自微乳缓释片中西罗莫司的稳定性提高研究

Improvement of stability of sirolimus in self-microemulsifying sustained release tablets

目的:提高自微乳缓释片中西罗莫司(SRL)的稳定性。方法:考察SRL在不同pH条件下的稳定性,再利用柠檬酸或苹果酸调节自微乳的pH并制备缓释片,利用铝塑材料对自微乳缓释片进行包装,考察在高温、高湿和强光照射条件下SRL的含量变化。结果:SRL原料药在高温、高湿和强光照射条件下稳定,市售片中的SRL含量仅在强光照射下少量降低,而自制自微乳缓释片中的SRL在高温和强光照射试验下均不稳定。自微乳的碱性环境可能是导致SRL高温不稳定的主要原因,测定发现SRL稳定的pH为4.5~5.8。利用苹果酸和柠檬酸均可提高自微乳中药物的高温稳定性,使(40±2)℃条件下,缓释片中药物的含量达到98%以上。苹果酸的吸湿性导致片重增加,表面有湿润感,因此确定选用0.20%的柠檬酸作为pH调节剂。光照对自微乳缓释片中的药物有不利影响,采用铝塑包装(内含暗黑色避光层),可使SRL含量由94.06%提高至99.37%。综合应用0.20%柠檬酸和铝塑包装所得的SRL自微乳缓释片在高温、高湿和强光照射条件下,10 d时的含量均在99%以上。结论:经铝塑包装的含0.20%柠檬酸的SRL自微乳缓释片,在高温、高湿、强光照射条件下均具有良好的稳定性。

OBJECTIVE To improve the stability of sirolimus（SRL）in solid self-microemulsifying sustained release tablets.METHODS The stability of SRL in media of various pH values was investigated.Citric acid and malic acid were used to adjust the pH of the self-microemulsifying drug delivery system（SMEDDS）,and the tablets were prepared and packed in blister packs.The contents of SRL in the tablets were investigated by the stress test,including high temperature,high humidity or strong light irradiation tests.RESULTS Raw SRL was stable under high temperature,high humidity or strong light irradiation conditions,while tiny decrease of SRL in commercial tablets was only found under strong light irradiation.SRL in the self-made tablets was unstable throughout the stress test.The alkaline conditions of the SMEDDS might lead to degradation of SRL.The most favorable pH range for SRL was 4.5-5.8.Citric acid and malic acid could be used to enhance the stability of SRL under high temperatures,with98% of SRL remaining under（40±2）℃.The hygroscopicity caused increased weight of the tablets.Thus,0.20% of citric acid was determined to be the pH adjuvant.Light irradiation was not favorable for the stability of SRL in the tablets.Thus,blister packs were applied and the percentage of SRL in the tablets was increased from94.06%to 99.37%.Combination of citric acid and blister packs contributed to99% of SRL remaining at day 10 in the stress test.CONCLUSION The SRL self-microemulsifying sustained-release tablets containing 0.20% of citric acid in blister packs are stable under high temperature,high humidity and strong light irradiation conditions.