| Aditoprim(ADP),as a new type of benzylamine pyrimidine antibacterial synergist,has higher safety and better antibacterial effect compared with similar veterinary drugs.Its characteristics are long half-life and high bioavailability.Based on the pilot production of ADP API with the research of ADP injection and ADP-SMZ injection,the pilot scale-up production,product quality research and stability study of aditoprim injection and aditoprim-sulfamethoxazole(SMZ)injection were carried out according to The guiding principles of veterinary drug research technology(chemical and natural drugs).These provide data support for the application of new veterinary drug preparations such as aditoprim injection and aditoprim-sulfamethoxazole compound injection,and supply safe,stable and effective qualified products for clinical application.According to the dissolution characteristics of drugs,the composition of injection was optimized by single factor test.The content of ADP API in ADP injection was 5%.The dosage of 1,2-propanediol,10% HCl,sodium bisulfite and ethyl paraben was 30%,2.5%,0.1% and 0.18%,respectively,which used as corresponding cosolvents,antioxidant and preservative.Water for injection was used as solvent to fix the volume.The content of ADP and SMZ in ADP-SMZ injection was 2% and 10%,respectively.The dosage of1,2-propanediol,triethanolamine,lactic acidas,poloxamer,sodium thiosulfate,and ethyl paraben was 50%,9%,2%,5%,0.1% and 0.18%,which used as cosolvent,cosolvent,cosolvent and preservative.Water for injection was used as solvent to fix the volume to the specified volume.Based on the laboratory preparation process,the preparation process was optimized.The key process parameters of each key step were determined by the injection characteristics,p H value,stability,drug content and the amount of related substances.The temperature of the solution was determined to be 40℃ and the stirring time was 30 min.the filter membrane of 0.22 μm was used for filtration;the sterilization condition was 121℃ for 30 min.The process was verified by step to ensure the safety and stability of the prescription process.The laboratory process verification is amplified from 100 m L to 500 m L and then amplified to 5 L.Each batch of products shall be inspected according to the quality test items,and then the pilot production shall be conducted after passing the test.At the end of February 2019,the pilot scale-up production of ADP injection and ADP-SMZ injection was carried out in the GMP standard preparation workshop of Henan Houyi Industrial Group Co.,Ltd.ADP injection 30 L/batch,a total of three batches,the specification of 10 m L/tube.The 20190225 batch had 2827 injections,while 20190226 batch and 20190227 batch had 2883 and 2835 injections,respectively.The yields of each batch were 94.23%,96.10% and 94.50%,respectively.ADP-SMZ injection was 150L/batch and the specification was 10 m L/piece.The 20190228 batch had 14165 injections,while 20190301 batch and 20190302 batch had 14202 and 14131 injections,respectively.The yields of each batch were 94.43%,94.68% and 94.21%,respectively.The quality research of preparation is an important scientific basis for formulation screening and process optimization.The results of formulation and process optimization can provide data support and reference for the establishment of quality standards.A HPLC method for the determination of aditoprim,sulfamethoxazole and their related substances was established.This method has high sensitivity and specificity,and can be applied to the determination of aditoprim,sulfamethoxazole and their related substances IMP-1,4-p-aminobenzenesulfonic acid(SA).An Agilent Eclipse XDB-Phenyl column was used with the column temperature of 30℃.The UV detection wavelength was 283 nm.The mobile phase was triethylamine: acetonitrile: water(1:150:849).The p H value of the solution was adjusted to 6.50 with phosphoric acid.The flow rate was 1.0 m L/min.Under these chromatographic conditions,IMP-1 and p-aminobenzenesulfonic acid could be separated from aditoeprim and sulfamethoxazole,and the resolution between adjacentpeaks was more than 1.5.According to the quality standards of ADP injection and ADP-SMZ injection,three batches of pilot products were inspected.ADP injection is a light yellow transparent liquid with p H value of about 5.88.The content of ADP drug is102.56% and the content of related substances is 0.12%.According to the general principles of preparation,all tests are qualified,and there is no hemolysis and irritation.ADP-SMZ injection is a light yellow clear and transparent liquid with p H value of 7.51.The drug content of ADP and SMZ is 101.56% and 103.56%,and the content of related substances is 0.11%.According to the general principles of preparation,all tests are qualified,without hemolysis and irritation.According to The guiding principle of veterinary drug stability research,the influencing factors test of one batch and accelerated test and long-term test of three batches of ADP injection and ADP-SMZ injection were carried out.The package stability test was carried out together with accelerated test and long-term test.The appearance of the injection was observed,and the p H value,drug content and related substances content were determined.The appearance of the injection was observed,and the p H value,drug content and related substances content were determined.The results showed that the content of related substances in the injection increased slightly under the condition of normal temperature and accelerated thawing for 3 months,and the content of related substances increased slightly by 53.0% under the condition of long-term exposure to high temperature and accelerated thawing test,and the content of related substances increased slightly under the condition of high temperature and accelerated thawing for 6 months.The color of the pilot product ADP-SMZ injection was slightly deepened under high temperature,and the content of related substances increased by 0.28%,which needed to be placed at room temperature;it was stable under strong light irradiation and low-temperature freeze-thaw cycle;the total content of drugs in accelerated test for 6months decreased by 2.88%,the content of related substances increased by 0.25%,and the p H value increased by 0.47;the long-term test results of 15 months showed that its quality indicators met the standards.Each research has its focus and key problems to be solved,which are independent and closely related.Through the above research,aditoprim raw material drug wasprepared into injection.ADP injection and ADP-SMZ injection were obtained,which were safe,effective,stable and easy to use.The overall objective of this study is to scientifically develop of the ADP injection and ADP-SMZ compound injection according to the complete preparation research standards.So as to ensure that the preparation can be applied to industrial production with sufficient basis for selection of dosage forms,reasonable formulation,stable process and controllable production process.The success of the pilot production of this injection is the basis of transforming laboratory research step by step into practical industrial production,and is the guarantee for the transformation of scientific research achievements into clinical therapeutic drugs.Clinical studies have shown that it has a wide range of applications and has more advantages compared with similar preparations and has a broad application prospect. |
