Preparation Of Tilmicosin Solid Dispersion And The Pharmacokinetics In Pigs

Tilmicosin is a macrolide antibiotic for livestock and poultry,which exhibit strong antibacterial activity and broad antibacterial spectrum.Tilmicosin is insoluble in water,bitter,alkaline and the bioavailability is low.Tilmicosin is mainly mixed with feedstuff to treat diseases in veterinarian clinic.However,the popularization and application of tilmicosin in clinic were hamper by the inappetence when the animal was sick.Currently,the water-soluble dosage form of tilmicosin has became a hot spot in veterinary drug manufacturer.In order to improve the solubility of tilmicosin,enhance the bioavailability and facilitate administration via drinking water,PEG6000 and P188 were used as carriers to prepare tilmicosin solid dispersion by melting method;The cumulative dissolution in vitro was used as the evaluation index to investigate the effects of carrier type,drug loading ratio,stirring time and curing time on the dissolution of solid dispersion.The optimal preparation process was obtained by carrier screening and orthogonal experiment;X-ray diffraction,Fourier transform infrared spectroscopy and Scanning electron microscopy were used to identify the phase;The susceptibility,stability investigation and pharmacokinetics of tilmicosin solid dispersion in the healthy pigs were carried out to provide a reference for the storage and rational use of this dosage form in veterinarian clinic.There results of preparation of tilmicosin solid dispersion are shown as following?1?the optimal preparation process:the combined carrier was PEG6000:P188=20:1,drug loading ratio was 1:3,water bath heating temperature was 57?,stirring time was1 hour,curing temperature was-20?,curing time was 12 hours,drying temperature was 35?and the drying time was 24 hours.?2?X-ray diffraction showed that tilmicosin had no characteristic diffraction peak and was amorphous.Tilmicosin solid dispersion had strong diffraction peaks at 19°and 23°,which was a kind of crystalline substance;In the infrared spectrum,tilmicosin had some characteristic absorption peaks with different intensities at different locations.Moved,descrease or disappear in the infrared spectrum of these characteristic absorption peaks were observed in tilmicosin solid dispersion;Tilmicosin was amorphous structure and the solid dispersion was a crystal structure by scanning electron microscopy;The phase identification indicated that the tilmicosin solid dispersion was formed.?3?The dissolution rate of tilmicosin solid dispersion reached 72%at 2 minutes.It was completely dissolved at 15 minutes.The dissolution rate of tilmicosin was improved obviously.?4?The susceptibility indicated that the susceptibility of tilmicosin solid dispersion was similar with tilmicosin.?5?The tilmicosin solid dispersion had a good stability when it was stored at room temperature for 90 days under dry conditions,and the content and dissolution did not be significantly affected by moisture absorption and crystallization.The method was established to determine the concentration of tilmicosin in plasma of pig by HPLC.The mobile phase was water:acetonitrile:dibutylamine phosphate:tetrahydrofuran?790:130:25:55,V/V/V/V?;the detection wavelength was290 nm;the column temperature was 30?,and the flow rate was 1.0 m L/min.The concentration of tilmicosin in plasma was at the range of 0.05?10?g/m L;the linear relationship was y=23073x+173.02,R²=0.9998;the limit of detection was 0.025?g/m L and the limit of quantification was 0.05?g/m L.The recovery of tilmicosin was 98.47±2.94%?113.85±4.32%,the intra-assay coefficient of variation was1.57%?4.82%,and the inter-assay coefficient of variation was 2.87%?4.78%.The results showed that this method was stable and reliable,which could be used to detect the concentration of tilmicosin in the plasma of healthy pig.Twelve healthy piglets were divided into two groups?10?2 kg?.The tilmicosin and tilmicosin solid dispersion were administered as a single dose of 50 mg/kg·bw,the blood samples were collected from precaval vein at 0.25,05,0.75,1,2,3,4,6,8,12,24,48,72 and 96 h after administration.The concentration of tilmicosin in the plasma were determined by HPLC.The result showed that the concentration-time profile of tilmicosin and its solid dispersion in plasma fitted to a two-compartment model with first-order absorption after pigs were administered with.The pharmacokinetic parameters of tilmicosin and its solid dispersion in healthy pigs were as following:the time of peak concentration(T_max)was 4.46 h and 3.62 h;peak drug concentration(C_max)was 1.48?g/m L and 2.55?g/m L;half-life of the absorption phase(t_1/2ka)was 2.77 h and 2.24 h;half-life of the distribution phase(t_1/2?)was 2.75 h and 2.30 h;half-life of the elimination phase(t_1/2?)was 21.85 h and 18.08 h;area under the concentration-time curve?AUC?was 28.51?g·h/m L and 38.95?g·h/m L;clearance of total body?CL?was 1.75 L/kg/h and 1.28 L/kg/h;the bioavailability?F?was 136.62%.It could be concluded that the tilmicosin solid dispersion dosage form was easy to dissolve in water,which could be convenient for administration via drinking water.The stability was good and the dissolution rate was fast.Tilmicosin solid dispersion was easy to absorb by oral administration.The peak concentrations was observed in a short time.The relative bioavailability was high.