2 - 羟甲基 - 3 ， 5 ， 6 - 三甲基吡嗪 棕榈酸酯的合成及其静脉乳剂的制备

 目的 研制 2- 羟甲基 -3,5,6- 三甲基吡嗪的前药 2- 羟甲基 -3 ， 5 ， 6- 三甲基吡嗪棕榈酸酯静脉乳剂，以期延长川芎嗪的生物半衰期。 方法 以川芎嗪为原料，经氧化、酰化、水解、酯化等反应合成 2- 羟甲基 -3 ， 5 ， 6- 三甲基吡嗪棕榈酸酯，进而以大豆油为油相，注射用大豆磷脂与泊洛沙姆 188 为乳化剂，制备其初乳，再经高压乳匀机匀化，制得其静脉乳剂。 结果 所得产物经核磁共振氢谱、质谱、元素分析及紫外光谱确证其结构为 2- 羟甲基 -3 ， 5 ， 6- 三甲基吡嗪棕榈酸酯，色谱纯度大于 98% ， 乳剂平均粒径为 253.2 nm ， Zeta 电位为 - 28.7 mV ；长期留样放置 12 个月，制剂外观性状、粒径、 Zeta 电位、 pH 及含量等指标均未见明显变化。 结论 研制的 2- 羟甲基 -3 ， 5 ， 6- 三甲基吡嗪棕榈酸酯乳剂理化性质稳定，可达到静脉注射制剂要求，为进一步考察其药动学奠定了基础。

Synthesis of 2-Hydroxy-Methyl-3,5,6-Trimethyl-Pyrazine Palmitate and Preparation of Intravenous Emulsion

OBJECTIVE To prepare an emulsion of 2-hydroxy-methyl-3,5,6-trimethyl-pyrazine palmitate(HTMPP), a prodrug of 2-hydroxy-methyl-3,5,6-trimethyl-pyrazine(HTMP) metabolised from tetramethylpyrazine(TMP) and to expect a longer biological half life of HTMPP than that of TMP. METHODS HTMPP was synthesized from tetramethylpyrazine by oxidation, acylation, hydrolysis and esterification process. Soybean oil and mixture of fabaceous lecithin and poloxamer188 were selected as the oil phase and the mixed emulsifier, respectively. The primary emulsion of HTMPP was first prepared, and following homogenization was carried out using a high pressure homogenizer. RESULTS The chemical structure of the prepared HTMPP was characterized by 1H-NMR,MS,elemental analysis and UV. The purity of HTMPP was above 98%. The average diameter of the HTMPP emulsion was 253.2 nm with Zeta potential of -28.7 mV. The appearance, diameter, Zeta potential, pH value and content of the HTMPP emulsion were stable after it was stored for twelve months at 25 ℃. CONCLUSION The prepared HTMPP emulsion was relatively stable and could meet the requirements for intravenous administration. This study provided the expected pharmaceutical preparation for further pharmacokinetics investigation of the HTMPP emulsion.