| Pidotimod is a synthetic dipeptide of high purity. It is the broad-spectrum immune enhancer with biological active by oral. Besides, it has various characteristics, such as anti-toxic, anti-infective, anti-oxidation and anti-irritant, etc. Studies have shown that it can promote non-specific immune response and specific reaction, thus it plays an antibacterial and antiviral activity.Pidotimod with high solubility and low permeability, good security features, variety of pidotimod dosage forms has been developed as to tablets, granules, capsules, oral liquids, injections. Pidotimod preparations were first successfully synthesized by Italian Poli industria chimica company and obtained approval for clinical use abroad in1993."Chinese Pharmacopoeia"(2000edition) has received a set piece pidotimod, and currently there is a domestic pidotimod tablet, namely pidotimod piece by Sunstone (Tang shan) pharmaceutical company.Based on the physicochemical properties of pidotimod and the prescription of pidotimod tablets sold in domestic, and combined with the supply of adjuvant, we find out the optimal types and dosages of bulking agents, binders, disintegrating agents and lubricants for this product. Lactose and microcrystalline cellulose were selected as the bulking agents. Microcrystalline cellulose, hydroxypropyl cellulose, and crosslinked povidone were selected as the disintegrating agents. Hydroxypropyl cellulose and povidone K30were chosen as the binders. And magnesium stearate and silica powder were chosen as the lubricants.In the research of preparation technology, the traits of particles before and after drying, the fluidity and hydroscopicity of particles, the compressibility, smoothness, hardness, friability and disintegrability of tablets were selected as indicators to screen and optimize the prescription, as well study the preparation technology, so that a reasonable prescription and a practicable preparation technology of pidotimod tablets were obtained. Finally, the optimized prescription was composed by:400mg of pidotimod,90mg of microcrystalline cellulose,45mg of lactose,30mg of crosslinked povidone,65mg of hydroxypropylcellulose,5mg of magnesium stearate,15mg of silica powder, and sufficient quantum of5%povidone K30and ethanol. In addition, wet granulation was used to prepare the pidotimod tablets. The prepared tablets were slick and neat, and the preparation technology was simple and cheap,and the hardness and tablet weight variation were in the limits range.The similarity of dissolution curves between the imitation goods-pidotimod tablets and the original preparation was assessed by using F2factor method. The result showed both of them had good reproducibility on dissolution.After the pidotimod tablets were prepared, their quality and stability were studied to achieve the purpose of quality control, and in the quality of research pidotimod impurities of bulk drugs and formulations were analysed preliminarily. And the protocol of pidotimod tablets’ quality standards was subsequently established.In order to know whether the quality measurement method is applicable to the pidotimod tablets or not, we made a preliminary study on character, identification, inspection, determination method,dissolution method, related substances substance and impurities of pidotimod tablets. Experimental results showed that:(1) Pidotimod tablets were white tablets. They were glabrous without any spots or shadows in the surface.(2) Two different methods were used to identify Pidotimod tablet, where in the other components didn’t interfere in the color reaction identification and HPLC identification, and the active ingredients are the same substance,so those two methods could be used for the identification.(3)The results of moisture content test, weight difference testand microbial limits test were proved to be qualified.(4) The HPLC method was established for the determination of the content assay, dissolution and related substances in the study. In the study of content, linear range of Pidotimod was62.5～1000μg·mL-1. The HPLC method was accurate, reliable and easy to operate. In the study of dissolution, the determination of dissolution medium, medium size and rotation speed were investigated. When the dissolution medium was900mL of water, and determined according to paddle operations at a speed of50r·min-1, the samples had good dissolution and were compliance with the requirements. In the related substances study, linear range of Pidotimod was1.25～20μg·mL-1. The HPLC method was also proved to be accurate, reliable and easy to operate.(5)The HPLC method was measured the main impurities of pidotimod. The results showed that Pidotimod raw material and three batches of formulations are free of impurities X, namely pidotimod diketopiperazine-6-propionic acid, containing a very small amount of impurities Y, namely pidotimod diketopiperazine.The results showed that the quality of this product was as good as the original pharmaceutical. It was stable and controllable. The measuring method for it was feasible, too.We also investigated the stability of pidotimod tablets by factors affecting test, accelerated test and long-term test. The results showed that the appearance, weight variation, content, dissolution, and related substances of pidotimod tablets had no significant change, which met the requirements. The factors affecting test showed that at a high humidity of92.5%, the pidotimod tablets showed up a bit of swelling, which indicated they were of some hydroscopicity. Therefore, the pidotimod tablets should be sealed and stored at dry places. The accelerated test and long-term test were conducted by using commercially available simulation package, the results indicated that pidotimod tablets were of stable quality, without founded lobes and fragmentation phenomena. The dissolution meeted the requirements. The content were unchanged. And the related substances did not increase much. It showed pidotimod tablets were stable under conditions of a sealed package. The above test results provided a corresponding basis for the production, transportation, storage conditions, and valid formulation of pidotimod tablets. |
PDF Full Text Request