The purpose of this study was to predict the stability of meropenem in a mixed infusion. The hydrolysis of meropenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (k obs ) of pH, SBS and L-cysteine, and fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (E a ) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the characteristic pH curve. From these results, an equation was derived giving the residual ratio (%) of meropenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature, and in the pH range 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; meropenem; pH; sodium bisulfite (SBS); L-cysteine; degradation rate constant Carbapenems are the most potent β-lactam antibiotics and were first developed in the 1980s to enhance resistance to β-lactamases. The early carbapenems were not very hydrolytically stable, however, limiting drug administration to controlled intravenous infusions. In the search for a more stable compound with better toxicity profile, the basic nuclear structure was maintained and a dimethyl carbamoyl-pyrrolidinylthio group was added as a weakly basic C-2 side-chain. This resulted in a reduction of central toxicity and nephrotoxicity, while maintaining anti-pseudomonal activity. In addition, the improvement of stability (DHP-I stability) in vivo and the improvement of activity against Haemophilus influenzae, etc., were achieved by introducing 1-β-methyl group into the carbapenem frame, resulting in the creation of meropenem. The improvement in nephrotoxicity was the key advance in allowing the global development of meropenem as a single agent. 1)Meropenem is a broad-spectrum carbapenem, active against several clinically relevant Gram-positive and Gram-negative aerobes, anaerobic bacteria and Pseudomonas aeruginosa. The bactericidal activity of meropenem results from the inhibition of cell wall synthesis through the inactivation of penicillin-binding proteins.Sodium and fluorouracil. 8) However, there are no reports of detailed kinetic studies on the degradation of meropenem in the presence of SBS.The prediction of the stability of a drug in an intravenous admixture (mixed infusion) is important for accurate and safe drug administration. Generally, the stability of a drug in a mixed infusion can be predicted from the pH profile and Arrhenius equation of the degradation rate constants, if the temperature and pH of the test solution are known. Although meropenem is generally administered as an infusion in saline, in some cases it may be mixed with other substances, such as amino acids. 9)A method for predicting the pH of mixed infusions was developed in orde...
The purpose of this study was to compare the compatibility of ROCEPHINE ® Intravenous, the original manufacturer's ceftriaxone sodium preparation for injection, and seven generic versions thereof, with various calcium chloride injection 2%. The influence of calcium ion concentration, storage time and shaking strength on the appearance and quantity of insoluble microparticles in mixed solutions was examined using a light obscuration particle counter. In all products, the observed number of insoluble microparticles was proportional to the calcium ion concentration, storage time and shaking strength after the addition of calcium chloride solution. In several of the generic products, the number of insoluble microparticles was significantly higher than those of the original product, while in others it was lower. We evaluated the quality of the original and 7 generic preparations, measured the content of impurity and pH of the various ceftriaxone solutions, as impurity content and pH of solution are possible factor affecting compatibility. Three impurities were found in all products. The impurity content of several generic products, as estimated from their peak area on high performance liquid chromatography (HPLC), was significantly lower than that of the original product. pH of solution was difference between products. Although it was difficult that impurity and pH of solution verify critical factor affecting compatibility. The results show that there are differences in the appearance of insoluble microparticles between the original product and seven generic products, when calcium chloride injection 2% solution is added to the product.
Ceftriaxone sodium preparation for injection is known to form insoluble microparticles with calcium. The purpose of this study was to evaluate the role of an impurity in the ceftriaxone sodium preparation on this incompatibility. Firstly, using HPLC, two impurities were identified in the ceftriaxone sodium solution. The major impurity (impurity 1) was identified as tetrahydro-2-methyl-3-thioxo-1,2,4-triazine-5,6-dione by LC/MS. Secondly, the role played by this impurity in the incompatibility with calcium was examined. Using seven different ceftriaxone preparations for injection, the effect of adding impurity 1 to mixed solutions of ceftriaxone sodium and calcium chloride on the appearance of insoluble microparticles, was examined using a light obscuration particle counter. Although incompatibility was not completely suppressed by the addition of impurity 1, the number of insoluble microparticles formed with calcium chloride solution was decreased in proportion to the concentration of impurity 1, and the concentration of calcium ion decreased as the concentration of added impurity 1 increased. These results show that impurity 1 plays a concentration-dependent role in incompatibility between ceftriaxone sodium preparation for injection and calcium-containing solutions.
The purpose of the study was to evaluate the adsorption of filgrastim on infusion sets (comprising infusion bag, line and filter) and to compare the adsorption of the original filgrastim preparation with biosimilar preparations using HPLC. The inhibitory effect of polysorbate 80 on this adsorption was also evaluated. Filgrastim was mixed with isotonic sodium chloride solution or 5% (w/v) glucose solution in the infusion fluid. Filgrastim adsorption on infusion sets was observed with all preparations and with both types of infusion solution. The adsorption ratio was about 30% in all circumstances. Filgrastim adsorption on all parts of the infusion set (bag, line and filter) was dramatically decreased by the addition of polysorbate 80 solution at concentrations at or over its critical micelle concentration (CMC). The filgrastim adsorption ratio was highest at a solution pH of 5.65, which is the isoelectric point (pI) of filgrastim. This study showed that the degree of filgrastim adsorption on infusion sets is similar for original and biosimilar preparations, but that the addition of polysorbate 80 to the infusion solution at concentrations at or above its CMC is effective in preventing filgrastim adsorption. The addition of a total-vitamin preparation with a polysorbate 80 concentration over its CMC may be an effective way of preventing filgrastim adsorption on infusion sets. Key words filgrastim; adsorption; infusion set; polysorbate 80The Japanese government now actively promotes the use of generic drugs in order to reduce national medical expenditure.1) As part of the drive to reduce health costs, biosimilar preparations are also beginning to be used in clinical practice in place of original biologicals. However, there are growing concerns about switching from the original preparation to biosimilar preparations in clinical practice.2) In contrast to generic preparations, it is widely considered to be impossible to make biosimilar preparations with identical biophysical properties to the original preparations. The uptake of biosimilar preparations has not been as rapid as the change to generic preparations as switching to a biosimilar preparation does not result in as much cost savings as switching to a generic preparation, bio-pharmaceuticals also being covered by high-cost illness insurance.Filgrastim is a granulocyte colony-stimulating factor used to treat neutropenia. Generally, filgrastim is administered subcutaneously but in patients with a known bleeding disorder, intravenous infusions may be required. In previous reports, original and biosimilar preparations of filgrastim have been shown to have similar clinical effects. [3][4][5] In previous reports, it has been demonstrated that protein preparations, such as insulin, adsorb to infusion sets, 6-8) and filgrastim adsorption on infusion sets has also been reported.9-13) Thus, it is possible that the actual dose of filgrastim infused will be smaller than the theoretical dose predicted. Yagi and Kawa have also found that differences in flow rate affect the ...
This study aimed to compare the dissolution rate of eight different formulations of ceftriaxone sodium preparation for injection, the original product and seven generic versions. The dissolution time was measured precisely as the point at which the freeze-dried ceftriaxone sodium preparation became a transparent solution on the addition of 0.9% sodium chloride solution. To investigate whether differences in the crystalline structure may explain the differences in dissolution rates, the eight products were subjected to X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Powder surface characteristics were examined, including surface area, amount of water adsorbed, water interactions and morphology. The measurement of near-infrared spectroscopy of powder preparations was conducted, and we predicted dissolution time by partial least squares (PLS). The dissolution time of the eight products were different. There were no differences in XRD and DSC findings between the original and generic products, surface characteristics, i.e., surface area, morphology etc., were different between preparations. On near-infrared (NIR) spectroscopy, a good relationship was demonstrated between the actual and predicted dissolution time for each ceftriaxone preparation. The difference in dissolution time between the eight products was due to differences in powder surface characteristics, such as water interaction and crystal shape. Finally, it was shown that the dissolution rates of the products could be predicted by NIR analysis.Key words dissolution rate; near-infrared spectroscopy; X-ray diffraction; differential scanning calorimetry; generic drug; powder property Dissolution properties are important in the formulation design of pharmaceutical preparations, and improvement in dissolution rate is a critical issue in drug development for nonparenteral preparations. There are a number of mathematical models for dissolution profile.
The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (k obs ) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasiNewton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; octreotide; pH; sodium bisulfite (SBS); pH characteristic (PHC) curve; degradation rate constant, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.1-3) The cyclic structure of octreotide ( Fig. 1) seems to play an important role in determining its unique pharmacological activity.Octreotide is increasingly used to treat symptoms of sickness and vomiting in terminal care patients suffering from gastrointestinal ileus. It is also used, in combination with standard therapies, in the symptom management of inoperable bowel obstructions in terminal cancer patients. [4][5][6] In Japan, octreotide is usually administered subcutaneously, but in the U.S. it is more often administered by deep subcutaneous (intrafat) or intravenous injection.3) The pharmacokinetics of octreotide are similar to those of many other agents administered continuously via intravenous or subcutaneous infusion, 7) and similar changes in pharmacokinetics would be expected if octreotide were to be administered by continuous intravenous administration instead of sustained subcutaneous administration, i.e., without the need for special equipment (e.g., miniature pump).We have been unable to find any reports describing the time-dependent stability of octreotide in amino acid infusions under different pH, temperature and ingredient such as sodium bisulfite. Especially, we have been unable to find reports evaluating such time-dependent stability of octreotide in amino acid infusions quantitatively.Hanamura et al. 8) report on the stability of octreotide in glucose and saline infusions, but its stability in amino acid infusion fluids was not investigated in detail. We have been unable to find any reports describing the stability of octreotide in amino acid infusions. Sodium bisulfite (SBS), which is used as a stabilizer in injectable preparations, is known to degrade various drugs, including thiamine, 9) epinephrine, 10) gabexate mesilate, 11) nafamostat mesilate, 12) urokinase, 13) morphine, 14)fluorouracil 15) and imipenem. 16) However, there ...
The purpose of the study was to evaluate the compatibility of ozagrel sodium solution and calciumcontaining transfusions using solubility product constants. We calculated the solubility product constant of mixtures of ozagrel sodium and calcium chloride and evaluated the compatibility of ozagrel sodium solution (both the original and generic products) with calcium chloride solution using a light obscuration particle counter. Various volumes of ozagrel solution were added to the calcium solutions to make final ozagrel concentrations of 0, 0.8, 1.6, 2.0, 2.4, 3.2 and 4.0 mmol/L. The solutions were gently agitated and stored at 25 and 40°C. The ozagrel concentration, calcium ion concentration and number of microparticles were measured. The solubility product constants obtained were 11.89×10 −9 mol 3 /L 3 (at 25°C) and 7.82×10 −9 mol 3 /L 3 (40°C). The number of insoluble microparticles was significantly increased when the ionic product was larger than the solubility product constant. In all ozagrel sodium products, the number of insoluble microparticles was within the allowable range according to the Japanese Pharmacopoeia. These results suggest that mixing ozagrel sodium with calcium-containing products is safe and without appreciable risk of incompatibility under clinical conditions.
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