Studies On Quality Of Carbazochrome Sodium Sulfonate Injection And Novel Drug Gel

Carbazochrome sodium sulfonate is a new generation of adrenaline hydrazone derivatives hemostatic agents,the main ingredient is adrenochrome shrinkage ammonia urea sodium sulfonate. It's commonly used for multiple hemorrhages which caused by the increase of capillary permeability, such as the bleeding of urinary system, digestive tract, respiratory tract and gynecology diseases. Carbazochrome sodium sulfonate has significant effect on the treatment of urinary tract hemorrhage; it also can be used for trauma and surgical bleeding. But because of Carbazochrome sodium sulfonate injection its poor stability, drug release too fast, need to medicine for many times, thus increasing the probability of adverse drug reaction, and limit it's widely used in clinical practice. As a new drug delivery system, in situ gel delivery system can effectively prolong the retention time of the drug which used in the application site, then achieve the objective of slow releasing, as well as improve the bioavailability of the drug. This study of Carbazochrome sodium sulfonate injection in situ gel delivery system has its practical significance.Objective: This research, based carbazochrome sodium sulfonate as a model drug,optimized the original carbazochrime sodium sulfonate injection formulation, and then discussed the reason of injection insoluble particles increase; At the same time, it studied the prescription and preparation of carbazochrome sodium sulfonate thermosensitive hydrogel and investigated the in vitro release and in vivo pharmacokinetics study, in order to develop a safe, effective and stable injection carbazochrome sodium sulfonate preparation.Methods:This study established the HPLC quantitative analysis method of Carbazochrome sodium sulfonate, and investigated its basic physical and chemical properties. Using the Cold solution method to prepare Carbazochrome sodium sulfonate thermosensitive gel, on the basis of single factor investigation, the gelling temperature, gelation time and gel viscosity as the evaluation index, The formulation was optimized by the Box-Behnken response surface design optimization, and to verify the best prescription; Use methods to determine the in vitro release rate, then research the in vitro drug release kinetics by equation fitting analysis; By taking appearance, drug content, related substances and insoluble particles as the evaluation index, to optimize the prescription and technology of carbazochrome sodium sulfonate and sodium chloride injection, and correlation between the content of known impurities Kaba Chloe and insoluble particles; using rabbits as experimental animal, randomly divided into two groups which are the control group(using Carbazochrome sodium sulfonate) and experimental group(using Carbazochrome sodium sulfonate thermosensitive gel), HPLC method is applied to detect the concentration of carbazochrome sodium sulfonate in plasma of samples rabbits, the pharmacodynamics in rabbits were studied simultaneously and the study evaluate the biological utilization rate of Carbazochrome sodium sulfonate thermosensitive gel.Results:(1)The equilibrium solubility of CSS in water and physiological saline are 22.77mg·m L-1and 7.58mg·m L-1respectively. It shows that the solubility of the salt water in the physiological saline is obviously smaller than that in the water, and solution temperature affects the equilibrium solubility of the drug in the medium. In addition,high temperature test shows that high temperature will affect the stability of medicine carbazochrome sodium sulfonate. With the increase of time and temperature, related substances of CSS will gradually increase.(2)The results of single factor test and orthogonal test indicate that the kinds of antioxidants, p H and sterilization process will affect the number of insoluble particles in injection.Accelerated test results show that the existence of carbazochrome was positively related to the number of insoluble particles.(3)With the Box-Behnken response surface design,the optimization formulation of CSS-TISG was 18.12%P407+5.02%P188+0.24%SA+0.046%CSS.Its T gel was 36.5?.(4)In vitro drug release experiments indicate that 24 hours uniform drug release formulation was reached without burst release, well fitted to the drug release mechanism of Ritger-Peppas model comprised of both drug diffusion and gel erosion.(5)In the bioavailability study, the maximum plasma concentrations of self-in situ gel group were much belower than that of the CSS solution,and have less side effect. And MRT in vivo was prolonged significantly,which can play a long-lasting efficacy and improve the fraction of bioavailability.Conclusion:This research optimized the original carbazochrime sodium sulfonate injection formulation, and prepared the prescription and preparation of carbazochrome sodium sulfonate thermosensitive hydrogel. This self-made gel preparation has good stability, slow-release function; It can prolong the retention time of drugs in vivo obviously, and enhance its bioavailability.