| Background Recently,lung cancer had become the most common malignant tumors due to the increasing incidence and mortality year by year.About 80% of it was non-small cell lung cancer.Surgery,radiotherapy and chemotherapy et al,were combined in the clinical treatment and had large adverse effects because of the poor selectivity of anticancer drugs which could not be effectively targeted to lung.Therefore,in order to improve the curative effect and reduce the adverse effects,it will be of great significance and practical value to construct a lung-targeting drug delivery system.New docetaxel liposome(DTX-LP),prepared by solid dispersion method(a new technology patent named DBaum NC),were confirmed to be remarkable lung-targeting in rabbits and may improve the curative effect of lung cancer while reducing systemic toxicity.Object To determine the preparation process of DTX-LP and complete the scaling up test,DBaum NC patent technology was used.To establish qualityevaluation system and quality standard.Method 1.High performance liquid chromatography was established for the determination of DTX in vivo and in vitro.2.Single factor experiment was carried out to investigate and establish the preparation process via scale-up method through small test,5 times,10 times,20 times et al.3.Tissue distribution in rabbit after administrated for 1.5h was investigated to evaluate the lung-targeting of DTX-LP and establish the quality evaluation index in vivo.Combining with the quality evaluation index in vitro,the quality evaluation system of DTX-LP was established.4.Scanning electron microscopy was used to observe the surface morphology of solid dispersion powder and the morphology of DTX-LP was observed by transmission electron microscope.5.Differential Scanning Calorimetry and Fourier Transform Infrared Spectroscopy were used to identify the physical existence form in solid dispersion.6.The size and Zeta charge of DTX-LP were determined by Malvern laser particle size analyzer.7.The encapsulation efficiency of DTX-LP was determined by the method of protamine aggregation.8.To investigate the sustained release property of DTX-LP,release study in vitro of DTX-LP was performed by dialysis bag.Result 1.Effective and specific HPLC methods were established to determine the drug content of DTX in vivo and in vitro.2.The preparation process of DTX-LP was determined via scale-up method through small test,5 times,10 times,20 times et al.Firstly prepared three batches DTX-LP scaled up to 40 times.DTX-LP were in round shape,uniformed size whose bi-layer structure were visible.Almost no crystallization of raw material was found.The solid dispersion were with good fluidity The lung-targeting of DTX-LP were confirmed through quality evaluation in vivo.3.Quality evaluation system was established by combining quality evaluation of DTX-LP in vivo and in vitro.4.Through quality evaluation in vitro,it was showed that the round shaped DTX-LP had a size range from 500 to 800 nm with negative charged.The encapsulation efficiency was more over than 80%.The suspension is close to neutral with sustained release characteristics.The solid dispersion powder was white with good fluidity.The drug content of DTX was 6.55±0.08mg/g in the presence of amorphous or solid solution state.Drugcontent and encapsulation efficiency did not change significantly after 12 months storage at a temperature of 2 to 8?.5.The quality standard of DTX-LP was preliminary drafted.Conclusion 1.Successfully determined the preparation process of DTX-LP via scale-up method through small test,5 times,10 times,20 times et al.The process is easy to operate with stable quality and good repeatability,laying the good foundation for the industrial production of DTX-LP.2.Quality evaluation system was firstly established.The quality standard of DTX-LP was preliminary drafted. |
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