The use of simple dynamic mucosal models and confocal microscopy for the evaluation of lyophilised nasal formulations.

A range of methods is reported in the literature for assessing hydration and adhesion parameters in the performance of nasal bioadhesive formulations; however, these tests do not always represent the dynamic conditions in the nasal cavity. Lyophilised formulations intended for nasal administration were evaluated using in-vitro tests designed in an attempt to mimic relevant processes in the nasal cavity, and intended to discriminate between different formulations. Initial investigative studies using scanning electron microscopy revealed that the lyophilisate had a highly porous internal structure, expected to provide an ideal porous pathway for re-hydration. Vapour sorption analysis demonstrated substantial weight gain of the lyophilisates on exposure to 95% relative humidity, ranging from 38% to 66%. Agar was used as a synthetic mucosal model designed to provide a standardised quantity of water available for rehydration of the formulations in in-vitro tests. A dynamic adhesion test and a texture analyser sliding test were designed to quantify different aspects of the spreading and adhesion of the hydrating formulations on the synthetic mucosal surface. Examination of the lyophilised formulations using confocal microscopy allowed visualisation and quantification of the initial rate of water ingress into the lyophilisates, which was found to consist of an initial rapid phase, followed by a slower steady-state phase. The results demonstrated that the use of a combination of methods representing the dynamic conditions of the nasal cavity is advisable in order to evaluate a formulation fully and to avoid misleading conclusions.

In vivo evaluation of nicotine lyophilised nasal insert in sheep.

The nasal route offers an attractive means of delivering a drug directly to the systemic circulation and avoiding hepatic first-pass metabolism, although rapid mucociliary clearance can be detrimental to nasal absorption. The in vitro and in vivo characteristics of a nasal insert formulation prepared by lyophilisation of a viscous HPMC gel solution designed to overcome this problem were studied. In vitro release of nicotine from the lyophilised insert was compared with powder and spray formulations. Stability and characterisation studies were carried out using dynamic vapour sorption, scanning electron microscopy and HPLC analysis. Nicotine formulations were administered to eight wether sheep in a randomised four-way cross-over study, and plasma nicotine assessed comparing the nasal insert formulation with conventional nasal powder, nasal spray and IV doses. In vitro release studies demonstrated prolonged nicotine release from the nasal insert formulation compared to a powder and liquid. In vivo plasma profiles appeared to show prolonged plasma nicotine levels compared to the conventional formulations, although T(max), C(max) and AUC parameters for the insert were not significantly different due to high variability in the pharmacokinetic data. In conclusion, the nasal insert displayed a promising prolonged plasma profile, which must be investigated further to provide statistical significance to prove the effect.