Design and development of lipid modified chitosan containing muco-adhesive self-emulsifying drug delivery systems for cefixime oral delivery.

Current study was aimed to design and develop muco-adhesive self-nano emulsifying drug delivery system (SNEDDs) for improved pharmacokinetics of Cefixime (CFX) in rabbits. The components of SNEDDs formulation i.e., cinnamon oil, Tween® 80, and PEG 200 as oil, surfactant, and co-surfactant respectively were selected based on their high solubilizing capability of the drug. SNEDDs formulation was optimized using Design of experiments (D-optimal design) in terms of droplet size, poly dispersity index and zeta potential. The optimized SNEDDs formulation was studied for various parameters like droplet size, morphology, zeta potential, emulsification, optical clarity, thermodynamic stability, GIT stability, and robustness to dilution. CFX was loaded to optimized formulation to form CFX-SNEDDs. Furthermore, acyl-chitosan, a muco-adhesive agent, was added to CFX-SNEDDS to prepare CHT-CFX-SNEDDS. In vitro drug release showed the controlled release behavior reached a maximum value of 70 % at pH 6.8 within 24 h. The droplet size, atomic force microscopy, and optical clarity analysis revealed the formation of nanosized emulsion (156 ± 25 nm) with spherical morphology. Also in vivo pharmacokinetic studies on rabbits showed an increased drug plasma concentration for CHT-CFX-SNEDDs (15 ± 3 µg/mL) and CFX-SNEDDs (9 ± 2 µg/mL) in comparison with control CFX (4 ± 1 µg/mL). The results indicated that the developed CHT-CFX-SNEDDs with an increased degree of solubilization, permeation, and nanosized range emulsion enhance the oral performance of CFX.

A sensitive fluorescent sensor based on the photoinduced electron transfer mechanism for cefixime and ctDNA.

Cefixime is a third generation orally administered cephalosporin that is frequently used as a broad spectrum antibiotic against various gram-negative and gram-positive bacteria. In this study, a simple and sensitive fluorescent sensor for the determination of the cefixime and ctDNA was established based on the CdTe:Zn2+ quantum dots (QDs). The fluorescence of CdTe:Zn2+ QDs can be effectively quenched by cefixime in virtue of the surface binding of cefixime on CdTe:Zn2+ QDs and the subsequent photoinduced electron transfer process from CdTe:Zn2+ QDs to cefixime, in particular, the high sensitivity of QDs fluorescence emission to cefixime at the micromole per liter level, which render the cefixime-CdTe:Zn2+ QDs system into fluorescence "OFF" status, then turn on in the presence of ctDNA. Furthermore, the Fourier transform infrared (FTIR) spectra of characteristic bands of C-N and N-H groups of cefixime endow evidence for the interaction of cefixime with CdTe:Zn2+ QDs. The relative electrochemical behavior of the affinity of CdTe:Zn2+ QDs for cefixime and ctDNA reveals the potential molecular binding mechanism.

Disposition kinetics, renal clearance and urinary excretion of cefixime in adolescent Pakistani boys - DRUG ANALYSIS REPORT.

OBJECTIVE: To investigate the role of environmental variation, genetic differences and age on disposition kinetics, renal clearance and urinary excretion of oral cefixime 400mg in healthy boys. METHODS: The cross-sectional study was conducted at the University of Agriculture, Faisalabad, Pakistan, from August 2014 to July 2015, and comprised healthy boys aged 12-17 years after oral administration of cefixime capsule 400mg. Serum and urine samples were collected before and after drug administration and were stored at - 20oC until evaluation of cefixime concentration in each sample by high performance liquid chromatography. Drug concentration versus time data was used for pharmacokinetic calculations using one compartment model. Data obtained for urinary excretion and renal clearance of cefixime was analysed using regression-correlation analysis. RESULTS: There were eight boys in the study. Mean values for elimination half-life, volume of distribution and total body clearance were 2.4}0.2 hours, 0.9}0.0L/kg and 0.3}0.0L/h/kg, respectively. The ratio of renal clearance of cefixime (0.7 ml/min/kg) to that of endogenous creatinine (0.8ml/min/kg) was 0.9. Cumulative mean percentage of cefixime excreted from young adolescent boys was 11.6 } 0.5%. CONCLUSION: Other than filtration, back-diffusion was also involved in renal handling of cefixime. There was enough indication that major portion of cefixime was excreted from a young body through bile.

Pharmacokinetic Data Are Predictive of In Vivo Efficacy for Cefixime and Ceftriaxone against Susceptible and Resistant Neisseria gonorrhoeae Strains in the Gonorrhea Mouse Model.

There is a pressing need for drug development for gonorrhea. Here we describe a pharmacokinetic (PK)/pharmacodynamic (PD) analysis of extended-spectrum cephalosporins (ESC) against drug-susceptible and drug-resistant gonococcal strains in a murine genital tract infection model. The PK determined in uninfected mice displayed a clear dose-response in plasma levels following single doses of ceftriaxone (CRO) (intraperitoneal) or cefixime (CFM) (oral). The observed doses required for efficacy against ESC-susceptible (ESCs) strain FA1090 were 5 mg/kg of body weight (CRO) and 12 mg/kg (CFM); these doses had estimated therapeutic times (the time that the free drug concentration remains above the MIC [fTMIC]) of 24 h and 37 h, respectively. No single dose of CRO or CFM was effective against ESC-resistant (ESCr) strain H041. However, fractionation (three times a day every 8 h [TIDq8h]) of a 120-mg/kg dose of CRO resulted in estimated therapeutic times in the range of 23 h and cleared H041 infection in a majority (90%) of mice, comparable to the findings for gentamicin. In contrast, multiple CFM doses of 120 or 300 mg/kg administered TIDq8h cleared infection in ≤50% of mice, with the therapeutic times estimated from single-dose PK data being 13 and 27 h, respectively. This study reveals a clear relationship between plasma ESC levels and bacterial clearance rates in the gonorrhea mouse model. The PK/PD relationships observed in mice reflected those observed in humans, with in vivo efficacy against an ESCs strain requiring doses that yielded an fTMIC in excess of 20 to 24 h. PK data also accurately predicted the failure of single doses of ESCs against an ESCr strain and were useful in designing effective dosing regimens.

Employment of modified Fe3 O4 nanoparticles using thermo-sensitive polymer for extraction and pre-concentration of cefexime in biological samples.

Cefexime is a useful antibiotic that can be prescribed to treat bacterial infections. Nanoparticles have been widely marketed as a universal solution among scientists. Many studies have been performed to modify nanoparticles to make them functional as extraction and pre-concentration agents and drug carriers. Temperature-sensitive polymers belong to a group of substances that undergo a major change in their physical features in response to temperature. Recently developed polymers can be used in many different areas, including modification of nanoparticles. In order to modify this nanoparticle, grafting copolymerization of Fe3 O4 nanoparticles was performed using poly (N-vinylcaprolactam) and 3-allyloxy-1,2-propanediol. The optimum conditions for pre-concentration of cefexime were studied. Under these optimum conditions, extraction recovery of biological samples in the range of 71-89% was obtained. The limit of detection and precision of proposed method were 4.5 × 10-4 µg mL-1 and <4.11% (relative standard deviation), respectively. Based on the results from analysis of cefexime, in biological samples using the proposed method, the ability of this method to extract and pre-concentrate cefexime was confirmed. Also, satisfactory results from an in vitro study on drug release in simulated intestine media were obtained.

Bioanalytical method development and validation for simultaneous estimation of cefixime and dicloxacillin by RP-HPLC in human plasma.

An accurate, rapid and simple reversed-phase high performance liquid chromatography (RP-HPLC) bioanalytical method was developed and validated for simultaneous estimation of cefixime, dicloxacillin in human plasma using ezetimibe as an internal standard. The cefixime, dicloxacillin and internal standard were extracted by liquid-liquid extraction technique. Chromatographic separation is accomplished using CAPCELL PAK C18 (4.6 mm × 250 mm, 5 m) analytical column. The mobile phase consisted of phosphate buffer, acetonitrile and methanol in 42:55:03 proportions. Detection and quantification were performed by UV/Vis detection at 225 nm. The lower limit of quantification was 0.5 µg mL(-1) for both cefixime and dicloxacillin in human plasma. The calibration curves were linear over the concentration range 0.5 to 40 µg mL(-1) for both drugs in human plasma. The method was quantitatively evaluated in terms of linearity, precision, accuracy, recovery, selectivity, and stability. The method was found to be simple, convenient and suitable for the analysis of cefixime and dicloxacillin from biological fluids.

PEPT1- and OAT1/3-mediated drug-drug interactions between bestatin and cefixime in vivo and in vitro in rats, and in vitro in human.

The purpose of the present study was to elucidate the transporter-mediated pharmacokinetics mechanism of drug-drug interactions (DDIs) between bestatin and cefixime. The plasma concentrations and bioavailabilities of bestatin and cefixime were decreased after oral co-administration in rats. The uptake in rat everted intestinal sacs of bestatin and cefixime were dramatically declined after co-administration of the two drugs. Bestatin and cefixime can mutually competitively inhibit the uptake by hPEPT1-HeLa cells. The plasma concentrations of bestatin and cefixime were increased; however, the cumulative biliary excretion had no significant change, and the cumulative urinary excretion and renal clearance of the two drugs in rats decreased after intravenous coadministration. Moreover, decreased uptake of the two drugs was observed in human kidney slices, rat kidney slices and hOAT1/hOAT3-transfected HEK293 cells when bestatin and cefixime were coadministered. The accumulation of bestatin and cefixime in kidney slices can be inhibited by p-aminohippurate, benzylpenicillin and probenecid, but not by tetraethyl ammonium. The results suggest that intestinal absorption and renal excretion of bestatin and cefixime can be inhibited when the two drugs were co-administered in rats. The pharmacokinetic mechanism indicates that the DDIs between bestatin and cefixime are mainly mediated by Pept1 and Oat1/3 in rats. PEPT1 and OAT1/3 are the target transporters of DDIs between bestatin and cefixime in human kidney slices and human transfected cells, proposing possible drug-drug interaction in humans.

Molecularly imprinted electrochemical biosensor based on Fe@Au nanoparticles involved in 2-aminoethanethiol functionalized multi-walled carbon nanotubes for sensitive determination of cefexime in human plasma.

The molecular imprinting technique depends on the molecular recognition. It is a polymerization method around the target molecule. Hence, this technique creates specific cavities in the cross-linked polymeric matrices. In present study, a sensitive imprinted electrochemical biosensor based on Fe@Au nanoparticles (Fe@AuNPs) involved in 2-aminoethanethiol (2-AET) functionalized multi-walled carbon nanotubes (f-MWCNs) modified glassy carbon (GC) electrode was developed for determination of cefexime (CEF). The results of X-ray photoelectron spectroscopy (XPS) and reflection-absorption infrared spectroscopy (RAIRS) confirmed the formation of the developed surfaces. CEF imprinted film was constructed by cyclic voltammetry (CV) for 9 cycles in the presence of 80 mM pyrrole in phosphate buffer solution (pH 6.0) containing 20mM CEF. The developed electrochemical biosensor was validated according to the International Conference on Harmonisation (ICH) guideline and found to be linear, sensitive, selective, precise and accurate. The linearity range and the detection limit were obtained as 1.0 × 10(-10)-1.0 × 10(-8)M and 2.2 × 10(-11)M, respectively. The developed CEF imprinted sensor was successfully applied to real samples such as human plasma. In addition, the stability and reproducibility of the prepared molecular imprinted electrode were investigated. The excellent long-term stability and reproducibility of the prepared CEF imprinted electrodes make them attractive in electrochemical sensors.

Simultaneous determination of cefdinir and cefixime in human plasma by RP-HPLC/UV detection method: Method development, optimization, validation, and its application to a pharmacokinetic study.

A novel isocratic reversed-phase high performance liquid-chromatography/ultraviolet detection method for simultaneous determination of cefdinir and cefixime in human plasma was developed and validated after optimization of various chromatographic conditions and other experimental parameters. Sample preparation based on a simple extraction procedure consisting of deproteination and extraction with 3 parts of 6% trichloroacetic acid aqueous solution followed by volume make up with the aqueous component of the mobile phase obtained best recoveries of the two analytes. Samples were separated on a Supelco Discovery HS C(18) (150 mm × 4.6 mm, 5 µm) analytical column protected by a Perkin Elmer C(18) (30 mm × 4.6 mm, 10 µm) guard cartridge. The mobile phase, methanol/acetonitrile (50/50, v/v):0.05% trifluoroacetic acid (19:81, v/v), operated at 50°C column oven temperature was pumped at a flow rate of 2.0 mL min(-1) and the column eluents were monitored at a wavelength of 285 nm. When Sample was injected into the Perkin Elmer high performance liquid-chromatography system through Rheodyne manual (or auto-sampler) injector equipped with 20 µL loop, separation was achieved within 4 min. The present method demonstrated acceptable values for selectivity, linearity within the expected concentration range (0.004-5.0 µg mL(-1); r(2)>0.999 for both analytes), recovery (>95% for cefdinir and >96% for cefixime), precision (%RSD<2.0 for cefdinir and <2.2 for cefixime), sensitivity (limit of detection: 1 ng mL(-1) and lower limit of quantification: 4 ng mL(-1) for both analytes), stability of solutions, and robustness. The method was efficiently applied to a pharmacokinetic study in healthy volunteers.

Maternal blood and amniotic fluid levels of moxifloxacin, levofloxacin and cefixime.

AIM: Moxifloxacin and levofloxacin are wide spectrum quinolones and cefixime is a third-generation cephalosporin with a wider spectrum of activity against gram-positive and gram-negative bacteria and anaerobics. Although they are widely used, little is known about the amniotic fluid levels of these antibiotics. The aim of the present investigation was to study and compare the maternal blood and amniotic fluid levels of these antibiotics in second trimester pregnancy. METHODS: To assess the amniotic fluid levels of these antibiotics, 10 pregnant women were given moxifloxacin, 10 were given levofloxacin and 6 were given cefixime orally 2 h before amniocentesis as a single dose for prophylaxis. During amniocentesis, an extra 2 mL amniotic fluid sample and 2 mL maternal venous blood were drawn. The levels of these agents in samples were analyzed using high performance liquid chromatography. RESULTS: The amniotic fluid levels of moxifloxacin and levofloxacin were 0.27 +/- 0.21 microg/mL and 0.60 +/- 0.41 microg/mL, respectively. The maternal blood levels were 3.53 +/- 0.65 microg/mL and 3.95 +/- 0.77 microg/mL in the moxifloxacin and levofloxacin groups, respectively. The maternal blood level of cefixime was 2.59 +/- 1.10 microg/mL and the amniotic fluid level was 0.85 +/- 0.42 microg/mL. The amniotic fluid passage rates were 7.83% for moxifloxacin, 15.67% for levofloxacin and 37.55% for cefixime. CONCLUSION: Of these three antibiotics, cefixime has the highest transplacental passage rate and, therefore, can be used as a therapeutic agent in infectious conditions in which membranes and the placenta are involved. Moxifloxacin and levofloxacin have low passage rates, which should be considered when using as a therapeutic agent.

Simultaneous multiresponse optimization of an HPLC method to separate seven cephalosporins in plasma and amniotic fluid: application to validation and quantification of cefepime, cefixime and cefoperazone.

An HPLC method for the separation of seven cephalosporins [Cefepime (CEP), ceftazidime (CTA), ceftizaxime (CTI), ceftriaxone (CTR), cefotaxime (COT), cefixime (CIX) and cefoperazone (COP)] in human plasma and amniotic fluid has been developed. Optimization of the chromatographic method was performed in three steps: a series of initial experiments followed by two sets of experiments based on different experimental designs. The initial experiments were performed to decide the basic analytical requirements of the method. Then screening experiment fractional factorial design was used in order to decrease the number of parameters by eliminating parameters which having insignificant effect on responses. The parameters having significant effect were further optimized through a full factorial design. Having studied two responses (retention times and resolutions), a desirability function that assess the responses together, was used to find experimental conditions where the system generated desirable results. The desirable results were obtained with XTerra C18 (250 mm x 4.6mm, 5 microm i.d.) column, 40 mM phosphate buffer, pH 3.2, 18% MeOH, 0.85 mL min(-1) flow rate and 32 degrees C column temperature. Gradient elution with MeOH was applied. A simple and efficient solid-phase extraction was applied for the preparation of plasma and amniotic fluid samples. The validation parameters of the method were evaluated in accordance with ICH guideline. The method validated was applied to the analysis of CEP and COP in maternal venous, fetal venous and fetal arterial plasma, and to the analysis of CIX in maternal venous plasma and amniotic fluid.

Mechanism and implication of cephalosporin penetration into oropharyngeal mucosa.

The aim of this study was to explore the mechanism(s) by which oral cephalosporins penetrate into human oropharyngeal mucosa, and thus, the availability of sufficient concentrations at the site of infection. Two oral cephalosporin prototypes, cephalexin (first generation) and cefixime (third generation), were administered to five healthy subjects at two different visits with a 1-week washout period. Plasma and saliva samples were collected and drug concentrations were measured using an appropriate HPLC method. The maximum plasma concentrations (Cmax) of cefixime and cephalexin were 2.97+/-0.24 microg ml(-1) and 77.65+/-18.91 microg ml(-1), respectively. These concentrations were associated with a maximum salivary concentration (CSmax) of 0.56 microg ml(-1) for cefixime and 3.34 microg ml(-1) for cephalexin. Such levels exceed the reported minimal inhibitory concentration (MIC) for Streptococcus pyogenes and Streptococcus pneumoniae. The average concentration of cefixime in saliva corresponded to its plasma free fraction (saliva/plasma [S/P] ratio; 0.34). However, this observation was not true for cephalexin, for which antibiotic concentrations in the saliva did not appear to correspond to its plasma free fraction (0.8-0.85), with an S/P ratio of only 0.092. Our findings indicate that an active transport mechanism exists for cefixime excretion into human oropharyngeal mucosa, whereas cephalexin is passively diffused, although to a limited extent, as measured by its salivary concentrations.

[Determination of cefixime blood plasma levels by HPLC].

For comparative study of the pharmacokinetics of Cemidexor (capsules of 100 mg) and Suprax (capsules of 400 mg), a method of HPLC with quantitative determination of cefixime (the active substance in the drugs) in the blood plasma of patients with UV detection was developed. The data teproducibility with an account of the admissibility criterion was observed within the interval of all the concentrations (0.06-10 mcg/ml). The accuracy and correctness of the method also corresponded to the admissibility criteria. The lower limit of the quantitative determimation of the cefexime blood plasma levels was 0.06 mcg/ml. The pharmacokinetics was studied with the open crossed randomized method. The results were used for calculation of the pharmacokinetic parameters required for estimation of the bioequivalence of the drugs. The statistical analysis of the pharmacokinetic parameters showed that Cemidoxor and Suprax were bioequivalent.

Comparative bioavailability study of cefixime (equivalent to 100 mg/5 ml) suspension (Winex vs Suprax) in healthy male volunteers.

This investigation was carried out to evaluate the bioavailability of a new suspension formulation of cefixime (100 mg/5 ml), Winex, relative to the reference product, Suprax (100 mg/5 ml) suspension. The bio-availability study was carried out in 24 healthy male volunteers who received a single oral dose (200 mg) of the test (A) and the reference (B) products on 2 treatment days after an overnight fast of at least 10 hours. The treatment periods were separated by a one-week washout period. A randomized, balanced two-way crossover design was used. After dosing, serial blood samples were collected over a period of 16 hours. Plasma concentrations of cefixime were analyzed using a sensitive high-performance liquid chromatographic assay. The pharmacokinetic parameters for cefixime were determined using standard non-compartmental method. The parameters AUC(0-t), AUC(0-infinity), Cmax, Kel, t1/2 and Cmax/AUC(0-infinity) were analyzed statistically using raw and log-transformed data. The time to maximum concentration (tmax) was analyzed using raw data. The parametric 90% confidence intervals of the mean values of the pnfinity harmacokinetic parameters: AUC(0-t), AUC(0-infinity) Cmax, and Cmax/AUC(0-infinity) were within the range 80 - 125% which is acceptable for bioequivalence (using log-transformed data). The calculated 90% confidence intervals based on the ANOVA analysis for the mean test/reference ratios of AUC(0-t), AUC(0-infinity), Cmax, and Cmax/AUC(0-infinity) were 88.93 - 107.10%, 89.09 - 107.11%, 89.63 - 108.58% and 96.85 - 105.29%, respectively. The test formulation was found bioequivalent to the reference formulation with regard to AUC(0-t), AUC(0-infinity), and Cmax using the Schuirmann's two one-sided t-tests. Therefore, the two formulations were considered to be bioequivalent.

Sensitive liquid chromatography-tandem mass spectrometry method for the determination of cefixime in human plasma: application to a pharmacokinetic study.

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS-MS) method was developed to determine cefixime ((6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxymethoxyimino)acetamido]-8-oxo-3-vinyl-5-thia-1-azabicyclo-[4,2,0]-oct-2-ene-2-carboxylic acid) in human plasma. After a simple protein precipitation using acetonitrile, the post-treatment samples were analyzed on a C(8) column interfaced with a triple quadrupole tandem mass spectrometer. Positive electrospray ionization was employed as the ionization source. The mobile phase consisted of acetonitrile-water-formic acid (40:60:0.5, v/v/v). The analyte and internal standard cefetamet were both detected by use of selected reaction monitoring mode. The method was linear in the concentration range of 0.05-8.0 microg/ml. The lower limit of quantification was 0.05 microg/ml. The intra- and inter-day relative standard deviation across three validation runs over the entire concentration range was less than 12.7%. The accuracy determined at three concentrations (0.05, 0.80 and 7.2 microg/ml for cefixime) was within +/-2.0% in terms of relative error. Each plasma sample was chromatographed within 3.5 min. The method herein described was successfully applied for the evaluation of pharmacokinetic profiles of cefixime capsule in 24 healthy volunteers.