| 2-Methoxyestradiol (2-ME) is the natural metabolite substance of estradiol, andit’s very less in human body. In recent years, researches have found that thiscompound well tolerated and lack of cytotoxicity for normal cells can inhibit multipletypes of cancer cells.2-ME could be a newly candidate for prevention and treatmentof malignant tumor,and several clinical studies have been performed in PhaseⅡ.However, due to its poor solubility, when2-ME was administrated orally, there aresome unsatisfying results, such as first-pass effect of hepar, lower bioavailability, andso on. When2-ME was administrated injection, the half-life of2-ME is shorter andthe significant level of plasma concentration is inaccessible in vivo. Thus, it’s veryimportant how to maintain the significant level of plasma concentration. In this article,we we explore the2-ME injection suspension which is made with2-ME and otherdifferent accessories. The preparation was achieved the aims of long acting, improvedpatient compliance and sustained release via slowly release drugs by intramuscularinjection.Firstly,HPLC method for the determination of2-ME and in vitro release wasestablished. The optimum condition was as follows: C18column (Akasil C18,5μm,4.6×250mm); column temperature30℃; mobile phase consisted of methanol andwater (70/30, v/v); flow rate1.0mL/min; UV-detector at288nm; sample size20μl.The2-ME regression equation was y=0.2949x+0.0752(r2=0.9999), precision indays was1.33%, precision between days was3.45%, recovery was99.97%(RSD=1.32%). The result indicated that this method was fitted for the demand ofsample analysis and detection. To establish a HPLC method for determining solubilityand lipo-hydro partition coefficient (P) of2-ME. The solubility was (1.579±1.131)μg·mL-1in water of37℃and l ogP was (2.79±1.43). It’s very an important basis todesign new formulations for2-ME.Through single factor test and orthogonal test the final selection of suspensionincluded70mg·mL-12-ME,8mg·mL-1CMC-Na and6mg·mL-1poloxamer. The dispersion method was used to prepare the2-ME injection suspension.To evaluate the quality of the2-ME injection suspension, includingsedimentation rate, redispersibility, syringeability, morphology, particle sizedistribution and the stability. The suspension had excellent stability, redispersibilitysyringeability and it’s sedimentation volume ratio of98%, average particle diameter8.31μm.2-ME suspension was prepared and in vitro release experiment were carriedout by flow cell method. The conditions of the in vitro release experiment was asfollows: release medium0.3%SDS and temperature37℃. After36hours, the drugreleased92.69%and could been considered fully released.Pharmacokinetics of2-ME injection suspension were investigated in mice,indicating that2-ME injection suspension was established into a one-compartmentmodel in mice, with the half-life t1/2Ke(7.52±0.26) h, respectively, MRT (16.18±1.25)h，AUC0→48h(27.81±2.09) μg·mL-1·h.2-ME suspension was prepared and invivo release experiment were carried out in mices. The experiment results showedthat the pattern of drug release for48hours in vivo fitted to Ritger-Peppas releaseplot, and the in vivo release rate of drug reach82.82%during treatment for48hours.The results of in vivo-in vitro correlation of2-ME suspension showed that releasedata had a certain correlation.In this study, animal model was built to assess the anti-tumor effects of2-MEsuspension by subcutaneous injection of mice S180ascites tumor cell, and theestablished animal model might provide an ideal means for drug efficacy study. Theexperiment of anti tumor on animals indicated that relative tumor growth rate was31.51%~63.84%, indicating that the result did not achieved the expected results, andthe reasons needed to be further studied. |
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