Song Hongtao, Guo Tao, Zhang Ruhua, Zheng Chunli, Ma Yan, Li Xian, Bi Kaishun, Tang Xing
Department of Pharmacy, The General Hospital of Shenyang Military Region, Shenyang 110016, China.
Drug Dev Ind Pharm. 2002 Nov;28(10):1261-73. doi: 10.1081/ddc-120015360.
In this study a sustained-release formulation of traditional Chinese medicine compound recipe (TCMCR) was developed by selecting heart-protecting musk pills (HPMP) as the model drug. Heart-protecting musk pellets were prepared with the refined medicinal materials contained in the recipe of HPMP. Two kinds of coated pellets were prepared by using pH-dependent methacrylic acid as film-forming material, which could dissolve under different pH values in accordance with the physiological range of human gastrointestinal tract (GIT). The pellets coated with Eudragit L30D-55, which dissolves at pH value over 5.5, were designed to disintegrate and release drug in the duodenum. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5, which dissolve at pH value 6.8 or above, were designed to disintegrate and release drug in the jejunum to ileum. The pellets coated with HPMC, which dissolves in water at any pH value, were designed to disintegrate and release drug in the stomach. Finally, the heart-protecting musk sustained-release capsules (HPMSRC) with a pH-dependent gradient-release pattern were prepared by encapsulating the above three kinds of coated pellets at a certain ratio in hard gelatin capsule. The results of dissolution of borneol (one of the active compounds of the TCMCR) in vitro demonstrated that the coating load and the pH value of the dissolution medium had little effect on the release rate of borneol from pellets coated with hydroxypropyl methyl cellulose (HPMC), but had a significant effect on the release rate of borneol from pellets coated with Eudragit L30D-55 or Eudragit L100-Eudragit S100 combinations in the ratio of 1:5. The pellets coated with Eudragit L30D-55 at 30% (w/w) coating load or above had little drug release in 0.1 mol/L HCl for 3 hr and started to release drug at pH value over 5.5. The pellets coated with Eudragit L100-Eudragit S100 combinations in the ratio of 1:5 at 36% (w/w) coating load or higher had little drug release in 0.1 mol/L HCl for 3 hr and in phosphate buffer of pH value 6.6 for 2 hr, and started to release drug at pH value 6.8 or above. The release profiles of lipophilic bornoel and hydrophilic total ginsenoside from HPMSRC, consisting of three kinds of pellets respectively coated at a certain ratio with HPMC, Eudragit L30D-55, and Eudragit L100-Eudragit S100 in the ratio of 1:5, showed a characteristic of pH-dependent gradient release under the simulated gastrointestinal pH conditions and no significant difference between them. The results indicated that various components with extremely different physicochemical properties in the pH-dependent gradient-release delivery system of TCMCR could release synchronously while sustained-releasing. This complies with the organic whole concept of compound compatibility of TCMCR.
在本研究中，通过选用护心麝香丸（HPMP）作为模型药物，开发了一种中药复方缓释制剂（TCMCR）。采用HPMP配方中的精制药材制备了护心麝香微丸。以pH依赖型甲基丙烯酸为成膜材料制备了两种包衣微丸，它们可根据人体胃肠道（GIT）的生理范围在不同pH值下溶解。用Eudragit L30D - 55包衣的微丸，其在pH值高于5.5时溶解，设计为在十二指肠中崩解并释放药物。用比例为1:5的Eudragit L100 - Eudragit S100组合包衣的微丸，其在pH值6.8或更高时溶解，设计为在空肠至回肠中崩解并释放药物。用羟丙基甲基纤维素（HPMC）包衣的微丸，其在任何pH值的水中都能溶解，设计为在胃中崩解并释放药物。最后，通过将上述三种包衣微丸按一定比例装入硬明胶胶囊中，制备了具有pH依赖型梯度释放模式的护心麝香缓释胶囊（HPMSRC）。体外冰片（TCMCR的活性成分之一）溶出结果表明，包衣量和溶出介质的pH值对羟丙基甲基纤维素（HPMC）包衣微丸中冰片的释放速率影响较小，但对Eudragit L30D - 55或比例为1:5的Eudragit L100 - Eudragit S100组合包衣微丸中冰片的释放速率有显著影响。包衣量为30%（w/w）及以上的Eudragit L30D - 55包衣微丸在0.1 mol/L HCl中3小时几乎无药物释放，在pH值高于5.5时开始释放药物。包衣量为36%（w/w）及以上的比例为1:5的Eudragit L100 - Eudragit S100组合包衣微丸在0.1 mol/L HCl中3小时和pH值为6.6的磷酸盐缓冲液中2小时几乎无药物释放，在pH值6.8或更高时开始释放药物。由分别以一定比例用HPMC、Eudragit L30D - 55和比例为1:5的Eudragit L100 - Eudragit S100包衣的三种微丸组成的HPMSRC中亲脂性冰片和亲水性总人参皂苷的释放曲线在模拟胃肠道pH条件下呈现pH依赖型梯度释放特征，且它们之间无显著差异。结果表明，TCMCR的pH依赖型梯度释放给药系统中理化性质差异极大的各组分在缓释的同时能够同步释放。这符合TCMCR复方配伍的有机整体观念。
