Abstract
This study examined the efficacy of the percutaneous delivery of a tetramethylpyrazine-loaded microemulsion (TMP-ME) on skin pretreated with microneedles (MN). The TMP-ME formulation was optimized in vitro with skin permeation experiments, using a uniform experimental design, guided by a pseudo-ternary phase diagram, in which the TMP skin permeation level and mean particle size were indices. The effects of MN pretreatment on skin permeation by TMP-ME were assessed using in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic studies in rats. The influence of MN pretreatment on the skin barrier function was evaluated by measuring the electrical resistance of rat skin before and after MN insertion. In the optimal formulation of TMP-ME, the weight percentages of Maisine® 35-1 (oil phase), Labrasol® (surfactant), and Transcutol® P (co-surfactant) were 7%, 30% and 10%, respectively, with 1.5% TMP loading. In the in vitro skin permeation study, MN-assisted TMP-ME exhibited a two-fold increase in a 24-h cumulative TMP permeation compared with TMP-ME alone (p < 0.05). In the skin microdialysis study, TMP in MN-assisted TMP-ME exhibited a 1.25-fold increase in Cmax, a 0.93-fold decrease in Tmax, and a 0.88-fold increase in AUC0–t (p < 0.05). Similarly, in the pharmacokinetic study, TMP in MN-assisted TMP-ME exhibited a 2.11-fold increase in Cmax, a 0.67-fold decrease in Tmax, and a 1.07-fold increase in AUC0–t (p < 0.05). The percutaneous electrical resistance of rat skin before and after MN insertion was 850 ± 50 Ω/cm2 and 283 ± 104 Ω/cm2 respectively, indicating that MN dramatically compromises the skin barrier. These results suggest that MN assistance increases the skin permeation rate and the extent of percutaneous absorption of TMP-ME, and that the mechanism may involve the reversible barrier perturbation effect. The rate and extent of percutaneous absorption of TMP-ME can be significantly enhanced by MN assistance, possibly because MN causes a reversible barrier perturbation effect on skin.
Highlights
The percutaneous route is attractive for drug delivery because it facilitates a stable level of drug in the plasma, avoids the first pass effect, and has a high patient compliance
To optimize the formulation, nine tetramethylpyrazine-loaded microemulsion (TMP-ME) formulations were compared using a uniform experimental design guided by the pseudo-ternary phase diagram
These results suggest that MN assistance can dramatically facilitate the penetration of μg/cm skin by in vitro, withdramatically the results obtained previously
Summary
The percutaneous route is attractive for drug delivery because it facilitates a stable level of drug in the plasma, avoids the first pass effect, and has a high patient compliance. Transdermal delivery is currently limited to potent compounds that have low molecular weights and favorable n-Octanol/water partition coefficients, due to the formidable barrier function of the stratum corneum (SC). To address this challenge, methods for enhancing passive and active skin penetration are being. Silicon or metal MNs are usually combined with other skin penetration enhancement techniques. Transdermal TMP administration has attracted increased attention, in part because of improved patient compliance associated with this route, and due to the physical and chemical properties of TMP (small molecular weight and an ideal n-Octanol/water partition coefficient) [22,23,24]. Active (MN) and passive (ME) skin penetration enhancement techniques were combined to improve TMP skin permeation efficiency. The effects of MN treatment on the skin permeation and transdermal absorption characteristics of TMP-ME were evaluated by in vitro skin permeation, in vivo skin microdialysis, and pharmacokinetic analysis in rats
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