Design of Experiments-Assisted Development of Clotrimazole-Loaded Ionic Polymeric Micelles Based on Hyaluronic Acid.

Laura Catenacci,Maria Cristina Bonferoni,Silvia Rossi,Valentina Fagnani,Caterina Valentino,Franca Ferrari,Milena Sorrenti,Giorgio Marrubini,Giuseppina Sandri

doi:10.3390/nano10040635

Abstract

Polymeric micelles based on amphiphilic polysaccharides have some advantages as a carrier of poorly soluble lipophilic drugs thanks to their characteristic "core–shell" structure. Previously, ionic polymeric micelles based on chitosan and fatty acids have been developed. The aim of the present study was the preparation and characterization of hyaluronic acid (HA) derivatives by direct ionic interaction between the HA carboxylic groups and the amine groups of dodecyl amine (DDA) and hexadecyl amine (HDA). The HA–HDA polymeric micelles were loaded with a poorly soluble hydrophobic antifungal drug, clotrimazole (CLO). A 23 full factorial experimental design was used to evaluate the effect of the following factors: HA/HDA ratio from 1:0.25 to 1:0.75, cholesterol (CHOL%) as percentage of HA from 10% to 30%, and preparation temperature from 20 to 40 °C. As dependent variables (responses), nanoparticle dimensions and clotrimazole concentration in the final colloidal dispersion were considered. To optimize the drug final concentration, the design was therefore expanded into a rotatable central composite design (CCD). The effects of the formulation variables and the composition of the optimized formulation were confirmed by a mixture design. Physicochemical characterization of the optimized formulation was performed, confirming the ionic interaction between the polysaccharide and the HDA.

Highlights

IntroductionThe use of amphiphilic derivatives of bioactive polymers in the preparation of polymeric micelles presents peculiar advantages for the delivery of poorly soluble lipophilic active principles, such as those belonging to class II and IV of the Biopharmaceutical Classification System whose bioavailability is impaired by low solubility [1]
Polymeric micelles based on amphiphilic polysaccharides have some advantages as a carrier of poorly soluble lipophilic drugs thanks to their characteristic "core–shell" structure
The use of amphiphilic derivatives of bioactive polymers in the preparation of polymeric micelles presents peculiar advantages for the delivery of poorly soluble lipophilic active principles, such as those belonging to class II and IV of the Biopharmaceutical Classification System whose bioavailability is impaired by low solubility [1]

Summary

Introduction

The use of amphiphilic derivatives of bioactive polymers in the preparation of polymeric micelles presents peculiar advantages for the delivery of poorly soluble lipophilic active principles, such as those belonging to class II and IV of the Biopharmaceutical Classification System whose bioavailability is impaired by low solubility [1]. The literature largely described the polymer ability to interact with the cluster of differentiation protein CD44, which is a receptor that is physiologically involved in regulating cell adhesion and migration and is overexpressed in different kind of tumors. This behavior suggested the use of HA nanocarriers for tumor targeting [4,5]. Low molecular weight HA (5 kDa) was able to improve penetration in intact skin even of a macromolecule such as bovine serum albumin, thanks to stratum corneum hydration, interaction with keratin, and cotransport of the protein together with HA. In the case of tape-stripped skin, higher molecular weight HA (100 kDa) showed interaction with stratum corneum lipids and the highest improvement in HA penetration [7]

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Results