Lipid emulsions as vehicles for enhanced nasal delivery of insulin

Abstract

The objective of this work is to explore lipid emulsion based formulations of insulin as an enhancer of nasal absorption. Insulin was incorporated into the aqueous phases of water-in-oil (w/o) and oil-in-water (o/w) emulsions. The formulations were perfused through the nasal cavity of rats in situ. Enhancement of insulin absorption was observed when insulin was incorporated into the continuous aqueous phase of an o/w emulsion. The presence of a small fraction of oil droplets along with insulin in the aqueous phase appeared to favor insulin absorption. When the oil phase constitutes the external phase, as in w/o emulsion, no insulin absorption was noted. Inhibition of insulin absorption might arise from a rate limiting barrier effect of the membrane completely covered by a stagnant oil layer. The in situ model was validated by in vivo experiments, which also revealed an increase in insulin absorption with o/w emulsions. However at lower insulin doses there was no statistically significant enhancing effect. In situ perfusion experiments across rat nasal pathway appear to be an appropriate model to study the enhancement effect of nasal formulations.

Introduction

Nasal administration may be a promising route for long term systemic delivery particularly when the drug is ineffective orally due to first-pass metabolism (Quraishi et al., 1997, Hussain, 1998). Small lipophilic molecules are generally well absorbed through the nasal mucosa. However the same is not true for high molecular weight hydrophilic peptides like insulin, which requires the use of absorption promoters. Many formulations incorporating amphiphilic molecules, i.e. bile salts (monomers or micelles) (Gordon et al., 1985, Shao and Mitra, 1992), fatty acids (Suzuki et al., 1998), bile salt/fatty acid mixed micelles (Tengamnuay and Mitra, 1990, Shao and Mitra, 1992), phospholipids (Drekker et al., 1992, Chandler et al., 1994), surfactants (Hirai et al., 1981a), cyclodextrins (Merkus et al., 1991, Shao et al., 1992), and water soluble polymers or microspheres (Pereswetoff-Morath, 1998) have been studied as enhancers of insulin absorption. The mechanisms of absorption enhancement may involve many factors, i.e. a local alteration in the membrane structure and modification of its permeability (Hirai et al., 1981b, Martin et al., 1995), bioadhesion to the mucosal surface and lowering of the mucociliary clearance (Martin et al., 1998), opening of cellular tight junctions (Pereswetoff-Morath, 1998), oligomer dissociation (Shao et al., 1993) and/or the reduction in the permeant metabolism (Sakar, 1992, Shao and Mitra, 1992).

Most of the work found in the literature concerning emulsions of insulin deals with oral delivery using w/o emulsions (Tenktrog and Muller, 1995), microemulsions (Constantidines et al., 1994) or multiple emulsions (Silva Cuhna et al., 1997, Suzuki et al., 1998) in which the polypeptide is entrapped in a water core primarily for protection against intestinal proteases. To the authors’ knowledge, emulsion systems have not been employed so far for nasal delivery purpose and in this article, nasal administration of insulin formulated in lipid emulsions is reported for the first time.

In situ rat nasal perfusion technique has been selected as an experimental model to study insulin absorption from lipid emulsion vehicles. This technique allows a continuous contact between the emulsion and the nasal epithelia through stirring and recirculation and generates reproducible results. Insulin, which has a very low water to oil partition coefficient (Banks et al., 1985), is solubilized in the aqueous phase of different types of emulsion. The peptide is either incorporated in the continuous phase of an oil-in-water (o/w) emulsion or entrapped in the aqueous core of a water-in-oil (w/o) emulsion. The in situ perfusion model has been validated by in vivo experiments, which also showed an increase in insulin absorption from o/w emulsion vehicle. Correlation between the emulsion physicochemical properties and nasal absorption of insulin has been attempted in order to achieve a better understanding of the enhancement mechanism.