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This work aimed to deepen the lately acquired knowledge about parenteral nanoemulsions as carriers for brain delivery of risperidone, a poorly water-soluble antipsychotic drug, through establishing the prospective relationship between their physicochemical, pharmacokinetic, biodistribution, and behavioral performances. For this purpose, two optimized risperidone-loaded nanoemulsions, stabilized by lecithin or lecithin/polysorbate 80 mixture, and costabilized by sodium oleate, were produced by high-pressure homogenization. The characterization revealed the favorable droplet size, narrow size distribution, high surface charge, with proven stability to autoclaving and long-term stability for at least one year at 25 +/- 2 degrees C. Pharmacokinetic and tissue distribution results demonstrated improved plasma, liver, and brain pharmacokinetic parameters, resulting in 1.2-1.5-fold increased relative bioavailability, 1.1-1.8-fold decreased liver distribution, and about 1.3-fold improved brain uptake of risperidone active moiety following intraperitoneal administration of nanoemulsions relative to solution in rats. In behavioral study, investigated nanoemulsions showed pronounced reduction in basal and, more pertinently, amphetamine-induced locomotor activity in rats, with an early onset of antipsychotic action, and this effect lasted at least 90 min after drug injection. Together, these findings corroborate the applicability of parenteral nanoemulsions as carriers for enhanced brain delivery of risperidone, further suggesting their promise in acute psychosis treatment or other emergency situations.

This study focuses on the properties of topical vehicles based on alkylpolyglucoside natural surfactant-mixed emulsifier, cetearyl glucoside and cetearyl alcohol, in order to propose their use as “ready to use” pharmaceutical bases for a number of model drugs. We were interested to investigate how the alternative use of three lipophilic excipients (Ph. Eur. 6.0), differing in their polarity indexes (medium chain triglycerides (MG), decyl oleate (DO), and isopropyl myristate (IPM), respectively), affects the colloidal structure of the alkylpolyglucoside-based vehicles and in vitro permeation profiles of two model drugs: diclofenac sodium (DC) and caffeine (CF), both sparingly soluble in water. Finally, we aimed to evaluate the safety profile of such vehicles in vitro (acute skin irritation test using a cytotoxicity assay), comparing it with in vivo data obtained by the methods of skin bioengineering. The results have shown that the emulsion vehicles consisted of a complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type. Varying of lipophilic excipient influenced noteworthy variations in the colloidal structure demonstrated as different rheological profiles accompanied to the certain degree by different water distribution modes, but notably provoked by drug nature (an amphiphilic electrolyte drug vs. nonelectrolyte). In vitro permeation data obtained using ASC membranes in an infinite dose-type of experiment stressed the importance of the vehicle/solute interactions in case of small variation in formulation composition, asserting the drug properties in the first hours of permeation and rheological profile of the vehicles in the later phase of experiment as decisive factors. In vitro skin irritation test demonstrated a mild nature of the emulsifying wax and the absence of negative effects of used oil phases on cell viability in formulation concentrations correspondent to the therapeutic need. This result alongside with data obtained from in vivo study, could additionally promote investigated topical vehicles as prospective “ready to use” pharmaceutical bases.

To elaborate the decisive role of surfactants in promotion of aceclofenac' skin absorption, potentially avoiding irritation, we developed non-ionic microemulsions varying natural or synthetic surfactants: sucrose esters (laurate or myristate) vs. polysorbate 80. A comprehensive physicochemical characterization indicated no significant influence of the solubilized nonsteroidal anti-inflammatory drug on the bicontinuous structure of blank formulations. To evaluate skin tolerability of isopropyl alcohol, a sucrose ester-based microemulsion containing transcutol P as a cosurfactant was also developed. The measured skin parameters strongly depended on the (co)surfactant type, showing higher compatibility of the microemulsions containing sucrose ester and isopropyl alcohol. In vitro release results, in vivo tape stripping and pharmacokinetics in rats confirmed superiority of the sucrose ester-over polysorbate-based microemulsions (total amounts of aceclofenac penetrated 60.81 +/- 5.97 and 60.86 +/- 3.67 vs. 27.00 +/- 5.09 mu g/cm(2), and its maximum plasma concentrations 275.57 +/- 109.49 and 281.31 +/- 76.76 vs. 150.23 +/- 69.74 ng/ml for sucrose laurate- and myristate- vs. polysorbate 80-based microemulsions, respectively). Hence, sugar-based excipients increased delivery of aceclofenac through stratum corneum by increasing its fluidity, showing overall more satisfying safety profiles. In conclusion, sucrose ester-based microemulsions proved to be promising carriers for dermal/transdermal aceclofenac delivery. This is peer-reviewed version of the artcle: M.N. Todosijević, M.M. Savić, B.B. Batinić, B.D. Marković, M. Gašperlin, D. V Ranđelović, M.Ž. Lukić, S.D. Savić, Biocompatible microemulsions of a model NSAID for skin delivery: A decisive role of surfactants in skin penetration/irritation profiles and pharmacokinetic performance, Int. J. Pharm. 496 (2015) 931–941. [https://doi.org/10.1016/j.ijpharm.2015.10.048] Published version: [http://cer.ihtm.bg.ac.rs/handle/123456789/1805]

An emerging class of natural surfactants, named alkylpolyglucosides, which can form both, the thermotropic and the lyotropic liquid crystalline phases, were focused. The aim of the study was to integrate some physicochemical properties (characterised through the polarization and transmission electron microscopy, wide-angle X-ray diffraction, thermal analysis and rheology) of the three formulations based on cetearyl glucoside and cetearyl alcohol, with the in vitro (the artificial skin constructs) and in vivo bioavailability of hydrocortisone (HC), in comparison with a standard pharmacopoeial vehicle. The parameters measured in vivo were erythema index (an instrumental human skin blanching assay), transepidermal water loss (TEWL) and stratum corneum hydration. A complex colloidal structure of lamellar liquid crystalline and lamellar gel crystalline type was deduced for sugar surfactant-based vehicles. In dependence on surfactant/water/oil ratio, several thermodynamically variable fractions of water were predicted. Rheological profile of the vehicle appeared to influence the in vitro profile of permeation. A surplus of total amount of drug permeated in vitro from the alkylpolyglucoside-based vehicles coincided with the more pronounced increase of TEWL and less marked blanching action of HC from the selected alkylpolyglucoside-based vehicle tested in vivo, related to the pharmacopoeial one. These findings imply an enhanced delivery of HC from this vehicle and its putative penetration enhancing effect, probably dependent on specific distribution of the vehicle's inherent water.