Study On Tilmicosin Premix Based On Hot Melt Extrusion Technology

Tilmicosin（TMS）is a macrolide antibiotic specially used in veterinary clinic,but the extremely bitterness limited its use.Therefore,it is necessary to develop its oral taste-masking preparation to provide a new dosage form choice for clinical treatment.This study aimed to obtain a TMS premix by hot melt extrusion（HME）,and the preliminary quality standard,stability and pharmacokinetic study of TMS premix were studied.Firstly,ultraviolet spectrophotometry（UV）method for determination of TMS content was established;The equilibrium solubility and oil-water partition coefficient were investigated.The results showed that:TMS had the maximum absorption at 290 nm;TMS was soluble in buffers of p H 1 and p H 5.8,and slightly soluble in buffers of p H 6.8,distilled water and p H 7.4;the Pow values of TMS in water/n-octanol were 0.009,0.047,3.640,5.984,8.427 in p H 1.0,p H 5.8,p H 6.8,distilled water and p H 7.4,respectively.The lg_Powvalues were-2.025、-1.330、0.561、0.777 and 0.926,which indicates TMS is well absorbed in the intestine and poorly absorbed in the stomach.The above pre-prescription research provided a good the foundation for prescription design and pharmaceutical research.Secondly,the TMS premix was prepared by hot-melt extrusion technology via HME technology.The best excipients were screened using the solubility parameter as an indicator.the dissolution of TMS in artificial saliva as the reference,the HME parameters was optimized utilizing orthogonal design.The optimization results were:extrusion temperature 135℃,screw speed 100 rpm and 30%drug loads.The TMS premix was characterized by DSC,TGA and FT-IR.The results showed that the masking properties of the preparation may be attributed to the physical embedding of the active ingredient in the carrier.The masking efficiency of the formulation was evaluated by both simulated oral drug release in vitro test and electronic tongue test.The release of the TMS premix in artificial saliva medium was significantly reduced within 60 s（less than 1%）,while the release in 0.1 M HCl buffer was fast（more than80%）within 30 min.As suggested by the results of an electronic tongue,the TMS premix had a better taste-masked effect than the commercially premix and enteric granules.Thirdly,preliminary quality standard of the TMS premix was studied.The standard of identification,content determination,dissolution,particle size inspection and loss on drying were formulated according to"Chinese Veterinary Pharmacopoeia"（2015 edition）and related documents.Three batches of pilot product were tested.The results showed that the pilot samples met the quality standard.This study supplied foundation for the establishment of specific quality standard.Fourthly,The stability study of the TMS premix was carried out based on the"Chinese Veterinary Pharmacopoeia"（2015 edition）,including strong light irradiation test,accelerated test and long-term test.The results show that the stability of TMS premix was good under the experimental conditions.Finally,the pharmacokinetics of TMS premix was investigated in pigs.The HPLC method for FM in plasma was developed and the specificity,recovery,reproducibility,and linearity of this method all reached the pharmacokinetic requirement.The C_max,T_max,AUC_0-∞,t_1/2λand MRT_0-∞of TMS premix,commercially available premix and commercially available enteric granules were:（1.21±0.11）μg/m L,（1.50-3.00）h,（11.38±1.57）μg·h/m L,（8.44±1.89）h,（12.42±2.05）h;（0.95±0.12）μg/m L,（2.00-4.00）h,（10.33±3.29）μg·h/m L,（10.75±2.72）h,（14.94±4.00）h;（0.31±0.07）μg/m L,（3.00-6.00）h,（5.59±1.36）μg·h/m L,（16.23±4.23）h,（24.28±5.23）h.The analysis of variance demonstrated that the pharmacokinetic behavior of TMS premix was similar to commercial premix,while the absorption effect was better than the commercially enteric granules.