Préparations de docosanol nanoformulées pour usage topique

Reducing the particle size to nanocrystals is one of the approaches used to improve the percutaneous penetration of topical dosage form. We propose that the preparation of a semi solid formulation of docosanol, can lead to higher diffusion of docosanol than in commercial product Abreva® through polycarbonate membranes. Wet ball milling is the proposed technique for docosanol nanoparticles preparation. We propose also the preparation of topical semi-solid formulation from docosanol nanosuspension. Docosanol nanosuspension is obtained from docosanol dispersion in aqueous solution in presence of the stabilizer polymer hydroxypropylcellulose (HPC) and the surfactant sodium laurylsulfate (SDS) followed by wet ball milling at low or high energy. Nanoformulated hydrogel of docosanol is prepared from docosanol nanosuspension which is gellified by carbopol Ultrez 21 under vigorous stirring followed by neutralization with triethanolamine TEA.  Nanosuspension and hydrogel particle size was characterized by dynamic light scattering. An analytical method of high performance liquid chromatography (HPLC) with an evaporative detector (ELSD) has been developed and validated for docosanol content quantification in liquid preparation, in different nanosuspensions and in docosanol hydrogels. The crystalline state of nanosuspension and hydrogel nanocrystals was studied by scanning differential calorimetry (DSC). The morphology of nanosuspension and hydrogel was evaluated by Scanning electronic microscopy SEM. Rheological properties and physical stability at different temperatures were studied for semi-solid formulation. In vitro docosanol release from hydrogel and from the commercial product Abreva® was studied through two polycarbonate membranes of pore size 400 and 800 nm.  In nanosuspensions, nanosized crystals of docosanol have been successfully produced by wet ball milling. Nanoparticles of size ranged from 197 nm to 312 nm could be obtained by percentage variation of docosanol, of polymer HPC and surfactant SDS. After freeze drying, an increase in size relative to formulation composition was observed but the size particle is in nanometric range for almost all studied formulations. In case of prepared hydrogels, mean particle size of docosanol is maintained in nanometric range before and after freeze drying. Thermal analysis of physical mixtures, docosanol nanosuspensions and hydrogels showed that crystalline structure of docosanol nanocrystals was conserved after milling and after hydrogel preparation. The SEM exam showed that the nanosuspension and hydrogel has similar regular crystal morphology and nanoparticles shape is spherical. Nanosuspension particles have almost the same particle size, less than 300 nm in agreement with DLS result. Hydrogel size particle showed a slight increase comparing to nanosuspension’s one which is in agreement with DLS result. Up to rheological measurement, docosanol hydrogel has a pseudoplastic behavior and small thixotropic degree. Physical stability study showed that the hydrogel is stable at 5 °C and 21°C during 13 weeks and instable above 30°C after two weeks. HPLC-ELSD determined that docosanol content is in the acceptance limit range [90% to 110%] for docosanol nanosuspension and close to 100% in docosanol hydrogel. In vitro diffusion test revealed that docosanol nanoparticles were diffused from hydrogel through polycarbonates membranes that was greater for the 800 nm pore membrane, while the commercial product Abreva® does not diffuse through any of the membranes (400 nm and 800 nm).  Wet ball milling is a great technique for docosanol nanosuspension preparation. Nanosuspensions can be used as base for the preparation of semi-solid nanoformulation of docosanol.   

Keyphrases: HPLC-ELSD, Wet ball milling, Docosanol nanosuspension, Hydrogel of docosanol, HPLC-ELSD