| As an broad-spectrum.high-performance. hypotoxic antibacterial agent, Trimethoprim (TMP) can obviously enhance the antibacterial action of some other antibacterial agents. It's poor solubility and bioavailibility discount it's clinical effect. Hydroxypropyl-β-cyclodextrin (HP-β-CD), as a kind of noval pharmaceutical excipient, is often used to include some guest molecule to improve guest's solubility and dissolution rate.In this thesis, TMP was chosen as model drug and trimethoprim-hydroxypropyl-β-cyclodextrin inclusion complex (TMP-HP-(β-CD) was prepared, identified and evaluated. Meanwhile, a comparison of pharmacokinetic between TMP powderer and TMP-HP-β-CD by intramuscular injection were also studied.During the preparation of TMP-HP-β-CD, solution-stiring was chosen firstly, then the factors which influenced preparation were studied one by one and the main three factors were find out. Finally, the orthogonal filter design and analysis of variance on the main factors was done to optimize the preparation procedure, the preparation procedure were:the ratio of host molecules and guest molecules was 3:1, inclusion system pH was 7.5. inclusion time was 4h.The inclusion complex made in this way was stable.With the purpose of further investigating the inner constructure and inclusion mechanism, inclusion complexes were identified by phase solubility analysis, thin layer chromatography and differential scanning calorimeter. It was infered that TMP was set into HP-β-CD molecular cavity as guest, and inclusion complexes were different from simple physical fixture of TMP and HP-β-CD. According to phase solubility analysis, molar ratio analysis and equimolar analysis, in this inlusion complex the host and guest bonded at 1:1 molecules ratio and the clathration was exothermic reaction.The method was established by ultraviolet spectrophotometry for determining the content of inclusion and inclusion rate. The regression equation of concentration and absorbance of trimethoprim was:A= 0.02239*C+0.002454(r=0.9999).The linear range was 0-40μg/mL. The intro-day and inter-day precision was 0.25-0.60%and 0.30-0.53% respectively. The recovery rate was 99.46-100.02%. The TMP inclsion rate was 74.62%, and content which was 8.65%valued by this method. Compared with the crude drug, the solubility of TMP-HP-β-CD increased about 26 times. It was proved that their potential application in water-soluble injection. In vitro dissloution results were shown that TMP-HP-β-CD could dissolve more quickly and completely than TMP powder and physical mixture. Accelerated stability test showed that the inclusion complex of light and heat are relatively stable.but it was greatly influenced by humidity. Hemolysis experiments of TMP-HP-P-CD showed that there was no hemolysis when the concentration of TMP-HP-P-CD was failde to achieve 4mg/ml. Intramuscular injection experiments showed that the inclusion complex has higher security.In the pharmacokinetic study of TMP-HP-β-CD in rabbit, a HPLC method was established to determine the concentration of TMP in rabbit plasma after intramuscular injection of TMP powder and TMP-HP-P-CD. The results showed that data of TMP powder, TMP-HP-P-CD were in line with a first-order absorption two-compartment model, Cmax of (10.267±0.025) vs. (14.932±0.06)mg/L, Tmax of 1.5 vs. l.0h. and AUC(0-1) of (41.282±0.17) vs.(62.729±0.102)mg/L*h, respetively. TMP-HP-β-CD had shortened peak time as well as enhanced AUC to 153.9%by contrary with TMP powder.On the whole, the TMP-HP-β-CD was successfully prepared and the purpose of this project was basically achieved. There was no report about the TMP preparation by inclusion with HP-β-CD in the literature. The result of this project provided a new approach for the development of TMP preparation. |
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