紅麴滴丸之最佳化處方製備及藥物動力學評估

Optimization of monascus dripping pills and pharmacokinetic evaluation

賴美雲(Mai-Yun Lai)

指導教授 ： 蔡東榮

高雄醫學大學/藥學院/藥學研究所/碩士(2009年)

摘要

Monacolin K是紅麴(Monascus purpureus)的主要次級代謝物，主要用於降低膽固醇；但是Monacolin K的水溶解度低以至於生體可用率低。
本研究的目的是利用固體分散的技術將紅麴製成滴丸的劑型，以增加Monacolin K的水溶性及生體可用率。利用23複因子實驗設計法，以不同比例的界面活性劑，輔界面活性劑，還有油相當作變因，觀察三個因子對Monacolin K水溶解度，溶離速率的影響，得到最佳紅麴滴丸處方。評估紅麴滴丸物化特性，包括以HPLC測藥物含量；利用示差掃描熱量分析圖譜和傅立葉轉換紅外光譜分析觀察晶型及結構的改變；以掃描式電子顯微鏡觀察外觀；並比較紅麴滴丸及市售膠囊之體外溶離釋出及老鼠口服投與紅麴滴丸及紅麴粉末後之體內藥物動力學參數的比較。
結果顯示在溶解度試驗紅麴滴丸(96.85±7.75μg/ml)比市售膠囊增加了一倍以上；以示差掃描熱量分析圖譜可觀察到Monacolin K標準品在173℃有內吸熱波峰，經由製成紅麴滴丸的內吸熱波峰消失，可看出藥物被包在載體當中形成非結晶態，傅立葉轉換紅外光譜分析可看出Monacolin K被包覆在載體中，結構沒有改變。以掃描式電子顯微鏡可觀察到滴丸的劑型除了圓整度佳，表面光滑外同時改善了表面結晶化的情況；在體外溶離試驗，紅麴粉末Monacolin K(十二小時有3.74％溶離)溶離情況非常的低，經過製成滴丸劑型Monacolin K在一小時內溶離57％，相對市售膠囊膠囊(十二小時溶離25％)具有較快的溶離，證實了滴丸劑型能有效的改善Monacolin K溶解度及溶離率。在動物體內實驗可以觀察到紅麴滴丸，Monacolin K在大白鼠最高血中濃度(Cmax：1.9505±0.4419 μg/ml)比使用紅麴粉末(0.50154±0.1136 μg/ml)增加了三倍，紅麴滴丸能夠顯著的增加Monacolin K之水溶性及口服生體可用率，有利於臨床上應用。

關鍵字

Monacolin K ； 紅麴滴丸 ； 藥物動力學

並列摘要

Monacolin K is the major secondary metabolite of Red yeast rice, which mainly uses in lowering the cholesterol; Monacolin K is a poorly water-soluble drug, which is one of the reasons that it has a low bioavailability. The objective of this study is using the technology of solid dispersion to make red yeast rice Dripping Pills form to increased Monacolin K solubility and bioavailability. The 23 full factorial experimental design was used to investigate the different factors (surfactant, co-surfactant, lipid) in preparing Dripping Pills, and to look for physiochemical properties, including monitor Monacolin K concentration by HPLC, to observe the amorphous and changing of structure by Differential scanning calorimetry and Fourier transform infrared spectroscopy, to observation outward appearance change of Scanning electron microscope. The final experimental design from was evaluated with regard to its in vitro dissolution, and bioavailability in Sprague-Dawley (SD) rat compared with the red yeast rice powder or market capsule.
Comparing with market capsule (45.27 ± 4.53, 1.52 ± 1.14 μg/ml), Monacolin K Dripping Pills (96.85 ±7.75 μg/ml) has better solubility. Differential scanning calorimetry recording of the pure Monacolin K exhibits a sharp endothermic peak around 173 ºC, but Monacolin K Dripping Pills resulted in a complete suppression of the drug fusion peak. Suggest that Monacolin K has completely converted into an amorphous state; Fourier transform infrared spectroscopy recording Monacolin K bedding bag in the carrier, the structure dose not have the significance change. Scanning electron microscope recording after design, Dripping Pills has the surface to be smooth, pellet circle entire, simultaneously reduces the crystallization. In phosphate buffer (pH6.8), Monacolin K powder dissolution was quite low (3.74% within 12 hr). However, after being prepared as a Dripping Pills, substantially was improved (about 57% in 1 hr), and became greater than the dissolution of market capsule (about 25% in 12 hr). This is mainly because in the Dripping Pills, it was effective to increase Monacolin K solubility and dissolution. In SD rat pharmacokinetics study, the maximum plasma concentration of Monacolin K of Dripping Pills (Cmax:1.9505 ± 0.4419 μg/ml) increases three times than those in red yeast rice powder (0.50154 ± 0.1136 μg/ml). We can conclude that Dripping Pill form can increase its both water solubility and oral bioavailability and clinical efficacy.

並列關鍵字

Monacolin K ； Monascus Dripping Pills ； Pharmacokinetics

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