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研究生:林金霖
研究生(外文):Chin-Lin Lin
論文名稱:黃芩之解熱效應及其指標成分Baicalein經固相脂質奈米顆粒化之藥物輸送系統研究
論文名稱(外文):Antipyretic effect of the extract from Scutellaria in vivo study and the SLN formulation design of its biomaker, baicalein, as drug delivery system
指導教授:吳寶珠吳寶珠引用關係
指導教授(外文):Pao-Chu Wu
學位類別:碩士
校院名稱:高雄醫學大學
系所名稱:藥學研究所碩士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:103
中文關鍵詞:黃芩解熱固相脂質奈米顆粒化
外文關鍵詞:ScutellariaAntipyreticSolid lipid nanoparticles(SLN)
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黃芩為唇型科植物,自古以來為中國傳統中藥,具有解熱、抗炎的作用。Baicalein為黃芩的主成分,在生物體內扮演著重要的角色,能夠抑制促發炎(pro-inflammatory )酵素的產生和減少PGE2的產生,以達到解熱的目的。本實驗主要是利用酵母誘導大鼠體溫升高,藉由口服黃芩煎煮液及其主成分baicalein和baicalin,在不同劑量下觀察時間與抑制率的關係,由實驗結果得知,黃芩在低劑量時就可以看出其解熱效果。經由口服及腹腔注射黃芩冷凍乾燥粉末,都無法明顯的經由HPLC偵測出baicalein在血漿中的濃度,證實了baicalein在血漿中的不安定性。所以將baicalein製成SLN的劑型,觀察是否能增加baicalein在血漿中的安定性,選用Gelucire(62/5、48/9、44/14)及glyceryl monostearate當作脂質的部份,配合不同劑量之抗氧化劑vitamin C及vitamin E,評估處方在6天內粒徑平均大小和baicalein的含量,篩選出具有高包埋率的處方為含8 mg vitamin C之Gelucire 62/5,將其製成SLN,以靜脈注射投予,觀察大鼠體內血漿中藥物動力學情形以及腦部組織的分布。由實驗結果得知,將baicalein製成SLN的劑型,可以發現t1/2及MRT都增加1個小時,清除率有顯著減少,血漿中AUC提高,平均血中濃度的波峰比baicalein-solusion高出5倍,使得baicalein能在血漿濃度提高,說明baicalein-SLN有助於延長baicalein在血漿中的時間。HPLC偵測結果發現視丘中具有高濃度的baicalein,證明baicalein能穿透血腦障壁,抵達腦部視丘,以致能夠影響視丘調解體溫的功能,達到解熱的目的。
The medicinal plant Scutellaria baicalensis Georgi (Lamiaceae) (SR) has been used widely in traditional Chinese medicine for antipyretic and anti-inflammation. Baicalein is the main ingredient of SR and plays an import role in medicine due to its mechanism of reducing the production of pro-inflammatory enzyme and consequently decreasing the release of PEG2. This study was to estimate the antipyretic effect of baicalin and baicalein with different dose in rats by observing the relationship between time and rate of antipyretic effect. The results was shown that low dose of SR could produce better antipyretic effect than of higher dose. After orally and intravenously administration of freeze-dried powder of SR decoction injected into the rat, the blood concentration of baicalein could not be detected by HPLC. It was confirmed that baicalein was fastly eliminated in blood. The formulation of SLN prepared with Gelucire (62/5, 48/9 and 44/14) and glyceryl monostearate as lipid phase and Vitamin C and Vitamine E as antioxidant to overcome the problem. The formulation was evaluated by measuring the average particle size and the content of baicalein at 6th day. The SLN with the highest entrapment efficiency was composed of Gelucire 62/5 with 8 mg of Vitamin C, and then was intravenously administrated into the rat. The pharmacokinetics and distribution of baicalein in brain tissue were evaluated in rat. It was found that baicalein formulated by SLN could increase the t1/2 and MRT by 1 hr, decrease the clearance and increase the AUC in plasma. The Cmax of baicalein-SLN was 5-fold higher than that resulted from baicalein-solution and thereby increased the plasma concentration. It was suggested that SLN could extend the period of baicalein in blood. High concentration of baicalein was found in the thalamus of the rat. It proved that baicalein could transport through the blood-brain barrier to consequently produce the antipyretic effect.
表次目錄 ------------------------------------------------------------------------------------------ Ⅵ
圖次目錄 ------------------------------------------------------------------------------------------ Ⅷ
中文摘要 ------------------------------------------------------------------------------------------ Ⅸ
英文摘要 ------------------------------------------------------------------------------------------ Ⅹ
壹、緒論 ------------------------------------------------------------------------------------------- 1
一、研究背景 ------------------------------------------------------------------------------- 1
二、黃芩基本概述 ------------------------------------------------------------------------- 2
1. 植物簡介 -------------------------------------------------------------------------- 2
2. 成分 -------------------------------------------------------------------------------- 2
3. 藥理作用 -------------------------------------------------------------------------- 3
三、黃芩之解熱作用 ---------------------------------------------------------------------- 5
1. 體溫的調節 ----------------------------------------------------------------------- 5
2. COX-2與發熱反應的關係 ------------------------------------------------------ 5
3. iNOS 與發熱反應的關係 ------------------------------------------------------ 6
4. 發熱的病理機轉 ----------------------------------------------------------------- 6
5. 黃芩之解熱原理 ----------------------------------------------------------------- 7
四、黃芩藥物動力學研究 ---------------------------------------------------------------- 9
五、 Solid lipid nanoparticles之概述 --------------------------------------------------- 12
1. Solid lipid nanoparticles之目的 ------------------------------------------------ 12
2. SLN的組成 ----------------------------------------------------------------------- 12
3. SLN之製備方法 ------------------------------------------------------------------ 15
4. SLN的優點 ------------------------------------------------------------------------ 16
5. 藥物釋放模式 -------------------------------------------------------------------- 16
6. 安定性評估 ----------------------------------------------------------------------- 17
7. Pharmacokinetic profile ----------------------------------------------------------- 18
貳、實驗目的 ------------------------------------------------------------------------------------- 19
參、實驗材料及儀器設備 ---------------------------------------------------------------------- 20
一、材料 ------------------------------------------------------------------------------------- 20
A. 藥品 ------------------------------------------------------------------------------- 20
B. 化學試藥 -------------------------------------------------------------------------- 20
二、儀器設備 ------------------------------------------------------------------------------- 21
三、高效能液相層析儀 ------------------------------------------------------------------- 22
1. HPLC分析條件 ------------------------------------------------------------------- 22
2. Retention time ---------------------------------------------------------------------- 22
肆、實驗方法 ------------------------------------------------------------------------------------- 23
一、實驗動物 ------------------------------------------------------------------------------- 23
二、黃芩萃取物及其指標成分之分析方法 ------------------------------------------- 23
1. 體外檢量線的建立 -------------------------------------------------------------- 23
2. 體內檢量線的建立 -------------------------------------------------------------- 24
3. Baicalein於大鼠腦部檢量線的建立 ------------------------------------------ 24
三、黃芩生藥活性成分含量的分析 ---------------------------------------------------- 25
1. 黃芩冷凍乾燥粉末製備 -------------------------------------------------------- 25
2. 利用不同溶媒萃取黃芩生藥有效成分含量的分析 ----------------------- 25
四、解熱藥效學實驗 ---------------------------------------------------------------------- 26
1. brewer’s yeast powder濃度選擇 ----------------------------------------------- 26
2. 給予三黃水萃取物之解熱效應 ----------------------------------------------- 27
3. 給予黃芩水萃取物之解熱效應 ----------------------------------------------- 27
4. 給予黃芩的主要指標成分baicalin及baicalein之解熱效應 ------------- 27
五、黃芩於動物體內藥動實驗 ---------------------------------------------------------- 28
六、Baicalein 進行solid lipid nanoparticles之製備 ---------------------------------- 29
1. Baicalein 之stock solution 的製備 ------------------------------------------- 29
2. SLN的製備 ------------------------------------------------------------------------ 29
3. Particle size測定 ------------------------------------------------------------------ 30
4. 包埋率的測定 -------------------------------------------------------------------- 30
5. SLN之體內藥物動力學 --------------------------------------------------------- 32
七、黃芩藥動學資料分析 ---------------------------------------------------------------- 33
伍、結果與討論 ---------------------------------------------------------------------------------- 34
一、 黃芩指標成分baicalin及baicalein分析方法之建立 -------------------------- 34
1. 黃芩水萃取物中指標成分含量之定量分析方法 -------------------------- 34
2. 黃芩指標成分於血漿含量之定量分析方法 -------------------------------- 38
3. 黃芩指標成分Baicalein於腦部含量之定量分析方法 -------------------- 44
二、黃芩指標成分含量的分析結果 ---------------------------------------------------- 46
三、解熱效應之藥效學實驗 ------------------------------------------------------------- 52
1. 致熱原brewer’s yeast powder濃度之選擇結果 ---------------------------- 52
2. 給予大黃、黃連和黃芩水萃取物之解熱藥效實驗結果 ------------------ 54
3. 給予黃芩水萃取物之解熱藥效實驗結果 ----------------------------------- 57
4. 黃芩主要指標成分baicalin及baicalein之解熱藥效實驗結果 ---------- 58
四、黃芩水萃取物之體內藥動學實驗 ------------------------------------------------- 62
五、Baicalein-SLN之製備與評估 ------------------------------------------------------- 67
六、Baicalein-SLN在大白鼠體內之藥物動力學評估 ------------------------------- 77
1. Baicalein-SLN經靜脈注射給藥後在體內藥物動力學的評估 ------------- 77
2. Baicalein-SLN經靜脈注射給藥後在腦部藥物含量之評估 ---------------- 85
陸、結論 ------------------------------------------------------------------------------------------- 87
柒、參考文獻 ------------------------------------------------------------------------------------- 88
Abena AA, Diatewa M, Gakosso G, Gbeassor M, Hondi-Assaha Th, Ouamba JM. 2003. Analgesic, antipyretic and anti-inflammatory effects of essential oil of Lippia multiflora. Fitoterapia. 74: 231 – 236.
ABU TM, Serajuddin, Cheen PC. 1988. Effect of vehicle amphiphilicity on the dissolution and bioavailability of a poorly water-soluble drug from solid dispersions. Journal of Pharmaceutical Sciences. 77 (5): 414 - 417.
Akao T, Kawabata K, Yanagisawa E, Ishihara K, Mizuhara Y, Wakui Y, Sakashita Y, Kobashi, K. 2000. Baicalin, the predominant flavone glucuronide of Scutellariae Radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original from. Journal of Pharmacy and Pharmacology. 52: 1563 - 1568.
Amellal M, Bronner C, Briancon F. 1985. Inhibition of Mast Cell Histamine Release by Flavonoids and Bio-Flavonoids. Planta Medica. 51: 16-20.
Barkera SA, Yapb SP, Yuenb KH. 2003. An investigation into the structure and bioavailability of tocopherol dispersions in Gelucire 44/14. Journal of Controlled Release. 91: 477 - 488.
Boulant JA. 1997.Thermoregulation. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed. 35 - 58.
Chang YZ, Chu WB, Sheng YX, Qiang W, Liang R. 2004. The synergistic activity of antibiotics combined with eight traditional Chinese medicines against two different strains of Staphylococcus aureus. Colloids and Surfaces B. 41: 79 - 81.
Chen F, Chan KH, Jiang Y, Kao RYT, Lu HT, Fan KW, Cheng VCC , Tsui WHW, Hung IFN, Lee TSW, Guan Y, Peiris JSM, Yuen KY. 2004. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. Journal of Clinical Virology. 31: 69 - 75.
Chen F, Chan KH, Jiang Y, Kao RYT, Lu HT, Fan KW, Cheng VCC, Tsui WHW, Hung IFN, Lee TSW, Guan Y, Peiris JSM, Yuen KY. 2004. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. Journal of Clinical Virology. 31 (1): 69 - 75.
Chen YC, Shen SC, Chen LC, Lee TJF, Yang LL. 2000. Wogonin, baicalin and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expression induced by NOS inhibitors and lipopolysaccharide. Biochemical Pharmacology. 59: 1445 - 1457.
Chen YC, Shen SC, Chen LG, Lee TJ, Yang LL. 2001. Wogonin, baicalin, and baicalein inhibition of inducible nitric oxide synthase and cyclooxygenase-2 gene expression induced by nitric oxide synthase inhibitor and lipopolysaccharide. Biochemical Pharmacology. 61: 1417 - 1427.
David M, Aronoff MD, Eric G, Neilson MD. 2001. Antipyretics: Mechanisms of Action and Clinical Use in Fever Suppression. The American Journal of Medicine. 111 (4): 304 - 315.
Dinarello CA, Gatti S, Bartfai T. 1999. Links with an ancient receptor. Current Biology. 9: R147 - 150.
DiPaola RS, Zhang H, Lambert G, Meeker R, Licitra E, Rafi M. 1998. Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. The New England Journal of Medicine. 339: 785 - 791.
Doxastakis G, Sherman P. 1996. The interaction of sodium caseinate with monoglyceride and diglyceride at the oil-water interface and its effect on interfacial rheological properties. Colloid & Polymer Science. 264 (3): 254 - 259.
Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Rompay MV, Kessler RC. 1998. Trends in alternative medicine use in the united states, 1990-1997: Results of a Follow-up National Survey. The Journal of the American Medical Association. 280: 1569 - 1575.
Fundaro A, Cavalli R, Bargoni A, Vighetto D, G.P. Zara, MR Gasco. 2000. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmaceutical Research. 42 (4): 337 - 343.
Hannig J, Zhang D, Canaday DJ, Beckett MA, Astumian RD, Weichselbaum RR, Lee RC. 2000. Surfactant sealing of membranes permeabilized by ionizing radiation. Radiation research. 154:171–177.
Hsiu SL,Lai MY, Chen CC, Hou YC, Lee Chao PD. 2003. Urinary pharmacokinetics of baicalein, wogonin and their glycosides after oral administration of scutellariae radix in humans. Biological & Pharmaceutical Bulletin. 26 (1): 79 - 83.
Lai MY, Hsiu SL, Tsai SY, Hou YC, Lee Chao PD. 2003. Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats. Journal of Pharmacy and Pharmacology. 55: 205 - 209.
Lander R, Manger W, Scouloudis M, Ku A, Davis C, Lee A. 2000. Gaulin homogenization: a mechanistic study. Biotechnology Progress. 16: 80 - 85.
Li BQ, Fu T , Gong WH, Dunlop N, Kung H, Yan Y, Kang J, Wang JM. 2000. The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines. Immunopharmacology . 49: 295 - 306.
Luheshi GN. 1998. Cytokines and fever: mechanisms and sites of action. Annals of the New York Academy of Sciences. 856: 83 - 89.
Mackowiak PA. 1997. Normal “body” temperature. In: Mackowiak PA, ed. Fever: Basic Mechanisms and Management. 2nd ed.: 207 - 213.
Mehnert W, Mäder K. 2001. Solid lipid nanoparticles Production, characterization and applications. Advanced Drug Delivery Reviews. 47: 165 - 196.
Moncada S, Palmer RMJ, Higgs EA. 1991. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacological Reviews. 43: 109 - 142.
Mü ller RH, Lucks JS. 1996. Arzneistoffträger aus festen Lipidteilchen, Feste Lipidnanosphären (SLN). European Patent Office. 0605497.
Mühlen A, Schwarz C, Mehnert W. 1998. Solid lipid nanoparticles for controlled drug delivery-drug release and release mechanism. European Journal of Pharmaceutics and Biopharmaceutics. 45: 149 - 155.
Muto R, MotozukaT, Nakano M, Tatsumi Y, Sakamoto F, Kosaka N. 1997. The chemical structure of new substance as the metabolite of baicalin and time profiles for the plasma concentration after oral administration of Sho-Saiko-To in human. Yakugaku Zasshi. 188: 79 - 87.
Romero MR, Efferth T, Serrano MA, Castãno B, Macias RIR, Briz O, Marin JJG. 2005. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an “in vitro” replicative system. Antiviral Research. 68: 75 - 83.
Saper CB, Breder CD. 1994. The neurologic basis of fever. The New England Journal of Medicine. 330: 1880 - 1886.
Schöler N, Hahn H, Mü ller RH, Liesenfeld O. 2002. Effect of lipid matrix and size of solid lipid nanoparticles (SLN) on the viability and cytokine production of macrophages. International Journal of Pharmaceutics. 231: 167 - 176.
Schwartz JI, Chan CC, Mukhopadhyay S. 1999. Cyclooxygenase-2 inhibition by rofecoxib reverses naturally occurring fever in humans. Clinical Pharmacology and Therapeutics. 65: 653 - 660.
Schwarz C, Mehnert W, Lucks JS, Mü ller RH. 1994. Solid lipid nanoparticles (SLN) for controlled drug delivery: I. Production, characterization and sterilization. Journal of Controlled Release. 30: 83 - 96.
Shahgaldian P, Da Silva E, Coleman AW, Rather B, Zaworotko MJ. 2003. Para-acyl-calix-arene based solid lipid nanoparticles (SLN): a detailed study of preparation and stability parameters. International Journal of Pharmaceutics. 253: 23 - 38.
Shen YC, Chiou WF, Chou YC, Chen CF. 2003. Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. European Journal of Pharmacology. 465: 171 - 181.
Sheu MT, Hsia AHO. 2001. Polyglycolized saturated glycerides as carrier and enhancer for drug penetration. Chinese pharmaceutical journal. 53: 107 - 111.
Siekmann B, Bunjes H, Koch MHJ, Westesen K. 2002. Preparation and structural investigations of colloidal dispersions prepared from cubic monoglyceride-water phases, International Journal of Pharmaceutics. 244: 33 - 43.
Siekmann B, Westesen K. 1994. Melt-homogenized solid lipid nanoparticles stabilized by the nonionic surfactant tyloxapol. I. Preparation and particle size determination. Pharmacy and Pharmacology Letter. 3: 194 - 197.
Simon LS. 1999. Role and regulation of cyclooxygenase-2 during inflammation. The American Journal of Medicine. 106:37 - 42.
Terry MA, Hannig J, Carrillo CS, Beckett MA, Weichselbaum RR, Lee RC. 1999. Oxidative cell membrane alteration: evidence for surfactant- mediated sealing. Annals of the New York Academy of Sciences. 888:274–284.
Tsai WY, Chang WH, Chen CH, Lu FJ. 2000. Enchancing effect of patented whey protein isolate (Immunocal) on cytotoxicity of an anticancer drug. Nutrition & Cancer. 38 (2): 200 - 208.
Ushikubi F, Segi E, Sugimoto Y. 1998. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature. 395: 281 - 284.
Wakui T, Yanagisawa E, Ishibashi E, Matsuzaki Y, Takeda S,Sasaki H, Aburada M, Oyama V. 1992. Determination of baicalin and baicalein in rat plasma by high-performance liquid chromatography with electro- chemical detection. Journal of Chromatography. 57: 131 - 136.
Zara GP, Cavalli R, Fundaro A, Bargoni A, Caputo O, Gasco MR. 1999. Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN). Pharmaceutical Research. 40 (3): 281- 286.
Zhang C, Zhang Y, Chen J, Liang X. 2005. Purification and characterization of baicalin-β-D-glucuronidase hydrolyzing baicalin to baicalein from fresh roots of Scutellaria viscidula Bge. Process Biochemistry. 40: 1911 - 1915.
Zuo F, Zhou ZM, Yan ME, Liu ML, Xiong YL, Zhang Q, Song HY, Ye WH. 2002. Metabolism of constituents Huangqin-Tang, aprescription in traditional Chinese medicince, by Human Intestinal Flora. Biological & Pharmaceutical Bulletin. 25 (5): 558 - 563.
莊恭仁,2000,瀉火劑-黃芩湯,莊松榮複方選集,425-426。
黃黎等,1990,黃芩湯及其組成藥物藥理作用的初步研究,中國中藥雜誌,15 (2):115。
劉長山,馬麗麗,李萍,2001,黃芩對糖尿病患者紅血球細胞醛糖還原酶活性及腎小球濾過率的影響,中國中藥雜誌,26 (9):632 - 633。
蘇志杰,2004,奈米機械技術專輯,機械工業雜誌,255:131-139。
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