Study On Nasal Spray Of G-0608

Objective: As cancer inception rate continuely raising, the field to cure nausea and vormiting, which gain a lot of attention. At present, 5- hydroxytryptamine type3 is the primarily choose to cure nausea and vormiting by clinical doctor, but most dosage of these drug are Injection, so our aim is to prepare a G-0608 nasal spray with high bioavailability, fast onset and low or without toxicity, for chemotherapy patient supportting a novel dosage to deal with nausea and vomiting, and reducing the patient's pain from injection.Method and Results:Firstly, we prepared the same concentration of G-0608 solution with posphate buffer solution at different power of hydrogen, which was to investigate the stability of G-0608 in 80℃after ten days; the air tightness of the dispenser in high temperature(60℃)and high humidity(RH=92.5%), and the precise of spray volume were counted in ten times continuouly, which were investigated too. Choosing Hydroxyl ethyl benzene and Triclosan tert-butyl alcohol as preservatives, investigated whether G-0608 was interacted. Then isolated sheep nasal mucous was employed, single factor factorial design, detected the concentration in 20,40,60,120,180min, in order to evaluate the influence of three kinds of absorption enhancers in single concentration and different concentrations in single absorption enhancer on the penetration enhancement effect of the model drug in vitro. The G-0608 nasal spray was stable in 80℃at pH range from3.5 to 6.5, after ten days, the contents were higher than 80%; the device have a good tightness and a accurate spray volume. Two kinds of preservatives were not interact G-0608, but Triclosan tert-butyl alcohol have camphor-like odour, will have a little stimulus to nasal cavity, so we chosed Hydroxyl ethyl benzene as our formula preservative.The results of transmucoas absorption test showed that the penetration multiple of enhancer A and C have a good penetration, considering the factor of economic costs,we chosed the penetration enhancer C to do the next investigation, research proved 5% enhancer C has a wonderful penetration effect.Secondly,"Ex vivo toad palate mucoas method"was used to assay the ciliotoxicity of each single component and the formula in different concentration, record the lasting time of cilliary movement, then compared them with phsiological saline group's, calculate the relative percentage. The results showed that phosphate buffer solution, as pH moderator, has a certain ciliotoxicity, so we will not use pH moderator to adjust the pH of formulation, and enhancer C can reduce the ciliotoxicity of Hydroxyl ethyl benzene, extend the lasting time of cilliary movement with concentration.Thirdly, technique process study was made, G-0608's quality standard was build, three batch of G-0608 nasal spray was investigated in clarity, pH, contents, each jet contents, related substance. Have been fixed the formulation with distilled water as solvent, 0.1% Hydroxyl ethyl benzene as preservative, 5% enhancer C as penetration enhancer, and confirmed technique process; the quality standard method was established; Three sample batches have a promising results. Clarity was good, pH was about 4.1, contents and each jet contents were between 95～105%,related substance was controlled under 2%.Fourthly, in the research of formulation stability, stay-at 40℃in 1,2,3,6month and stay-at room temperature in 3,6,9,12,18,24month were investigated, respectively. Accerlaring term storage study under 40℃showed that the nasal spray was very stable, clarity, pH, contents, each jet contents and related substance were fit with the requirement.Finally, building a new in vivo method based on HPLC, in vivo study was carried out with 2×2 latin square design, and pharmacokinetics research in four beagle between the G-0608 nasal spray and injection, 3P97 software was used to analysis those drug metabolism data and calculate absolute bioavailability of G-0608. The in vivo method indicated that linear range was 11.2～224ng?mL-1, limit fixed quantity was 11.2 ng?mL-1, relative recovery rate was 97.9%, absolute recovery rate was 25.6%. The results of pharmacokinetic study indicated that nasal spray was fit with two compartment model, each pharmacokinetic data were Tmax(7.21±1.6)min, Cmax(7.60±2.12)ng·mL-1, Ka 0.506 min-1, the absolute bioavailability was (57.21±10.0)%.Conclusion: The G-0608 nasal spray developed in this study was confirmed with coherent formulation, controllable quality, repeatable technique process, good stability, little ciliotoxicity, quick absorption and higher absolute bioavailability etc., which basically met the aim and requirements of this study.