黄连-干姜有效组分自微乳给药系统的制备与评价

Preparation and evaluation of self-microemulsion drug delivery system for effective components of Coptidis Rhizoma-Zingiberis Rhizoma

目的研究黄连-干姜有效组分自微乳给药系统(Coptidis Rhizoma-Zingiberis Rhizoma effective component self-microemulsion drug deliverysystem,Cop-Gin-SMEDDS)的处方与制备工艺,并且进行体外质量评价。方法通过溶解度实验、伪三元相图的绘制和D-最优混料设计确定Cop-Gin-SMEDDS的最佳处方组成;通过单因素考察,确定最佳制备工艺,并对Cop-Gin-SMEDDS理化性质、稳定性、体外释放等进行评价。结果最终确定Cop-Gin-SMEDDS的最优处方(不含黄连总生物碱)为油酸5%,1,2-丙二醇41%,聚氧乙烯(40)氢化蓖麻油49%,干姜油5%;黄连总生物碱的投药量为5%;最佳制备工艺为在37℃、转速300 r/min条件下磁力搅拌10 min。得到的Cop-Gin-SMEDDS为深红色澄清透明液体,稀释后为黄色、均一透明的微乳溶液;透射电镜下为圆球形,大小均匀,形态规则;平均粒径大小为(22.21±0.45)nm、多分散指数(polydispersity index,PDI)为0.195±0.019、ζ电位为(−2.67±0.11)mV。Cop-Gin-SMEDDS中盐酸小檗碱、盐酸巴马汀、盐酸黄连碱、表小檗碱及6-姜辣素的载药量分别为(13.51±0.71)、(1.37±0.06)、(2.36±0.27)、(0.83±0.14)、(6.34±0.04)mg/g,包封率分别为(96.36±0.34)%、(95.49±0.59)%、(92.56±0.81)%、(95.17±0.39)%、(94.39±1.63)%。Cop-Gin-SMEDDS中盐酸小檗碱在pH 7.4 PBS缓冲液、蒸馏水和pH 1.2盐酸溶液中的24 h累积释放率分别为(70.80±0.04)%、(96.17±0.10)%、(85.77±0.10)%;6-姜辣素在相应释放介质中的24 h累积释放率分别为(27.70±0.14)%、(32.48±0.14)%、(32.96±0.07)%。稳定性实验显示,将Cop-Gin-SMEDDS在不同温度下放置30 d后其指标成分及外观性状均无明显变化。结论制备的Cop-Gin-SMEDDS外观良好,载药量和包封率高,能提高药物的稳定性和释放量,有望进一步开发制备成口服给药制剂。

Objective To study the formulation and preparation technology of self-microemulsion drug delivery system of effective components of Huanglian(Coptidis Rhizoma)-Ganjiang(Zingiberis Rhizoma)(Cop-Gin-SMEDDS), and evaluate it. Methods The best prescription composition of Cop-Gin-SMEDDS was determined by solubility experiment, pseudo ternary phase diagram drawing and D-optimal mixture design. Through single factor investigation, the optimal preparation process was determined, and the physicochemical properties, stability and in vitro release of Cop-Gin-SMEDDS were evaluated. Results The optimal prescription of Cop-Gin-SMEDDS(excluding total alkaloids of Coptidis Rhizoma) was oleic acid 5%, 1,2-propanediol 41%, polyoxyethylene(40) hydrogenated castor oil 49%, dried ginger oil 5%. The dosage of coptis alkaloids was 5%. The optimum preparation process was magnetic stirring at 37 ℃ and 300 r/min for 10 min. The obtained Cop-Gin-SMEDDS was a dark red clear and transparent concentrate, and after dilution, it was a yellow, homogeneous and transparent microemulsion solution. Under transmission electron microscope, it was round and spherical, with uniform size and regular shape. The average particle size was(22.21 ± 0.45) nm, PDI was 0.195 ± 0.019, and ζ potential was(-2.67 ± 0.11) mV. The drug loading of berberine hydrochloride, palmatine hydrochloride,coptisine hydrochloride, epiberberine and 6-gingerol in Cop-Gin-SMEDDS were(13.51 ± 0.71),(1.37 ± 0.06),(2.36 ± 0.27),(0.83 ±0.14) and(6.34 ± 0.04) mg/g, respectively. The encapsulation efficiency were(96.36 ± 0.34)%,(95.49 ± 0.59)%,(92.56 ± 0.81)%,(95.17 ± 0.39)% and(94.39 ± 1.63)%, respectively. The 24 h cumulative release rates of berberine hydrochloride in Cop-GinSMEDDS in pH 7.4 PBS buffer, water and pH 1.2 hydrochloric acid solution were(70.80 ± 0.04)%,(96.17 ± 0.10)%, and(85.77 ±0.10)%, respectively;the 6-gingerol in corresponding release media were(27.7 ± 0.14)%,(32.48 ± 0.14)% and(32.96 ± 0.07)%,respectively. The stability experiment showed that there was no significant change in the index components and appearance properties of cop-gin-SMEDDS after it was placed at different temperatures for 30 d. Conclusion The prepared Cop-Gin-SMEDDS has good appearance, high drug loading and encapsulation efficiency. It can improve the stability and release of drugs. It is expected to be further developed into oral drug delivery preparations.