| Pridinol Mesylate (PM) is one of the central anticholinergic drugs with skeletal muscle relaxant effects, which is mainly used to treat muscle cramps and the pain or contractions of movement disorders, such as low back pain, shoulder carpal tunnel syndrome, omarthritis and spine deformation. PM also have certain curative effect to Parkinson syndrome. So far, PM ordinary tablets, enteric-coated tablets, injections and powder for injection have been listed in Japan, South Korea, Argentina and other countries and Taiwan. However, there are not any reports about sustained-release tablets of PM. Instruction books of PM ordinary tablets listed in Japan show that the elimination half-life is about two hours in human body. Therefore, PM Sustained-release tablets were studied in this paper could extend the dosing interval to reduce the number of medication, to improve patient adherence, to avoid the "peak and valley" phenomenon and reduce side effects, which has important practical significance and the potential prospect of its market application. The project studied the formula and preparation technique, standard of quality, general pharmacology and bioequivalence for the application and clinical trial of new drug.The first part. The prescription and preparation study of PM sustained-release tablets. The aim of the present study was to prepare Sustained-release tablets of pridinol mesylate, and to determine the in-vitro dissolution rates of the tablets. The formula was optimized according to the release of pellets with single-factor and orthogonal test, and the Sustained-release tablets of pridinol mesylate release rate in-vitro was determined by rotate basket method with HPLC spectrophotometry. The release mechanism was discussed by Ritger-Peppas model. The optimized prescription is composed of pridinol mesylate12mg, HPMCK4M60mg, EC40mg, starch82mg, CMC-Na4mg, magnesium stearate2mg. Drug release property in-vitro were as follows:the release time is over12h, the drug release behaviors follow the first order equation, and the process of drug releasing is drug diffusion with frame erosion.The second part. The quality standard study of PM sustained-release tablets. The character, release in vitro, identification, content and related substances of PM sustained-release tablets were researched. RP-HPLC for content and related substances determination in PM sustained-release tablets was established. The separation was performed on a VP-ODSC18column (4.6mm×150mm,4.6μm). The mobile phase consisted of methanol containing0.05mol·L-1-Octanesulfonic acid sodium salt solution0.1M and0.1%phosphoric acid. The ratio was60to40. Butyl p-hydroxybenzoate was used as internal standard. The flow rate was1.0mL/min and the injection volume was10μL. The column temperature was maintained at30℃and the detection wavelength was215nm. Result showed that the RP-HPLC method is efficient, specific, applicable to the determination of the content and related substances in PM sustained-release tablets. The release in vitro of the three batches of PM sustained-release tablets complied with the relevant requirements.The third part. The stability study of PM sustained-release tablets. The strong illumination test, accelerated test and long term test were researched on the PM sustained-release tablets. The condition of light testing was keep the strong light(4500±500Lx) for10days; The condition of accelerated testing was40℃±2℃and RH75%±5%for6months; The condition of long-term testing was25℃±2℃and RH60%±10%for6months. The results showed that the PM sustained-release tablets were stable in the strong illumination test, condition of accelerated test and long term test conditions.The fourth part. The general pharmacology of PM sustained-release tablets. The study researched the effect of PM sustained-release tablets on the central nervous system, respiratory apparatus and cardiovascular system. The results showed that the PM sustained-release tablets show no impact on harmonious movement and general behavior; there is no cooperativity with the hypnosis after giving pentobarbital sodium at subthreshold dose; there is no significant effect on spontaneous activity with low and medium dose group, but after the high dose, the freedom movement of mice grow downwards, which may mesylate the general site promise antagonistic central Ml receptors and producesome sedation. The results showed that the drug did not affect the blood pressure, electrocardiogram, heart rate, respiratory rate of rats.The fifth part. The pharmacokinetic study of PM sustained-release tablets in Beagle dogs. The pharmacokinetic characteristics in Beagle dogs of PM sustained-release tablets were studied with the PM common tablets from Japan as the reference preparation. Crossover administration test program, comparison of the pharmacokinetic parameters and relative bioavailability evaluation mesylate the PM sustained-release tablets and the PM common tablets in Beagle dogs. The result showed that the AUCo-24of test and reference preparation were1903.34ng/mL*h and1354.9ng/mL*h, Tmax were3.00h and1.00h, Cmax were243.71ng·mL-1and286.04ng·mL-1, the relative bioavailability of PM sustained-release tablets was140.48%calculated as AUC0～24. |
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