Role of Polyethylene Glycol and Silica for Dissolution Enhancement of Cefuroxime Axetil: In-Vitro Performance Evaluation and Characterization

Cefuroxime Axetil (CA) a widely used cephalosporin antibiotic displays low aqueous solubility and high membrane penetrability. This results in its solubility driven variable and/or low oral bioavailability and therapeutic efficacy as a major drawback. Thus, most of the goal of our study was to increase the solubility as well as dissolution rate of CA using the simple and cost-effective solid dispersion (SD) method. At first, the SD formulations of CA were prepared at various weight ratios of Carplex-67 and PEG-4000 by solvent evaporation technique. These new formulations were then subjected to an in-vitro drug release performance study and tested for physicochemical characterization to distinguish the thermal behavior, crystallinity, interactions phenomena, and surface morphology. Among the formulated Cefuroxime Axetil Solid Dispersion (CSD), CSD-8 which contained CA, Carplex-67, and PEG-4000 at the weight ratio 1:3:2, respectively showed the most significant (p in-vitro dissolution in water, Gastric Simulated Fluid (GSF), and Intestinal Simulated Fluid (ISF). This study also showed a significant (p < 0.001) increase in drug release compared to the marketed product. Therefore, it is supposed to be a promising alternative to conventional antimicrobial therapy.

Inclusion complexes of cefuroxime axetil with β-cyclodextrin:Physicochemical characterization, molecular modeling and effect of Larginine on complexation

The inclusion complexes of poorly water-soluble cephalosporin, cefuroxime axetil(CFA), were prepared with β-cyclodextrin(βCD) with or without addition of L-arginine(ARG) to improve its physicochemical properties. We also investigated the effect of ARG on complexation efficiency(CE) of βCD towards CFA in an aqueous medium through phase solubility behaviour according to Higuchi and Connors. Although phase solubility studies showed AL(linear) type of solubility curve in presence and absence of ARG, the CE and association constant(Ks) of βCD towards CFA were significantly promoted in presence of ARG,justifying its use as a ternary component. The solid systems of CFA with βCD were obtained by spray drying technique with or without incorporation of ARG and characterized by differential scanning calorimetry(DSC), X-ray powder diffractometry(XRPD), scanning electron microscopy(SEM), and saturation solubility and dissolution studies. The molecular modeling studies provided a better insight into geometry and inclusion mode of CFA inside βCD cavity. The solubility and dissolution rate of CFA were significantly improved upon complexation with βCD as compared to CFA alone. However, ternary system incorporated with ARG performed better than binary system in physicochemical evaluation. In conclusion, ARG could be exploited as a ternary component to improve the physicochemical properties of CFA via βCD complexation.

Development and evaluation of taste-masked dry suspension of cefuroxime axetil for enhancement of oral bioavailability

Cefuroxime axetil(CA)is an ester prodrug of cefuroxime with an unpleasant taste when administrated orally.This work was to mask the bitter taste of CA and enhance its oral bioavailability.Dry suspensions were prepared by means of wet granulation method and solid dispersion method.Binders,suspending agents and other compositions involved in the formulation were optimized.The differential scanning calorimetry(DSC)analysis indicated that CA was amorphous in the solid dispersion with stearic acid as the carrier,which contributed to an improvement of the dissolution rate.Taste evaluation was performed by three volunteers and taste masking was successfully achieved by the methods mentioned above.A pH 7.0 phosphate buffer was adopted to study the in vitro dissolution performance of the three formulations,i.e.,two self-made dry suspensions and the commercial one.With a better release characteristic and a satisfying taste masking ability,the solid dispersion suspension was selected as the optimal formulation for the further pharmacokinetic study in beagle dogs.The values of Cmax and AUC0e12 for the solid dispersion suspension were about 1.78-fold and 2.17-fold higher than these of reference suspension,respectively.The obtained results demonstrated that the solid dispersion can efficiently mask the bitter taste of CA and significantly enhance its oral bioavailability.

Incompatibility of Paracetamol with Pediatric Suspensions Containing Amoxicillin, Azithromycin and Cefuroxime Axetil

The main objective of this work was to use the Differential Scanning Calorimetry (DSC) and FTIR spectroscopy to study the possible drug-drug or drug-excipient (s) interaction in case of concomitant oral administration of paracetamol with the most common used antibiotics for children. Amoxicillin, azithromycin, cefuroxime axetil and their commercially available suspensions, Amoxil?, Azithromax? and Zinnat? were used. DSC curves for paracetamol, pure antibiotics, commercially available antibiotics and all binary mixtures used in this study showed drug-drug or drug-excipient (s) physical interaction and indicated a possible chemical interaction. To confirm chemical drug-drug or drug-excipient (s) interaction additional ATR-IR spectra for all samples used in this study were obtained. Results obtained from ATR-IR spectra showed drug-excipient (s) interaction in Zinnat?, Azithromax? and binary mixture Azithromax?-paracetamol, while chemical drug-drug interaction was not observed. From this study it can be concluded that the concomitant oral administration of paracetamol with commercially available antibiotics used in this study is not recommended and duration of two hours between the oral administrations of these drugs is strongly recommended to avoid drug-drug or drug-excipient (s) interaction.

Accelerated Aqueous Solubility and Antibacterial Activity of Cefuroxime Axetil Using Microcrystalline Cellulose as Carrier

This investigation was undertaken to enhance the solubility and consequent antibacterial activity of cefuroxime axetil (CA), a β-lactamase-stable broad spectrum second generation cephalosporin through solid dispersion (SD) technique. For this purpose, CA loaded SDs (CSDs) were prepared by solvent evaporation method using different concentrations of microcrystalline cellulose (MCC) as carrier. The CSDs were characterized by in-vitro dissolution study, thermal analysis (DSC), crystallinity (PXRD), interactions (FTIR) and morphology (SEM). Among the formulations, CSD-2 showed the highest dissolution rate which was 2.59-fold higher than pure CA with a drug-carrier (CA: MCC) ratio of 1:3. Enhanced dissolution rate was attributed to conversion of drug from crystalline to amorphous state during preparation of SDs, which was validated by DSC, PXRD, FTIR and SEM analyses. Antibacterial activity of CSD-2 against Staphylococcus aureus (ATCC 25923) and Escherichia coli (ATCC 25922) showed 1.94- and 6.75-fold higher relative zone of inhibition (RZOI), respectively than pure CA. CSD-2 has been found to be the most effective optimized formulation in terms of both enhanced dissolution rate and antibacterial activity. Thus, it can be an effective alternative to conventional dosage forms of CA. However, further investigations are needed to validate its pharmacokinetic properties, in-vivo antibacterial efficacy and safety before recommending as a novel

Influence of anastomoses on intestine ischemia and cefuroxime concentrations:Evaluated in the ileum and colon in a porcine model

BACKGROUND Anastomotic leakage is a serious complication following gastrointestinal surgery and is associated with increased morbidity and mortality.The incidence of anastomotic leakage is determined by anatomy and is reported to be between 4%-33%for colon anastomosis and 1%-3%for small intestine anastomosis.The etiology of anastomotic leakage of the intestine has been divided into three main factors:healing disturbances,communication between intra-and extra-luminal compartments,and infection.All three factors interact,and one factor will inevitably lead to the other two factors resulting in tissue ischemia,tissue necrosis,and anastomotic leakage.AIM To evaluate ischemic metabolites and cefuroxime concentrations in both anastomosis and non-anastomosis ileum and colon in a porcine model.METHODS Eight healthy female pigs(Danish Landrace breed,weight 58-62 kg)were included in this study.Microdialysis catheters were placed for sampling of ischemic metabolites(glucose,lactate,glycerol,and pyruvate)and cefuroxime concentrations in both anastomosis and non-anastomosis ileum and colon.Cefuroxime 1.5 g was administered as an intravenous infusion over 15 min.Subsequently,dialysates and blood samples were collected over 8 h and the ischemic metabolites and cefuroxime concentrations were quantified in all samples.The concentrations of glucose,lactate,glycerol and pyruvate were determined using the CMA 600 Microdialysis Analyzer with Reagent Set A(M Dialysis AB,Sweden),and the concentrations of cefuroxime and meropenem were quantified using a validated ultra-high-performance liquid chromatography assay.RESULTS Only the colon anastomosis induced mean ischemic lactate/pyruvate ratios above 25(ischemic cut-off)throughout the entire sampling interval,and simultaneously decreased glucose concentrations.The mean time for which cefuroxime concentrations were maintained above the clinical breakpoint minimal inhibitory concentration for Escherichia coli(8μg/mL)ranged between 116-128 min across all the investigated compartments,and was similar between the anastomosis and non-anastomosis ileum and colon.For all pigs and in all the investigated compartments,a cefuroxime concentration of 8μg/mL was reached within 10 min after administration.When comparing the pharmacokinetic parameters between the anastomosis and non-anastomosis sites for both ileum and colon,only colon Tmax and half-life differed between anastomosis and non-anastomosis(P<0.03).Incomplete tissue penetrations were found in all tissues except for the nonanastomosis colon.CONCLUSION Administering 1.5 g cefuroxime 10 min prior to intestine surgery seems sufficient,and effective concentrations are sustained for approximately 2 h.Only colon anastomosis was locally vulnerable to ischemia.

Antimicrobial prophylaxis in patients with colorectal lesions undergoing endoscopic resection

AIM: To investigate the effect of prophylaxis withantibiotics on clinical adverse events in patients who underwent endoscopic submucosal dissection(ESD) or endoscopic mucosal resection(EMR) for colorectal lesions.METHODS: From June 2011 to December 2013, a total of 428 patients were enrolled into the study, of which 214 patients admitted to hospital underwent EMR or ESD procedures. These patients were randomized to an antibiotic group, in which patients were given cefuroxime 1.5 g iv half an hour before and 6 h after surgery respectively, and a control group, in which patients were not given any antibiotic. A further 214 outpatients with small polyps treated by polypectomy were compared with controls that were matched by age and gender, and operations were performed as outpatient surgery. Recorded patient parameters were demographics, characteristics of lesions and treatment modality, and the size of the wound area. The primary outcome measures were clinical adverse events, including abdominal pain, diarrhea, hemotachezia, and fever. Secondary outcome measures were white blood cell count, C-reactive protein and blood culture. Additionlly, the relationship between the size of the wound area and clinical adverse events was analyzed. RESULTS: A total of 409 patients were enrolled in this study, with 107 patients in the control group, 107 patients in the antibiotic group, and another 195 cases in the follow-up outpatient group. The patients' demographic characteristics, including age, gender, characteristics of lesions, treatment modality, and the size of the wound area were similar between the 2 groups. The rates of adverse events in the antibiotic group were significantly lower than in the control group: abdominal pain(2.8% vs 14.9%, P < 0.01), diarrhea(2.0% vs 9.3%, P < 0.05), and fever(0.9% vs 8.4%, P < 0.05) respectively. The levels of inflammatory markers also decreased significantly in the antibiotic group compared with the control group: leukocytosis(2.0% vs 11.2%, P < 0.01), and C-reactiveprotein(2.0% vs 10.7%, P < 0.05). Additionally, clinica adverse events were related to the size of the surgica wound area. When the surgical wound area was larger than 10 mm × 10 mm, there were more clinica adverse events.CONCLUSION: Clinical adverse events are not uncommon after EMR or ESD procedures. Prophylactic antibiotics can reduce the incidence of clinical adverse events. This should be further explored.