Binary Polymeric Surfactant Mixtures for the Development of Novel Loteprednol Etabonate Nanomicellar Eyedrops

Abstract

The treatment of several ocular inflammatory conditions affecting different areas of the ocular globe involves the administration of topical ophthalmic formulations containing corticosteroids. This research was aimed at evaluating the solubilising efficacy of 5.0% w/w of different binary mixtures of commercial amphiphilic polymeric surfactants with the purpose of obtaining nanomicellar solutions containing a high amount of loteprednol etabonate (LE). The selected LE-TPGS/HS nanomicelles, containing 0.253 mg/mL of the drug, had a small size (=13.57 nm) and uniform distribution (Polydispersity Index = 0.271), appeared completely transparent and perfectly filterable through 0.2 μm membrane filter, and remained stable up to 30 days at 4 °C. The critical micellar concentration (CMC_TPGS/HS) was 0.0983 mM and the negative value of the interaction parameter between the polymeric-surfactant-building unit (β_TPGS/HS = -0.1322) confirmed the ability of the polymeric surfactants to interact, favouring the dissolution of LE into nanomicelles. The disappearance of the endothermic peak of LE in the DSC analysis confirmed the interactions of LE with the polymeric surfactants. LE-TPGS/HS produced in vitro LE which sustained diffusion for 44 h (more than 40% of encapsulated LE). Furthermore, the lack of a significant cytotoxic effect on a sensitive corneal epithelial cell line makes it a candidate for further biological studies.

Keywords: D-alpha-tocopheryl polyethylene glycol 1000 succinate; Kolliphor® HS-15; TPGS; critical micellar concentration; loteprednol etabonate; mixed nanomicelles; ocular drug delivery.

Figure 1

Solubility of LE in presence of 5.0% w/w of different polymeric surfactants (Isodel^® Vitamin E TPGS 1000 (TPGS), Kolliphor^® HS-15 (HS), Soluplus^® (SolP) and Kolliphor^®-EL (EL)) (mean ± SD, n = 3).

Figure 2

Amount of LE solubilised (LE-In) in PBS in presence of different concentrations of the 1:1 ratio of TPGS/HS of the binary mixture (mean ± SD, n = 3).

Figure 3

DSC thermograms of TPGS (red line) and HS (black line) surfactant polymers, LE pure drug (blue line), TPGS/HS-F mixed freeze-dried nanomicelles (brown line) and LE-TPGS-F drug-encapsulated freeze-dried nanomicelles (green line).

Figure 4

In vitro drug release profiles of LE-TPGS/HS and commercial-suspension Lotemax^TM eye drop (mean ± SD, n = 3).

Figure 5

Cytotoxicity of RCE of LE-TPGS/HS and commercial-suspension Lotemax™ eye drop (mean ± SD, n = 3).