新合成抗癌化合物 CYL 及其固相脂質奈米顆粒化處方之藥物動力學研究

Pharmacokinetic study of new synthetic anti-tumor compound, CYL, and its SLN formulation

林蕙蘭(Hui-Lan Lin)

指導教授 ： 蔡義弘

高雄醫學大學/藥學院/藥學研究所/碩士(2006年)

摘要

Amsacrine為半衰期非常短之抗癌藥物，在大鼠體內僅約為20-30分鐘，本研究之模式藥物(3-chloro-7-methoxyfuro[2,3-b]-quinolin-4-yl)-(4-methoxy- phenyl)amine（CYL）為依amsacrine主結構所合成之一種新的抗癌化合物期能延長其半衰期，並藉由CYL之固體脂質奈米顆粒劑型之處方設計，使藥品在體內具緩慢釋出及標的化作用。研究中建立CYL之高效能液相層析儀（HPLC）定量分析方法，其分析條件為以C18 層析管柱，移動相由40% acetonitrile，10% methanol及 50% 的sodium 1-pentansulfonate 緩衝液（pH 3.0）所組成，以ECD為檢出器。經以靜脈投與不同劑量（5.1、3.825 及 2.55 mg/kg）之CYL水溶液後，可依二室模式計算相關之藥物動力學參數。結果顯示在這此劑量範圍中該藥物在血中之濃度呈線性關係，其半衰期為2.84小時，明顯較amsacrine為長，但尚未達到目標。因此欲將CYL進行固相脂質奈米顆粒化劑型（SLN）之處方設計，由trimyristin，glycerol monostearate，soybean lecithin及 poloxmer 188，配合超音波震盪法製備。其顆粒大小為100-200 nm，包埋率在90%以上，經包覆成SLN處方之藥品，其在動物體內之藥物動力學顯示，雖在血漿中半衰期並未延長，但卻可藉由單核巨嗜系統（MPS），促使藥物累積於肺臟、肝臟和胰臟。且在標的器官之血中濃度曲線下面積（AUC0→∞）及平均滯留時間（MRT）數值皆較水溶液大。由本研究得知經結構修飾後之CYL，其半衰期較amsacrine長，且在CYL包覆成SLN處方後，可增加標的器官之藥物累積量。

關鍵字

固相脂質奈米顆粒化處方 ； 藥物動力學

並列摘要

A new anti-tumor compound, (3-chloro-7-methoxyfuro[2,3-b]-quinolin-4-yl) -(4-methoxyphenyl)amine (CYL) was modified from the structure of amsacrine. Due to the half-life of amsacrine was only 20-30 min in rat, the aim of this study was to evaluate the pharmacokinetics of CYL in order to prolong the half-life by modified structure of amsacrine. In addition, solid lipid nanoparticle (SLN) of CYL was developed to increase the retention of CYL in plasma and the accumulation of CYL in target organs. Firstly, the analytical method was established using high performance liquid chromatography (HPLC) with electrochemical detector (ECD). The condition of HPLC was carried out using a C18 column with an isocratic mobile phase consisting of 40% acetonitrile, 10% methanol, and 50% sodium 1-pentanesulfonate solution (pH 3.0). The pharmacokinetic parameters were estimated after intravenous administration with CYL of 5.1, 3.825, and 2.55 mg/kg. The result was found that the linear relationship between the doses and concentrations of CYL was observed by two-compartment model and the half-life of CYL was calculated about 2.84 hr which was longer than that of amsacrine. The SLN of CYL was developed by ultrasonication method using trimyristin, glycerol monostearate, soybean lecithin, and poloxmer 188 as components. The sizes of CYL were from 100 to 200 nm, and entrapment efficiencies of CYL were more than 90%. In this study, the pharmacokinetic parameters of CYL incorporated in SLN were shown that the half-life wasn’t longer than that of free type in plasma, but SLN formulation was promoted CYL to accumulate in the lung, liver, and spleen by mononuclear phagocytes system (MPS). In target organs, the AUC0–∞ and MRT of SLNs were higher than that of free type. CYL was modified from amsacrine and shown a longer half-life than that of amsacrine, and CYL incorporated in SLN could increase its accumulation in target organs.

並列關鍵字

pharmacokinetic ； solid lipid nanoparticles

參考文獻

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