Application of flash nanoprecipitation to fabricate poorly water-soluble drug nanoparticles

Nanoparticles are considered to be a powerful approach for the delivery of poorly water-soluble drugs. One of the main challenges is developing an appropriate method for preparation of drug nanoparticles. As a simple, rapid and scalable method, the flash nanoprecipitation (FNP) has been widely used to fabricate these drug nanoparticles, including pure drug nanocrystals, polymeric micelles, polymeric nanoparticles, solid lipid nanoparticles, and polyelectrolyte complexes. This review introduces the application of FNP to produce poorly water-soluble drug nanoparticles by controllable mixing devices, such as confined impinging jets mixer (CIJM), multi-inlet vortex mixer (MIVM) and many other microfluidic mixer systems. The formation mechanisms and processes of drug nanoparticles by FNP are described in detail. Then, the controlling of supersaturation level and mixing rate during the FNP process to tailor the ultrafine drug nanoparticles as well as the influence of drugs, solvent, anti-solvent, stabilizers and temperature on the fabrication are discussed. The ultrafine and uniform nanoparticles of poorly water-soluble drug nanoparticles prepared by CIJM, MIVM and microfluidic mixer systems are reviewed briefly. We believe that the application of microfluidic mixing devices in laboratory with continuous process control and good reproducibility will be benefit for industrial formulation scale-up.

Application of Powder Comprehensive Properties Characterization in Batch Changes of Cefuroxime Axetil / 中国药师

Objective:To study the application of powder comprehensive properties characterization of cefuroxime axetil in batch changes .Methods:The stability and change of the powder before the batch change of cefuroxime axetil were measured by an FT 4 mul-tifunctional powder flow tester .The flow rate, compression rate, shear property, air inflation and air permeability were measured .The corresponding powder index was established .After the batch change , the above indices were detected to assess whether meeting the re-quirements.Results:The volume index of three batches of products after the batch change was within the optimal range .Conclusion:The batch changes of cefuroxime axetil have no effect on the smooth progress of cefuroxime axetil production , which provides a new rap-id verification method for preparation manufacturers .

Preparation and characterization of cefuroxime axetil solid dispersions using poloxamer 188

The main objective of the present work was to enhance the solubility and dissolution rate of poorly water-soluble drug cefuroxime axetil (CA) by formulating it into solid dispersions (SDs) with water soluble carrier poloxamer 188. Different methods were employed to prepare the dispersion, such as: Solvent method (SM), Kneading method (KM), Melt evaporation method (MEM) and Physical mixture (PM) in different drug: carrier ratios 1:1, 1:2 and 1:3 (cefuroxime axetil: poloxamer 188). The physical mixture(s) and solid dispersion(s) were characterized for drug carrier interaction, drug content, solubility, dissolution rate, differential scanning calorimetry (DSC) and FT-IR study. The dissolution rate of the prepared solid dispersion systems was determined in phosphate buffer (pH 6.8) for 1 h. The solubility of drug from different systems was also determined in water. All SD formulations were found to have a higher dissolution rate comparatively to pure CA. The dissolution rate was enhanced in the following order SM > MEM > KM. The enhancement of dissolution rate may be caused by increase wettability, dispersibillity reduction in particle size or the formation of CA ß crystalline. The FT-IR study probability revealed that there was no chemical interaction between drug and poloxamer 188

Effects of High-fat and High-calorie Diets on Pharmacokinetics of Cefuroxime Axetil Tablets / 中国药学杂志

OBJECTIVE: To investigate the effect of high-fat and high-calorie diets on pharmacokinetics of cefuroxime axetil in healthy Chinese subjects. METHODS: A randomized, open-label, single dose and two-way crossover clinical study was conducted. Twelve healthy subjects were randomly divided into two groups, each of which includes six males, then they were given 250 mg of cefuroxime axetil respectively before and after meal. Blood samples were collected at different time points before and after drug administration. The concentration of cefuroxime in plasma was determined by HPLC-MS/MS. The pharmacokinetic parameters were calculated by DAS3.2.8 and were analyzed by DAS3.2.8 and SPSS19.0. RESULTS: The main pharmacokinetic parameters of fasting and postprandial were as follows: AUC0-t was (11 402.8±3 556.7) and (18 565.7±2 917.9) ng·h·mL-1, AUC0-∞ was (11 492.5±3 581.8) and (18 754.7±2 885.6) ng·h·mL-1, ρmax was (3 406.7±1 188.9) and (5 439.2±1 118.2) ng·mL-1, tmax was (2.01±0.64) and (2.08±0.79) h, t1/2 was (1.66±0.38) and (1.60±0.60) h, respectively. The main pharmacokinetic parameters between fasting and high-fat meal groups were analyzed by SPSS19.0 software. There was significant difference in AUC0-t, AUC0-∞ and ρmax(P0.05). The ρmax and AUC were increased by 59.7% and 63.2% respectively, tmax is almost unchanged. The equivalence analysis was performed with DAS.3.2.8 software, the 90% confidence intervals for the ratios of AUC0-t, AUC0-∞ and ρmax for the postprandial/fasting were 137.6%-217.5%, 138.4%-217.3%, 135.4%-207.6%, respectively. None of them fall within the acceptable interval of 80%-125%. CONCLUSION: High-fat and high-calorie diets can significantly improve the extent of absorption of cefuroxime axetil in vivo, but does not affect the absorption rate of cefuroxime axetil.

Clinical Observation of Shuanghuanglian Oral Liquid Combined with Cefuroxime Axetil in the Treatment of Bacterial Respiratory Tract Infection / 中国药房

OBJECTIVE:To observe the clinical efficacy and safety of Shuanghuanglian oral liquid combined with cefuroxime axetil in the treatment of bacterial respiratory tract infection. METHODS:184 patients with bacterial respiratory tract infection were randomly divided into test group and control group. Test group was orally given 250 mg Cefuroxime axetil tablet,twice a day+20 ml Shuanghuanglian oral liquid,3 times a day. Control group was only given Cefuroxime axetil tablet (the same dosage as test group). The treatment course for 2 groups was 2 weeks. The cough duration,body temperature recovery time and runny nose disap-pearing time before and after treatment and bacterial clearance rate in 2 groups were observed,clinical efficacy and incidence of ad-verse reactions were recorded. RESULTS:After treatment,the total effective rate in test group was significantly higher than control group,cough duration,body temperature recovery time and runny nose disappearing time were significantly shorter than control group,the differences were statistically significant(P0.05). CONCLUSIONS:The efficacy of Shuanghuanglian oral liquid combined with ce-furoxime axetil is superior to cefuroxime axetil alone in the treatment of bacterial respiratory infections,with similar safety.

Inclusion complexes of cefuroxime axetil withβ-cyclodextrin:Physicochemical characterization, molecular modeling and effect of L-arginine on complexation$ / 药物分析学报

The inclusion complexes of poorly water-soluble cephalosporin, cefuroxime axetil (CFA), were prepared withβ-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) ofβCD 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) ofβCD towards CFA were significantly promoted in presence of ARG, justifying its use as a ternary component. The solid systems of CFA withβCD were obtained by spray drying technique with or without incorporation of ARG and characterized by differential scanning ca-lorimetry (DSC), X-ray powder diffractometry (XRPD), scanning electron microscopy (SEM), and sa-turation solubility and dissolution studies. The molecular modeling studies provided a better insight into geometry and inclusion mode of CFA insideβCD cavity. The solubility and dissolution rate of CFA were significantly improved upon complexation withβCD as compared to CFA alone. However, ternary system incorporated with ARG performed better than binary system in physicochemical evaluation. In conclu-sion, ARG could be exploited as a ternary component to improve the physicochemical properties of CFA viaβCD complexation.

Evaluation on similarity of dissolution profiles of different cefuroxime axetil tablets by factor2 method / 国际检验医学杂志

Objective To evaluate the similarity of dissolution profiles of self-produced and original drug cefuroxime axetil tab-lets.Methods Based on the dissolution detection method in the Chinese Pharmacopoeia,the dissolution behaviors of the self-pro-duced preparation and original drug were investigated in pure water,0.1 mol/L hydrochloric acid,0.05 mol/L hydrochloric acid, pH4.5 and pH6.8 medium and the rotation speed of 50,25,75 r/mim.The stripping curves were evaluated by the f2 factor method. Results In the rotation speed of 50 r/min,the f2 factors in different mediums were 57.65,79.17,73.56,66.83 and 62.33 respec-tively;the medium was 0.1 mol/L hydrochloric acid with the rotation speed of 25,75 r/min,the f2 factors were 65.35 and 78.48 re-spectively.Conclusion The stripping curves of self-produced preparation and original drug are similar under various conditions.

Formulation design and evaluation of Cefuroxime axetil 125 mg immediate release tablets using different concentration of sodium lauryl sulphate as solubility enhancer

Cefuroxime axetil immediate release tablets were formulated by direct compression method with different percentages of sodium lauryl sulphate (SLS) such as 0.5, 1.0, 1.5 and also without SLS. Resulting batches of tablets were evaluated by both pharmacopeial and non-pharmacopeial methods to ascertain the physico-mechanical properties. Dissolution test were carried out in different medium like 0.07 M HCl, distilled water, 0.1M HCl of pH 1.2 and phosphate buffers at pH 4.5 and 6.8 to observe the drug release against the respective concentration of SLS used. Later, test formulations were compared by f1 (dissimilarity) and f2 (similarity) factors using a reference brand of cefuroxime axetil. Significant differences (p<0.05) in dissolution rate were recorded with the change in concentration of SLS in different media. Test formulation T3 containing 1% SLS was found to be best optimized formulation based on assay, disintegration, dissolution and similarity and dissimilarity factors.

Formularam-se comprimidos de liberação imediata à base de cefuroxima axetil, pelo método de compressão direta, com diferentes percentagens de lauril sulfato de sódio (LSS), tais como 0,5, 1,0, 1,5, e também sem SLS. Os lotes resultantes dos comprimidos foram avaliados por ambos os métodos da farmacopeia e não farmacopeicos para determinar as propriedades físico-mecânicas. O teste de dissolução foi realizado em meios diferentes, como HCl 0,07 M, água destilada, HCl 0,1 M com pH 1,2 e os tampões fosfato (pH 4,5 e 6,8) para observar a liberação do fármaco contra a correspondente concentração de LSS utilizado. Em seguida, as formulações de teste foram comparadas por fatores f1 (dissimilaridade) e f2 (similaridade), utilizando uma marca de referência de cefuroxima axetil. Diferenças significativas (p<0,05) na taxa de dissolução foram registradas com a mudança na concentração de LSS em diferentes meios de dissolução. A formulação T3 contendo LSS a 1% foi considerada a melhor formulação otimizada com base nos ensaios de desintegração, dissolução e fatores de semelhança e dissimilaridade.

Analytical profile of raw material and finished product of cefuroxime axetil.

Cefuroxime Axetil is the 1-acetoxyethyl ester of Cefuroxime. Chemically cefuroxime axetil is (RS)-1-hydroxyethyl (6R, 7R)-7-[2-(2-furyl) glyoxyl-amido]- 3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo-Oct-2-ene-2-carboxylate, 72-(Z)-(O-me-thyl-oxime), 1-acetate-3-carbamate. Its molecular formula is C20H22N4O10S, and it has a molecular weight of 510.48. The cefuroxime raw material was identified by HPLC and IR Spectroscopy. The sample is tested for the solubility, diastereoisomer ratio, crystallinity and bulk density. The amount of cefuroxime axetil was estimated by HPLC assay method. The Cefuroxime axetil finished product was identified by HPLC and IR Spectroscopy. The average weight of tablets was calculated by taking the weights of 20 tablets. The content uniformity of the dosage units was calculated by weight variation method. The dissolution rate was calculated by HPLC method by using Paddle apparatus. The amount of Cefuroxime present in the sample was estimated by HPLC assay method. The known and unknown related substances present in the compound were estimated by HPLC method. Results obtained during the study were satisfactory and can be used for commercial purpose.

Efficacy and Safety of Fixed Dose Combination of Cefpodoxime Proxetil and Potassium Clavulanate (Cefchamp) in Comparison with Cefuroxime Axetil in Patients with Lower Respiratory Tract Infections.

Objectives: To evaluate the efficacy and safety of Fixed Dose Combination of Cefpodoxime Proxetil and Potassium Clavulanate (Cefchamp) in comparison with Cefuroxime Axetil in patients with Lower Respiratory Tract Infections.Methods:In this open, randomized, and controlled, parallel-group study of 7 days, 57 patients of both gender above 18 years of age with diagnosis of lower respiratory tract infection were randomized to receive Fixed Dose Combination (FDC) of Cefpodoxime Proxetil plus Potassium Clavulanate (Cefchamp), or Cefuroxime Axetil (CA) for a period of 7 days. Efficacy was assessed by symptoms of cough, dyspnoea, wheezing, Rhonchi, and chest pain based on 4-point scale as 0=none,1=mild, 2=moderate, 3=severe. Fever was recorded as the patient’s actual temperature. Safety assessment included adverse events and adverse drug reactions during the study period.Results: Three patients lost to follow up with CA.The improvement in all symptoms except cough was greater with CC as compared to CA group(p, >0.05). Fever improved from 37.18°C at baseline to 37.01 on day 3 with CC, whereas with CA the fever improved from 37.l5 at baseline to 37.05 on day 3 with CA. Fever subsided in all the patients in both treatments by day 5 of study therapy. Clinical cure was seen in 57.14% (16/28) patients on CC, whereas 42.3% patients (11/26) on CA had clinical cure.Conclusions:The fixed dose combination of Cefpodoxime Proxetil 200 mg and Potassium Clavulanate 125mg (Cefchamp) in comparison with Cefuroxime Axetil 500 mg showed improvement in the cure of respiratory tract infections in terms of decreasing the patient’s LRTI symptoms, improving the patient’s general health and with few adverse events and adverse drug reactions. However, further studies of greater sample size and blinded nature are needed to further substantiate this effect.

Cefuroxime axetil loaded gastroretentive floating tabletsbased on hydrophilic polymers: preparation and in vitro evaluation

The aim of this work was to study the formulation and in vitro characterization of hydro dynamically balanced floating matrix tablets using Cefuroxime axetil (CA) as model drug. Different excipients such as hydroxy propyl methyl cellulose (HPMC) K15M, E5LV (gelling agent), sodium bicarbonate (gas generating agent) and sodium lauryl sulfate (SLS) (solubility enhancer) were used in order to optimize the drug release profile as well as floating property. Decrease in release characteristics with high viscous polymer were observed due to increased gel strength, tortuosity and length of drug diffusion path. Significant difference (p<0.5) in release rate was found at different concentration of SLS. The release mechanisms were explored and explained with zero order, first order, Higuchi, Korsmeyer and Hixson-Crowell equations. The release rate, extent and mechanism were governed by the content of polymer. The polymer content and amount of floating agent significantly affected the time required for 50%of drug release (t50%), mean dissolution time (MDT), release rate constant, and diffusion exponent (n).Kinetic modeling of dissolution profile revealed that the drug release mechanism could range from diffusion controlled to case II transport, which was co-dominated by diffusion polymer erosion in the release mechanism.

Ion-exchange resin complexation: Masking the bitter taste of cefuroxime axetil / Complejación de la resina de intercambio de iones: enmascaramiento del sabor amargo de cefuroxime acetil

OBJECTIVE: the purpose of this research was to formulate taste masked complexes of cefuroxime axetil and to evaluate them for taste, drug loading and characterized by FTIR, XRD. Tablets were formulated of selected batches and evaluated for drug release and physical parameters. METHODS: complexation technique is used to prepare complexes of drug where ion exchange resins such as Indion® 214, Indion® 234 and Indion® 414 were used with a drug-resin ratio of 1:0.5, 1:1, 1:2. The drug resinates were characterized by Infrared Spectroscopy, DSC and X-Ray Diffraction pattern and evaluated for drug loading and taste. Direct compression method was used to formulate tablets. In vitro dissolution was carried out using USP II apparatus. RESULT: potential taste masking increased with increasing concentration of resin. Indion® 214 resin showed better taste masking effect as compared to Indion® 234 and Indion® 414. Percent of drug loading was maximum at drug : resin ratio of 1:1, after that it decreased. Prolonged (upto 5 h) and slow drug release was observed with resin 214 at higher concentration. CONCLUSIONS: out of three resins chosen, Indion® 214 at higher concentration exhibit excellent taste masking as well as sustained drug release action.

OBJETIVO: el objetivo de esta investigación fue formular los complejos con sabor amargo de cefuroxime acetil y evaluarlos por sabor, carga medicamentosa y caracterización por FTIR, XRD. Las tabletas fueron formuladas a partir de lotes seleccionados y evaluados en busca de la liberación medicamentosa y parámetros físicos. MÉTODOS: la técnica de complejación se utilizó para preparar complejos farmacológicos donde las resinas de intercambio iónico como Indion® 214, Indion® 234 y el Indion® 414 se emplearon a una proporción resina-medicamento de 1:0.5, 1:1, 1:2. Los resinados medicamentosos fueron caracterizados mediante espectroscopia infrarroja, DSC y el patrón de difracción-rayos-X, y evaluados para determinar la carga medicamentosa y el sabor. El método de compresión directa fue empleado para formular las tabletas. Se efectuó una disolución in vitro utilizando el equipo USP II. RESULTADOS: el posible enmascaramiento del sabor aumentó con la creciente concentración de resina. La resina Indion® 214 mostró el mejor enmascaramiento del gusto amargo en comparación con Indion® 234 e Indion® 414. El porcentaje de carga medicamentosa fue máximo en el fármaco: proporción de la resina 1:1, después disminuyó. Se observó una liberación medicamentosa prolongada (hasta 5 h) y lenta con la resina 214 a una mayor concentración. CONCLUSIONES: de las 3 resinas escogidas, Indion®214 a una mayor concentración muestra un excelente enmascaramiento del sabor así como una mantenida acción liberadora del fármaco.

Preparation of Cefuroxime Axetil Bitter-masked Pellets / 中国药房

OBJECTIVE:To prepare bitter masked-pellets of cefuroxime axetil.METHODS:Cefuroxime axetil pellets were prepared by means of powder layering with the centrifugal granulation equipment,cefuroxime axetil pellets were coated in a fluid-bed equipment and the bitter was masked,and the dissolution of the preparation was determined.RESULTS:The recovery of the pellets between 40～50 meshes and yield rates was 89.5%;the drug content was 6.29% and the dissolution was 80% at 45 min.CONCLUSION:Bitter masked-pellets of cefuroxime axetil can be prepared by the fluid-bed coating method.

GCF concentration and minimal inhibitory concentration of cefuroxime axetil against periodontopathogens / 대한치주과학회지

The purpose of this study was to determine the minimal inhibitory concentration (MIC) of cefuroxime axetil, semisynthetic cefalosporin, for some putative periodotopathogens; F. nucleatum, A. actinomycetemcomitans P. intermedia and P. gingivalis. To investigate the efficacy of cefuroxime axetil, several antibiotics, amoxicillin, metronidazole, and ciprofoxacine, were used as control. The MIC was measured by Murray's method. The MIC of cefuroxime axetil against some putative microbes, as a single use regimen, was relatively high in comparison with that of the other antibiotics used in this study. The MIC of cefuroxime axetil/metronidazole against some putative microbes, as a simultaneous regimen, was similar to that of the other antibiotics used in this study. The manimal level of cefuroxime concentration in gingival fluid was 9 microgram/ml at 36hr after the first dose. In conclusion, within the limited experiment, metronidazole/ cefuroxime axetil therapy of periodontitis may provide a therapeutic benefits in reducing the periodontopathogens.

Comparison of Quality Evaluation of Cefuroxime Axetil Tablets from 4 Pharmaceutical Factories / 中国药房

OBJECTIVE:To evaluate the quality of cefuroxime axetil tablets from four pharmaceutical factories. METHODS:3 batches of samples of each factory were collected from A,B,C,D pharmaceutical factories. The quality of them were evaluated according to Chinese Pharmacopeia(2005 edition)with contents,isomers,moisture,weight variation and in vitro dissolution as indexes. The dissolution parameters(T50,Td,m)were adopted for variance analysis. RESULTS:Contents,isomers,moisture, weight variation and in vitro dissolution of samples from four pharmaceutical factories were up to standard. There was no significant difference in dissolution parameter T50 among four pharmaceutical factories;the difference of parameters(Td,m)was very significant. There was relatively significant difference in parameters(Td,T50)of 3 batches from B factory. CONCLUSION:The quality of cefuroxime axetil tablets from four pharmceutical factories is almost in line with standards stated in Chinese Pharmacopeia while samples from B factory need to be improved in uniformity.

Preparation of Cefuroxime Axetil Tablets by Dry Granulation / 中国药房

OBJECTIVE:To study the dry granulating technology in the preparation of cefuroxime axetil tablets so as to establish the preparative method.METHODS:With granule size,fluidity and yield as indexes to optimize the dry granulating technology for cefuroxime axetil tablets,and a comparative study was conducted on quality and stability of the samples prepared by wet process.RESULTS:The optimum conditions for the dry granulating technique were as follows:hydraulic pressure = 2.5～3 MPa,extrusion rate = 15～20 r?min-1,powder feed rate=200～300 g?min-1.The extrusion thickness was controlled at 1～2 mm.By circular dry granulating method,the proportion of qualified granules(16～30 meshes) was as high as above 90%,with an angle of repose of 30? and good mobility,and the yield was about 94%,with all indexes in line with the standards specified in Chinese Pharmacopoeia(2005 edition) in the accelerated test and permanent stability test.CONCLUSION:The optimized technological parameters and the mildly readjusted formulation can meet the requirements for the dry granulation method,with the stability of the product superior to that by wet method,and this method has a good reproducibility and shorter production cycle.

Treatment of Lower Respiratory Infections:A Cost-effectiveness Analysis of Two Cephalosporins / 中华医院感染学杂志

0.05). The total cost of two drugs were 163.85 yuan and 104.04 yuan respectively,showing significant difference (P