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| 姜黄素Soluplus胶束的制备及其在保护酒精性组织损伤中的作用研究
摘 要
研究背景与目的：
姜黄素（Curcumin，CUR）在酗酒导致的组织损伤的治疗中显示出巨大的潜力。然而，由于其溶解度低、稳定性差、肠通透性低以及口服生物利用度不足1%，导致CUR对酒精诱导的组织损伤治疗效果有限。本课题针对此问题采用薄膜水化法制备了载CUR的Soluplus胶束（CUR-loaded Soluplus micelles，CUR-Ms），以提高CUR的吸收、改善其药物药动学特性，从而提高其抗酒精性组织损伤的治疗效果，为将来开发高吸收、低代谢、长效的高生物利用度口服复方CUR制剂提供实验依据。
材料与方法:
采用薄膜水化法制备载CUR的Soluplus胶束。建立体外、体内LC-Ms/Ms测定CUR的方法，通过粒径测定仪、透射电镜（关键词：
Abstract
Research background and purpose：
Curcumin (CUR) has shown great potential in the treatment of tissue damage caused by alcohol abuse.However, due to its low solubility, poor stability, low intestinal permeability,and oral bioavailability of less than 1%, the therapeutic effect of CUR on alcohol-induced tissue damage is limited. To solve this problem, CUR-loaded Soluplus micelles (CUR-Ms) were prepared by filmhydration to improve the absorption of CUR and the pharmacokinetic properties of the drug, so as to improve its anti-alcohol tissue injury treatment effect,which provide experimental basis for the development of high-absorption,low-metabolism, long-acting, high-bioavailability oral compound CUR preparations in the future
Materials and Methods：
1.Prepare CUR-loaded Soluplus micelles by film hydration method.The performance of micelles was characterized by particle size analyzer,transmission electron microscopy (TEM) and differential scanning calorimetry (DSC). The LC-Ms/Ms method was used to determine the encapsulation efficiency and drug loading of the drug to ensure that the laboratory successfully prepared CUR-Ms.
2.Establish a method for determining the content of CUR in micelles in vitro.Through solubility, in vitro release performance,stability tests under different buffers and in gastrointestinal and hepatic homogenates, it was verified that CUR-MS improved the solubility and stability of CUR and had better in vitro release performance.
3.Established a LC-MS/MS method for determination the content of CUR in intestinal perfusion fluid in rats in vivo. The absorption of CUR, CUR,CUR+ Verapamil (VER) in jejunum was investigated, and it was verified that CUR could improve the intestinal permeability of CUR suspension by inhibiting p-glycoprotein (P-gp).
4.Establish a LC-MS/MS method to determine the blood concentration of CUR in rats, and conduct a methodological investigation. After oral gavage, the drug concentration in rat plasma was measured, the pharmacokinetic parameters were obtained through DAS 3.0 software, and statistical analysis was performed to evaluate the pharmacokineticcharacteristics of CUR-Ms and verify its effect to improve bioavailability.
4.Preliminary study on the protective effect and mechanism of curcumin on acute alcoholism in mice.
(1) Kunming mice were intragastrically given absolute ethanol (0.10 mL/10 g) to establish an acute alcoholism gastric mucosal injury model in vivo.Evaluate of CUR-Ms on acute alcoholism mice gastric mucosa damage of protection by observing the type morphological and pathological morphological changes of gastric mucosa in general,and by comparing groups of mice gastric mucosa damage index and damageinhibition rate and histopathological difference,Measure the activity of Superoxide Dismutase (SOD) and the content of Malonaldehyde (MDA) in the gastric tissues of mice in each group, and observe the effect of CUR-Ms on the protection of gastric mucosa by enhancing the antioxidant capacity of gastric mucosa.
(2) C57BL/6 mice were intragastrically given 50% absolute ethanol (0.12 mL/10 g) to establish an acute alcohol liver injury model in vivo.Evaluate of CUR-Ms on acute alcoholism mice liver injury of protection by detecting Serum Alanine aminotransferase (ALT) and Aspartic acid aminotransferase (AST) levels in each group., Measure the activity of Superoxide Dismutase (SOD) and the content of Malonaldehyde(MDA) in the liver tissues of mice in each group,and observe the effect of CUR-Ms on the protection of liver tissues by enhancing the antioxidant capacity of liver.
Result：
vo.The absorption of CUR, CUR,CUR+ Verapamil (VER) in jejunum was investigated, and it was verified that CUR could improve the intestinal permeability of CUR suspension by inhibiting p-glycoprotein (P-gp).
4.Establish a LC-MS/MS method to determine the blood concentration of CUR in rats, and conduct a methodological investigation. After oral gavage, the drug concentration in rat plasma was measured, the pharmacokinetic parameters were obtained through DAS 3.0 software, and statistical analysis was performed to evaluate the pharmacokineticcharacteristics of CUR-Ms and verify its effect to improve bioavailability.
4.Preliminary study on the protective effect and mechanism of curcumin on acute alcoholism in mice.
(1) Kunming mice were intragastrically given absolute ethanol (0.10 mL/10 g) to establish an acute alcoholism gastric mucosal injury model in vivo.Evaluate of CUR-Ms on acute alcoholism mice gastric mucosa damage of protection by observing the type morphological and pathological morphological changes of gastric mucosa in general,and by comparing groups of mice gastric mucosa damage index and damageinhibition rate and histopathological difference,Measure the activity of Superoxide Dismutase (SOD) and the content of Malonaldehyde (MDA) in the gastric tissues of mice in each group, and observe the effect of CUR-Ms on the protection of gastric mucosa by enhancing the antioxidant capacity of gastric mucosa.
(2) C57BL/6 mice were intragastrically given 50% absolute ethanol (0.12 mL/10 g) to establish an acute alcohol liver injury model in vivo.Evaluate of CUR-Ms on acute alcoholism mice liver injury of protection by detecting Serum Alanine aminotransferase (ALT) and Aspartic acid aminotransferase (AST) levels in each group., Measure the activity of Superoxide Dismutase (SOD) and the content of Malonaldehyde(MDA) in the liver tissues of mice in each group,and observe the effect of CUR-Ms on the protection of liver tissues by enhancing the antioxidant capacity of liver.
Result：
1.CUR-Ms were prepared by thin film hydration.The micelles are nearly spherical with an average particle size of 62.80 ±1.29 nm.DSC analysis indicated that CUR-MS may exist in molecular or amorphous form.CUR-MS showed better stability, solubility and in vitro release than CUR.
2.The absorption rate constant (Ka) and apparent permeability coefficient (Papp) of CUR-MS were 3.50 and 4.10 times higher than that of CUR, respectively,and the permeability of CUR-MS was significantly enhanced in the in situ unidirectional intestinal perfusion experiment of the small intestine of rats.
3.In pharmacokinetic studies, the Cmax (841.47 μg/L) in blood of CUR-MS was 47.38 times that of CUR (17.76 μg/L).The AUC(0-24) value of CUR-MS (656.74 μg/L* h) was also 9.45 times higher than that of CUR (69.51 μg/L* h).CUR-MS has higher bioavailability.
4.In the protective effect of CUR on gastric injury in mice with acutealcoholism, compared with the CUR group,CUR-MS significantly reduced the gastric mucosal injury index of mice in the model group (P < 0.01), reduce the congestion, edema, bleeding and inflammatory infiltration of gastric mucosa.Significantly increased the SOD activity in the stomach (P < 0.05), significantly decreased MDA in gastric mucosa content (P < 0.01); In the protective effect of CUR on liver injury in mice with acute alcoholism,compared with the CUR group, CUR-MS significantly increased the activity of gastric SOD (P < 0.05), significantly decreased MDA in gastric mucosa content (P < 0.01).
Conclusion：
The CUR-Ms prepared in our laboratory can significantly improve the solubility, dissolution rate and stability of gastrointestinal liver homogenate of CUR. At the same time, CUR-Ms can effectively inhibit intestinal P-glycoprotein (P-gp).In the end, CUR-Ms increased the oral bioavailability of CUR by 9.45 times, and its ability to resist alcohol-induced tissue damage was also significantly improved.Therefore, Soluplus micelles provide a new method for improvingthe oral absorption and clinical application value of CUR.
Key words：
Curcumin; Oral bioavailability; Soluplus; Alcoholism; Alcohol-induced tissue injury;
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