Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies
This study was aimed at preparing, characterising and evaluating in situ gel formulations based on a blend of two hydrophilic polymers i.e. poloxamer 407 (P407) and poloxamer 188 (P188) for a sustained ocular delivery of ketorolac tromethamine (KT). Drug-polymer interaction studies were performed using DSC and FT-IR. The gelation temperature (Tsol-gel), gelation time, rheological behaviour, mucoadhesive characteristics of these gels, transcorneal permeation and ocular irritation as well as toxicity was investigated. DSC and FT-IR studies revealed that there may be electrostatic interactions between the drug and the polymers used. P188 modified the Tsol/gel of P407 bringing it close to eye temperature (35 °C) compared with the formulation containing P407 alone. Moreover, gels that comprised P407 and P188 exhibited a pseudoplastic behaviour at different concentrations. Furthermore, mucoadhesion study using mucin discs showed that in situ gel formulations have good mucoadhesive characteristics upon increasing the concentration of P407. When comparing formulations PP11 and PP12, the work of adhesion decreased significantly (P < 0.001) from 377.9 ± 7.79 mN mm to 272.3 ± 6.11 mN mm. In vitro release and ex vivo permeation experiments indicated that the in situ gels were able to prolong and control KT release as only 48% of the KT released within 12 h. In addition, the HET-CAM and BCOP tests confirmed the non-irritancy of KT loaded in situ gels, and HET-CAM test demonstrated the ability of ocular protection against strongly irritant substances. MTT assay on primary corneal epithelial cells revealed that in situ gel formulations loaded with KT showed reasonable and acceptable percent cell viability compared with control samples.Graphical abstract
In this study, the thermoresponsive behaviour of poloxamers was employed as a trigger for the formation of in situ gel systems incorporating ketorolac tromethamine (KT) (A). The protective effect of KT loaded in situ gel preparation on 10 day old chorioallantoic membrane (CAM) has been investigated after treating the CAM with a strong irritant, NaOH (B). The BCOP test revealed the corneal opacity and permeability of the prepared in situ gel system (C). The MTT cytotoxicity assay demonstrated that the cell viability when treated with the selected in situ gel preparations was at an acceptable level compared to the control samples (D).