鞘蕊苏有效部位长吸收特征及分散片研制
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摘要
鞘蕊苏为毛喉鞘蕊花的干燥全草,其有效成分佛司可林类化合物能直接激动腺苷酸环化酶,提高细胞内的环腺苷酸浓度,从而调节细胞的生理功能,发挥相应生理活性,具有强心、降血压、扩张支气管、抑制肿瘤、促进脂肪、糖原分解和抑制血小板凝聚等作用。本文以佛司可林和异佛司可林为研究对象,考察它们与吸收相关的理化性质、肠吸收特征。并在此基础上设计研发鞘蕊苏提取物分散片。
以高效液相色谱法为分析手段,测定了佛司可林与异佛司可林在各种介质中的溶解度、脂水分配系数及稳定性。异佛司可林的溶解度约为110μg/mL,佛司可林约为10μg/mL；异佛司可林的Log P6.5=2.63,佛司可林的Log P6.5=3.06；佛司可林在pH 7.5～9.5的条件下降解生成异佛司可林,反应速度随碱性增加而增大,而异佛司可林在这些条件下稳定。异佛司可林的水溶性和稳定性均优于佛司可林。
采用大鼠小肠单向灌流法,考察佛司可林的肠吸收特征。结果表明,佛司可林在整个肠段都有吸收,十二指肠为最佳吸收部位；吸收机制主要为被动扩散,但在十二指肠和结肠伴随有载体转运；静水层对佛司可林的吸收没有明显影响；P-gp抑制剂可增加佛司可林的吸收。异佛司可林在空肠段的渗透系数与佛司可林相似。结果表明,溶解状态的佛司可林和异佛司可林均属于高粘膜渗透性药物,制剂研发应以提高溶解度和溶解速度为主要技术突破点。
以鞘蕊苏为原料,用大孔树脂吸附、洗脱、分离提纯得到含异佛司可林70.5%的鞘蕊苏提取物。采用粉末直接压片工艺制备鞘蕊苏提取物分散片。处方中提取物的含量为2%,以复合乳糖为填充剂、交联聚维酮为崩解剂,并加入表面活性剂加快药物的溶出。考察了分散片的外观、硬度、脆碎度、含量均匀度,崩解时限,溶出度、分散均匀性等质量指标,均符合2010年版《中国药典》的相关规定。分散片中异佛司可林溶出迅速,20 min内溶出大于96%。
综上所述,异佛司可林的类药性质优于佛司可林,在给药途径和剂型上拥有更广泛的选择。以异佛司可林为指标性成分制备了鞘蕊苏提取物分散片,具有崩解溶出迅速的显著优点,有望为临床提供一种活性成分明确、药效确切、起效迅速、质量可控的现代化中药制剂。
Coleus forskohlii (Willd) Briq. is an important indigenous medicinal plant. The main active ingredients of Coleus Forskohlii-forskolin or isoforskolin can directly activate adenylate cyclase and thus increases intracellular cAMP levels greatly. The main pharmacological effects of forskolin or isoforskolin such as strengthening the heart, reducing blood pressure, expanding the bronchus, inhibiting tumor, promoting adipolysis and glycogenolysis, and preventing platelet aggregation are mediated by the increase of cAMP. In this paper, the physicochemical properties and intestinal absorption characteristics of forskolin and isoforskolin were investigated. Based on the results of these studies, a dispersible tablet of the extract of C. forskohlii was developed.
The solubility, lipid/water partition coefficient and stability of forskolin and isoforskolin were investigated using HPLC as an analytical method. The solubility of isoforskolin and forskolin was about 110μg/mL and 10μg/mL, respectively. The lipid/water partition coefficient (log P6.5) was 2.63 for isoforskolin and 3.06 for forskolin. Forskolin was unstable in the pH range of 7.5～9.5. The degradation product was isoforskolin. The degradation rate increased with the increase of pH value. However, isoforskolin remained stable in these conditions. Isoforskolin had better drug-like properties than forskolin.
Intestinal absorption characteristics was investigated using in situ single pass perfusion method. The results showed that forskolin could be absorbed in the whole intestinal segments. The effective permeability (Peff) was the highest in the duodenum compared to other intestinal segments. The main mechanism of intestinal absorption was passive diffusion, as well as a saturable transport process in the duodenum and colon. Unstirred water layer had no obvious impact on the absorption. Addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across rat jejunum. There was no statistical difference in Peff values between isoforskolin and forskolin in rat jejunum. The absorbed fractions of dissolved forskolin and isoforskolin after oral administration in human were estimated to be 100% calculated from rat Peff values. In conclusion, dissolved forskolin and isoforskolin could be absorbed readily in the intestine. It was of high importance to come up with innovative strategies to increase the solubility and dissolution rate to avoid losing an interesting drug candidate.
The extract of C. forskohlii (ECF) containing 70.5% of isoforskolin was prepared by macroporous resin adsorption followed by elution, separation and purification procedures. Dispersible tablets of ECF was prepared by direct compression method, using lactose complex as filler, PVPP as disintegrant, and surfactant as solubilizer. The content of ECF in the tablet was 2%. The appearance, hardness, frangibility, dose uniformity, disintegration time, dissolution rate and uniformity of dispersion of ECF tablets were investigated. The results complied with the requirements of Chinese Pharmacopoeia 2010. Isoforkolin could be released promptly from ECF tablets, cumulative dissolution was> 96% within 20 min.
In conclusion, the drug likeness of isoforskohlin is better than that of forskohlin, which provides a broader selection in administration route and formulation. The ECF dispersible tablet prepared has a significant advantage of high disintegration and dissolution rate. It is expected to be a modern Chinese medicine preparation with definite constituents, good effect, and high quality.
以高效液相色谱法为分析手段,测定了佛司可林与异佛司可林在各种介质中的溶解度、脂水分配系数及稳定性。异佛司可林的溶解度约为110μg/mL,佛司可林约为10μg/mL；异佛司可林的Log P6.5=2.63,佛司可林的Log P6.5=3.06；佛司可林在pH 7.5～9.5的条件下降解生成异佛司可林,反应速度随碱性增加而增大,而异佛司可林在这些条件下稳定。异佛司可林的水溶性和稳定性均优于佛司可林。
采用大鼠小肠单向灌流法,考察佛司可林的肠吸收特征。结果表明,佛司可林在整个肠段都有吸收,十二指肠为最佳吸收部位；吸收机制主要为被动扩散,但在十二指肠和结肠伴随有载体转运；静水层对佛司可林的吸收没有明显影响；P-gp抑制剂可增加佛司可林的吸收。异佛司可林在空肠段的渗透系数与佛司可林相似。结果表明,溶解状态的佛司可林和异佛司可林均属于高粘膜渗透性药物,制剂研发应以提高溶解度和溶解速度为主要技术突破点。
以鞘蕊苏为原料,用大孔树脂吸附、洗脱、分离提纯得到含异佛司可林70.5%的鞘蕊苏提取物。采用粉末直接压片工艺制备鞘蕊苏提取物分散片。处方中提取物的含量为2%,以复合乳糖为填充剂、交联聚维酮为崩解剂,并加入表面活性剂加快药物的溶出。考察了分散片的外观、硬度、脆碎度、含量均匀度,崩解时限,溶出度、分散均匀性等质量指标,均符合2010年版《中国药典》的相关规定。分散片中异佛司可林溶出迅速,20 min内溶出大于96%。
综上所述,异佛司可林的类药性质优于佛司可林,在给药途径和剂型上拥有更广泛的选择。以异佛司可林为指标性成分制备了鞘蕊苏提取物分散片,具有崩解溶出迅速的显著优点,有望为临床提供一种活性成分明确、药效确切、起效迅速、质量可控的现代化中药制剂。
Coleus forskohlii (Willd) Briq. is an important indigenous medicinal plant. The main active ingredients of Coleus Forskohlii-forskolin or isoforskolin can directly activate adenylate cyclase and thus increases intracellular cAMP levels greatly. The main pharmacological effects of forskolin or isoforskolin such as strengthening the heart, reducing blood pressure, expanding the bronchus, inhibiting tumor, promoting adipolysis and glycogenolysis, and preventing platelet aggregation are mediated by the increase of cAMP. In this paper, the physicochemical properties and intestinal absorption characteristics of forskolin and isoforskolin were investigated. Based on the results of these studies, a dispersible tablet of the extract of C. forskohlii was developed.
The solubility, lipid/water partition coefficient and stability of forskolin and isoforskolin were investigated using HPLC as an analytical method. The solubility of isoforskolin and forskolin was about 110μg/mL and 10μg/mL, respectively. The lipid/water partition coefficient (log P6.5) was 2.63 for isoforskolin and 3.06 for forskolin. Forskolin was unstable in the pH range of 7.5～9.5. The degradation product was isoforskolin. The degradation rate increased with the increase of pH value. However, isoforskolin remained stable in these conditions. Isoforskolin had better drug-like properties than forskolin.
Intestinal absorption characteristics was investigated using in situ single pass perfusion method. The results showed that forskolin could be absorbed in the whole intestinal segments. The effective permeability (Peff) was the highest in the duodenum compared to other intestinal segments. The main mechanism of intestinal absorption was passive diffusion, as well as a saturable transport process in the duodenum and colon. Unstirred water layer had no obvious impact on the absorption. Addition of verapamil, a P-glycoprotein inhibitor, significantly enhanced the permeability of forskolin across rat jejunum. There was no statistical difference in Peff values between isoforskolin and forskolin in rat jejunum. The absorbed fractions of dissolved forskolin and isoforskolin after oral administration in human were estimated to be 100% calculated from rat Peff values. In conclusion, dissolved forskolin and isoforskolin could be absorbed readily in the intestine. It was of high importance to come up with innovative strategies to increase the solubility and dissolution rate to avoid losing an interesting drug candidate.
The extract of C. forskohlii (ECF) containing 70.5% of isoforskolin was prepared by macroporous resin adsorption followed by elution, separation and purification procedures. Dispersible tablets of ECF was prepared by direct compression method, using lactose complex as filler, PVPP as disintegrant, and surfactant as solubilizer. The content of ECF in the tablet was 2%. The appearance, hardness, frangibility, dose uniformity, disintegration time, dissolution rate and uniformity of dispersion of ECF tablets were investigated. The results complied with the requirements of Chinese Pharmacopoeia 2010. Isoforkolin could be released promptly from ECF tablets, cumulative dissolution was> 96% within 20 min.
In conclusion, the drug likeness of isoforskohlin is better than that of forskohlin, which provides a broader selection in administration route and formulation. The ECF dispersible tablet prepared has a significant advantage of high disintegration and dissolution rate. It is expected to be a modern Chinese medicine preparation with definite constituents, good effect, and high quality.
引文
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