title: Nasal administration of liquid crystal precursor mucoadhesive vehicle as an alternative antiretroviral therapy.
abstract: The purpose of this study was to develop a mucoadhesive stimuli-sensitive drug delivery system for nasal administration of zidovudine (AZT). The system was prepared by formulating a low viscosity precursor of a liquid crystal phase, taking advantage of its lyotropic phase behavior. Flow rheology measurements showed that the formulation composed of PPG-5-CETETH-20, oleic acid and water (55, 30, 15% w/w), denominated P, has Newtonian flow behavior. Polarized light microscopy (PLM) revealed that formulation P is isotropic, whereas its 1:1 (w/w) dilution with artificial nasal mucus (ANM) changed the system to an anisotropic lamellar phase (PD). Oscillatory frequency sweep analysis showed that PD has a high storage modulus (G') at nasal temperatures. Measurement of the mucoadhesive force against excised porcine nasal mucosa or a mucin disk proved that the transition to the lamellar phase tripled the work of mucoadhesion. Ex vivo permeation studies across porcine nasal mucosa exhibited an 18-fold rise in the permeability of AZT from the formulation. The Weibull mathematical model suggested that the AZT is released by Fickian diffusion mechanisms. Hence, the physicochemical characterization, combined with ex vivo studies, revealed that the PPG-5-CETETH-20, oleic acid, and water formulation could form a mucoadhesive matrix in contact with nasal mucus that promoted nasal absorption of the AZT. For an in vivo assessment, the plasma concentrations of AZT in rats were determined by HPLC method following intravenous and intranasal administration of AZT-loaded P formulation (PA) and AZT solution, respectively, at a dose of 8mg/kg. The intranasal administration of PA resulted in a fast absorption process (Tmax=6.7min). Therefore, a liquid crystal precursor formulation administered by the nasal route might represent a promising novel tool for the systemic delivery of AZT and other antiretroviral drugs. In the present study, the uptake of AZT absorption in the nasal mucosa was demonstrated, providing new foundations for clinical trials in patients with AIDS.
authors.affiliation: School of Pharmaceutical Sciences, Universidade Estadual Paulista UNESP, Araraquara, Brazil. flavia_chiva@yahoo.com.br
authors.forename: Flávia Chiva
authors.initials: FC
authors.lastname: Carvalho
authors.forename: Michel Leandro
authors.initials: ML
authors.lastname: Campos
authors.forename: Rosângela Gonçalves
authors.initials: RG
authors.lastname: Peccinini
authors.forename: Maria Palmira Daflon
authors.initials: MP
authors.lastname: Gremião
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D044966:Anti-Retroviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems / Q000379:methods*; D050866:Liquid Crystals; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013552:Swine
chemical_list: D044966:Anti-Retroviral Agents