Pharmacokinetic Studies With Ivermectin Sustained-release Microcapsules In Piglets And In Vitro Release Studies

Ivermectin has the characteristics of high efficiency,low toxicity,wide spectrum of insect resistance.It is another promising drug after benzimidazole anthelmintics.In this study,the comparative pharmacokinetics and in vitro release of ivermectin sustained-release microcapsules and ivermectin premixes in healthy pigs were studied.The best prescription for the ivermectin sustained-release microcapsules was screened by in vitro release studies and further validated by in vivo pharmacokinetic parameters comparison.To provide scientific basis for the further development of ivermectin sustained-release microcapsules.The in vitro release test is based on the first method?basket method?of Chinese Veterinary Pharmacopoeia release assay method,100 r/min rotation speed,and pH1.2hydrochloric acid buffer,pH4.3 acetate buffer,pH6.8 phosphate buffer?containing 0.5%SDS?,water?containing 0.5%SDS?as an in vitro release medium.Samples were taken at different time points and assayed by UV-HPLC to calculate the cumulative release of ivermectin preparations at different time points.Using the software of Origin Pro8.0,the cumulative release-time data of drugs were fitted with zero-order equation,first-order equation and Higuchi equation respectively.The results showed that the cumulative dissolution of ivermectin premix in the pH6.8phosphate buffer?containing 0.5%SDS?and water?containing 0.5%SDS?in 0.5 h,the dissolution rate reached 79.69%to 98.36%;ivermectin sustained release microcapsule?batch number 2017070702?is stable and does not release at pH1.2 hydrochloric acid buffer and pH4.3 acetate buffer,which ensures that ivermectin can pass through the stomach and avoid acidic environment damage the ivermectin sustained-release microcapsules are slowly released and released completely in pH6.8 phosphate buffer?containing 0.5%SDS?and water?containing 0.5%SDS?within 8 h to avoid burst release and ensure that Ivermectin sustained-release microcapsules are released throughout the pig intestine before the pig's bowel movements.In 24 healthy piglets,24 piglets were randomly numbered using a parallel experimental design method,in which 8 were injected with 1.0%ivermectin injection,8were given orally with 0.25%ivermectin premix,and 8 were given orally with 0.25%ivermectin microcapsules.The plasma samples were extracted and derivatized and then detected by fluorescence-high performance liquid chromatography?FLD-HPLC?.The non-compartmental model in Winnonlin5.2.1 software was used to fit the plasma concentration-time data.The main pharmacokinetic parameters of healthy piglet 0.3 mg/kg bw subcutaneous injection of 1%ivermectin injection were as follows:the elimination rate constant?Kel?was 0.008±0.005 1/h.The mean residence time?MRT?was 148.14±42.59 h,and the elimination half-life(t_1/2)was 140.31±89.05 h.The area under the drug curve?AUC?was2723.69±641.73 h·ng/mL.The peak time(T_max)was 82.50±33.60 h,and the peak concentration(C_max)was 15.88±4.78 ng/mL.The main pharmacokinetic parameters of the healthy piglet 0.3 mg/kg·bw in the ivermectin premix group were as follows:the elimination rate constant?Kel?was0.013±0.004 1/h.The mean residence time?MRT?was 34.99±9.55 h,the elimination half-life(t_1/2)was 45.21±27.39 h,and the area under the curve when drug was used?AUC?was 1129.76±245.62 h·ng/mL.The peak time(T_max)was 7.00±2.14 h,and the peak concentration(C_max)was 39.81±5.83 ng/mL.The main pharmacokinetic parameters of the healthy piglet 0.3 mg/kg·bw in the ivermectin sustained-release granule group were as follows:the elimination rate constant?Kel?was 0.01245±0.00313 1/h.The residence time?MRT?was 55.96±11.40 h,the elimination half-life(t_1/2)was 59.94±20.18 h,and the area under the curve?AUC?It is1607.33±343.35 h·ng/mL.The peak time(T_max)was 9.50±0.93 h,and the peak concentration(C_max)was 37.75±3.45 ng/mL.In this study,piglets were fed with ivermectin sustained-release microcapsules and ivermectin premixes respectively.The comparison of the pharmacokinetic parameters between the two groups showed that piglets fed ivermectin sustained-release microcapsules compared to ivermectin premixes,The T_maxax of the former was significantly delayed,the C_maxax was significantly decreased and the absolute bioavailability increased by an average of16.57%,Statistical analysis showed that AUC,T_maxax and F were significantly different between the sustained-release microcapsule group and the premix group?P<0.05?,indicating that the ivermectin sustained-release microcapsules in this test can effectively avoid the gastric acid environment,achieve its full release and absorption in the intestine.The reduction of peak concentration avoids peak-to-valley effects and improves the safety of clinical use.The increase of relative bioavailability effectively increases epidermal plasma concentrations in animals,effectively treating body surface parasiteand strengthening inhibition of nematode infection in vivo.