As discussed by Rabinovich-Guilatt et al. [21], there are several mechanisms of absorption of nanoparticles in the cornea. In the case of cationic nanoemulsions, positively charged nanodroplets of oil are not likely to penetrate the cornea as the drops are bound to the negatively charged mucus. Therefore, the PF-06463922 price delivery of the active

ingredient is probably related to a passive diffusion linked to the enhanced retention time. An additional factor favoring drug absorption is linked to the small size of the nanodroplets, that is, the interfacial area available for drug exchange. If the mean diameter of an oil droplet is 150nm, and the volume Inhibitors,research,lifescience,medical of emulsion administered on the ocular surface is about 30μL, the number of oil nanodroplets administered is close to 1010. Consequently, with such an extraordinarily elevated specific surface Inhibitors,research,lifescience,medical of exchange (almost 1,000mm2) the diffusion of the active ingredients to the targeted tissues is greatly improved. Thus, a small droplet size of the nanoemulsion should consequently be associated with an improved clinical efficacy of the drug. The manufacturing process is a three-step process as described in Figure 2. The first step is a phase mixing under magnetic stirring at 100rpm for a few minutes followed by a high shear mixing at 16,000rpm

during 10min at that stage the oil droplets Inhibitors,research,lifescience,medical of the emulsion have a size of approximately 1μm. To reach a submicronic size (150–200nm) the emulsion is submitted to a high pressure homogenization at 1,000 bars under cooling. Figure 2 Three manufacturing steps of the process necessary to

decrease the oil droplet size of the emulsion. Inhibitors,research,lifescience,medical Optical microscopy pictures of the emulsions are presented. Stable cationic nanoemulsions Inhibitors,research,lifescience,medical were selected over hundreds of prototypes after being submitted to screening stress tests (freeze/thaw cycles, centrifugation, and heat test at 80°C). In addition, a deep physicochemical characterization including measurement of pH, osmolality, zeta potential, droplets size, interfacial and surface tension, aspect, and viscosity was systemically performed on prototypes. All these tests are able to discriminate a potential destabilization of the emulsions like creaming, coalescence Ostwald ripening, and phase separation and to set final specifications of the drug product as described in Table 4. Finally, the product should be sterile. Since the sterilization process can have a major impact on the physical medroxyprogesterone integrity of the emulsion, it should be taken into account at an early stage during the development of the formulation. A sterilizing filtration is not possible for emulsions as it uses a filter with 0.22μm size pores that can clog during filtration. Aseptic processes are too expensive. The remaining option was heat sterilization; however, this can be performed only on very stable emulsions, and hence the need of a careful choice of the above-mentioned excipients. 3.3.