount of goblet cells, while hypoplasia was considerably moderate in the E-PVP group. Finally, intranasal administration of IND emulsion with PVP may be considered as an alternative to intravenous and per oral administrations of IND to overcome their adverse effects.
authors.affiliation: Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ege, Izmir, Turkey. ercument.karasulu@ege.edu.tr
authors.forename: Ercüment
authors.initials: E
authors.lastname: Karasulu
authors.forename: Altug
authors.initials: A
authors.lastname: Yavasoğlu
authors.forename: Z
authors.initials: Z
authors.lastname: Evrensanal
authors.forename: Yigit
authors.initials: Y
authors.lastname: Uyanikgil
authors.forename: H Yesim
authors.initials: HY
authors.lastname: Karasulu
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019343:Citric Acid / Q000737:chemistry; D004655:Emulsions / Q000737:chemistry / Q000493:pharmacokinetics; D005079:Excipients / Q000737:chemistry*; D005110:Extracellular Space / Q000378:metabolism; D020397:Goblet Cells / Q000378:metabolism; D007213:Indomethacin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008853:Microscopy; D009297:Nasal Mucosa / Q000378:metabolism*; D009821:Oils / Q000737:chemistry; D010539:Permeability; D019999:Pharmaceutical Solutions; D011205:Povidone / Q000737:chemistry; D011897:Random Allocation; D012756:Sheep; D013656:Taurocholic Acid / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004655:Emulsions; D005079:Excipients; D009821:Oils; D019999:Pharmaceutical Solutions; D014867:Water; D019343:Citric Acid; D013656:Taurocholic Acid; D011205:Povidone; D007213:Indomethacin