title: Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies.
abstract: 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/gelof 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±7.79mNmm to 272.3±6.11mNmm. 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 12h. 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.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minya, Egypt; School of Pharmacy and Chemistry, Faculty of Science, Engineering & Computing, Kingston University, London, UK.
authors.forename: Zeinab
authors.initials: Z
authors.lastname: M A Fathalla
authors.affiliation: School of Pharmacy and Chemistry, Faculty of Science, Engineering & Computing, Kingston University, London, UK. Electronic address: A.Vangala@kingston.ac.uk.
authors.forename: Anil
authors.initials: A
authors.lastname: Vangala
authors.affiliation: School of Pharmacy and Chemistry, Faculty of Science, Engineering & Computing, Kingston University, London, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Longman
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minya, Egypt.
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Khaled
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minya, Egypt.
authors.forename: Amal K
authors.initials: AK
authors.lastname: Hussein
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minya, Egypt.
authors.forename: Omar H
authors.initials: OH
authors.lastname: El-Garhy
authors.affiliation: School of Pharmacy and Chemistry, Faculty of Science, Engineering & Computing, Kingston University, London, UK; School of Pharmacy, The University of Auckland, Auckland, New Zealand.
authors.forename: Raid G
authors.initials: RG
authors.lastname: Alany
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D002417:Cattle; D003315:Cornea / Q000187:drug effects; D004339:Drug Compounding; D005079:Excipients; D005782:Gels; D020911:Ketorolac Tromethamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D020442:Poloxamer / Q000737:chemistry*; D012869:Skin Absorption; D013696:Temperature; D014014:Tissue Adhesives
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D005079:Excipients; D005782:Gels; D014014:Tissue Adhesives; D020442:Poloxamer; D020911:Ketorolac Tromethamine
keywords: BCOP test; Ex vivo permeation; HET-CAM test; In situ gel; In vitro release; Ketorolac; Mucoadhesion; Ocular delivery; Physico-chemical characterisation; Poloxamer; Toxicity studies