Study Of2-methoxyestradiol Inhalation Powder

2-Methoxyestradiol is an endogenous metabolite of estradiol, the studies ofpharmacological activity have shown that it has better efficacy against a variety of cancercells and a broadspectrum anti-tumor effects. Previously we conducted extensive research onits oral preparation and injections in our laboratory, and found that its oral absorption wasn’tregular pattern, bioavailability was low, and its injections fast metabolized, half-life was short,couldn’t maintain an effective plasma concentration for a long time. So it is necessary toactively explore other modes of administration so that changing these disadvantages whichthe above dosage form exist. Inhalation powder is administered through the lung, which canavoid the first pass effect of the liver, increases the drug’s bioavailability, besides the drug’sabsorption and onset are also relatively fast, and can achieve the targeted pulmonaryadministration, more conducive to the treatment of lung diseases. Therefore, the presentstudy intends to make the inhalation powder of2-ME, investigating its feasibility forpulmonary drug delivery, and to develop new formulation for the treatment of lung tumors.Firstly, the study established the analysis method of the HPLC of2-ME inhalationpowder in vitro. By these studes of methodologies, we knew that the specificity of theHPLC’s analytical method was strong, these precisions of intra-day and inter-day wererespectively0.99%and1.06%, the average recovery was100.18%, the above study resultswere in accordance with the provision of HPLC analysis application, and when2-ME was inthe concentration range of0.2～40μg·ml-1, there was a good linear relationship between theconcentration and peak area, the regression equation and correlation coefficients wereA=6×107C+106, r=0.9999. Therefore, this method is suitable for the determination analysisof2-ME in vitro.Secondly, the range of the respirable particulate diameter by pulmonary administrationis1～5μm, so the present study firstly made the respirable particles of the2-ME by themethod of controlled crystallization. The best conditions of prescription and process whichwere selected by the studies of the morphology, the size and the stability of particles wererespectively that the concentration of2-ME was2.5mg·ml-1, the concentration of poloxamerwas5mg·ml-1, the stirring speed was1200r·min-1, the proportion of ethanol and water was 1:3. After preparing the solution of2-ME particles by the above method, and then thepowder of the respirable particles of2-ME was prepared by these methods of centrifugation,dispersion and freeze-dried.Thirdly, the best conditions of the prepared formulation and process of2-ME inhalationpowder were selected in the evaluation indicators of the property of powder physical andchemical and the characteristic of powder atomization, such as solubility, powdermorphology, hygroscopicity, particles size and distribution, moisture content, angle of repose,atomization characteristic, emptying rate and deposition in vitro and so on. Finally, the bestprepared conditions of2-ME inhalation powder were got. The formulation was that theproportion of2-ME with lactose and leucine was2:1:1, the amount of poloxamer was2%ofthe above three. When preparing the product,2-ME and carriers were made into a certainconcentration of the suspension, and then were sprayed drying. The prepared process werethat inlet temperature was140℃, the atomized gas flow was470L·h-1, aspiration flow was80%, pump speed was240ml·h-1, the solution concentration was1%.Fourthly, the evaluation indicators of2-ME inhalation powder which was prepared inthe best prepared conditions were measured, the results show that the solubility of carrierswas good, and could release the respirable particles of2-ME quickly; the aerodynamicdiameter was2.72μm, and was suitable for pulmonary inhalation; there was hygroscopic, themoisture content was2.224±0.73%; the surface morphology was irregular, the angle ofrepose was42.36°±1.42°, the fluidity wasn’ts good; the class of atomization characteristicswas B, the emptying rate was greater than90%, the deposition amount of the effective partwas greater than30%. Therefore, all the indicators were in accordance with the requirementsof inhalation.Fifthly, the present study initially researched on the pharmacokinetic and the releasingbehavior of2-ME inhalation powder in rats by the established animal inhalation model. Theresults showed that the metabolism of2-ME inhalation powder in rats was a one-compartment model, the half-life of distribution (t1/2ka) was0.6±0.22h, the half-life ofelimination (t1/2ke) was3.49±1.26h, AUC0-12hwas2.95±1.24μg·ml-1·h, the release behaviorwas the Higuchi release, r=0.9945.Last, the safety of the pulmonary administration of2-ME inhalation powder waspreliminary evaluated, the result showed that2-ME inhalation powder had some irritation to the lung, but there weren’t severe irritation and the phenomena of fibroblast proliferation, sothe biocompatibility and the safety of2-ME inhalation powder could be able to meet therequirement of pulmonary administration.