The Preclinical Pharmaceutical Research And The Primary Research Of The Pharmacokinetics In Human Of Mildronate

Mildronate[THP,MET-88,3-(2,2,2-trimethylhydrazinium)-propionate dihydrate], being anew cardioprotective agent, its molecular formulas is C₆H₁₄N₂O₂₂H₂O and MW is 182.22At present, drugs commonly used in treating cardiovascular disorder include: nitrate ester, acceptor blocker,Ca²⁺ channels blocker and so on, they mostly act through increasing blood supply to cardiac muscle, reducing oxygen use, protecting blood insufficient cardiac muscle cells, ameliorating cardiac muscle metabolism. Mildronate ,a drug synthesized 20 years ago at the Latvian Institute of Organic Synthesis, it is different from drugs mentioned above, there is no changes on blood supply and oxygen use when protecting the heart. It lowers the intracellular concentration of free caraitine and thus suppresses fatty acid oxidation and facilitates glycolysis during ischemia.Considering its good effect in the treatment of cardiovascular disorders and low side effect, we are going to work over mildronate material and its preparations (capsule and intravenous infusion),to investigate it's quality control, and to develop the method of pharmacokinetics in Chinese healthy volunteers.First:The preclinical pharmaceutical research partThe quality control of mildronate material:first identify it's structure by elements analysis, IR, 1HNMR, 13CNMR, MS, powder X-Ray diffraction, TGA .we developped a GC analytical procedures for the residual solvent.Considering mildronate has no ultraviolet absorption and it is freely soluble in water ethanol, practically insoluble in acetone and chloroform. We use HPLC accompanying ELSD2000 detector to check up impurities and determine the assay. No related literatures have been found until now. The other test of the drug substances meet the pharmacopoeia.The quality control of mildronate capsules: Use the same HPLC-ELSD method as mildronate material to check up impurities and determine the assay since the adjuvants doesn't interfere the determination.And also used in the test of the dissolution of capsules . The other test of the drug substances meet the pharmacopoeia.The quality control of mildronate sodium chloride injection:because of the interference of sodium chloride,the old method is not fit for the test of impurities and assay of mildronate sodium chloride injection,so we build another method,use NH3 column,and change the fluid phase. The other test of the drug substances meet pharmacopoeia.Second: The research of the pharmacokinetic in humanSince the ELSD doesn't fit for the blood sample,so we developed a new HPLC-MS/MS method to determine the biological sample ,to use to the pharmacokinetic test of mildronate.MS/MS act as the detector,is more selective and sensitive.The preparation of blood sample using ethonol to precipitate the protein.Based on the method above and the application of mildronate,design a rational, normative research program of the pharmacokinetic of mildronate,including the object, health examination items,design of progress,drugs and methods, monitoring and so on.