Preparation And Pharmacokinetic Study Of Compound Sulfamonomethoxine Sodium Soluble Powder

The solubility of drugs is an important factor affecting the bioavailability of drugs.Poorly soluble drugs are mainly due to their poor water solubility and are difficult to be absorbed by the body,resulting in poor bioavailability.Sulfamethoxine sodium（SMM-Na）has strong antibacterial activity,and it is often combined with trimethoprim（TMP）in clinical practice to increase its antibacterial effect.However,due to poor water solubility and slow dissolution rate of TMP,it will cause poor oral absorption.Solid dispersion technology can improve bioavailability by enhancing the solubility of poorly soluble drugs.In order to improve the bioavailability of TMP,the solvent method was used to prepare TMP solid dispersion（TMP-SD）,and phase identification and stability studies were conducted.The pharmacokinetic properties of APIs,commercial drugs and self-made drugs in rats and chickens were compared.The UV method and high performance liquid chromatography（HPLC）were established to determine the in vitro content of SMM-Na and TMP,and the HPLC method was used to determine the in vivo content of SMM-Na and TMP.MCX mixed cation solid phase extraction column was used to remove the interference of endogenous substances in plasma,during the processing of plasma samples.The standard curves was drawn,and the linear relationship,precision,recovery rate and stability of the method were all met the method requirements.By single factor method,the best preparation method and carrier were determined as solvent method and poloxamer 188（P188）.The L₉（3³）orthogonal test was carried out with the ratio of TMP to P188,the preparation temperature,and the cooling temperature,and the optimal preparation process was determined to be TMP:P188=1:6,the preparation temperature was 90℃,and the cooling temperature was-20℃.For further investigation,P188 and Al₂O₃were used as the combined carrier to prepare the binary TMP-SD preparation process,and finally the best prescription for TMP-SD is TMP:Al₂O₃:P188=1:0.6:5.4.From the DSC and SEM results,it can be seen that TMP exists in an amorphous form in the solid dispersion.From the dissolution results,the TMP API dissolved only 54%within 1 h,while the dissolution of TMP-SD was 89.2%.It was further explained that the preparation of TMP into TMP-SD greatly improved its solubility and dissolution,and the stability results also showed that TMP-Al₂O₃-P188 solid dispersion had good stability.Compound SMM-Na soluble powder was composed of SMM-Na and TMP-SD,screen out suitable fillers and glidants.Determine the prescription of compound SMM-Na soluble powder is 20%SMM-Na（content is calculated by SMM）,28%TMP-SD,4%sodium lauryl sulfate,1%disodium ethylenediaminetetraacetic acid,1%Sodium sulfite,the rest was supplemented with lactose to 100%.After the prescription was determined,the quality of the compound SMM-Na soluble powder was preliminarily evaluated from the aspects of traits,content,solubility and stability.From the appearance and shape,it can be seen that the prepared compound SMM-Na soluble powder was a white solid powder,and the appearance was uniform,and the content and solubility meet the requirements of"Chinese Veterinary Pharmacopoeia".According to the stability results of TMP-SD,it had certain hygroscopicity.Therefore,in the process of drug storage,it should be sealed and placed in a cool and dry place.Comparing the pharmacokinetics of APIs,commercially drugs,and prepared compound SMM-Na soluble powders in rats and chickens,using DAS 2.0 to fit the blood drug concentrations at different time points,the results showed that the three groups of preparations All belong to the first-class absorption two-compartment model.In the self-pharmaceutical group,the AUC_（0-t）of TMP in rats was 9.279±1.479 mg/L*h,T_maxwas 0.641±0.289 h,and C_maxwas 2.653±0.137 mg/L;AUC_（0-t）in chickens is 31.542±1.61 mg/L*h,T_maxis 3±1.732 h,and C_maxis 3.928±0.111 mg/L.From the above pharmacokinetic parameters,the parameters of the same drug in different animals are significantly different.It can be seen that the preparation of TMP as a solid dispersion can effectively improve the solubility of the drug and significantly improve the bioavailability in the body.The above results show that TMP-SD and SMM-Na can be prepared into a compound soluble powder formulation,which can realize the drinking water system in production Administration.