瑞巴派特缓释片的处方优选及稳定性考察

Optimization and stability study of the formulation of Rebamipide sustained-release tablets

目的 优选瑞巴派特缓释片处方,并考察所制片剂的稳定性。方法 在单因素考察的基础上,采用中心点复合设计-响应面法,以羟丙甲纤维素K100M(HPMC K100M)和泊洛沙姆188的用量作为考察因素,以缓释片在0.5、2、6、10、12 h时体外累积释放度(Y0.5、Y2、Y6、Y10、Y12)的综合评分(Y)、体外累积释放曲线的相关系数(R)及黏冲程度(N)为评价指标进行处方优化并验证;对按最优处方所制片剂的稳定性进行考察。结果 瑞巴派特缓释片最优处方为瑞巴派特150.0 mg、L-精氨酸75.0 mg、泊洛沙姆18865.6 mg(13.12%)、HPMC K100M 114.5 mg(22.90%)、微晶纤维素适量、微粉硅胶5 mg(1%),总处方量为500 mg。经3次验证实验证实,缓释片中瑞巴派特的含量分别为100.61%、98.69%、99.01%,所制缓释片可持续12 h释药,体外累积释放度≥90%,且重复性良好。Y、N、R 3个指标的实测值与预测值的偏差均小于10%。稳定性考察中,光照会使含量略下降;在温度25℃、相对湿度(90±5)%条件下放置10 d后,片剂从第5天起出现膨胀、开裂、释放速率减慢现象;高温实验和加速、长期稳定性实验中,片剂的性状无明显变化,含量及体外累积释放度与第0天或第0个月相比无明显差异。结论 成功优化瑞巴派特缓释片处方;所得缓释片具有缓释效果,应于干燥条件下遮光保存。

OBJECTIVE To optimize the formulation of Rebamipide sustained-release tablets and investigate its stability.METHODS On the basis of single factor investigation,the central composite design-response surface method was adopted to optimize and validate the formulation using the dosage of hypromellose K100M(HPMC K100M)and poloxamer 188 as factors,comprehensive scores(Y)of the in vitro cumulative release(Y0.5,Y2,Y6,Y10,Y12)of sustained-release tablets at 0.5,2,6,10 and12 h,correlation coefficient of in vitro cumulative release curve(R)and viscosity(N)as evaluation indexes. The stability of the optimized prescription was validated. RESULTS The optimized formulation was as follows:rebamipide 150.0 mg,L-arginine 75.0mg,poloxamer 188 65.6 mg(13.12%),HPMC K100M 114.5 mg(22.90%),microcrystalline cellulose proper amount,micropowder silica gel 5 mg(1%),and the total prescription amount was 500 mg. According to 3 validation experiments,the contents of rebamipide in sustained-release tablets were 100.61%,98.69% and 99.01%,respectively. The obtained sustained-release tablets released for 12 h continuously,with in vitro cumulative release ≥90%,with good repeatability. The deviation between the real values and the predicted values of the 3 indicators Y,N and R were all less than 10%. In the stability tests,light would silightly reduce the content after 10 days of storage at 25 ℃ and relative humidity(90±5)%,the tablets expanded and split from the 5th day,and the release rate slowed down;in high temperature,accelerated and long-term stability tests,the properties of the tablets have no significant changes,and the content and in vitro cumulative release have no significant differences compared with the 0th day or 0th month. CONCLUSIONS Successfully optimized the formlation of Rebamipide sustained-release tablets. The sustainedrelease tablets obtained have sustained-release effect and should be stored in a dark place under dry conditions.