Preclinical Studies Pridinol Mesylate Injection

Pridinol mesylate (PM) is a central anticholinergic drugs(Mainly antagonizing M1and M4receptor subtypes). It can improved the symptoms of Parkinson’s patients with movement disorders and delayed the time of patient’s disability. Secondly, PM is a central skeletal muscle relaxants and can play major role in the cerebral cortex and the brainstem reticular formation. The drug is most frequently used for muscle spasm and dyscinesia diseases and Parkinson disease in clinical practice.Pridinol mesylate is just included by 《The Japanese Pharmaceutical Codex (2002Edition)》, not included by 《Chinese Pharmacopoeia》. There is few study reported in china and no related product listed either, except the patent our research group applied for. 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, author made a study on the part of its preclinical, which was for the destination of accumulation of data of PM injection and clinical trials and registration.Formulation and Technology. The formulation was optimized with suitable pH range and pH buffering agents by physicochemical property investigation. The optimized prescription is0.2%pridinol methanesulfonate,1.0%taurine,0.1%sodium metabisulfite,0.7%NaCl,0.4%sodium hydroxide solution (adjust pH to6.5-7.5). In the prescription, taurine is known as a pH buffer, sodium metabisulfite is used as an antioxidant, sodium chloride is used as isotonizing agent, sodium hydroxide is used as pH adjusting agent. This formulation and preparation technique made the injection clarity, osmotic qualified and pH suitable. The content was up to specification, and the specifications is1mL:2mg.The research for quality standards. The separation was performed on a Ultimate XB C18(250x4.6mm,5μm) column.. The mobile phase consisted of methanol:O.Olmol/L phosphate buffer (70:30, v/v, contain4mmol/L sodium octanesulfonate). The detection wavelength was215nm, the flow rate was1.0mL/min, The injection volume was20μL and the column temperature was30℃. The method was proved to be convenient, accurate, selective and reliable, and can be applied for the quality control of PM injection.Meanwhile, the research consist of characteristics, identification and examination of pridinol mesylate, the results were colorless transparent liquid, sensitive identification, and the indexes of examination meet the requirements.Stability studies. Stability of the PM injection was observed by placing different temperatures and light conditions. Including high-temperature test (temperature60℃placed under10days), strong light test (4500±500Lx for10days); acceleration test (temperature of40℃±2℃, relative humidity of75%±5%under the conditions of placing six Temperature month, instrument control at±2℃, humidity control at±5%); placed under long-term test (temperature of25℃±2℃, relative humidity of60%±5%of the conditions of12months, temperature control equipment at±2℃, humidity control at±5%). The results showed that the PM injection of traits, clarity, content, pH and other indicators were no changes in the influencing factors and acceleration tests; and no significant changes in long-term trial to12months.General pharmacology. The study researched the effect of pridinol mesylate in low, medium and high leve on the central nervous system, cardiovascular system and respiratory apparatus.The orally disintegrating tablets showed no impact on general behavior and harmonious movement; there was no cooperativity with the hypnosis after giving pentobarbitale sodium at subthreshold dose. There was no significant effect on blood pressure, ECG, heart rate and respiratory rate of SDSafety evaluation. The LD50of PM injection was determined by modified Karber method, and the drug hemolytic, muscle and vascular irritation were measured by conventional method in New Zealand rabbits. The LD50of pridinol mesylate injection was82.05mg/kg (95%confidence range:72.49mg/kg-92.83mg/kg). The dosage of LD50is1025.5times that of normal for oral administration. The result suggests that PM injection has high security. There was no hemolysis, muscle and vascular irritation occurred in New Zealand white rabbits, and these results indicate that the drug can not only be used for intramuscular administration, but also be used for intravenous injection.Pharmacokinetic studies. The measurement method of PM blood concentration were established by using DAS2.0practical pharmacokinetic analysis software in this study. The results showed that the PM in vivo process were accorded to the two-compartment model and linear kinetics after a single intramuscular of pridinol mesylate.