| As the sulfonamide synergist, Trimethoprim(TMP) has the advantages of broad spectrum, high efficiency and low toxicity. Its antimicrobial spectrum is similar to sulfa drugs. It is often prepared into compound preparation associated with a variety of antibiotics and it is also used alone for the treatment of simple urinary tract infection caused by bacteria. However, the very low solubility and poor dissolution seriously affect the drug absorption and curative effect. Therefore, in this paper, the hot melt extrusion technology was used to improve the dissolution of TMP in water, then the tablet was made in order to achieve rapid release, high efficiency, improve bioavailability and reduce the cost of production.In this article, the determination methods of TMP in vivo and vitro were established. UV spectrometry was used for the determination of TMP in vitro and the standard curves in different medium were drawn. The results showed that the linearity, precision, accuracy and the stability of solution were all good; HPLC Internal standard method was adopted for the detection of TMP in vivo, using aniline as the internal standard and plasma endogenous substances had no interference on the determination of TMP.According to the peak of TMP, the theoretical plate number was12660, the degree of separation was 25.32 and the average correction factor was 0.8256. Above all, both of the two methods met the requirements of methodology. At the same time, the dissolution method of TMP was determined and the solubility, oil-water partition coefficient, melting point, and the thermal stability of TMP were investigated.Combining with the single factor experimental results, specific preparation process conditions were selected by orthogonal test of L9(33) consisting of three factors ratio of drug and carrier, section temperature and speed at three different levels, taking the cumulative dissolution rate of TMP in water in45 min as index. In order to further improve the dissolution and stability of TMP, binary vector was used to prepare the solid dispersion(SD).The experimental results indicated that TMP-SD could be prepared by three methods for different carriers, all of which could increase the dissolution rate of TMP in water, and TMP-PEG6000-SD prepared by hot melt extrusion method had the best dissolution. Optimum process conditions that TMP: PEG6000 was 1:5, temperature was 22-40-65-65-65-65-65-50?and speed was 48r?min-1were got by adopting orthogonal experiment. Compared with TMP-SD prepared by single carrier,TMP-SD prepared by binary vector had faster dissolution. After filtering, the optimal prescription was TMP/ PEG6000/SY-6 of 1:2:3.The phases of TMP solid dispersions(1:2:3) obtained by the optimal prescription was identified by DSC, infrared spectrum, scanning electron microscopy(SEM), dissolution, and so on. The results showed that the specific absorption peaks of TMP disappeared and the IR map was the same as the physical mixture and TMP crystal disappeared in SEM diagram, which suggested that TMP solid dispersions was solid solution and drugs dispersed in the carrier in the form of molecules. In vitro release experiment revealed that the dissolution of TMP-SD was up to 73% in 2 minutes while TMP was only 35% in 60 minutes, which indicated that TMP-SD could significantly improve the dissolution and the dissolution rates of TMP raw materials.TMP solid dispersions tablets were produced by wet granule tablet and the formulation was optimized, taking the appearance of tablet, the angle of repose, the time of disintegration and the cumulative dissolution rate of 45 min of TMP in water as index. Results showed that TMP solid dispersion tablets had the fastest dissolution, which were manufactured by 80% ethanol as adhesive, 0.5% magnesium stearate as lubricant, 6% PVPP as disintegrating agent and pregelatinized starch as filler. Compared with the cumulative dissolution rate of 63.2% of TMP commercially available tablets in 37.53 min, the cumulative dissolution rate of 63.2% of TMP-SD-tablets in 13.72 min meant that the dissolution rate of TMP was significantly increased. Study on the dissolution showed that the dissolution of TMP-SD-tablets met the Weibull distribution and the dissolution mechanism belonged to the Fick diffusion.The stability of TMP raw materials, TMP-SD and TMP-SD-tablets were studied. The results demonstrated that the contents and dissolution of the three were almost unchanged in the heat and the contents of the three were decreased under strong light condition and the moisture absorption of TMP-SD and TMP-SD-tablets was serious under the condition of high humidity. So the humidity in the environment needed special attention during the production and manipulation process.The pharmacokinetics of TMP-SD-tablets in dogs were studied in vivo. The data was analyzed by pharmacokinetics software DAS2.0 and the pharmacokinetic parameters were calculated. Experimental results showed that both of the TMP-SD-tablets and the market tablets of TMP fitted to the two compartment model. The relative bioavailability of TMP-SD-tablets to market tablets of TMP was116.70%. Compared with the TMP commercial tablets, the elimination half-life(t1/2?) and the time to peak(Tmax) were shortened by 13 h and 2h and the peak concentration(Cmax) and the area under concentration curve(AUC) were increased by 7.83mg·L-1 and 202.528mg·h/L respectively, which indicated that the tests achieved the purpose of immediate release and had the vital significance. |
PDF Full Text Request