title: Formulation optimization of water-in-oil-water multiple emulsion for intestinal insulin delivery.
abstract: Formulation optimization of the water-in-oil-in-water multiple emulsion incorporating insulin was performed based on statistical methods such as the orthogonal experimental design and the response surface evaluation. As model formulations, 16 types of emulsions were prepared according to the orthogonal experimental design. To optimize the formulation, the influence of causal factors such as amounts of gelatin, insulin, oleic acid (OA) and the volume ratio of the outer aqueous phase to total and agitation time of the second emulsification process on individual characteristics of the emulsion, such as inner droplet size, viscosity, stability and pharmacological effect, was evaluated first. Based on the analysis of ANOVA, it was concluded that the droplet size of the emulsion was influenced by the volume ratio of the outer aqueous phase significantly. The viscosity of the emulsion was affected by these causal factors and their interactions; however, the most predominant contribution of all causal factors was the volume ratio of the outer aqueous phase. Similarly, one of the most important characteristics in the design of the formulation, stability, was affected by the causal factors. With regard to the hypoglycemic effect, the most influential factor was the content of OA in the emulsion. By means of a novel optimization technique involving a multivariate spline interpolation (MSI), formulation optimization was performed with respect to pharmacological effect and stability, and the optimum formulation with a desirable pharmacological effect and high stability was successfully estimated.
authors.affiliation: Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Onuki
authors.forename: Mariko
authors.initials: M
authors.lastname: Morishita
authors.forename: Kozo
authors.initials: K
authors.lastname: Takayama
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D007328:Insulin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D009821:Oils / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014867:Water / Q000008:administration & dosage* / Q000378:metabolism
chemical_list: D007328:Insulin; D009821:Oils; D014867:Water