Transdermal agomelatine microemulsion gel: pyramidal screening, statistical optimization and in vivo bioavailability

Abstract

Agomelatine is a new antidepressant having very low oral drug bioavailability less than 5% due to being liable to extensive hepatic 1st pass effect. This study aimed to deliver agomelatine by transdermal route through formulation and optimization of microemulsion gel. Pyramidal screening was performed to select the most suitable ingredients combinations and then, the design expert software was utilized to optimize the microemulsion formulations. The independent variables of the employed mixture design were the percentages of capryol 90 as an oily phase (X 1 ), Cremophor RH40 and Transcutol HP in a ratio of (1:2) as surfactant/cosurfactant mixture 'S mix ' (X 2 ) and water (X 3 ). The dependent variables were globule size, optical clarity, cumulative amount permeated after 1 and 24 h, respectively (Q1 and Q 24 ) and enhancement ratio (ER). The optimized formula was composed of 5% oil, 45% S mix and 50% water. The optimized microemulsion formula was converted into carbopol-based gel to improve its retention on the skin. It enhanced the drug permeation through rat skin with an enhancement ratio of 37.30 when compared to the drug hydrogel. The optimum ME gel formula was found to have significantly higher C max , AUC 0-24 h and AUC 0-1 than that of the reference agomelatine hydrogel and oral solution. This could reveal the prosperity of the optimized microemulsion gel formula to augment the transdermal bioavailability of agomelatine. ARTICLE HISTORY

<p>Low-Frequency versus High-Frequency Ultrasound-Mediated Transdermal Delivery of Agomelatine-Loaded Invasomes: Development, Optimization and in-vivo Pharmacokinetic Assessment</p>

“…Newly born male Wistar rats (weighing 70 ± 20 g) were euthanized and the dorsal hair was shaved. 4,5 The fullthickness skin was carefully removed and inspected for any abnormalities, bites, or scratches. The epidermal layers were separated from the underlying subcutaneous fats and stored at -20 °C until use within 3 days.…”

“…AGM-loaded samples of the optimum invasomes or the aqueous AGM dispersion (containing the equivalent of 5 mg of AMG) were added to the donor compartments while the receptor compartments were loaded with a 50:50 (v/v) mixture of ethanol and phosphate buffer saline (pH 7.4, 10 mL) to maintain sink conditions. 4,5 The stirring rate was set at 100 rpm, and the temperature was adjusted at 32 ± 0.5 °C. [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Aliquots (1 mL) of the receptor compartments were collected and immediately replaced…”

“…This could be attributed to the extensive first pass metabolism, mainly by the hepatic cytochrome P450 1A2 . 4 AGM possesses an intermediate molecular weight (243.3 g/mol) and promising lipophilic properties (log P value, 2.83). In view of the aforementioned, few studies were conducted to enhance the transdermal delivery of AGM via the development of microemulsion gels, 4 liquid nanocrystals 5 and polymeric nanoparticles 6 to bypass the first pass metabolism and enhance drug bioavailability.…”

Enhanced Nematocidal Activity of a Novel Artemisia Extract Formulated as a Microemulsion

“…These results support the validation of the model to be used for point-prediction or optimization. [20][21][22] The model equation was assessed and the coefficients are shown in Table 3. The magnitude of coefficients indicates the positive or negative contribution of the components to the system conductivity.…”

“…These methodologies estimate the effect of the components on the formulation properties, such as droplet size. 19,20 D-optimal mixture designs allow optimization of the composition of an ME formulation in order to enhance the oral bioavailability of the AAE. The main aim of the present study was to design a novel ME formulation of a thujones-free AAE to improve its solubility and subsequently, to enhance its oral bioavailability and nematocidal activity.…”