Study The Prescription Technique And Stability Of Fungi Fibrinolytic Compound FGFC1 Freeze-dried Powder Injection

Thrombotic disease is caused by two kinds of pathological process of disease( the formation of thrombosis and thrombosis embolism). With not only high incidence, but also high mortality and morbidity, it is the first factor of death and disability both domestic and abroad, can be said to be one of the most important threaten to the elderly health. Dissolve thrombus is one of the most effective treatments. Although the clinical use of the three generations of thrombolysis medicine has the effect of thrombolysis, there are still some side effects like bleeding. In recent years, some small molecular compounds are found, which can be used in fibrinolytic enzyme and urokinase precursor to make the physiological fibrinolytic response steady. Domestic and foreign research on these compounds is becoming an important way to explore a new type of fibrinolytic therapy drugs.Laboratory found a new type of Fibrinolytic activity of the small molecular compound FGFC1(Fungi Fibrinolytic Compound 1) from marine microorganisms grow spore grape grain mildew FG216 metabolites. FGFC1 belongs to pyran and indole ketone derivatives. It is soluble in methanol, ethanol and other organic reagents. It is also slightly soluble in water. The pharmacodynamics and toxicology studies have shown that FGFC1 is a safe and effective compound to dissolve thrombus. Its elimination half-life is about 22.37 min. However, due to its low solubility, poor oral absorption effect, aqueous solution in strong acid, strong light is not stable, and many other reasons, it is difficult to make common formulation using FGFC1. In this article, we study the stability of FGFC1 and how to make FGFC1 freeze-dried powder injection. Through studying the stability of the powder injection, we try to optimize prescription technology of powder injection. Finally, we do some research about the possible structure of degradation products.The first chapter summarizes the status of clinical thrombolytic drugs; expounds the freeze-dried powder injection and significance of drug stability studies. The technology for FGFC1 pharmacy research especially oral preparation research provides a good theoretical basis.The second chapter is the study of FGFC1 physical and chemical properties. It also determines the HPLC quantitative detection method of FGFC1. Using FGFC1 content as indexes, we study the effect of strong acid, strong alkali, strong light, strong oxidizer and different pH on FGFC1. The research shows that HPLC method of FGFC1 is feasible. FGFC1 in strong acid, strong oxidizer, high temperature and strong light conditions is unstable. Under the condition of strong base FGFC1 is relatively stable. Under the condition of different pH it has different degradation speed. These research provides direction for further clinical preparation of FGFC1.The third chapter is the study of prescription technology of FGFC1 freeze-dried powder injection. According to the help dissolve effect of latent solvent, the appearance and after dissolving time of the FGFC1 powder injection, we found three kinds of powder injection technology is better: FGFC1: sodium citrate: mannitol(w: w: w) = 1:3:10, FGFC1: sodium bicarbonate: mannitol(w: w: w) = 1:1:5, FGFC1: L- lysine: mannitol = 1:5:10, FGFC1 content is 10 mg per bottle, vacuum freeze drying 48 h(-48 ℃). Preparation and study of three kinds of powder injection samples shows that the appearance, pH and after dissolving time meet the requirements.The fourth chapter studies stability of three FGFC1 powder injection. Optimized process was determined by the stability test for three FGFC1 powder injection: FGFC1: sodium citrate: mannitol = 1:3:10. Classical stress test shows that high temperature, high humidity and strong light has different influence on three powder injection. Powder injection 1(sodium citrate group) is stable under the environment of high humidity. Its content basically remains the same. Under the condition of heat and light it will show a certain degree of degradation; powder injection 2(sodium bicarbonate group) is relatively stable under the condition of high temperature; powder injection 3(L- lysine group) is more stable under the condition of strong light. Accelerated test results show that when the three kinds of FGFC1 powder injection are sealed without light and stored in place with 40 ± 2℃, relative humidity of 75% plus or minus 5% for three months, they all have a certain degree of decline. The content of sodium citrate group appearance has not changed, which is still white and osteoporosis. The pH also has no obvious change. The rest of the two groups have significant appearance change. Another research shows that after powder injection is dark sealed and placed in 4 ℃ low temperature refrigerator for eight months, its FGFC1 content does not decrease. The pH and appearance has no change. This shows that the powder injection prescription process is reasonable and feasible. Moreover, the powder injection should be placed in the brown schering bottles under the condition of low temperature. Because there will be a rapid degradation when powder injection is placed under the condition of high temperature and high humidity, we use high performance liquid chromatograph and TOF – MS to analyze the degradation products. According to the high performance liquid chromatography(HPLC) figure and MSMS chromatogram, we make the speculation of the chemical structure of the degraded content. And we found that degradation products is probably created by FGFC1 dehydrogenation, methylation, and C-N alkylation. The degradation pathway of FGFC1 standard and FGFC1 powder injection is also different.