棕榈酸 2-羟甲基-3,5,6-三甲基吡嗪酯载脂乳剂的研制：制剂、优化、表征、药代动力学、生物分布和药效学。
Development of 2-hydroxymethyl-3,5,6-trimethylpyrazine palmitate-loaded lipid emulsion: formulation, optimization, characterization, pharmacokinetics, biodistribution and pharmacodynamics.
机构信息
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China.
出版信息
J Drug Target. 2013 May;21(4):341-53. doi: 10.3109/1061186X.2012.751536. Epub 2013 Jan 12.
BACKGROUND
Tetramethylpyrazine (TMP) is used to treat cerebrovascular and cardiovascular diseases. However, it displays a short half-life that restricts clinical applications. 2-Hydroxymethyl-3,5,6-trimethylpyrazine (HTMP) is the principal active metabolite of TMP, with similar activity of TMP. Therefore, it makes sense to improve the biopharmaceutical characteristics via HTMP bypassing TMP.
PURPOSE
To prolong the half-life of HTMP and achieve improved bioavailability and efficacy compared to commercially available product of tetramethylpyrazine phosphate injection (TMPP-I).
METHODS
A lipophilic prodrug of HTMP, palmitate of HTMP (HTMPP) was synthesized, and then the lipid emulsion of HTMPP was developed. The middle cerebral artery occlusion (MCAO) model was applied to evaluate the efficacy in different administration group.
RESULTS AND DISCUSSION
The optimized formulation consisted of 1.5% (w/v) HTMPP, 15% (w/v) soybean oil, 1.2% (w/v) soybean lecithin and 0.3% (w/v) poloxamer 188. The AUC0-180 min and the half-life of HTMP in HTMPP-LE was 2.05-fold and 1.48-fold greater than that in TMPP-I. The brain AUC0-120 min of HTMP in HTMPP-LE group increased by 145.6% compared to that in TMPP-I group. These differences could be primarily attributed to dissimilar metabolism between HTMPP and TMP. Consistently, HTMPP-LE exhibited better efficacy on ischemia/reperfusion model than TMPP-I.
CONCLUSION
The developed HTMPP-LE suggests a great therapeutic potential for clinical applications.
背景
川芎嗪（TMP）用于治疗心脑血管疾病。然而，它的半衰期较短，限制了其临床应用。2-羟甲基-3,5,6-三甲基吡嗪（HTMP）是 TMP 的主要活性代谢物，具有与 TMP 相似的活性。因此，通过 HTMP 绕过 TMP 来改善生物制药特性是有意义的。
目的
延长 HTMP 的半衰期，与市售四甲基吡嗪磷酸盐注射液（TMPP-I）相比，提高生物利用度和疗效。
方法
合成 HTMP 的亲脂前体 HTMP 棕榈酸酯（HTMPP），然后开发 HTMPP 的脂质乳剂。采用大脑中动脉闭塞（MCAO）模型评估不同给药组的疗效。
结果与讨论
优化的配方由 1.5%（w/v）HTMPP、15%（w/v）大豆油、1.2%（w/v）大豆卵磷脂和 0.3%（w/v）泊洛沙姆 188 组成。HTMPP-LE 的 AUC0-180 min 和半衰期分别是 TMPP-I 的 2.05 倍和 1.48 倍。HTMPP-LE 组 HTMP 的脑 AUC0-120 min 比 TMPP-I 组增加了 145.6%。这些差异主要归因于 HTMPP 和 TMP 之间不同的代谢。一致地，HTMPP-LE 在缺血/再灌注模型中表现出比 TMPP-I 更好的疗效。
结论
开发的 HTMPP-LE 为临床应用提供了巨大的治疗潜力。
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