Preparation Of Ivermectin Prolonged-release Injection And Its Pharmacokinetics In Rabbits

Parasitic disease is one of the more serious zoonotic diseases,and it also brings great economic losses to the animal husbandry.China is a big country in animal husbandry and breeding.The amount of rabbits,chickens,sheep and pigs raised ranks the first in the world,while the amount of cattle raised ranks only behind India.Parasitosis leads to the increase of animal feed consumption and the decrease of body weight instead of the increase,which results in a decline in its production performance;Secondly,zoonotic parasitic diseases will also bring many hidden dangers to human health and safety.Therefore,in order to prevent and control parasitic diseases,reduce the economic losses of the animal husbandry industry and avoid endangering the public health of people and animals,it is urgent to develop a broad-spectrum,efficient and practical anti-parasitic drug.Ivermectin is a semi-synthetic macrolide multicomponent antibiotic produced by the fermentation of Streptomyces avermitilis.Ivermectin is a new anti-parasite drug,which has attracted much attention due to its advantages of simple operation,low toxicity,wide insecticidal spectrum,not easy to develop drug resistance and low residue.In this study,we plan to prepare an ivermectin oil-based prolonged-release injection and through the injection through the establishment of in vitro content determination method,injection stability test,in vitro drug release behavior and pharmacokinetic studies in rabbit to evaluate whether it can be used for clinical use and mass production.First,the optimal prescription of ivermectin prolonged-release injection is determined through the selection of drug vehicle,drug carrier and other auxiliary materials in the injection and the orthogonal test of L9?3⁴?.Then,according to the guiding principle of quality control analysis method validation in 2015 edition of veterinary medicine code,the in vitro content determination method of ivermectin is optimized,and a high-efficiency,accurate,reproducible and easy to operate method for ivermectin content determination is established,which is applied to the stability test of the ivermectin prolonged-release injection.In addition,through the accelerates release test in vitro,the sustained-release effect of ivermectin prolonged-release injection is better than that of fu keqing,IVOMEC and qu chongjing,and the release in vitro conforms to Higuchi equation,mainly based on the diffusion mechanism.Finally,we establish the extraction method and HPLC detection method of ivermectin in rabbit plasma,the weight of the selected healthy rabbit was 2.5±0.5 kg and the dosage was 5 mg/kg.The pharmacokinetics of ivermectin rabbits is studied after a single subcutaneous injection.The pharmacokinetic characteristics of ivermectin prolonged-release injection and fu keqing are compared and analyzed.The AUC?0-t?of ivermectin prolonged-release injection and fu keqing is 33186.52,36713.88 ng/L*h;AUC?0-??is 57143.28,46385.79 ng/L*h;MRT?0-t?is 514.95,434.14 h;MRT?0-??is 1980.15,913.19 h;T_max is 96,48 h;C_max is 52.45,140.34 ng/h.The results shows that,although AUC of drug time curve area in the prolonged-release injection group is not significantly higher than that in the fu keqing,ivermectin prolonged-release injection significantly delays the end elimination half-life(T_1/2Z)of ivermectin,and the blood concentration is stable,which could reduce the stress response of animals.Therefore,ivermectin prolonged-release injection improves the bioavailability of ivermectin and delays its half-life elimination,and the simple administration method gives the injection a certain advantage.In summary,the excipients of the ivermectin prolonged-release injection are cheap and easily available,and the preparation process is simple,the production cost is low,the administration method is simple,and the bioavailability is high;In vitro drug release behavior and pharmacokinetic studies in rabbits have proved that it can be further studied as a potential ivermectin prolonged-release.