The Study On Quality Control And Stability Of The Innovative Drug DZ2002

The research on quality control and stability of drugs is an important part of drug pre-clinical studies. During the study on drug quality standards, it’s necessary to check drug quality to guarantee the safety and reliability of drugs, and guarantee the smooth progress of pre-clinical research, as well as the safety of post-marketing drugs. Drug storage conditions and validity of drugs are determined by the stability research.According to the study on drug quality standards and stability, the contents and methods of the quality standards and stability of DZ2002and the draft quality standards of DZ2002were established. By elemental analysis, UV, IR, NMR (13C,.H) and mass spectrometry for structural confirmation of DZ2002, reliable raw material for the study on quality standards and stability was provided. The work was divided into the following four chapters:chapter Ⅰ is study on quality control of the innovative drug DZ2002, chapter Ⅱ is stability research of DZ2002, chapter Ⅲ is draft quality standards of DZ2002and drafting instructions and chapter IV is bioequivalence evaluation of two brands of rivastigmine of different salt forms in healthy beagle dogs.Chapter Ⅰ The study on quality control of the innovative drug DZ2002The quality standard of DZ2002was investigated according to Chinese Pharmacopoeia and technical specifications of the drug quality standards. According to the structure and property of the DZ2002, we selected the appropriate method for its quality control. The items of solubility, melting point, rotation, identification, examination of inorganic impurities, moisture, weight of moisture absorption, residue on ignition et al were studied to determine the appropriate test methods and results.The methods of residual organic solvents inspection, the related substances and chiral isomer R-DZ2002inspection and assay were established for the first time. Verification methodology was conducted, and was used for the determination of relevant contents of DZ2002.The results indicated that organic solvent residues of DZ2002met Chinese Pharmacopoeia requirements. The DZ2002content determined by nonaqueous titration and high performance liquid chromatography were greater than98.5%.Chapter Ⅱ The study on stability of the innovative drug DZ2002 Stability of DZ2002was conducted according to the guiding principles of drug stability test. Impact factors test, accelerated test and long-term test were carried out respectively. The sample characteristics, the main component content and related substances content of stability samples were analyzed.It’s found that DZ2002is insensitive to light, temperature and humidity. After the accelerated tests at40℃, humidity of75%, and long-term test at25℃, humidity of60%, the related substances content increased to1.08%and0.70%, R-DZ2002content changed to0.67%and0.69%, and main component content decreased to98.75%and99.10%.For statistical analysis on the validity, if main component content of DZ2002becomes98.5%, the retention time is33.2months. So the DZ2002is valid for33months.DZ2002should be stored under the condition of room temperature, dark and dry.Chapter III The draft quality standards of DZ2002and drafting instructionsThe draft quality standards of DZ2002and drafting instructions were formulated and drafted according to the first two chapters. This chapter provides norms and basis for quality control of DZ2002.Chapter IV Bioequivalence evaluation of two brands of rivastigmine of different salt forms in healthy beagle dogsThe bioequivalence of two brands of rivastigmine capsules, of different salt forms, was demonstrated in6healthy beagle dogs after a single oral dose in a randomized cross-over study. Reference (Rivastigmine hydrochloride, Sunve, CN) and test (Rivastigmine tartrate, Novartis, CH) products were administered to fasting beagles on2treatment days separated by a2-day washout period; blood samples were collected at specified time intervals, and the plasma was separated and analyzed for rivastigmine using a validated GC-MS method. The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, Tmax and t1/2were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by the State Food and Drug Administration (SFDA) of China. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and90%confidence intervals fell within the acceptable ranges for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Sanwei’s Rivastigmine hydrochloride was bioequivalent to Rivastigmine tartrate of Novartis, CH.