Preparation Of Ivermectin And Doramectin Orally Disintegrating Tablets And Pharmacokinetic Evaluation In Dogs

The living standards of human beings have been gradually improved with the continuous development of the economy and society,More and more pets have been raised?mainly referring to dogs?,the number of breeds and breeds of pets are increasing year by year,and pet breeding management has received much attention.It is necessary to study a new prescription with a new type of anthelmintics with high therapeutic efficiency,convenient feeding,low liver first-pass effect and low residual amount.Therefore,in this study,were select a new orally disintegrating tablets in solid immediate-release dosage forms.It is a new dosage form that is very suitable for preparing insect repellent.Oral disintegrating tablets are administered in a special way,which has the unique advantages of fast administration,convenient operation,high bioavailability,and the ability to avoid the first-pass effect of the liver.Ivermectin?IVM?and doramectin?DOR?are both macrolide antibiotics,which have special effects on gastrointestinal nematodes and internal and external parasites of pets.As the third-generation derivative of ivermectin,doramectin has the advantages of better deworming effect,maintain the drug concentra tion in the blood longer,longer half-life,and higher bioavailability compared with ivermectin.To this end,this study explored the formulation process of orally disintegrating tablets in the laboratory stage,and selected the best prescription based on single-factor test and orthogonal test,in vitro analysis method of doramectin,quality research and pharmacokinetics research on the developed oral disintegration tablets,in order to do theoretical research for subsequent production.Through single factor test,we select suitable fillers and disintegrants,which were mannitol and low-substituted hydroxypropyl cellulose,and the optimal lubricant micropowder silica gel and magnesium stearate were selected.Through orthogonal optimization test,we design th e three factors of microcrystalline cellulose,low-substituted hydroxypropyl cellulose,and magnesium stearate to conduct orthogonal tests at three levels,and use the length of the disintegration time as an indicator to select the optimal prescription and determine the prescription of each component content.The final specification of ivermectin orally disintegrating tablets is 60?g,and the doramectin orally disintegrating tablets is 300?g,and the best prescriptions were:ivermectin 0.3mg,microcrystalline cellulose 105 mg,low-substituted hydroxypropyl cellulose 245 mg,mannitol158.7 mg,and micronized powder Silica gel 0.6 mg,magnesium stearate 2.4 mg,aspartame 9 mg;doramectin 1.5 mg,microcrystalline cellulose 102 mg,low-substituted hydroxypropyl cellulose 15mg,mannitol 152.4 mg,micronized silica gel 0.6 mg,magnesium stearate 1.5 mg,aspartame 9 mg.In this study,a method for the determination of ivermectin was mainly established by high performance liquid chromatography.The results showed that ivermectin had a good linear relationship in the range of 1.563-50?g/m L.The regression equation was y=17348x+10185,R²=0.999982.We designed a test solution with three concentrations from low to high and injected it 5 times respectively.The RSD values were 1.32%,1.16%and 1.13%,respectively.25?g/m L,50?g/m L and 100?g/m L reference solutions were injected 5 times in the same day and the IVM precision was measured at the same time for 5 consecutive days.The RSD values of the day precision were 1.68%,1.78%and 1.85%,respectively.The day-to-day precision RSD values were1.75%,1.23%and 1.05%,respectively,and the RSD values of sample recovery and precision were less than 2%.The above experimental results show that the method has strong specif icity and high accuracy good repeatability and meet the requirements of methodology.In this study,a method for the determination of doramectin in vitro was mainly established by high-performance liquid chromatography.The results show that doramectin has a good linear relationship in the range of 1.563-50?g/m L.The regression equation was y=16235x-19682,R²=0.99996.Designed three low,medium,and high concentrations of the test solution for five injections to determine the recovery of doramectin.The RSD values were 1.41%,1.77%and1.23%,respectively.25?g/m L,50?g/m L and 100?g/m L reference solutions were injected 5 times in the same day and the same time for 5 d for the same time to determine the precision of DOR.The results of the intra-day precision RSD values were 1.88%,1.89%and 1.03%,respectively.The day-to-day precision RSD values were 0.81%,1.88%and 1.36%,respectively,and the RSD values of the sample recovery and precision were less than 2%.The above experimental results show that the method's strong specificity,good repeatability,high accuracy,and meet the methodological requirements.Quality research was conducted on the two types of orally disintegrating tablets selected,mainly to examine the hardness,brittleness and disintegr ation time limit of orally disintegrating tablets,and stability tests and accelerated tests were conducted.The hardness of the three batches of ivermectin orally disintegrating tablets and doramectin orally disintegrating tablets are in the range of 3.0-4.5 kg,the friability is in the range of 1%,and the disintegration time limit is in the range of 1 min.all meet the requirements of the Pharmacopoeia.In the high temperature test at60?,the appearance and properties of ivermectin orally disintegrating tablets changed from white smooth discs on the 0th day to white slightly non-smooth discs on the 10th day.The content of avermectin decreased from 99.97±0.23%to 91.31±2.15%;the appearance and properties of doramectin orally disintegrating tablets did not change significantly.Both the 0th and 10th days were white smooth discs,and the disintegration time changed from 37.22±2.35 s to 30.24±1.36 s,the content of doramectin decreased from 99.95±1.23%to 92.63±1.31%.In the 90%±5%RH high humidity test,the appearance and properties of ivermectin orally disintegrating tablets changed from white smooth discs on day 0 to white matte discs on day 10,and the disintegration time changed from 35.59±2.16 s to 23.77±2.84 s,the content of ivermectin decreased from99.94±1.14%to 85.96±2.62%;the appearance and properties of doramectin orally disintegrating tablets changed from white smooth discs on day 0 to white matte discs on day 10 with tiny cracks,The disintegration time was changed from 34.33±1.59 s to 23.21±3.06 s,and the content of doramectin decreased from 99.91±0.86%to 90.21±2.19%.In the 4500 Lx±500 Lx intense light test,the appearance and properties of the ivermectin orally disintegrating tablets did not change significantly.Both day 0 and day 10 were white smooth discs,and the disintegration time range changed from 36.57±1.56 s to 34.39±3.27 s.The content of ivermectin decreased from99.89±1.10%to 92.69±1.71%;the appearance and properties of doramectin orally disintegrating tablets changed from white smooth discs on day 0 to white slightly matte discs on day 10,and the disintegration time was 34.00±2.12 s became 31.83±1.95 s,and the content of doramectin decreased from 99.93±1.08%to 91.76±2.98%.The above test results show that both types of orally disintegrating tablets should be stored in a cool place and protected from light and dry in high temperature.Take 6 beagle dogs of about 5 kg,of which 3 were given ivermectin orally disintegrating tablets 0.3 g,respectively,and 3 were given doramectin orally disintegrating tablets 0.3 g,respectively,2-3 m L of blood was collected at different time points,and determine the concentrations of ivermectin and doramectin by high performance liquid chromatography-fluorescence detector.The experimental results show that both ivermectin and doramectin meet the two-compartment open model with a weight coefficient of 1.Pharmacokinetic parameters t_1/2z are 75.279 h and 122.213 h,AUC_?0-t?is 1055.784?g/L*h and 6042.591?g/L*h,AUC_?0-??is 1122.183?g/L*h and 7098.339?g/L*h,T_max was 2 h and 48 h,C_max was 26.92?g/L and 30.45?g/L.In summary,the ivermectin orally disintegrating tablets and doramectin orally disintegrating tablets prepared in this study are convenient to use,have good absorption effect,and both types of orally disintegrating tablets have good stability,they are effective and feasible as a new kind of insect repellent for pets.