engleski

Development of a biorelevant in vitro method for prediction of nanoemulsion stability in tears

Cationic nanoemulsions (NEs) are a new type of artificial tears and a technological platform for poorly soluble drugs that functionally mimic a healthy tear film (TF) [1]. However, their fate after application on the ocular surface is not fully understood and the mechanism of their interaction with the TF is only based on theory or in silico modeling [1, 2]. The aim of this research is getting a deeper insight into cationic NE interaction with the TF components. Chitosan- coated NE (CNE) was prepared using microfluidizer LM20 (Microfluidics, USA) under the pressure of 1000 bar and 5 cycles. CNE was composed of Miglyol 812 (2.5 %, w/w, Kemig, Croatia), ibuprofen (0.2 %, w/w, Hubei Biocause Pharmaceutical, China), lecithin S45 (0.05 %, w/w, Lipoid, Germany), LMW chitosan (0.05 %, w/w, Sigma-Aldrich, Germany), Kolliphor EL (0.25 %, w/w, BASF, Germany), glycerol (2.5 %, w/w, T.T.T., Croatia) and purified water (up to 100 %, w/w). Cationic NE commercially available as artificial tears in EU (caNE) was also used. Artificial tear solution composed of salts only (ATS) or salts and lipids (ATS + lipids) naturally present in the TF was prepared as previously described [3]. The NEs were mixed with ATS or ATS + lipids in 25:7 (V/V) ratio and incubated during 40 min at 34 °C and 50 rpm. Each minute 16 % (V/V) of the mixture was removed and replaced with fresh ATS or ATS + lipids, to simulate TF turnover in vivo [4]. At predetermined time points NE droplet size, PDI and zeta- potential were measured using Zetasizer Ultra (Malvern, UK). NEs were characterized using Zetasizer Ultra and the results are shown in Table 1. Both, CNE and caNE had similar droplet size and PDI and a positive zeta-potential. After mixing with ATS or ATS + lipids both NEs showed changes in their physico-chemical properties, as shown in Figure 1. The zeta-potential of CNE and caNE dropped significantly, which could be caused by high concentration of salts in both ATSes. While caNE did not show bigger changes in droplet size or PDI, CNE showed sudden increase in droplet size after 40 min of incubation and a gradual PDI increase in ATS + lipids. This could be caused by destabilization of the NE droplets due to zeta- potential decrease or merging with lipids present in the ATS. The results presented in this research are a first step toward development of a biopharmaceutical method for testing of NE stability on the eye surface. Further research using more complex ATS (including TF mucins and proteins) is necessary to upgrade the current method. References: 1. Daull, P. et al. Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease. J. Ocul. Pharmacol. Ther. 36, 355–365 (2020). 2. Gan, L. et al. Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. Drug Discov. Today 18, 290–297 (2013). 3. Lorentz, H. et al. Contact lens physical properties and lipid deposition in a novel characterized artificial tear solution. Mol. Vis. 17, 3392–3405 (2011). 4. Pepić, I., Lovrić, J., Cetina-Čižmek, B., Reichl, S. & Filipović-Grčić, J. Toward the practical implementation of eye-related bioavailability prediction models. Drug Discov. Today 19, 31–44 (2014).

artificial tear solution, nanoemulsion, tear film, droplet size

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