Study on Synthesis and Preparation of Dry-absorbed Emulsion of Indomethacin 5-fluorouracil-1-ylmethyl Ester
|School||Shenyang Pharmaceutical University|
|Keywords||5-Fluorouracil Indomethacin Indomethacin5-fluorouracil-1-ylmethyl ester Dry-absorbed emulsion Acute toxicity Gastric mucous membrane damage Bone marrow depression|
Studies showed that 5-fluorouracil (5-FU) and indomethacin (IDM) have synergistic effect in cancer treatment. However, the side effects of 5-FU and IDM such as gastrointestinal injure and bone marrow depression was strong. Drugs that were high therapeutic effect and high toxicity were not applicable to use widely. In order to keep the high therapeutic effect and decrease the side effect of these two drugs, indomethacin 5-fluorouracil-1-ylmethyl ester (IFM) was synthesized and IFM dry-absorbed emulsion (IFM-DAE) was prepared for the first time. Experimental results showed that the antitumor activity of IFM was comparable to 5-FU. At the same time, IFM has anti-inflammatory and analgesic activity. IFM-DAE has anti-tumor activity and little bone marrow depression, but Tegafur tablet sold on market has obvious bone marrow depression. The major contents and conclusions were as followed.IFM was synthesized using 5-FU and IDM as the raw materials through two steps. The method was simple and the yield is 66%. The content of IFM after purification was 99.5%. The structure of IFM was confirmed by IR, MS and 1H-NMR. Molecular formula of IFM was C24H19FCIN3O6, and the relative molecular weight was 500. IFM was yellowish solid at ambient temperature and pressure.The physicochemical property of IFM was determined. The solubility of IFM in aqueous solution at pH 1.2～7.4 was too little to determine by UV and HPLC. Apparent partition coeffecient of IFM in n-octyl alcohol and aqueous solution of pH 7.4 and pH1.2 was 350.7 and 260.2, respectively. The melting point of IFM was 217～220℃. The observed activation energy of IFM degradation in solid was determined to be 100.2 kJ/mol by DTA. IFM was stable when exposed to higher temperature, high humility and strong light.Chemical stability of IFM in hydrochloric acid and buffer solution at different temperature was investigated. The result indicated that IFM was stable with pH range from 3.6 to 5.8 and decomposed faster at slight alkaline and strong acidic condition. The observed activation energy of IFM degradation in pH4.7 aqueous solution was 91.8±6.9 kJ/mol.IFM was incubated with the dilution contents of rat gastro-intestinal tract and 80% plasma at 37℃to investigate the release of 5-FU and IDM from IFM. The amount of 5-FU released from IFM was about 90% in 8h in small intestine and was about 50% in 8h in colon, the smallest amount of 5-FU released from IFM was in stomach and in caecum. The degradation of IFM in 80% rat plasma was fast, about 70% of IFM decomposed to 5-FU and IDM in 5 mm.IFM-phospholipid complex was prepared. The compling ratio of IFM was 100%. IFM-DAE was prepared and its formulation and process were optimized, which the ratio of sedimentation height was used as the evaluation index. IFM-DAE can be emulsified fast in artificial gastric and intestinal media and the mean diameter of emulsion drops was 0.800μm and 3.416μm, respectively.ξ-potential of emulsion in pH7.4 artificial media was-45.8mV. Releasing of IFM from emulsion in medium in vitro depends on penetration and diffusion, and follows Higuchi model in 12h. IFM-DRE is susceptible to light and should be stored away from light.Half lethal dose (LD50) of 5-FU, IDM, mixture of IDM and 5-FU (1mol/1mol) and IFM was observed to be 82.28,260.09,200.34and 1926.5 mg/kg, respectively. This showed that the acute toxicity of IFM was decreased obviously compared to the other three system. Our experiments showed that IFM has anti-tumor, analgesic and anti-inflammatory activity Gastric mucous membrane damage of IFM is slight. Compared to Tegafur tablet sold in market, IFM-DAE has better antitumor activity to mouse sarcoma S180 (Inhibition ratio of Tegafur tablet and IFM-DAE were 47.6% and 53.5% respectively) and has no obvious bone marrow depression..IFM would be a promising anti-cancer drug.