硫酸氨基葡萄糖固体口服制剂质量、企业执行标准评价及质控方法探索性研究

Quality,enterprise implementation standards and quality control methods evaluation of glucosamine sulfate solid oral preparation

目的评价国内目前市售的硫酸氨基葡萄糖固体口服制剂的质量,考察现行标准中存在的问题,为生产和质量控制提供参考。方法对硫酸氨基葡萄糖固体口服制剂进行国家药品抽检(共73批,涉及8家生产企业),采用现行各企业执行的注册标准(共9个标准)对抽检样品进行法定检验。同时对产品进行探索性研究,表观溶解度参照《美国药典》(USP)1236通则;含量测定方法参照USP43硫酸氨基葡萄糖氯化钠项下相关方法;有关物质方法参照原研企业标准;囊壳铬含量测定方法按照《中国药典》2020年版明胶空心胶囊项下相关方法;建立近红外光谱一致性检验模型。结果73批次硫酸氨基葡萄糖制剂合格率97.3%,2批样品有关物质检查项目不合格。各家质量标准存在一定差异,个别企业质量标准不完善,有待提高,质量标准中部分重要项目检测方法待改进。此外,个别企业应考虑制剂配方工艺的合理性、包装材料的密封性和防潮措施等。探索性研究结果显示,目前各企业执行标准中均没有原料药溶解性检验,建议企业关注晶型等可能影响溶解度的因素;法定检验采用C8色谱柱的结果较探索性结果整体偏高,采用氯离子作为主成分峰进行含量控制方法不专属,紫外可见分光光度法操作复杂、结果偏差较大,建议改为更为简便和专属的HPLC法;原料药为非复盐的受试批次制剂的杂质检出种类、已知杂质果糖嗪和脱氧果糖嗪含量、其他已知杂质类别和总杂含量高于其他受试企业样品,推断原因为其易吸湿;泡腾片中果糖嗪含量较高,未知杂质数量多于其他剂型,推测原因为辅料较多;与胶囊剂相比,片剂含有的杂质更多,提示片剂生产过程中制粒、整粒等温度较高的步骤会对产品质量产生一定影响;可按生产厂家建立近红外光谱一致性模型或相关系数模型,补充本品的快速筛查方法。结论各企业质量标准尚存在一定差异,个别企业质量标准不完善,有待提高,质量标准中部分重要项目的检测方法有待改进。应建立统一的国家标准,建立专属性强、准确度高的检测方法。

Objective To evaluate the quality of glucosamine sulfate solid oral preparations in China,and investigate the existing problems in the current standards,so as to provide reference for its production and quality control.Method The medicine post market quality surveillance of glucosamine sulfate solid oral preparations was conducted(73 batches in total,involving eight production enterprises).Use the current registration standards implemented by various enterprises(a total of nine standards)to conduct statutory inspections on sampled samples.At the same time,exploratory research was conducted on the product,with the apparent solubility referring to general rule 1236 of the United States Pharmacopoeia(USP).The content determination method shall refer to the relevant methods under USP43 glucosamine sulfate sodium chloride.Related substance methods refered to the standards of the original research enterprise for relevant material methods.The determination method for chromium content in the capsule shell shall be in accordance with the relevant methods under the gelatin hollow capsules section of the 2020 edition of the Chinese Pharmacopoeia.Establish a consistency testing model for near-infrared spectroscopy.Result The qualification rate of 73 batches of sulfated glucosamine preparations was 97.3%,and the relevant substance inspection items of two batches of samples are unqualified.There are certain differences in quality standards among different companies,and some companies have incomplete quality standards that need to be improved.The testing methods for some important items in the quality standards need to be improved.In addition,individual enterprises should consider the rationality of the formulation process,the sealing of packaging materials,and moisture-proof measures.The exploratory research results show that there was currently no testing for the solubility of raw materials in the execution standards of various enterprises.It is recommended that enterprises pay attention to factors such as crystal form that may affect solubility.The results of using C8 chromatographic column for statutory testing were generally higher than exploratory results.The method of using chloride ions as the main component peak for content control was not exclusive,and the operation of UV visible spectrophotometry was complex with significant deviation in results.It is recommended to change to a more convenient and exclusive HPLC method.The impurity detection types,levels of known impurity fructose and deoxyfructozine,other known impurity categories,and total impurity content of the test batch preparation with non double salt raw materials are higher than those of other test enterprise samples.It is inferred that the reason is that it is easy to absorb moisture.The content of fructosezine in effervescent tablets is relatively high,and the number of unknown impurities is higher than that of other dosage forms.It is speculated that the reason is due to a large number of excipients.Compared to capsule formulations,tablets contain more impurities,indicating that higher temperature steps such as granulation and granulation during the tablet production process can have a certain impact on product quality.A near-infrared spectral consistency model or correlation coefficient model can be established according to the manufacturer to supplement the rapid screening method for this product.Conclusion There were still some differences in the quality standards of various enterprises.The quality standards of individual enterprises and the detection methods of some important items in the quality standards need to be improved.A unified national standard,including specific and accurate detection methods,should be established.