, Poloxamer-based thermoresponsive ketorolac tromethamine in situ gel preparations: Design, characterisation, toxicity and transcorneal permeation studies, European Journal of Pharmaceutics and Biopharmaceutics (2017), doi: http://dx.doi.org/10. 1016/j.ejpb.2017.01.008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThis 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 (T sol-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 T sol/gel of P407 bringing it close to eye temperature (35 o 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 nonirritancy 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.

The pharmacokinetic and mean time tissue distribution parameters, after a single 50-mg/kg dose of quercetin administered as intravenous bolus, oral solution, and oral suspension, were determined using rat as an animal model. Following intravenous administration, the elimination rate constant and the elimination half-life were found to be 0.0062 min(-1) and 111 min, respectively. Examining the mean time tissue distribution parameters reflected a strong binding affinity of the drug molecules to both plasma and tissue proteins. In addition, the low permeability rate of drug molecules in the peripheral system was demonstrated. Following the oral administration of the drug, the extent of absorption was greater from solution than from suspension. Moreover, the solution showed a shorter Tmax and a higher Cmax than suspension. The absolute bioavailability for the solution was 0.275 and that for suspension was 0.162. The mean residence time (MRT) and the mean absorption time (MAT) were higher for suspension, reflecting the need for dissolving the drug in order to be absorbed. The mean (in-vivo) dissolution time (MDT(in-vivo)) was 34.5 min. Thus, an oral quercetin formulation that can readily form a drug solution in the gastrointestinal tract may enhance the absorption of the drug.

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The aim of this work was to formulate chitosan (CS) based nanoparticles (NPs) loaded with ketorolac tromethamine (KT) intended for topical ocular delivery. NPs were prepared using ionic gelation method incorporating tri-polyphosphate (TPP) as cross-linker. Following the preparation, the composition of the system was optimised in terms of their particle size, zeta potential, entrapment efficiency (EE) and morphology, as well as performing structural characterisation studies using FT-IR and DSC. The data suggested that the size of the NPs was affected by CS/TPP ratio where the diameter of the NPs ranged from 108.0 ± 2.4 nm to 257.2 ± 18.6 nm. A correlation between drug EE and the corresponding drug concentration added to the formulation was observed, where the EE of the NPs increased with increasing drug concentration, for up to 10 mg/mL. FT-IR and DSC revealed that KT was dispersed within the NPs where the phosphate groups of TPP were associated with the ammonium groups of CS. The in vitro release profile of KT from CS NPs showed significant differences (P<0.05) compared to KT solution. Furthermore, mucoadhesion studies revealed adhesive properties of the formulated NPs. The KT loaded NPs were found to be stable when stored at different storage conditions for a period of 3 months. The ex vivo corneal permeation studies performed on excised porcine eye balls confirmed the ability of NPs in retaining the drug on the eye surface for a relatively longer time. These results demonstrate the potential of CS based NPs for the ocular delivery of KT.

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Abstract. This study aimed at preparation of a sustained-release steroidal treatment for chronic inflammatory conditions, such as rheumatoid arthritis. To achieve such a goal, biodegradable polylactide-co-glycolide prednisolone-loaded microspheres were prepared using o/w emulsion solvent evaporation method. Formulation parameters were adjusted so as to optimize the microsphere characteristics. The prepared microspheres exhibited smooth and intact surfaces, with average size range not exceeding 65 µm. The encapsulation efficiency percent of most microsphere formulations fell within the range of 25-68%. Drug release from these microspheres took place over 4 weeks, with nearto-zero-order patterns. Two successful formulations were chosen for the treatment of unilateral arthritis, induced in mice using Freund's complete adjuvant (FCA). Inflammatory signs of adjuvant arthritis included severe swelling of the FCA-injected limbs, in addition to many histopathological lesions. These included inflammatory cell infiltration, synovial hyperplasia, cartilage, and bone erosion. Parenteral administration of the selected formulae dramatically reduced the swelling of the FCA-injected limbs. In addition, histological examination revealed that the microsphere treatment protocol efficiently protected cartilages and bones of mice, injected with FCA initial and booster doses, from erosion. These results could not be achieved by a single prednisolone dose of 5 mg/kg.

The aim of this work was to prepare a combined drug dosage form of famotidine (FAM) and quercetin (QRT) to augment treatment of gastric ulcer. FAM was prepared as freeze-dried floating alginate beads using ion gelation method and then coated with Eudragit RL100 to sustain FAM release. QRT was prepared as solid dispersion with polyvinyl pyrrolidone K30 to improve its solubility. Photo images and scanning electron microscope images of the prepared beads were carried out to detect floating behavior and to reveal surface and core shape of the prepared beads. Anti-ulcerogenic effect and histopathological examination of gastric tissues were carried out to investigate the effect of the combined drug formulation compared with commercial FAM tablets and FAM beads. Gastric glutathione (GSH), superoxide dismutase, catalase, tissue myeloperoxidase, and lipid peroxidation enzyme activities and levels in rat stomach tissues were also determined. Results revealed that spherical beads were formed with an average diameter of 1.64±0.33 mm. They floated immediately with no lag time before floating, and remained buoyant throughout the test period. Treatment with a combination of FAM beads plus QRT showed the absence of any signs of inflammation or hemorrhage, and significantly prevented the indomethacin-induced decrease in GSH levels (P<0.05) with regain of normal GSH gastric tissue levels. Also, there was a significant difference in the decrease of malondialdehyde level compared to FAM commercial tablets or beads alone (P<0.05). The combined formula significantly improved the myeloperoxidase level compared to both the disease control group and commercial FAM tablet-treated group (P<0.05). Formulation of FAM as floating beads in combination with solid dispersion of QRT improved the anti-ulcer activity compared to commercially available tablets, which reveals a promising application for treatment of peptic ulcer.