Development of a reservoir-type transdermal delivery system containing eucalyptus oil for tetramethylpyrazine

Abstract

The purpose of this study was to formulate a reservoir-type transdermal delivery system (TDS) for 2,3,5,6-tetramethylpyrazine (TMP) to enable the delivery of a sufficient dose through human skin to achieve an effective therapeutic plasma concentration. To improve the penetration of TMP in the reservoir-type TDS, several chemical penetration enhancers were investigated using in vitro rat dorsal skin permeation studies. Eucalyptus oil was found to enhance the permeation of TMP to the greatest extent, with the optimal concentration being 5% and the flux being 542.6 ± 49.7 μg/cm(2)/h, which was 4.5-fold greater than control with no enhancer (p < 0.01). The flux of the optimized reservoir-type TDS permeated through the human epidermis was 346.0 ± 27.7 μg/cm(2)/h. Based on the in vitro human skin permeation flux and the pharmacokinetics parameters observed, the clinical surface area of the TDS patch was predicted to be 20 cm(2). The in vivo study conducted in rabbits showed that the TMP TDS patch containing 5% eucalyptus oil had a more favorable pharmacokinetic profile, with a lower C(max) and prolonged T(max) and mean residence time than that observed with the oral administration of TMP. The TMP reservoir-type TDS was shown to be a promising alternative route to oral administration or intravenous infusion of TMP.

Development of essential oils as skin permeation enhancers: penetration enhancement effect and mechanism of action

“…Moreover, essential oils (EOs) and their volatile constituents have also been identified as one promising group of candidates to be employed as clinically acceptable PEs. Until now, EOs have been shown to be successful in delivering a range of different drugs across the skin, including vitamins (Valgimigli et al 2012), estradiol (Monti et al 2002), labetolol hydrochloride (Jain et al 2008), trazodone hydrochloride (Das et al 2006), tetramethylpyrazine (Shen et al 2013), carvedilol (Amin et al 2008), 5-fluorouracil (5-FU) (Lan et al 2014a), flurbiprofen (Zhang et al 2006;Charoo et al 2008), diclofenac sodium (Akbari et al 2015), indomethacin (Lan et al 2014a) and ibuprofen (Luo et al 2007;Shen et al 2007;Khan et al 2011).…”

Systematic Review on the Effectiveness of Essential and Carrier Oils as Skin Penetration Enhancers in Pharmaceutical Formulations

“…Thus, the effect of the type of polymer used [51], the amount of the polymer used [52], and the type and concentration of plasticizer used [2] can all impact its activity, and there are some contradictory reports regarding its efficacy. Although Yaqoob et al [51], Akram et al [50], and Zeng et al [52] found the penetration enhancement effect of eucalyptus oil to be less than isopropyl myristate [IPM] and Azone from matrix patches of metoprolol, glimepride, and elemene, respectively, El-Nabarawi et al [2], Shen et al [53], and Sharma and Mehra [13] reported the opposite. They found that eucalyptus oil exerted the highest penetration enhancement effect compared with other penetration enhancers from transdermal patches of sumatriptan, tetramethylpyrazine, and celecoxib.…”

Single- and Multiple-Dose Pharmacokinetics of a Novel Tetramethylpyrazine Reservoir-Type Transdermal Patch <i>versus</i> Tetramethylpyrazine Phosphate Oral Tablets in Healthy Normal Volunteers, and <i>in Vitro</i>/<i>in Vivo</i> Correlation

“…The transdermal flux rate from the patch increased steadily, reaching a maximum value of 459 µg/cm 2 /h at 3 to 5 h, and decreased slowly to a rate of about 283 µg/cm 2 /h from 12 to 24 h. This phenomenon has also been observed in an estradiol transdermal reservoir membrane system, which showed that the patients' C max of estradiol at 30 h corresponded with the maximum Estradiol flux through human skin at 20 to 30 h. 25) In our previous formulation studies on TMP transdermal patch, eucalyptus oil was selected as the penetration enhancer because of superior efficacy when compared to azone and menthol. 26) eucalyptus oil contains more than 80% cineole, a well-known skin penetration enhancer. Cineole enhances skin permeation by disrupting the inter-lamellar hydrogen-bonding network of the polar head group region in the stratum corneum bilayer, which facilitates the partition and permeation of small polar molecules through the skin.…”