盐酸二氟沙星混悬乳剂的研制及其在猪体内的药动学研究
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摘要
盐酸二氟沙星(Difloxacin Hydrochloride)是动物专用氟喹诺酮类药物,具有抗菌谱广、口服吸收迅速、半衰期长、低毒、高效等特点。混悬乳剂能降低药物毒副作用和刺激性,实现靶向、缓释、长效作用。本课题制备了盐酸二氟沙星混悬乳剂,并考察了其理化性质和稳定性,同时研究了其在猪体内的药动学特征。具体内容如下：
1盐酸二氟沙星混悬乳剂处方筛选和工艺考察
为了筛选出盐酸二氟沙星混悬乳剂的最佳处方和工艺。本试验采用多指标综合评价法,通过正交设计结合超声波乳化技术,筛选出最优处方和制备工艺,完成实验室初步筛选。再经高压均质中试放大生产,制备盐酸二氟沙星混悬乳剂。结果显示：盐酸二氟沙星混悬乳剂最佳处方为药物5%,注射用大豆油20%,乳化剂9%,油酸0.09%；实验室最佳制备工艺为制备温度70℃,乳化时间20 min,超声频率400 W。用高压均质机在15000 pa压力条件下,反复均质10次进行中试放大生产,即制得盐酸二氟沙星混悬乳剂。结果表明：盐酸二氟沙星混悬乳剂符合药典规定,中试放大制备的混悬乳剂性质稳定,可以进行工业化生产。
2盐酸二氟沙星混悬乳剂理化性质及稳定性考察
为了对盐酸二氟沙星混悬乳剂的质量进行评价。本试验考察了盐酸二氟沙星混悬乳剂的理化性质及稳定性,测定了其粒径、pH值、黏度和含量,同时分别进行了40℃高温试验、4500±500 Lx强光照射试验、加速试验及长期试验。结果显示,制备的盐酸二氟沙星混悬乳剂最佳处方的平均粒径为22.30μm, pH值为7.44,黏度为19.5mPa·s。光照对混悬乳剂稳定性的影响比较大；在30±2℃及室温条件下放置6个月后,平均粒径、pH值及含量等均无明显变化,理化性质稳定。结果表明,盐酸二氟沙星混悬乳剂符合药典规定,中试放大制备的混悬乳剂性质稳定,可以进行工业化生产。
3盐酸二氟沙星混悬乳剂在猪体内的药动学研究
为了评价盐酸二氟沙星混悬乳剂是否具有长效特征。本试验利用HPLC法测定猪血浆中盐酸二氟沙星浓度,并研究了盐酸二氟沙星混悬乳剂在猪体内的药动学特征。健康猪6头,单次肌肉注射推荐剂量(5 mg·kg-1)的5%盐酸二氟沙星混悬乳剂,血浆样品经甲醇沉淀血浆蛋白,高速离心,取上清液进行HPLC分析。色谱条件为C18反相柱,乙腈-0.03 mol·L-1四丁基溴化铵-水(150:70:780, V/V/V)为流动相,磷酸调pH至3.0。药-时数据用3P97药动软件分析。结果显示：猪单次肌肉注射盐酸二氟沙星混悬乳剂后,血药浓度和时间关系符合一级吸收一室模型,主要药动学参数为：吸收半衰期t1／2 ka 1.38±0.11 h,消除半衰期t1／2ke24.97±5.38 h,达峰时间tmax 6.07±0.46 h,达峰浓度Cmax1.38±0.07μg·ml-1,药时曲线下面积AUC 58.78±12.99μg·ml-1·h。结果表明：盐酸二氟沙星混悬乳剂在猪体内吸收、消除缓慢,峰浓度较低,有效血药浓度维持时间长,药物在体内作用时间延长,具有长效特征。
Difloxacin hydrochloride is one of fluoroquinolones used only for veterinary, and shows a broad spectrum and high performance of antimicrobial activity with low toxicity. It can be rapidly absorbed by oral administration, and has long half-life. Suspension emulsions can achieve the effect of target treatment, sustained release and long-acting, which can reduce the drug toxic, side effects and stimulation. Preparation of difloxacin hydrochloride suspension emulsions and its pharmacokinetics in pigs were studied in this paper.
1 Preparation and Characterization of Difloxacin Hydrochloride Suspension Emulsions for Injection
To select the best prescription and preparation method of difloxacini hydrochloride. The difloxacin hydrochloride suspension emulsions was prepared by ultrasonic method in laboratory, and produced by high pressure homogenizing method in factory. The prescription and preparation were optimized by orthogonal experimental design, with the compositive ingredient as criteria. The results showed that the optimal formulation was composed by soybean oil for injection 20%, emulsifier 9%, oleic acid 0.09%. The preparation was conducted by ultrasonic with 400 w, keeping 20 min, at 70℃in laboratory. And difloxacin hydrochloride suspension emulsion was prepared by a high pressure homogenizing method to practice in pharmaceutical factory under 15000 pa pressure. Prescription and preparation selected was consistented with the requirement that instituted by Pharmacopeia and could be produced in factory.
2 Physicochemical Property and Stability of Difloxacin Hydrochloride Suspension Emulsions
To evaluate the quality of difloxacin hydrochloride suspension emulsions. The physicochemical property, stability of difloxacin hydrochloride suspension emulsions and its particle size, pH, viscosity and contents were investigated. The suspension emulsions was evaluated at 40℃,4500±500 Lx illuminate for 10 d. The results showed that the average particle size of suspension emulsions was 22.30μm, the pH was 7.44, the viscosity was 19.8 mPa·s. This study revealed that highlight was the important factor in suspension emulsions stabilization. There were no obvious changes about average particle size, pH and content in 6 months at 30±2℃. Prescription and preparation selected was consistented with the requirement that instituted by Pharmacopeia and could be produced in factory.
3 Studies on Pharmacokinetics of Difloxacin Hydrochloride Suspension Emulsions in Pigs
To evaluate the prolonged release characteristic of difloxacin hydrochloride suspension emulsions. HPLC method was estabalished to determine difloxacin hydrochloride and to study its pharmacokinetics in swine plasma. Pharmacokinetics of difloxacin hydrochloride were investigated in 6 healthy pigs following single intramuscular administration at the dosage of 5 mg·kg-1 of the difloxacin hydrochloride suspension emulsions. Plasma samples were collected at different intervals after administration and difloxacin hydrochloride concentration were determined by HPLC with UV detector. was used as the revesed column, acetonitrile:0.03 mol·L-1 tetrabutyl ammonium bromide: water(150:70:780, V/V/V) as the mobile phase, pH=3.0. The concentration-time data were analyzed with 3p97 computer program. The results showed that the plasma concentration and relation were best fitted with one-compartment and 1st absorption model after i.m. injection. The main pharmacokinetic paramerter were:t1/2 ka 1.38±0.11 h, t1/2 ke 24.97±5.38 h, tmax 6.07±0.46 h, Cmax 1.38±0.07μg·ml-1, AUC 58.78±12.99μg·ml-1·h. The results indicated that the difloxacin hydrochloride suspension emulsions was slowly absorbed and eliminated in pigs, and had lower Cmax, the time that therapeutic plasma concentration and difloxacin hydrochloride action in pigs had been prolonged.
1盐酸二氟沙星混悬乳剂处方筛选和工艺考察
为了筛选出盐酸二氟沙星混悬乳剂的最佳处方和工艺。本试验采用多指标综合评价法,通过正交设计结合超声波乳化技术,筛选出最优处方和制备工艺,完成实验室初步筛选。再经高压均质中试放大生产,制备盐酸二氟沙星混悬乳剂。结果显示：盐酸二氟沙星混悬乳剂最佳处方为药物5%,注射用大豆油20%,乳化剂9%,油酸0.09%；实验室最佳制备工艺为制备温度70℃,乳化时间20 min,超声频率400 W。用高压均质机在15000 pa压力条件下,反复均质10次进行中试放大生产,即制得盐酸二氟沙星混悬乳剂。结果表明：盐酸二氟沙星混悬乳剂符合药典规定,中试放大制备的混悬乳剂性质稳定,可以进行工业化生产。
2盐酸二氟沙星混悬乳剂理化性质及稳定性考察
为了对盐酸二氟沙星混悬乳剂的质量进行评价。本试验考察了盐酸二氟沙星混悬乳剂的理化性质及稳定性,测定了其粒径、pH值、黏度和含量,同时分别进行了40℃高温试验、4500±500 Lx强光照射试验、加速试验及长期试验。结果显示,制备的盐酸二氟沙星混悬乳剂最佳处方的平均粒径为22.30μm, pH值为7.44,黏度为19.5mPa·s。光照对混悬乳剂稳定性的影响比较大；在30±2℃及室温条件下放置6个月后,平均粒径、pH值及含量等均无明显变化,理化性质稳定。结果表明,盐酸二氟沙星混悬乳剂符合药典规定,中试放大制备的混悬乳剂性质稳定,可以进行工业化生产。
3盐酸二氟沙星混悬乳剂在猪体内的药动学研究
为了评价盐酸二氟沙星混悬乳剂是否具有长效特征。本试验利用HPLC法测定猪血浆中盐酸二氟沙星浓度,并研究了盐酸二氟沙星混悬乳剂在猪体内的药动学特征。健康猪6头,单次肌肉注射推荐剂量(5 mg·kg-1)的5%盐酸二氟沙星混悬乳剂,血浆样品经甲醇沉淀血浆蛋白,高速离心,取上清液进行HPLC分析。色谱条件为C18反相柱,乙腈-0.03 mol·L-1四丁基溴化铵-水(150:70:780, V/V/V)为流动相,磷酸调pH至3.0。药-时数据用3P97药动软件分析。结果显示：猪单次肌肉注射盐酸二氟沙星混悬乳剂后,血药浓度和时间关系符合一级吸收一室模型,主要药动学参数为：吸收半衰期t1／2 ka 1.38±0.11 h,消除半衰期t1／2ke24.97±5.38 h,达峰时间tmax 6.07±0.46 h,达峰浓度Cmax1.38±0.07μg·ml-1,药时曲线下面积AUC 58.78±12.99μg·ml-1·h。结果表明：盐酸二氟沙星混悬乳剂在猪体内吸收、消除缓慢,峰浓度较低,有效血药浓度维持时间长,药物在体内作用时间延长,具有长效特征。
Difloxacin hydrochloride is one of fluoroquinolones used only for veterinary, and shows a broad spectrum and high performance of antimicrobial activity with low toxicity. It can be rapidly absorbed by oral administration, and has long half-life. Suspension emulsions can achieve the effect of target treatment, sustained release and long-acting, which can reduce the drug toxic, side effects and stimulation. Preparation of difloxacin hydrochloride suspension emulsions and its pharmacokinetics in pigs were studied in this paper.
1 Preparation and Characterization of Difloxacin Hydrochloride Suspension Emulsions for Injection
To select the best prescription and preparation method of difloxacini hydrochloride. The difloxacin hydrochloride suspension emulsions was prepared by ultrasonic method in laboratory, and produced by high pressure homogenizing method in factory. The prescription and preparation were optimized by orthogonal experimental design, with the compositive ingredient as criteria. The results showed that the optimal formulation was composed by soybean oil for injection 20%, emulsifier 9%, oleic acid 0.09%. The preparation was conducted by ultrasonic with 400 w, keeping 20 min, at 70℃in laboratory. And difloxacin hydrochloride suspension emulsion was prepared by a high pressure homogenizing method to practice in pharmaceutical factory under 15000 pa pressure. Prescription and preparation selected was consistented with the requirement that instituted by Pharmacopeia and could be produced in factory.
2 Physicochemical Property and Stability of Difloxacin Hydrochloride Suspension Emulsions
To evaluate the quality of difloxacin hydrochloride suspension emulsions. The physicochemical property, stability of difloxacin hydrochloride suspension emulsions and its particle size, pH, viscosity and contents were investigated. The suspension emulsions was evaluated at 40℃,4500±500 Lx illuminate for 10 d. The results showed that the average particle size of suspension emulsions was 22.30μm, the pH was 7.44, the viscosity was 19.8 mPa·s. This study revealed that highlight was the important factor in suspension emulsions stabilization. There were no obvious changes about average particle size, pH and content in 6 months at 30±2℃. Prescription and preparation selected was consistented with the requirement that instituted by Pharmacopeia and could be produced in factory.
3 Studies on Pharmacokinetics of Difloxacin Hydrochloride Suspension Emulsions in Pigs
To evaluate the prolonged release characteristic of difloxacin hydrochloride suspension emulsions. HPLC method was estabalished to determine difloxacin hydrochloride and to study its pharmacokinetics in swine plasma. Pharmacokinetics of difloxacin hydrochloride were investigated in 6 healthy pigs following single intramuscular administration at the dosage of 5 mg·kg-1 of the difloxacin hydrochloride suspension emulsions. Plasma samples were collected at different intervals after administration and difloxacin hydrochloride concentration were determined by HPLC with UV detector. was used as the revesed column, acetonitrile:0.03 mol·L-1 tetrabutyl ammonium bromide: water(150:70:780, V/V/V) as the mobile phase, pH=3.0. The concentration-time data were analyzed with 3p97 computer program. The results showed that the plasma concentration and relation were best fitted with one-compartment and 1st absorption model after i.m. injection. The main pharmacokinetic paramerter were:t1/2 ka 1.38±0.11 h, t1/2 ke 24.97±5.38 h, tmax 6.07±0.46 h, Cmax 1.38±0.07μg·ml-1, AUC 58.78±12.99μg·ml-1·h. The results indicated that the difloxacin hydrochloride suspension emulsions was slowly absorbed and eliminated in pigs, and had lower Cmax, the time that therapeutic plasma concentration and difloxacin hydrochloride action in pigs had been prolonged.
引文
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