| Pridinol mesylate is a type of central anticholinergic agents with skeletal muscle relaxing effect1.2which exhibits an obvious relaxation effect on muscle spasms. It is clinically applied in the treatment of muscle spasm and movement disorders accompanied by pain or shrinkage such as lumbar and back pain3-6, neck-shoulder-wrist syndrome7.8, omarthritis, spinal deformity, and Parkinson’s disease9.12,etc. diclofenac sodium is a type of non-steroidal antipyretic anti-inflammatory analgesics with good analgesia, anti-inflammatory and antipyretic effects, and is clinically used for the treatment of various rheumatisms, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, postoperative pains, and fever caused by various reasons13-16. Currently, the pridinol mesylate preparation listed in China Taiwan, Japan and Argentina is mainly in the varieties of compressed tablets, enterosoluble tablets, capsules and powders for injection. However, in the Chinese mainland, no study reported on single or compound pridinol mesylate injection, and no related product listed either, except the patent our research group applied for. We combined the pridinol mesylate and diclofenac sodium into a compound injection, in order to enhance the analgesic and anti-inflammatory effects of the injection on the basis of maintaining the muscle relaxing effect of pridinol mesylate. Thus, the injection will be more conducive to the treatment of muscle spasm and movement disorders with pains or shrinkage, and can be further applied in the treatment of arthralgia, neuralgia, courbature, dysmenorrhea and fevers caused by various inflammations. Pridinol mesylate-diclofenac sodium injection in this article belong to class3.2in our country’s new drugs registration. 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, a study on the part of its preclinical was made to accumulate data for clinical trials and registration of pridinol mesylate-diclofenac sodium injection. Research on formula and preparation technology of pridinol mesylate-diclofenac sodium injection. The study adopted the clarity, stability and pH of the injection as the index of investigation, and employed the single-factor test to screen out the types of excipients and the orthogonal test to determine the optimal dosage of the excipients. The optimal formulation of pridinol mesylate-diclofenac sodium injection was determined to consist of0.2%pridinol mesylate,2.5%diclofenac sodium,0.6%mannitol,27%polyethylene glycol400(PEG400),4%benzyl alcohol and0.3%sodium metabisulfite; its pH was adjusted to7.5with an appropriate amount of sodium hydroxide solution, and the volume was adjusted with water for injection. The preparation technique of pridinol mesylate-diclofenac sodium injection was as follows:weighed the water for injection with an amount of40%of the preparation volume, placed it into a suitable container, added the prescribed dose of pridinol mesylate, and stirred the solution for dissolution. Slowly added the prescribed dose of sodium metabisulfite and mannitol in sequence and stirred for dissolution, and the obtained solution was regarded as solution A. Added the prescribed dose of PEG400and benzyl alcohol into a suitable container, blended them, then slowly added the solution with prescribed dose of diclofenac sodium and stirred for dissolution,and the obtained solution was regarded as solution B. Mixed solution A and solution B, and then adjusted the pH to7.5using appropriate amount of0.4%sodium hydroxide solution. At last, supplemented the solution with water for injection to reach a specified volume, Mixing, filtration, potting, sterilization.Study on quality standard of pridinol mesylate-diclofenac sodium injection. The present study was to establish a method for simultaneous determination of pridinol mesylate-diclofenac sodium Injection. The separation was performed on a Shim-pack VP-ODS C18(250x4.6mm,5μm) column, the mobile phases of determination consisted of methanol-0.05%Phosphoric acid (with0.105%octane sulfonate)(60:40). The mobile phase was delivered at a flow rate of1.0mL·min-1, and the detection wavelength was215nm under the column temperature of30℃and the injection volume of10μ1. The well separated pridinol mesylate and diclofenac sodium were attained, in addition, there were well separated between impurities and the two drugs. The calibration curve was linear in the range of0.5-200μg·mL-1(r=0.9999) for pridinol mesylate and5-500μg·mL-1(r=0.9999) for diclofenac sodium, the minimal detection limit was0.2ng,and the minimal limit of quantification was1.5ng for pridinol mesylate; the minimal detection limit was2ng and the minimal limit of quantification was6ng for diclofenac sodium. The average recovery was98.09%(n=9) for pridinol mesylate and98.05%(n=9) for diclofenac sodium.The methods were validated and found to be simple, accurate, sensitive, specific, and can be used to simultaneous determination for pridinol mesylate-diclofenac sodium Injection.Study on sability of pridinol mesylate-diclofenac sodium injection. The strong illumination, accelerated and long term test were researched. The results showed that the injection content decreased in the condition of strong illumination. They should be stored in a Light shielding and sealed condition, the injection were stable in the condition of accelerated and long term test conditions. Continuing investigation into the long term test.Study on the part safety of pridinol mesylate-diclofenac sodium injection. The LD50of pridinol mesylate-diclofenac sodium injection was determined by improved karber method. Conventional method was used for the determination of its hemolytic muscle irritation and vascular irritation. The results showed that pridinol mesylate-diclofenac sodium injection LD50=40.95mg/kg (pridinol mesylate count); There was also no significant hemolysis and muscle irritation to rabbits.Study on general pharmacology of pridinol mesylate-diclofenac sodium injection. Respectively, administered made from low, medium and high dosage groups. Investigation of the three dose groups to central nervous system, cardiovascular system, respiratory system of the injection. The results showed, there was no significant difference between the experimental group and the control group (P>0.05), in functional of coordination and spontaneous motor activity; hypnotic effect of subthreshold dose of sodium pentobarbital; on rats breathing rate, blood pressure, heart rate.Study on Pharmacokinetics of pridinol mesylate-diclofenac sodium injection. To establish an HPLC Determination of plasma concentrations at different time points, investigation pharmacokinetics characteristics of pridinol mesylate-diclofenac sodium injection, in New Zealand rabbits. And plasma concentration analyzed adopt DAS2.0pharmacokinetic-processing software to calculated pharmacokinetic parameters. The injection in New Zealand rabbits corresponding pharmacokinetic two-compartment open model. The distribution half-life of pridinol mesylate T1/2ca=0.55±0.04h, the elimination half-life of pridinol mesylate T1/2β=4.24±0.41h, The distribution half-life of diclofenac sodium T1/2a=0.65±0.04h, the elimination half-life of T1/2β=6.25±0.41h, majority of the drug eliminated from plasma during24h. Tmax=1.15±0.04h, Cmax=0.84±0.08μg·mL-1,AUC=1.32±0.12μg/mL*h of pridinol mesylate; Tmax=0.87±0.07h, Cmax=1.61±0.05μg-mL-1, AUC=2.20±0.10μg/mL*h of diclofenac sodium, the result showed that, pridinol mesylate-diclofenac sodium injection fluid distribution in the plasma and the elimination process is quickly, after24h pridinol mesylate and diclofenac sodium not detected in plasma under our experimental conditions, apparent volume of distribution is much larger than New Zealand rabbit’s own blood volume, indicating that the injection chamber in peripheral tissues have a broad distribution of organs, confirmed the judgment two-compartment model. |
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