Fabrication of gastro-floating sustained-release etoricoxib and famotidine tablets: design, optimization, in-vitro, and in-vivo evaluation.

In this study, a new gastro-floating sustained-release tablet (GFT) with a combination of Etoricoxib (ET) and Famotidine (FM) was successfully developed. GFTs were prepared by using a combination of hydrophilic swellable natural/semi-synthetic polymers as a controlled-release layer. Through a 24 full factorial statistical experimental design, the effects of formulation factors on the release of GFTs were conducted. The ideal floating tablet (FT) comprised konjac-gum (150 mg), guar-gum (26.57 mg), xanthan-gum (54.17 mg), and HPMC-K15-M (69.25 mg). The ideal FT exhibited a high swelling index (SI) (297.7%) and rapid FLT (around 50 s) in 0.1 N HCl as well as controlled release of ET (22.43% in 1 h and 77.47% in 8 h) and FM (24.89% in 1 h and 93.82% in 8 h) with the absence of any drug-excipient interactions. The AUC0∼72 (ng h/mL) of ET and FM in the GFTs were approximately double-fold of the market, respectively. The relative bioavailability was (207.48 ± 12.02% and 208.51 ± 13.11%) compared with commercial tablets. The X-ray imaging showed a promising buoyancy ability for approximately 8 h. These findings revealed the successful preparation of the sustained-release floating tablet with improved dual drug delivery.

Eudragit®-S100 Coated PLGA Nanoparticles for Colon Targeting of Etoricoxib: Optimization and Pharmacokinetic Assessments in Healthy Human Volunteers.

AIM: Etoricoxib is a selective inhibitor of COX-2 enzyme. It is proposed as a potent anti-inflammatory drug intended for the control of irritable bowel syndrome. The current work aimed at developing etoricoxib-loaded nanoparticles for colon- targeting. MATERIALS AND METHODS: PLGA nanoparticles were developed via nano-spray drying technique. The D-optimal design was adopted for the investigation of the influence of i) DL-lactide-coglycolide (PLGA) concentration, ii) polyvinylpyrrolidone K30 (PVP K30) concentration and iii) lactide:glycolide ratio in the copolymer chain on the yield%, the encapsulation efficiency (EE%), particle size (PS) and percentage of drug release after 2h (P2h), 4h (P4h) and 12h (P12h). To promote colon targeting of the systems, the best achieved system (M14) was either directly coated with poly(methacrylic acid-co-methyl methacrylate) [Eudragit®-S100] or loaded into hard gelatin capsules and the capsules were coated with poly(methacrylic acid-co-methyl methacrylate) (E-M14C). The pharmacokinetic parameters of etoricoxib following oral administration of E-M14C in healthy volunteers were assessed relative to commercial etoricoxib tablets. RESULTS: M14 system was prepared using PLGA (0.5% w/v) at a lactide:glycolide ratio of 100:0, in the presence of PVP K30 (2% w/v). M14 system was nano-spherical particles of 488 nm size possessing promising yield% (63.5%) and EE% (91.2%). The percentage drug released after 2, 4 and 12 hours were 43.41%, 47.34 and 64.96%, respectively. Following M14-loading into hard gelatin capsules and coating with poly(methacrylic acid-co-methyl methacrylate) [Eudragit-S100], the respective P2h, P4h and P12h were 10.1%, 28.60% and 65.45%. Significant (p < 0.05) differences between the pharmacokinetic parameter of E-M14C in comparison with the commercial product were revealed with a delay in Tmax (from 2.5h to 6h), a prolongation in MRT0-∞ (from 24.4h to 34.7h) and an increase in the relative oral bioavailability (4.23 folds). CONCLUSION: E-M14C is a potential system for possible colon targeting of etoricoxib.

Design and optimization of film-forming gel of etoricoxib using research surface methodology.

The present investigation is focused on the development of transdermal film-forming gel (FFG) loaded with etoricoxib employing research surface methodology (RSM). Box-Behnken surface design method was used to develop experimental run using different concentrations of etoricoxib, hydroxypropyl methylcellulose (HPMC K100M), and eudragit RL100 as independent variables, and Derringer's optimization tool was employed to optimize best possible formulation. The dependent variables considered in this study were viscosity and drug permeation at 24 h (Q24, µg/cm2). Anti-inflammatory study was performed on Wistar albino rats for 8 h. Skin irritation studies and accelerated stability studies were performed for validated FFG formulations. Quadratic model was found to be best fit model (p < 0.0001) for both the responses. The influence of HPMC concentration on the viscosity was found to be highest whereas concentration of etoricoxib was maximum for Q24. The optimum composition of the FFG was observed to be 4% of etoricoxib, 1.1246% of HPMC, and 0.4% of eudragit. Above composition resulted in viscosity of 1549.5 mPa.s and maximum Q24 of 4639.11 µg/cm2 with desirability 0.918. The in vivo anti-inflammatory study demonstrated better sustained release effect (for 8 h) of optimized FFG compared to orally administered drug suspension. An average irritation score of 0.555 was observed on Draize scoring system. The validated FFG formulation was found to be stable for the 3 months in accelerated conditions. It can be concluded from the above investigations that the validated FFG formulation of etoricoxib is well tolerated and could provide sustained drug release for 8 h. Graphical abstract.

Facile synthesis of mesoporous alumina using hexadecyltrimethylammonium bromide (HTAB) as template: simplified sol-gel approach.

Herein the authors present the synthesis of surface functionalised mesoporous alumina (MeAl) for textural characterisation by a simplified sol-gel method obtained by using hexadecyltrimethylammonium bromide as a template. Etoricoxib (ETOX) was used as a model drug for the study. Alumina supported mesoporous material containing drug was characterised using instrumental technique namely Brunauer-Emmett-Teller surface area, Fourier transform-infrared, differential scanning calorimetry, transmission electron microscopy, X-ray diffraction, and field emission scanning electron microscopy. Diffusion study using a dialysis bag method used to check the release pattern of ETOX-loaded-MeAl. Results of characterisation study revealed the successful surface functionalisation of the drug on nanocomposite. The IC50 value obtained from cell viability study demonstrated the non-toxic behaviour of synthesised drug-loaded mesoporous alumina up to the tested concentration range. The present work has demonstrated that synthesised MeAl showed excellent stability with an expanded surface area suitable for carrier material for drug delivery system.

PEG-PLGA- hybrid nanoparticles loaded with etoricoxib - phospholipid complex for effective treatment of inflammation in rat model.

The aim of the present study was to increase the bioavailability of the etoricoxib by making PEG-PLGA-Hybrid nanoparticles using emulsion solvent evaporation method. Then the prepared nanoparticles were further characterised using TEM, particle size, PDI, zeta potential, encapsulation efficiency and drug release study. Lipid (Phospholipon 90-G) and drug thermal behaviour were studied using DSC, TGA. The results of optimised formulation of Particle size, PDI and zeta potential was found 216.6 ± 4.0 nm, 0.24 ± 0.19 and +36.3 ± 1.9 mV. Encapsulation efficiency was found in the range of 77.15% w/v to 93.88% w/v. In-vivo study shows that the optimised formulation at a particular dose decreases the swelling index and number of writhes. Stability study indicated that the nanoparticles can be stored at a temperature of 4 ± 2 °C/60 ± 5% RH in well-closed container, away from heat and damp places. The prepared formulation has significantly increased the bioavailability of etoricoxib via oral administration.

Rapid quantitative analysis of etoricoxib in human plasma by UPLC-MS/MS and application to a pharmacokinetic study in Chinese healthy volunteers.

A selective and sensitive liquid chromatography-tandem mass spectrometry method was developed for simultaneous determination of etoricoxib in human plasma. Chromatography was performed on an Acquity UPLC HSS T3 column (1.8 µm, 50 × 2.1 mm), with a flow rate of 0.600 mL/min, using a gradient elution with acetonitrile and water which contained 2 mm ammonium acetate as the mobile phase. Detection was carried out on Triple QuadTM 5500 mass spectrometer under positive-ion multiple reaction monitoring mode. The respective mass transitions used for quantification of etoricoxib and etoricoxib-d3 were m/z 359.0 → 280.1 and m/z 362.0 → 280.2. Calibration curves were linear over the concentration range of 5-5000 ng/mL. The validated method was applied in the pharmacokinetic study of etoricoxib in Chinese healthy volunteers under fed and fasted conditions. After a single oral dose of 120 mg, the main pharmacokinetic parameters of etoricoxib in fasted and fed groups were respectively as follows: peak concentration, 2364.78 ± 538.01 and 1874.55 ± 367.90 ng/mL; area under the concentration-time curve from 0 to 120 h, 44,605.53 ± 15,266.66 and 43,516.33 ± 12,425.91 ng h/mL; time to peak concentration, 2.00 and 2.50 h; and half-life, 24.08 ± 10.06 and 23.64± 6.72 h. High-fat food significantly reduced the peak concentration of etoricoxib (p = 0.001) but had no effect on the area under the concentration-time curve.

Effects of the highly COX-2-selective analgesic NSAID etoricoxib on the rate of orthodontic tooth movement and cranial growth.

BACKGROUND: NSAID analgesics have found widespread use in the treatment of pain, inflammation and fever. The highly COX-2-selective NSAID etoricoxib has shown a favorable side effect profile and excellent analgesic efficacy, particularly for dental and orthodontic pain, surpassing the current standard analgesic in orthodontics, acetaminophen. However, potential side effects on the rate of orthodontic tooth movement (OTM) and cranial growth, relevant for clinical usability during orthodontic treatment, have not yet been investigated. MATERIAL AND METHODS: 40 male Fischer344 rats were randomly assigned to 4 groups (n=10) - controls receiving only 1.5ml tap water per day by oral gavage for a total of 5 weeks (1) as well as rats receiving an additional daily normal etoricoxib dosage of 7.8mg/kg for 3d (2) and 7d/week (3) and a high dosage of 13.1mg/kg for 7d/week (4) with serum bioavailability assessed by liquid chromatography-mass spectrometry. After one week of premedication, the first upper left molars (M1) were moved orthodontically in anterior direction for 4 weeks using a closed NiTi coil spring (0.25N) and OTM as well as sagittal cranial growth were quantified cephalometrically by CBCT imaging at the start and end of OTM. RESULTS: OTM, quantified as anterior metric tipping of M1, was significantly inhibited by about 33% only in rats receiving high-dose etoricoxib 7d/week (p=0.046) with a respective, but insignificant tendency also detectable for the normal dosages, whereas sagittal cranial growth was by tendency slightly increased with rising etoricoxib dosages, reflected by corresponding steady-state serum concentrations, confirming etoricoxib bioavailability. CONCLUSIONS: An etoricoxib-induced clinically relevant deceleration of OTM is not to be expected at dosage regimens used in clinical practice to treat dental or orthodontic pain in contrast to a continuously administered high dosage. Due to its favorable side effect profile and higher analgesic efficiency regarding dental and orthodontic pain, etoricoxib should be a clinically valid alternative to the current standard orthodontic analgesic acetaminophen with its associated higher risk profile.