Preparation And Quality Study Of ITRAC Tablets For Pets

In recent years,due to the overuse of broad-spectrum antibiotics and immunosuppressants,antifungal drugs have developed resistance,which has caused great difficulties in the clinical treatment of invasive fungal infections.Existing antifungal drugs are greatly limited due to the interaction with other drugs and serious toxic and side effects.The incidence of deep fungal infection is increasing year by year,but the existing clinical antifungal drugs can not effectively cure deep fungal infection,how to effectively treat deep fungal infection has become a problem that the majority of medical workers pay close attention to.In recent years,several new antifungal compounds with broad spectrum,low toxicity and high efficiency have entered the stage of clinical research.ITRAC（ITRAC）is a highly effective and broad-spectrum antifungal triazole that binds to fungal cytochrome P450 isozyme to disrupt ergosterol synthesis in fungal cell membranes,which is a major component of fungal cell membranes.ITRAC can be used for systemic fungal infection,oral to esophageal fungal infection,vulvar and fungal conjunctivitis infection,superficial fungal infection and onychomycosis.ITRAC has the characteristics of fast oral absorption,long half-life and high bioavailability.Hydroxyl ITRAC,the main metabolite of ITRAC,has antibacterial effect and good clinical efficacy and high safety.Pet fungal skin diseases are often accompanied by severe itching,pet nails are sharp and easy to lick the lesions and then accompanied by bacterial infection,ITRAC also has a certain anti-inflammatory effect,this product exists in sefat,sweat is also a small amount of existence,compared with the use of other antifungal drugs,the effect of treating fungal skin diseases is better.Considering the best oral absorption of ITRAC,oral preparation is preferred.At present,pets use ITRAC as oral solution in the domestic market,while people use ITRAC as tablets and capsules.Under normal circumstances,the dissolution and bioavailability of tablets are better than pills,with accurate dosage and stable quality.Some drugs that are easy to oxidize and deliquescent can be protected by coating,and light,moisture and air have little influence on them.In this study,the dosage form of ITRAC,an anti-fungal dermatological drug for pets,was formulated as tablet.In this study,the formulation of ITRAC tablets was screened and the preparation process was optimized.The quality standard and stability of ITRAC tablets for pet were studied.The main research contents and results are as follows:1.Study on prescription screening and preparation process of ITRAC tablets.Referring to the domestic and foreign prescriptions of ITRAC tablets,the compatibility test of raw materials and auxiliary materials was conducted according to the Basic Technical Guidelines for Research on Chemical Pharmaceutical Preparations.The optimal prescription was determined as 40 g of ITRAC(C₃₅H₃₈C_l2N₈O₄),6 g of crosslinked polyethylene pyrrolidone（PPVP）through single factor test and orthogonal test.15%starch slurry 30 g,magnesium stearate 2 g,add lactose+microcrystalline cellulose（91.5g:30.5g）to 200 g.The preparation process is as follows:（1）Cooking slurry:30 g starch is suspended in an appropriate amount of water,heated and continuously stirred until gelatinized.（2）Granulation:weigh the API,the filler lactose and microcrystalline cellulose,and the disintegrating agent PPVP,and add them in equal increments.The disintegrating agent is added inside and outside,and then mixed.（1）The prepared adhesive starch slurry is granulated,screened through 16 mesh,and dried to 1%～3%moisture in the oven at60℃.（3）Tablet pressing:After the whole granule,add lubricant magnesium stearate and the remaining 50%disintegrating agent,mix evenly and press the tablet.The weight of the tablet is 0.2g,the specification is 20mg,and it is sealed with bubble cover.2.Study on quality standard of ITRAC tablets.High performance liquid chromatography（HPLC）was used to identify ITRAC tablets.The chromatographic conditions were Diamons C₁₈column（5μm,250×4.6 mm）.Mobile phase:acetonitrile-potassium dihydrogen phosphate（0.01 mol/L potassium dihydrogen phosphate aqueous solution,containing 0.2%triethylamine,adjusted p H to 3.5 with phosphoric acid）;Flow rate 1.0 m L/min;Column temperature 30℃;Injection volume 10μL;The detection wavelength was 261 nm.The method was validated and the linear equation was obtained in the range of 0～800μg/m L:A=23744×C+105631（r=0.9998）,indicating that the linear relationship of the method was good.The recoveries of low,medium and high concentrations（160,200 and 240μg/m L）were 98.64%,98.20%and 97.10%,respectively,with RSD of 0.66%（<2.0%）,indicating good accuracy of the method.Nine samples with a concentration of 200μg/m L were prepared,and the precision of the method was determined by continuous injection.The RSD was 0.4%（<2.0%）,indicating that the precision of the method was good.The RSD of the method was 0.21%（<2.0%）,indicating that the method had good repeatability.Stability test results showed that RSD of 200μg/m L reserve solution was 0.27%（<2.0%）after injection at 0,2,4,8,12 and 24 h,indicating that the solution was stable within 24 h after configuration.The above indicators are in line with the relevant provisions of the Guidelines for verification of Veterinary Drug Quality Standards and Analytical Methods.Three batches of samples were triallyprepared,and the characters,identification,examination（disintegration time limit,dissolution degree,hardness,related substances）and content determination of the tablets were studied according to the inspection requirements of the general Rules for tablets of one preparation in Chinese Pharmacopoeia（2020 edition）.The average value of content determination results was 105.62%.The inspection results of related substances showed that the peak area of single impurity was less than 0.50%of the main peak area of reference solution,and the total peak area of impurity was less than 1.25%（2.5 times）of the main peak area of reference solution.3.Preliminary study on stability of ITRAC tablets.Influence factor test,accelerated test and long-term test were carried out on ITRAC sample prepared according to"Technical Guidelines for stability Study of Veterinary Chemical Drugs".Factor test results showed that the content of ITRAC tablets and related substances did not change significantly under strong light condition,and the product was stable under light condition.Placed in high temperature conditions for 10 days,the appearance of the color had obvious changes,the content of related substances increased,ITRAC content decreased,the product was affected by temperature;The content of ITRAC decreased under high humidity condition,and the product was affected by humidity.Therefore,in order to ensure product quality,this product should be placed in a cool,dry place sealed storage.Due to time limitation,accelerated test and long-term test need to be further studied.In this study,the formulation and preparation process of ITRAC tablets are stable,reliable and quality controllable,which laid a foundation for the application of ITRAC tablets in the study of fungal skin diseases in dogs and cats.