Increased microneedle-mediated transdermal delivery of tetramethylpyrazine to the brain, combined with borneol and iontophoresis, for MCAO prevention.

The aim of this research was to improve transdermal delivery and distribution of tetramethylpyrazine (TMP) in the brain, by adding borneol (BN) and iontophoresis (ITP), and using microneedles (MN), to prevent middle cerebral artery occlusion (MCAO). BN was encapsulated into sulfobutylated-β-cyclodextrin (BN-SBE-β-CD), and then dispersed together with TMP. Four delivery groups were tested: passive (with no ITP and MN), ITP, MN, and MN combined with ITP (MN-ITP). In vitro transdermal fluxes of the drugs in those groups and in that corresponding order were 79.12±14.5, 395.43±12.37, 319.16±29.99, and 1018.07±108.92 μg/cm² (for TMP), and 39.34±1.31, 202.81±53.56, 715.47±75.52, and 1088.60±53.90μg/cm² (for BN), respectively, which indicated that the use of MN-ITP greatly enhanced transdermal TMP and BN delivery compared to the other groups. The AUC_0-t for the combined use of TMP and BN drugs was measured using two in vivo studies, cutaneous microdialysis and pharmacodynamic, yielding increased folds of 3.69 and 1.98 in ITP, 6.05 and 2.73 in MN, and 12.43 and 7.47 in MN-ITP groups, respectively, as compared to those in the passive group. In addition, the combined use of TMP and BN increased TMP distribution in the heart and the brain, indicated by TMP C_max of 1.76- and 1.59-fold higher (p < 0.05), and TMP AUC_0-t of 1.50 times and 1.19-fold higher (p < 0.01), than with administration of TMP in absence of BN, respectively. The brain infarction area and IL-β expression in the MCAO rat were significantly decreased in the MN-ITP group, compared with the control group (p < 0.05). In conclusion, combination of MN and ITP resulted in a synergistic enhancement of transdermal delivery and distribution of TMP in the brain, when in combination with BN, thereby significantly decreasing the infarct volumes and improving the neurological scores of MCAO.