Development of 2-hydroxymethyl-3,5,6-trimethylpyrazine palmitate-loaded lipid emulsion: formulation, optimization, characterization, pharmacokinetics, biodistribution and pharmacodynamics

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 AUC(0-180) (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 AUC(0-120) (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.