The Research Of Miriplatin Injection And The Preliminary Exploration Of The Combination With The Molecular Targeted Regorafenib Microspheres

Object:In the process of the liver cancer treatment, simply hepatic arterial infusion of Miriplatin will likely to create the hypoxic ischemic microenvironment, and then increase the expression of the vascular endothelial growth factor or its receptor, with promoting tumor angiogenesis and the possibility of recurrence. Regorafenib, a molecular targeted drug, can inhibit the angiopoietins of tumor formation(like VEGFR-2 and VEGFR-3) to control the angiogenesis and reduce the recurrence rate. In order to improve the safety and effectiveness of drugs, we hypothesize that whether the combination of Miriplatin and Regorafenib would reach synergies, reduce the drug dose and decrease adverse reactions, at the same time get a better therapeutic effect. The thesis here is to study a further research about the combination of Miriplatin and Regorafenib in dosing form to provide the theory basis for clinical application.Methods:(1)Research of Miriplatin injection: This section will use the Miriplatin iodinate oil injection which has been listed as a reference for prescription screening and the optimization research of lyophilized formulation and process optimization, optimal freeze-drying technology curve. Firstly, the relationship between process and product quality of freeze-dried. Comparison impact of pre-freezing, pre-freezing speed, degree of vacuum on the appearance, viscosity, etc.; Secondly, to compare moisture affect the appearance of a lyophilized formulation, viscosity, complex solubility, stability, etc;finally, determine moisture and freeze-drying process, the preparation of optimum formulation, and has been listed with the original development of contrast agents.(2)Regorafenib microspheres: This section is for the carrier material with PLGA, PVA as the external phase, using the solvent evaporation method, preparation reggae sorafenib microspheres. Firstly, according to the single factor screening out the main factors, theuse of composite design and response surface method to find the optimum. Secondly,the test is repeated three batches for optimal process for verification. Finally, to study its physical and chemical properties, investigate whether it meets the requirements of embolic agents.(3)Combined preparation: Mixed Miriplatin injectable formulations and Regorafenib microspheres to prepare a combined preparation, formulation after the inspection of the prepared mixture of the two formulation, and compared changes of its physical and chemical properties.Result:(1) Study of Miriplatin injection shows that when the water content of tert-butanol solution 3.0mg / ml, freeze-dried powder prepared in optimum. And finalize the process of freeze-drying:-40 ℃ to a moisture content of 3.0mg / ml of Miriplatin solution quickly into the box before pre-freezing 4h, to adjust the degree of vacuum after 4.00 mbar, 2h rose from-40 ℃-1 ℃, dried to a blank sublimation of volatile solvent after all, 1h from-1 ℃ rose to 40 ℃, 2h resolved to keep dry when the vacuum degree 0mbar.(2)Regorafenib microspheres research shows that when the ratio of PLGA and quality drugs for 24, PVA concentration of 1.75%, the oil-water ratio of 9,speed of 200 rpm, volatile time for 12 h, the average particle size of 73.740μm, drug amount of 5.56%, the encapsulation efficiency was 71.68%. Swelling tests showed,PLGA microspheres embolization in 20 minutes to have a fast-swelling process, the basic stability of 360 min after stable particle size after swelling 152.336μm; Cumulative in vitro release tests showed that the microspheres 28 days cumulative release rate of78.32%.( 3) Combined preparation: the joint preparation of both mixed prepared independent of the nature of each exhibit, appearance particle size, viscosity, and other indicators of Miriplatin unchanged insoluble complex, Regorafenib microsphere’s diameter, contained dose, encapsulation efficiency and other indicators is unchanged.Conclusions:(1)The optimized injection consistent with the original in appearance, solubility,stability and some other indices.(2)Regorafenib microspheres appearance optimizedprocess for the preparation of spherical or spherical, to achieve the purpose of stabilizing the swelling to ensure the effectiveness and safety of treatment, in line with the requirements of clinical embolism.(3)The new compound preparations more stable without interference, and provide theoretical basis for mechanism of pharmacological and drug production.