Potassium Citrate Sodium Chewable Preclinical Studies

The cause of gout is that purine metabolism happen disorder in vivo, uric acid synthesis increase or discharge reduction. When concentration of uric acid is high in the blood, the acid is deposited in the joints, cartilage and kidney in the form of sodium salt, and causes inflammatory reaction of organization foreign body[1,2].Incidence rate of the disease increases year by year, which has become common diseases of old male in the world. This paper developed potassium citrate sodium chewable tablet is new preparation that is used to treat the gout, hyperuricemia and body acidosis drugs, and belong to national3.2class new drugs. So far, potassium citrate and sodium citrate preparations have been marketed including common tablets and powder in Japan and syrup in American. However, there are not any reports about potassium citrate and sodium citrate chewable tablets. Our group has applied the China patent for the invention of the key preparation technology and the patent has been authorized (China: ZL201110432645.9)[3].The parts of preclinical reaserch were studied according to the "chemical registration requirements of the classification and reporting information" of "Drug Registration"of State Food and Drug Administration’s document of No.28,2007, which aimed to accumulate the data of potassium citrate and sodium citrate chewable tablets for clinical trials and registration.Formulation and Technology. Use the appearance, taste and hardness as reference parameters, the formulation was optimized by single-factor and orthogonal experiments. The best prescription contains:Potassium Citrate115.75mg, Sodium Citrate97.5mg, Citric acid14mg, Mannitol116mg, Aspartame0.7mg,2%hydroxypropyl methyl cellulose0.6mg, Peppermint Essence0.2mg, Magnesium Stearate3.5mg, Gum Acacia1.75mg. Tablet weight was350mg. The chewable tablets were prepared by the techniques of wet granulation, which was simple and low cost. The appearance of chewable tablets was integrity, the taste was refreshing and has mint fragrance in the mouth, the hardness was7.5-8.5kg and tablets weight differences was in the limits range.Quality Standards. The method established to determine the content, dissolution and related substances in potassium citrate and sodium citrate chewable tablets, and detected three batches of samples. RP-HPLC method was established to determinate content of total citrate and related substances in chewable tablets. It was content and dissolution of potassium citrate and sodium citrate that determinated by the ion chromatography. Refer to the Chinese pharmacopoeia,2010Edition of department2determination of citric acid content, the determination of the free citric acid content was determined by the acid-base titration method. All of these methods were simple, sensitive, accurate and good recovery. At the same time, we made a preliminary study about character, identification and inspection of potassium citrate and sodium citrate chewable tablets. The results were:identification was sensitive. All of the dissolution, content and related substances were accord with chewable tablet requirements. At last, we established the protocol of potassium citrate and sodium citrate chewable tablets quality standards.Stability. The influencing factor testing, accelerated testing and long-term testing were conducted to investigate the changes of potassium citrate and sodium citrate chewable tablets. The influencing factor was inspected by high humidity testing and strong illumination testing in this part. The results showed that chewable tablets were moisture absorption under high humidity testing easily. So they should be packaged airtightness and stored away from humid condition. The tablets were stable under strong illumination testing, accelerated testing and long term testing conditions.General Pharmacology. A low, medium and high dose of potassium citrate and sodium citrate chewable tablets were designed by the method of corrected for body surface area between the people and animals. The control groups were administrated0.9%isotonic Na chloride. Using KM mice and SD to be animal subject, we studied the effect on locomotor activity, coordination function and hypnosis function of subthreshold dose of Pentobarbital to mice and blood pressure, heart rate and respiratory frequency to rats. The results were that the low, medium and high doses of potassium citrate and sodium citrate chewable tablets had no significant effects on locomotor activity and coordination action to mice (P＞0.05). The low, medium and high dose of groups also had no significant effects compare with the control group on coordination functions of subthreshold dose of Pentobarbital to mice (P＞0.05). The low, medium and high doses of chewable tablets had no significant effect compare with the blank control on blood pressure, heart rate and respiratory frequency (P＞0.05).Pharmacokinetics and Bioavailability. The plasma concentrations of citrate in six beagle dogs were determined to inspect the pharmacokinetic characteristic of potassium citrate and sodium citrate chewable tablets by RP-HPLC. The data of drug concentration in blood was analyzed by DAS ver2.0pharmacokinetics intelligent analysis software, the pharmacokinetics parameter and relative bioavailability were calculated, AUC0～24and Cmax of test preparation and reference preparation were analyzed by the SPSS ver16.0software. The result showed that AUC0～24of test and reference preparation were453.381mg/L*h and449.006mg/L*h, Cmax were38.239mg-L-1and36.626mg-L-1, Tmax were0.792h and0.917h, the relative bioavailability of potassium citrate and sodium citrate chewable tablets was100.97%calculated as AUC0～24.The results of ANOVN of lnAUC0～24and lnCmax show that there is no statistical significance between chewable tablets and common tablets. The results of Non-parameter test of Tmax also show that two preparations have bioequiavalence.