title: Rational Design and Characterization of a Nanosuspension for Intraoral Administration Considering Physiological Conditions.
abstract: The oral cavity displays an attractive route in drug administration that is not associated with gastric transit and hepatic first-pass metabolism. However, limiting factors for an efficient transit of drugs through the oral mucosa are poor water solubility and permeability. Hence, various strategies exist to enhance solubility. Specifically, nanotechnology has attracted much research interest in the past decade. This study aimed at developing a stable nanosuspension of the model compound phenytoin via wet media milling. The nanosuspensions were carefully characterized regarding hydrodynamic particle sizes, crystallinity, and dissolution characteristics under nonphysiological or physiological (salivary) conditions. The permeability of bulk phenytoin and nanophenytoin through a buccal in vitro and ex vivo model was investigated, and the apparent permeability coefficients were determined. Moreover, cytotoxicity studies were conducted. The addition of Tween 80 as stabilizer resulted in a stable crystalline nanosuspension (330 nm). The solubility characteristics significantly increased under salivary conditions, which further impacted the permeability, as the steady state appearance rate of nanosized phenytoin was 1.4-fold higher. Cytotoxicity studies demonstrated that bulk-/nano-phenytoin exhibited no harmful effects. It can be concluded that the salivary environment (i.e., ionic strength, pH) strongly impacts the solubility and consequently the permeability of crystalline nanosuspensions across the buccal mucosa.
authors: Research Center Pharmaceutical Engineering GmbH, 8010 Graz, Austria.
authors: Ramona
authors: R
authors: Baumgartner
authors: Department of Pharmaceutical Technology, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
authors: Birgit J
authors: BJ
authors: Teubl
authors: Department of Pharmaceutical Technology, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria.
authors: Carolin
authors: C
authors: Tetyczka
authors: Research Center Pharmaceutical Engineering GmbH, 8010 Graz, Austria; Department of Pharmaceutical Technology, Institute of Pharmaceutical Sciences, University of Graz, 8010 Graz, Austria. Electronic address: eva.roblegg@uni-graz.at.
authors: Eva
authors: E
authors: Roblegg
mesh_terms: D058956:Administration, Mucosal; D000284:Administration, Oral; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics; D002460:Cell Line; D002470:Cell Survival; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding; D015195:Drug Design; D005079:Excipients; D006801:Humans; D049329:Nanostructures; D010316:Particle Size; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics; D011136:Polysorbates; D012463:Saliva / Q000378:metabolism; D012995:Solubility; D013535:Suspensions; D013552:Swine
chemical_list: D000927:Anticonvulsants; D005079:Excipients; D011136:Polysorbates; D013535:Suspensions; D010672:Phenytoin
keywords: dissolution rate; in vitro models; milling; nanoparticles; permeability; physicochemical properties; solubility; stability; toxicology; transmucosal drug delivery