| Objective: Marbofloxacin(MBF) belongs to the third generation quinolone antibacterial drugs, which has wide antimicrobial spectrum, long elimination half-life, and high bioavailability. It mainly used for the treatment of mastitis-metritis-agalactia syndrome(MMA) in sow and bacterial respiratory tract infection in cattle in the foreign countries. The dosage form of Marbofloxacin is mainly injection(2%, 10%), which has been widely used in the European Union, New Zealand, Japan and other countries. This study intends to develop marbofloxacin injection.Methods: The choice of solvent and excipients of Marbofloxacin injection were mainly based on the physicochemical properties of marbofloxacin and the injection General requirements under the 2010 edition of "Chinese Veterinary Pharmacopoeia". Marbofloxacin can dissolve in water stably by solubilizing, so injection water was chosen as solvent, and the excipients such as antioxidant and cosolvent were determined according to the related experiments. Several prescriptions were selected and examined by relevant studies, finally the prescription and the process were determined.Referring to the marbofloxacin quality standard of the "European Pharmacopoeia 8.0" recorded and the requirements of quality standards of marbofloxacin injection of the 2010 "China Veterinary Pharmacopoeia", the content was determined by high performance liquid chromatography.According to the marbofloxacin quality standard in "European Pharmacopoeia 8.0", storage provided showed that "this product preserved to avoid light". In our study, the stability test was conducted, the rules of changes of marbofloxacin injection with time in the effect of temperature and humidity were studied, the accelerated and long-term tests were carried out..In our study, sows were used as experimental animal. According to the two period crossover design, the drug release characteristics of marbofloxacin were determined in vivo using intravenous and intramuscular injection respectively. Drug concentration in the blood was Determined using internal standard method of HPLC. Silica gel column was used, mobile phase was p H3.0 formic acid solution acetonitrile and water =76:15:9, flow rate was 1.0 m L·min-1, column temperature was 30℃ and detection wavelength was 295 nm.Results: The selection of the prescription of marbofloxacin injection was mainly based on the requirements under the 2010 Edition "Chinese Veterinary Pharmacopoeia", the properties of marbofloxacin and the prescription of other relevant quinolone drugs. From the results of the preliminary investigation, hydrochloric acid, lactic acid, sulfuric acid, sodium hydroxide and potassium hydroxide with marbofloxacin with the molar ratio of 1.1:1, the marbofloxacin could be completely dissolved in water; above solutions were stayed 24 h at 60℃ water bath and HPLC detection of the related substances found that, in the alkaline solution(sodium hydroxide, potassium hydroxide solubilization), the related substances of marbofloxacin were observed obvious increase, and in the acidic solution, marbofloxacin was relatively stable. Therefore, acidic solvent was used in the marbofloxacin injection. The acidic and clarify solutions were stayed for 24 h at 3~8℃ and varying degrees of turbidity and precipitate phenomenon was observed. Using 1% EDTA-2Na as the stabilizer, low-temperature placing test found that 5% lactic acid as the cosolvent, we could achieve the 10% marbofloxacin solution which was stable.Marbofloxacin solution prepared was light yellow transparent liquid, p H value was 3.5-5.0, the content of sample was determined by high performance liquid chromatography and the results met the specification.The samples of marbofloxacin injection were stayed in the temperature of 40±2℃, relative humidity of 75±5% conditions, we found that sample characteristics, p H, related substances and content had no obvious changes, in the temperature of 25±2℃, relative humidity of 60±10% conditions, sample characteristics, p H, related substances and content of marbofloxacin injection had no obvious changes.The studies on pharmacokinetics of marbofloxacin in sows were conducted via intramuscular injection and intravenous injection and the results show that after the intravenous injection with marbofloxacin injection(2 mg·kg-1) in sparfloxacin healthy sows, the apparent volume of distribution Vd was 1.41 L·kg-1, the steady-state volume of distribution was 1.28 L·kg-1. The results showed that marbofloxacin was widely distributed. The half-life of elimination of marbofloxacin(t1/2 beta) was 16.09 h. Intramuscular injection of marbofloxacin injection(2 mg·kg-1) in the healthy sows were observed after administration of the drug, the concentration-time curve showed that marbofloxacin was absorbed very rapidly, tmax=2.39 h, Cmax=2.20 μg·m L-1; t1/2β =18.10 h, and eliminated slowly.Conclusion: This study selected the prescription for preparing marbofloxacin injection. By using 1% EDTA-2Na as the stabilizer, 5% lactic acid as the cosolvent, we could achieve the 10% marbofloxacin solution which was stable. Marbofloxacin injection prepared was light yellow transparent liquid and the indicators met the quality standards. Marbofloxacin injection prepared was stable under the conditions of high temperature and high humidity. Accelerated test and long-term test showed that the sample had good stability. The pharmacokinetics of marbofloxacin injection showed that after administration, marbofloxacin distributed widely, the half-life(t1/2β) was 16.09 h, the absorption was rapid, tmax=2.39 h, Cmax=2.20 g·m L-1; t1/2β was 18.10 h, and eliminated slowly. |
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