多单元型白头翁结肠靶向给药系统的设计与评价
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摘要
白头翁攻擅清热解毒、凉血止痢,尤善清大肠湿热及血分热毒,为临床治疗溃疡性结肠炎(UC)的常用药物。本文针对灌肠给药病人顺应性差及口服结肠靶向制剂个体间差异性大等问题,探索基于包衣微丸和粒子设计原理开展白头翁多单元型结肠靶向给药系统的研究,并进行了体内外相关评价。本文具体研究内容和结果如下：
1.白头翁提取物抗UC药效初筛及作用机制初步探讨
采用葡聚糖硫酸钠致UC小鼠模型进行白头翁提取物药效学试验。结果表明在三种不同产地白头翁中,黑龙江白头翁具有更好的抗UC作用,且醇提物作用效果较水提物好。因此,本文将黑龙江白头翁采用乙醇提取,并经大孔树脂分离纯化制成总皂苷提取物,通过药效学试验确证了其抗UC作用,并筛选了最佳给药剂量。同时,根据药效学试验中的生化指标测定结果分析,白头翁抗UC作用机制可能与抑制炎性因子、减少氧自由基的生成和增加氧自由基的清除有关。
2制剂处方前研究
本文对白头翁总皂苷提取物进行了粉体学、溶解性能及生物药剂学等方面的研究。粉体学研究结果表明其堆密度小,流动性较差,水分含量低,吸湿性不强；而沉淀法、指标成分溶解量法和粒径测定法均表明该提取物在水中溶解度较低；大鼠离体肠吸收试验表明指标成分常春藤皂苷元3-O-a-L-吡喃鼠李糖-(1→2)-[p-D-吡喃葡萄糖-(1→4)]-L-吡喃阿拉伯糖苷能够反映提取物的总体吸收状况,该成分在十二指肠、空肠、回肠、结肠等各个肠段的吸收无显著性差异,不存在特殊的“吸收窗”。
3.白头翁总皂苷包合物微丸的制备
由于总皂苷提取物水溶性差,制成微丸后溶出困难,本文分别采用固体分散技术和包合技术以改善其溶出性能,研究发现制成羟丙基-p-环糊精包合物后能显著增加药物的溶出。在优化的包合物制备工艺基础上筛选获得包合物素丸最佳处方工艺为：以制粒-滚圆法制备素丸,白头翁总皂苷包合物为原料、50%微晶纤维素为赋形剂、30%甘露醇为水溶性填充剂、30%乙醇为润湿剂。素丸采用Glatt流化床包衣,当流化压力为0.45bar、雾化压力为1.0bar、进液速度为2.0mL·min-1物料温度为30℃、40℃熟化1～2h时,包衣效率较高,物料无粘结现象。研究结果表明最佳包衣处方为：尤特奇S100为包衣材料、柠檬酸三乙酯为增塑剂(用量为聚合物的15%)、滑石粉(用量为聚合物的50%)为抗粘剂,包衣增重为12%。
4.白头翁总皂苷粒子设计粉的制备
采用粒子设计中的研磨法制备白头翁总皂苷粒子设计粉,通过外观性状描述、形貌结构扫描电镜观察、体外释放度、粒径、X-射线衍射、表面接触角等方法进行表征,结果表明粒子设计粉的最佳处方工艺为：总皂苷提取物与S100的质量比为3：17,研磨时间20min,药物的粉碎度对最终形成的粒子设计粉无明显影响。粒子设计粉中药物粒子被S100包覆,其特征衍射峰及表面润湿性均与S100一致。
5.白头翁总皂苷结肠靶向制剂体外质量评价
根据优化的处方和工艺制备三批包衣微丸和粒子设计粉,并对其进行性状、含量、体外释放度、初步稳定性等体外质量评价。研究表明,两种结肠靶向制剂外观均、不同批次间含量差异性小,体外释放度符合结肠靶向制剂的要求,稳定性较好。
6.白头翁总皂苷结肠靶向制剂体内质量评价
本文采用HPLC法测定药物口服给药不同时间后在大鼠胃肠道内容物中的含量及组织中药物含量,结果表明相比提取物原药,包合物包衣微丸和粒子设计粉有更多的药物到达回肠末端及结肠部位,结肠组织中药物含量均显著提高。
采用LC-MS建立了大鼠血浆中白头翁指标成分含量测定方法,研究了提取物原药、包含物包衣微丸及粒子设计粉口服给药后药物动力学过程。结果表明包合物包衣微丸Tmax、MRT分别为提取物原药的1.9倍、3.4倍,Cmax为提取物原药的0.4倍；粒子设计粉Tmax、MRT分别为提取物原药的4倍、2.4倍,Cmax为提取物原药的0.3倍。包合物包衣微丸与粒子设计粉口服给药后达峰时间和体内滞留时间延长,最大血药浓度降低,显示了一定的结肠靶向释药特性。
相比较而言,无论是结肠靶向性还是个体间差异性方面粒子设计粉均优于包衣微九。制剂药效学试验表明白头翁总皂苷结肠靶向粒子设计粉能够降低4倍剂量而达到与提取物原药相当的抗UC作用。
The traditional Chinese herb Pulsatilla has been reported to be effective in clearing away heat, detoxicating, removing heat from the blood and arresting dysentery, and especially in clearing large intestine damp-heat and noxious heat in blood system, so as being a common drug for clinical treatment of Ulcerative Colities(UC). Accoring to the low patient compliance of enema administration and large individual difference of oral colon-targeted preparations, this paper explored research of multiple unit type colon-targeted drug delivery system of Pulsatilla based on coated pellets and particle design technology, and evaluated the system in vitro and in vivo relatively. The dissertation is summarized as follows:
1. Primary screen for anti-UC action of Pulsatilla extract and its mechanism
The pharmacodynamic test of Pulsatilla extract(PE) was conducted using DSS-induced UC mice model. The results showed that Pulsatilla from Heilongjiang had the strongest anti-UC effect in the three kinds of different producing areas, and the effect of alcohol extrat was stronger than water extrat. Thus, Pulsatilla from Heilongjiang was extracted by ethanol, then separated and purified by macroporous resins to prepare PE. The anti-UC effect of PE was confirmed and the optimum dose was screened by pharmacodynamic test. Meanwhile, according to the results of biochemical indexes in the pharmacodynamic test, the mechanism of anti-UC action of PE might be related to the inhibition of inflammatory factor, the reduction of oxygen free radicals production, and the increase of oxygen free radicals clearance.
2. Pharmaceutical pre-formulation study
This paper researched the micromentic property, solubility and bio-pharmaceutical characteristics of PE. The results indicated that it had low bulk density, poor fluidity, low water content, and weak hygroscopicity; Precipitation method, index component dissolvability, and particle diameter measurement were used to evaluate the solubility and gived the similar result that its solibility in water was poor; The rat intestinal valgus test showed that the index component hederagenin3-0-a-L-rhamnopyranosyl(1→2)-[β-D-glucopyranosyl(1→4)]-a-L-arabinopyranoside could reflect the general absorption of the extract, while the absorption of the index component in different intestinal segments had no significant difference, and there was not a special absorption window.
3. Preparation of Pulsatilla inclusion complex pellets
In order to solove the dissolution problem, the paper used solid dispersion technology and inclusion technique respectively. The research showed that it significantly increased the dissolution after preparing PE-hydroxypropyl-β-cyclodextrin inclusion complex(PE-HP-β-CD). The optimum formulation and preparation of pellets were:granulation-spheronization process for preparation of pellets, PE-HP-β-CD as raw material,50%MCC as excipient,30%mannitol as bulking agent, and30%ethanol as wetting agent. The pellets were coated by Glatt fluid bed. When the flowing pressure was0.45bar, pressure of spray was1.0bar, intake flow velocity was2.0mL·min-1, material temperature was30℃, and aging3-4h at40℃, it had high coating efficiency and no bonding. The optimum formula of coating was:Eudragit S100as coating material, TEC as plasticizer(15%of the polymer), talc powder as antiadherent(50%of the polymer), with coating weight of12%.
4. Preparation of Pulsatilla particle design powder
This paper prepared Pulsatilla particle design powder(PPDP) by grinding method in the particle design technology. The PPDP was characterized by description of appearance characters, in vitro release, particle size, SEM, X-RD and surface contact angle etc. The research showed that the optimum formulation and preparation of PPDP were:mass ratio of PE to S100of3:17, grinding time of20min, and we find that comminution degree of PE had no significant effect on PPDP. The PE particles were coated by S100in PPDP, so PPDP had the same characteristic diffraction peaks and surface wettability with S100.
5. Quality evaluation of Pulsatilla colon-targeted preparation in vitro
The three batches PE-HP-β-CD coated pellets and PPDP were prepared according to the optimized formulation and preparation,and the character, content, in vitro release and preliminary stability were studied. The results showed that these two kinds of colon-targeted preparations had even appearance, small differences among different batches, in vitro release accorded with requirement of colon-targeted preparation, and good stability.
6. Quality evaluation of Pulsatilla colon-targeted preparation in vivo
The content of durgs in rat gastrointestinal contents and gastrointestinal tract tissues at different time after oral administration was determined by HPLC. The results showed that compared with the general suspension of extract, more drugs reached terminal ileum and colon in coated pellets and PPDP, and drugs in the colon tissues also significantly increased.
The paper established a method for determination of index component of Pulsatilla in rat plasma by LC-MS, and studied pharmacokinetics of Pulsatilla extrat, PE-HP-β-CD coated pellets and PPDP in rats by oral administration. The results indicated that the Tmax, MRT and Cmax of PE-HP-β-CD coated pellets were1.9,3.4and0.4times of PE extract respectively, while the Tmax, MRT and Cmax of PPDP were4,2.4and0.3times of PE extract respectively. PE-HP-β-CD coated pellets and PPDP had longer peak time and mean residence time, and lower maximum plasma concentration, so as to show colon-specific-drug-released characteristics.
PPDP was more superior than PE-HP-β-CD coated pellets no matter in colon-specific-drug-released characteristics or in individual differences. The pharmacodynamic test showed that PPDP of a quarter dose had equivalent effect of anti-UC action with Pulsatilla extract.
1.白头翁提取物抗UC药效初筛及作用机制初步探讨
采用葡聚糖硫酸钠致UC小鼠模型进行白头翁提取物药效学试验。结果表明在三种不同产地白头翁中,黑龙江白头翁具有更好的抗UC作用,且醇提物作用效果较水提物好。因此,本文将黑龙江白头翁采用乙醇提取,并经大孔树脂分离纯化制成总皂苷提取物,通过药效学试验确证了其抗UC作用,并筛选了最佳给药剂量。同时,根据药效学试验中的生化指标测定结果分析,白头翁抗UC作用机制可能与抑制炎性因子、减少氧自由基的生成和增加氧自由基的清除有关。
2制剂处方前研究
本文对白头翁总皂苷提取物进行了粉体学、溶解性能及生物药剂学等方面的研究。粉体学研究结果表明其堆密度小,流动性较差,水分含量低,吸湿性不强；而沉淀法、指标成分溶解量法和粒径测定法均表明该提取物在水中溶解度较低；大鼠离体肠吸收试验表明指标成分常春藤皂苷元3-O-a-L-吡喃鼠李糖-(1→2)-[p-D-吡喃葡萄糖-(1→4)]-L-吡喃阿拉伯糖苷能够反映提取物的总体吸收状况,该成分在十二指肠、空肠、回肠、结肠等各个肠段的吸收无显著性差异,不存在特殊的“吸收窗”。
3.白头翁总皂苷包合物微丸的制备
由于总皂苷提取物水溶性差,制成微丸后溶出困难,本文分别采用固体分散技术和包合技术以改善其溶出性能,研究发现制成羟丙基-p-环糊精包合物后能显著增加药物的溶出。在优化的包合物制备工艺基础上筛选获得包合物素丸最佳处方工艺为：以制粒-滚圆法制备素丸,白头翁总皂苷包合物为原料、50%微晶纤维素为赋形剂、30%甘露醇为水溶性填充剂、30%乙醇为润湿剂。素丸采用Glatt流化床包衣,当流化压力为0.45bar、雾化压力为1.0bar、进液速度为2.0mL·min-1物料温度为30℃、40℃熟化1～2h时,包衣效率较高,物料无粘结现象。研究结果表明最佳包衣处方为：尤特奇S100为包衣材料、柠檬酸三乙酯为增塑剂(用量为聚合物的15%)、滑石粉(用量为聚合物的50%)为抗粘剂,包衣增重为12%。
4.白头翁总皂苷粒子设计粉的制备
采用粒子设计中的研磨法制备白头翁总皂苷粒子设计粉,通过外观性状描述、形貌结构扫描电镜观察、体外释放度、粒径、X-射线衍射、表面接触角等方法进行表征,结果表明粒子设计粉的最佳处方工艺为：总皂苷提取物与S100的质量比为3：17,研磨时间20min,药物的粉碎度对最终形成的粒子设计粉无明显影响。粒子设计粉中药物粒子被S100包覆,其特征衍射峰及表面润湿性均与S100一致。
5.白头翁总皂苷结肠靶向制剂体外质量评价
根据优化的处方和工艺制备三批包衣微丸和粒子设计粉,并对其进行性状、含量、体外释放度、初步稳定性等体外质量评价。研究表明,两种结肠靶向制剂外观均、不同批次间含量差异性小,体外释放度符合结肠靶向制剂的要求,稳定性较好。
6.白头翁总皂苷结肠靶向制剂体内质量评价
本文采用HPLC法测定药物口服给药不同时间后在大鼠胃肠道内容物中的含量及组织中药物含量,结果表明相比提取物原药,包合物包衣微丸和粒子设计粉有更多的药物到达回肠末端及结肠部位,结肠组织中药物含量均显著提高。
采用LC-MS建立了大鼠血浆中白头翁指标成分含量测定方法,研究了提取物原药、包含物包衣微丸及粒子设计粉口服给药后药物动力学过程。结果表明包合物包衣微丸Tmax、MRT分别为提取物原药的1.9倍、3.4倍,Cmax为提取物原药的0.4倍；粒子设计粉Tmax、MRT分别为提取物原药的4倍、2.4倍,Cmax为提取物原药的0.3倍。包合物包衣微丸与粒子设计粉口服给药后达峰时间和体内滞留时间延长,最大血药浓度降低,显示了一定的结肠靶向释药特性。
相比较而言,无论是结肠靶向性还是个体间差异性方面粒子设计粉均优于包衣微九。制剂药效学试验表明白头翁总皂苷结肠靶向粒子设计粉能够降低4倍剂量而达到与提取物原药相当的抗UC作用。
The traditional Chinese herb Pulsatilla has been reported to be effective in clearing away heat, detoxicating, removing heat from the blood and arresting dysentery, and especially in clearing large intestine damp-heat and noxious heat in blood system, so as being a common drug for clinical treatment of Ulcerative Colities(UC). Accoring to the low patient compliance of enema administration and large individual difference of oral colon-targeted preparations, this paper explored research of multiple unit type colon-targeted drug delivery system of Pulsatilla based on coated pellets and particle design technology, and evaluated the system in vitro and in vivo relatively. The dissertation is summarized as follows:
1. Primary screen for anti-UC action of Pulsatilla extract and its mechanism
The pharmacodynamic test of Pulsatilla extract(PE) was conducted using DSS-induced UC mice model. The results showed that Pulsatilla from Heilongjiang had the strongest anti-UC effect in the three kinds of different producing areas, and the effect of alcohol extrat was stronger than water extrat. Thus, Pulsatilla from Heilongjiang was extracted by ethanol, then separated and purified by macroporous resins to prepare PE. The anti-UC effect of PE was confirmed and the optimum dose was screened by pharmacodynamic test. Meanwhile, according to the results of biochemical indexes in the pharmacodynamic test, the mechanism of anti-UC action of PE might be related to the inhibition of inflammatory factor, the reduction of oxygen free radicals production, and the increase of oxygen free radicals clearance.
2. Pharmaceutical pre-formulation study
This paper researched the micromentic property, solubility and bio-pharmaceutical characteristics of PE. The results indicated that it had low bulk density, poor fluidity, low water content, and weak hygroscopicity; Precipitation method, index component dissolvability, and particle diameter measurement were used to evaluate the solubility and gived the similar result that its solibility in water was poor; The rat intestinal valgus test showed that the index component hederagenin3-0-a-L-rhamnopyranosyl(1→2)-[β-D-glucopyranosyl(1→4)]-a-L-arabinopyranoside could reflect the general absorption of the extract, while the absorption of the index component in different intestinal segments had no significant difference, and there was not a special absorption window.
3. Preparation of Pulsatilla inclusion complex pellets
In order to solove the dissolution problem, the paper used solid dispersion technology and inclusion technique respectively. The research showed that it significantly increased the dissolution after preparing PE-hydroxypropyl-β-cyclodextrin inclusion complex(PE-HP-β-CD). The optimum formulation and preparation of pellets were:granulation-spheronization process for preparation of pellets, PE-HP-β-CD as raw material,50%MCC as excipient,30%mannitol as bulking agent, and30%ethanol as wetting agent. The pellets were coated by Glatt fluid bed. When the flowing pressure was0.45bar, pressure of spray was1.0bar, intake flow velocity was2.0mL·min-1, material temperature was30℃, and aging3-4h at40℃, it had high coating efficiency and no bonding. The optimum formula of coating was:Eudragit S100as coating material, TEC as plasticizer(15%of the polymer), talc powder as antiadherent(50%of the polymer), with coating weight of12%.
4. Preparation of Pulsatilla particle design powder
This paper prepared Pulsatilla particle design powder(PPDP) by grinding method in the particle design technology. The PPDP was characterized by description of appearance characters, in vitro release, particle size, SEM, X-RD and surface contact angle etc. The research showed that the optimum formulation and preparation of PPDP were:mass ratio of PE to S100of3:17, grinding time of20min, and we find that comminution degree of PE had no significant effect on PPDP. The PE particles were coated by S100in PPDP, so PPDP had the same characteristic diffraction peaks and surface wettability with S100.
5. Quality evaluation of Pulsatilla colon-targeted preparation in vitro
The three batches PE-HP-β-CD coated pellets and PPDP were prepared according to the optimized formulation and preparation,and the character, content, in vitro release and preliminary stability were studied. The results showed that these two kinds of colon-targeted preparations had even appearance, small differences among different batches, in vitro release accorded with requirement of colon-targeted preparation, and good stability.
6. Quality evaluation of Pulsatilla colon-targeted preparation in vivo
The content of durgs in rat gastrointestinal contents and gastrointestinal tract tissues at different time after oral administration was determined by HPLC. The results showed that compared with the general suspension of extract, more drugs reached terminal ileum and colon in coated pellets and PPDP, and drugs in the colon tissues also significantly increased.
The paper established a method for determination of index component of Pulsatilla in rat plasma by LC-MS, and studied pharmacokinetics of Pulsatilla extrat, PE-HP-β-CD coated pellets and PPDP in rats by oral administration. The results indicated that the Tmax, MRT and Cmax of PE-HP-β-CD coated pellets were1.9,3.4and0.4times of PE extract respectively, while the Tmax, MRT and Cmax of PPDP were4,2.4and0.3times of PE extract respectively. PE-HP-β-CD coated pellets and PPDP had longer peak time and mean residence time, and lower maximum plasma concentration, so as to show colon-specific-drug-released characteristics.
PPDP was more superior than PE-HP-β-CD coated pellets no matter in colon-specific-drug-released characteristics or in individual differences. The pharmacodynamic test showed that PPDP of a quarter dose had equivalent effect of anti-UC action with Pulsatilla extract.
引文
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