Application of albendazole_Kain Industrial Additive

Background and overview^【1】

Albendazole, also known as albendazole and albendazole, is a new type of benzimidazole antihelmintic drug with high efficiency, broad spectrum and low toxicity. The drug came out in the United States in 1976 and was successfully copied by the China Veterinary Drug Supervision Institute in 1979.

With the progress of the times and the continuous development of medical and health services, some developed countries and regions not only use it as a passive treatment, but also use it to spray grasslands and pastures to fundamentally eliminate the sources of various parasites. , so the demand is very large. At present, the annual domestic output is only more than 200 tons, and the process route is relatively backward, which is far from meeting the market demand.

Pharmacokinetics^【1】

After oral administration, albendazole is absorbed as the drug in the gastrointestinal tract of animals. Its absorption speed varies with different animal species. Marirner (1980) and others reported that after a single oral administration of 10 mg/kg.bw of albendazole to sheep, there was a long time lag, about 4 hours, and the unconverted prototype of albendazole in the plasma could not be detected, and its metabolic intermediates Alumite and sulfone reached peak concentrations of 141 in plasma at 20h (peak time Tm); after a single dose of albendazole in rats, T. is 3h, Tm is 4.54h. After giving the drug to cattle, T. It is about 4h, Tm is 16-20h, in chicken body, T of sulfoxide and sulfone. They are o.6lh and o.91h respectively, and Tm is 4.57h. It can be seen from the above parameters that various animals T. and Tm are both longer, indicating that the drug is absorbed slowly. Among the anti-dang beasts, cattle and sheep, T. and Tm are both similar, that is, the absorption rates are similar in frequency. Chickens and rats absorb the drug at similar speeds, but there is a big difference between them in other animals. This may be due to the different composition, structure and digestive characteristics of the digestive tract of anti-animal animals. Bogan (1983) and others also believed that the rumen of antagonized animals can prolong the action time of albendazole, probably because it slows down the absorption of albendazole.

The fat solubility of food and gastric volume affect the absorption and bioavailability of albendazole. Lange (1988) et al. reported that 6 patients with hydatid cystic depression increased the bioavailability of the drug when they took albendazole orally and ate human fat-soluble food; and compared with the fasting state, administration of albendazole after eating The mean plasma drug concentration and area under the concentration curve were 4.5 times higher. Different parts of the gastrointestinal tract have different degrees of absorption. Albhimidazole can be absorbed by both the stomach and the intestine. Test results in rats show that the degree of absorption and utilization in the stomach is higher than that in the intestine, which leads to different tissue drug concentrations.

Albendazole is distributed in various tissues and organs of the body. After a single oral administration of albendazole to rats, 16 hours later, it spread throughout all organs and tissues of the body examined, including pancreas, kidney, liver, lung, spinal cord, heart, spleen, brain, large intestine, small intestine, bladder, muscle, fat, stomach and fur etc. Among solid organ tissues, in addition to the pancreas, kidneys and liver are most widely distributed, and brain tissue is also distributed to a certain extent. It is suggested that in addition to being effective against intestinal parasites, albendazole is also effective against parasitic worms in kidneys, livers, lungs, brain and other organs and tissues.

Safety of albendazole^【1】

The intermediate metabolites of albendazole (sulfoxide and sulfone) are not only distributed to various tissues and organs of the body along with blood circulation, but also passively diffuse into the human abomasum and intestinal tract, resulting in a high drug concentration in the abomasal gastric juice. Equivalent to drug concentration in plasma. Thus albendazole can effectively expel parasitic worms from the gastrointestinal tract. The drug can also diffuse through the parasite capsule tissue (such as the hydatid capsule). The drug concentration in the cyst fluid reaches 22% of the drug concentration in the patient’s plasma, and the metabolites of the drug last longer in the cyst fluid than in the plasma. In the long run, the concentration of the drug in the cyst fluid depends on the dose.

After albendazole is absorbed, it is quickly metabolized by microsomal enzymes in animal liver cell microsomes. Its metabolic intermediate products are albendazole vitriol and albendazole sulfone, and the final metabolite is diaminosulfone. The antihelmintic activity of the drug is most likely borne by the alumite and sulfone. If sheep and calves are administered smg/k.gbw, unconverted albendazole prototype cannot be detected in their plasma. It has been confirmed that vitriol and sulfone also last for a shorter time in plasma, which is helpful for Dabai patients with hydatid cyst

The rats were orally administered albendazole for 8 days. One day after stopping the drug, its metabolic intermediates (sulfoxide and sulfone) disappeared from the plasma. The metabolic intermediates in the cyst fluid gradually decreased with time, but by 19-20 The time of day can still be measured. The rapid metabolism of albendazole after absorption is the result of the action of microsomal enzymes in liver cells. It has been confirmed that in pig liver cell microsomes, the metabolism of albendazole into sulfoxides and sulfones involves two different microsomal pathways. One pathway is composed of cytochrome P₄₅₀ monooxygenase; the other is Composed of monooxygenase containing flavin adenine dinucleotide. The relationship between the two pathways depends on the concentration of albendazole. In rat liver microsomes, the in vitro biological oxidation of albendazole into alum is related to the NADP-dependent enzyme system; and it was confirmed that the sulfur oxidation of albendazole in rat liver is not caused by cytochrome P45. Relying on monooxygenase catalysis, it is the product of monooxygenase containing flavin adenine dinucleotide. It can be seen that both pig and rat liver microsomal enzymes and flavin adenine dinucleotide-containing monooxygenase are involved in the oxidation of albendazole.

Albendazole and its metabolites can be excreted through feces and urine. Feces is the main route of excretion. After oral administration of albendazole to rats, 90.39% of the drug was excreted before 28 hours after administration, and 61.58% and 21.81% were excreted in feces and urine respectively. 95.74% of the drug was excreted before 60 hours, 6.421% and 31.53% were excreted in feces and urine respectively, and its elimination half-life (T_1/2) was 7.77h. Alum and sulfone are in��T,/2 in plasma are .48h7 and .2h5 respectively, and their elimination rate is faster. Marriner (1980) reported that the prototype of albendazole can exist in abomasal fluid, so it is speculated that the drug excreted in the feces may include unabsorbed drugs and metabolites processed by the liver. Albhimazole is eliminated quickly from the body, and the residual amount in tissues is low. After a single dose of albendazole (15 mg/kg.bw) was given to chickens for 7 days, except for the larger residual amount in the pancreas (sulfoxide 1.6888ug/g, sulfone 2.0907 ug/g), and the residual amounts in the heart, liver, lung, kidney and other tissues were reduced to low levels (alumite 0.1225-0.6761ug/g, sulfone 0.1230-0.7663ug/g). Therefore, it is estimated that even if it is used continuously for several weeks, albendazole will generally not cause accumulation poisoning in animals; chickens are ready for consumption 7 days after a single dose. However, it has also been confirmed that albendazole has teratogenic toxicity, and the metabolic intermediate product sulfoxide of albendazole is embryotoxic to rats. Therefore, for safety reasons, food animals and poultry that have taken albendazole in the near future should avoid giving it to pregnant women.

Application^【2】

Albendazole is a broad-spectrum antiparasitic drug with strong effects and low toxicity. It is effective against gastrointestinal nematodes (including larvae in the inhibitory stage), tapeworms, Fasciola hepatica and lungworm have good curative effect. In addition, albendazole also has a good effect on cysticercosis and trichinellosis in humans and animals. It is widely used to treat various types of cysticercosis, burning worm disease, ascariasis, hookworm disease, whipworm disease, garden nematodes and short hymenometa, etc. It also has good effects on Fasciola hepatica and Fasciola pulmonale. Efficacy.

Preparation^【2】

1. Chlorosulfonation

Add 46kg of chlorosulfonic acid to the chlorosulfonated enamel reaction kettle, then slowly add 12kg of carbendazim raw powder, and control the temperature below 13°C. After adding carbendazim, keep it at this temperature for 4 hours, and then keep it at 30°C for 3 hours before discharging.

2. Restore

Add 160kg of water and 20kg of iron filings into the reduction enamel kettle. Stir evenly and slowly add the above reacted materials. The temperature when adding is less than 30℃. After adding, keep h3 at 30℃, and then add 7kg of iron filings. , slowly heat up to 75°C and maintain this temperature, wait for natural cooling and then press filter.

3. Vulcanization

Add 130kg of water and 11kg of sodium sulfide into the sulfide enamel reaction kettle, mix well, then add the reducing materials, raise the temperature to 36°C and maintain it for 1.5h, and press filter.

4. Etherification

Add the vulcanization material into the etherification enamel reaction kettle, slowly add chloropropane 5,7%, and after the addition is completed, slowly raise the temperature to 46°C and maintain it for 2.5 hours until the material is discharged.

5. Refined

Dry the above materials, wash with water at about 45°C until the pH is 7-8; then undergo acidification and alkali precipitation to obtain the finished product of albendazole.

6. Three wastes treatment

In this process, a small amount of chlorine, hydrogen chloride and chlorine oxide gas are discharged during chlorosulfonation and reduction, which are absorbed by water circulation and neutralized with caustic soda. During the reduction process, there are ferrous sulfate and ferrous chloride. The liquid is discharged and received in a container, and is left to evaporate naturally or by heating to obtain a crystal water mixture of ferrous sulfate and ferrous chloride; during the etherification process, a small amount of liquid containing chloride and sulfate is discharged to clarify the lime water. Treatment, agglomeration with coagulant, and then discharged after adsorption with cinder. During the sulfurization process, there is a solid mixture of iron filings and iron sulfide, which is combined with the above-mentioned adsorbed cinder and sent to a solid garbage dump for centralized processing or incineration. Furnace incineration treatment.

Main references

【1】Cai Jun, Pan Baoliang. Pharmacokinetics and application of albendazole [J]. Liaoning Animal Husbandry and Veterinary Medicine, 2000(04):29-30.

【2】Cao Yanan. New synthesis process of albendazole [J]. Guangdong Chemical Industry, 1998(05):30-37.