明矾注射液的研制及其药效学和药动学研究
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摘要
制备明矾注射液，考察其稳定性、安全性、抗氰效果及在家兔体内的药物代谢情况。
1. 按输液剂生产工艺规程配制明矾注射液，其渗透压是410.10 mmol/L，为高渗溶液，注射液配制中应维持pH 3.0～4.5，三批次注射液中明矾标示量为98.93%～100.12% ，葡萄糖标示量为98.60%～100.21%，均为无色澄明液体。试验结果显示明矾注射液成品有效成分标示量、pH值、澄明度、渗透压、稳定性等指标符合静脉注射剂的质量要求，配制工艺简单，适合大批量生产。
2. 光加速试验结果显示明矾注射液对对自然光不稳定但对热较稳定。采用经典恒温热加速实验，研究温度对明矾注射液分解反应速率的影响，符合Arrhenius指数定律，由试验数据所得方程线形良好(r=-0.9376；n=4), 避光条件下室温25℃时的预测有效期为3年。长期试验数据可以看出,在不避光条件下室温放置12月后含量仍在97%以上。
3. 小白鼠注射2％明矾正常用量的11.4倍（0.25ml/10g）时，无毒性作用，达正常用量的22.8倍时，个别小鼠出现以血管扩张为主的病理变化，表明按正常用量不会产生毒性作用。通过安全性试验指标的检测证明，明矾注射液澄明度高不含细菌和霉菌，无溶血作用，热源检查符合药典规定。明矾注射液有一定的刺激性，注射时速度不宜太快，大部分家兔心电图正常，明矾注射液中的钾离子对心脏影响不大。
4．家兔按1LD（4.8mg/kg）的剂量皮下注射氰化钾，有足够的致死能力，可导致家兔迅速死亡。用明矾注射液按2.2ml/kg（44mg/kg）剂量静脉注射，对10只氰化钾中毒家兔进行治疗，治愈9只，治愈率高，疗效确实，使用方便，可以节约抢救时间，是一种较好的新型抗氰剂
5. 首次进行了明矾在家兔体内的药物代谢动力学研究，明矾在家兔体内的半衰期（half time，t1/2）为2.6797±0.6042h，体清除率CLB为0.5026±0.0116 dl·kg-1·h-1，药物总表观分布容积Vd值为1.9452±0.3371 dl·kg-1，说明明矾注射液代谢较快，在家兔体内分布较广。
6．通过铵明矾注射液制备、其稳定性、安全性的试验结果显示铵明矾注射液有效成分、标示量、pH值、渗透压、稳定性等指标符合静脉注射剂的质量要求，铵明矾也有与明矾类似的抗氰效果。
In present experiment, we prepared alum injection firstly, then studied it’s stability, security, effect on resisting cyanogens and the metabolize in the rabbit.
According to the technology of transfusion reagent preparation process, alum injection was made. Its osmotic pressure was 410.10 mmol/Ls, was a high osmotic pressure solution. The injection ought to maintain pH 3.0 ～4.5. The alum scalar quantity of three batches injection were 98.93%～100.12% and the glucose scalar quantity were 98.60% ～100.21%. All products were colorless and clear. The parameters of content’s scalar quantity, pH value, diaphaneity, osmotic pressure and stability accorded with the requirement of the vein injection. The producing process was simple and fits for a batch production.
The light accelerated testing displayed that the alum injection was not stable for sunlight but stable for heat.
The long term testing data showed that the 2% alum injection content maintained to 97% at normal temperature after 12 months. The classical constant temperature accelerating test results showed that the effect of the temperature on decomposition reaction rate accorded with Arrhenius index law. The linearity equation came from experiment data was well (r=-0.9376；n=4), the predicting value period of alum injection was three years at room temperature.
With 11.4 times regular dose （0.25ml/10g）injection of 2% alum injection to mouse, it was no toxicity. When injected 22.8 times regular dose, a few mouse appeared pathology change that the blood vessel enlarged mainly. All results showed it was no toxicity at the regular dose. The test of security experiment index revealed that the alum injections were colorless, clear, no bacteria and fungus, no hemolytic reaction. The pyrogen test was correspondence with the Veterinary Medicine Quality Standard and Rule of People’s Republic of china. There had a little stimulation of 2% alum injection and injecting it should be slow. The most rabbits electro- cardiogram was normal after injecting alum, the potassium ion was not effect on the heart.
With 1LD（4.8mg/kg）dose subcutaneous injection of potassuim cyanide to rabbits, that was enough to cause the rabbits die quickly. Injected alum injection with 44mg/kg dose into vein to treated 10 potassium cyanide poisoned rabbits, nine rabbits was recovered. The curing rate was high. The curative effect was creditable. It was convenient to use, and can save rescue time. Alum injection is a new good medicine to resisted cyanogens.
Study the pharmacokinetics of the 2% alum injection in the rabbit for the first time. Alum half life was 2.6797 ±0.6042 h. Body clearance was 0.5026 ±0.0116 dl·kg-1·h-1, Apparent volume of distribution was 1.9452 ±0.3371 dl·kg-1. It is indicated that the alum injection metabolized quickly, It’s distribution was widely in the rabbit body.
Prepared the ammonium alum injection, tested it’s stability, security, contain of ammonium alum、pH value and osmotic pressure. All results were corresponded with the quality requirement of vein injection. The effect of Ammonium alum injection was similar to alum injection to treatment cyanide poisoned rabbits.
1. 按输液剂生产工艺规程配制明矾注射液，其渗透压是410.10 mmol/L，为高渗溶液，注射液配制中应维持pH 3.0～4.5，三批次注射液中明矾标示量为98.93%～100.12% ，葡萄糖标示量为98.60%～100.21%，均为无色澄明液体。试验结果显示明矾注射液成品有效成分标示量、pH值、澄明度、渗透压、稳定性等指标符合静脉注射剂的质量要求，配制工艺简单，适合大批量生产。
2. 光加速试验结果显示明矾注射液对对自然光不稳定但对热较稳定。采用经典恒温热加速实验，研究温度对明矾注射液分解反应速率的影响，符合Arrhenius指数定律，由试验数据所得方程线形良好(r=-0.9376；n=4), 避光条件下室温25℃时的预测有效期为3年。长期试验数据可以看出,在不避光条件下室温放置12月后含量仍在97%以上。
3. 小白鼠注射2％明矾正常用量的11.4倍（0.25ml/10g）时，无毒性作用，达正常用量的22.8倍时，个别小鼠出现以血管扩张为主的病理变化，表明按正常用量不会产生毒性作用。通过安全性试验指标的检测证明，明矾注射液澄明度高不含细菌和霉菌，无溶血作用，热源检查符合药典规定。明矾注射液有一定的刺激性，注射时速度不宜太快，大部分家兔心电图正常，明矾注射液中的钾离子对心脏影响不大。
4．家兔按1LD（4.8mg/kg）的剂量皮下注射氰化钾，有足够的致死能力，可导致家兔迅速死亡。用明矾注射液按2.2ml/kg（44mg/kg）剂量静脉注射，对10只氰化钾中毒家兔进行治疗，治愈9只，治愈率高，疗效确实，使用方便，可以节约抢救时间，是一种较好的新型抗氰剂
5. 首次进行了明矾在家兔体内的药物代谢动力学研究，明矾在家兔体内的半衰期（half time，t1/2）为2.6797±0.6042h，体清除率CLB为0.5026±0.0116 dl·kg-1·h-1，药物总表观分布容积Vd值为1.9452±0.3371 dl·kg-1，说明明矾注射液代谢较快，在家兔体内分布较广。
6．通过铵明矾注射液制备、其稳定性、安全性的试验结果显示铵明矾注射液有效成分、标示量、pH值、渗透压、稳定性等指标符合静脉注射剂的质量要求，铵明矾也有与明矾类似的抗氰效果。
In present experiment, we prepared alum injection firstly, then studied it’s stability, security, effect on resisting cyanogens and the metabolize in the rabbit.
According to the technology of transfusion reagent preparation process, alum injection was made. Its osmotic pressure was 410.10 mmol/Ls, was a high osmotic pressure solution. The injection ought to maintain pH 3.0 ～4.5. The alum scalar quantity of three batches injection were 98.93%～100.12% and the glucose scalar quantity were 98.60% ～100.21%. All products were colorless and clear. The parameters of content’s scalar quantity, pH value, diaphaneity, osmotic pressure and stability accorded with the requirement of the vein injection. The producing process was simple and fits for a batch production.
The light accelerated testing displayed that the alum injection was not stable for sunlight but stable for heat.
The long term testing data showed that the 2% alum injection content maintained to 97% at normal temperature after 12 months. The classical constant temperature accelerating test results showed that the effect of the temperature on decomposition reaction rate accorded with Arrhenius index law. The linearity equation came from experiment data was well (r=-0.9376；n=4), the predicting value period of alum injection was three years at room temperature.
With 11.4 times regular dose （0.25ml/10g）injection of 2% alum injection to mouse, it was no toxicity. When injected 22.8 times regular dose, a few mouse appeared pathology change that the blood vessel enlarged mainly. All results showed it was no toxicity at the regular dose. The test of security experiment index revealed that the alum injections were colorless, clear, no bacteria and fungus, no hemolytic reaction. The pyrogen test was correspondence with the Veterinary Medicine Quality Standard and Rule of People’s Republic of china. There had a little stimulation of 2% alum injection and injecting it should be slow. The most rabbits electro- cardiogram was normal after injecting alum, the potassium ion was not effect on the heart.
With 1LD（4.8mg/kg）dose subcutaneous injection of potassuim cyanide to rabbits, that was enough to cause the rabbits die quickly. Injected alum injection with 44mg/kg dose into vein to treated 10 potassium cyanide poisoned rabbits, nine rabbits was recovered. The curing rate was high. The curative effect was creditable. It was convenient to use, and can save rescue time. Alum injection is a new good medicine to resisted cyanogens.
Study the pharmacokinetics of the 2% alum injection in the rabbit for the first time. Alum half life was 2.6797 ±0.6042 h. Body clearance was 0.5026 ±0.0116 dl·kg-1·h-1, Apparent volume of distribution was 1.9452 ±0.3371 dl·kg-1. It is indicated that the alum injection metabolized quickly, It’s distribution was widely in the rabbit body.
Prepared the ammonium alum injection, tested it’s stability, security, contain of ammonium alum、pH value and osmotic pressure. All results were corresponded with the quality requirement of vein injection. The effect of Ammonium alum injection was similar to alum injection to treatment cyanide poisoned rabbits.
引文
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