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

Figures & data

Table 1. The composition of ME formulations based on the D-optimal mixture design and the measured characteristics.

F	X1: oil	X2: Smix	X3: Water	Y1: GS (nm)	PDI	ZP (mV)	Y2: Optical clarity	Y3: Q1 (mg/cm^2)	Y4: Q24 (mg/cm^2)	Y5: ER
F1	5	35	60	34.0	0.38	−20.1	0.039	0.255	4.9	15.17
	5	35	60	33.6	0.32	−24.4	0.025	0.260	5.0	30.82
F2	5	45	50	46.8	0.26	−19.7	0.012	0.580	5.0	57.78
F3	5	55	40	42.8	0.33	−16.4	0.015	0.009	1.2	3.26
	5	55	40	28.9	0.33	−22.1	0.010	0.001	1.0	3.21
F4	6.25	38.75	55	36.4	0.23	−20.0	0.006	0.031	4.7	2.34
F5	6.25	48.75	45	26.3	0.29	−16.2	0.005	0.015	1.0	0.78
F6	7.5	32.5	60	19.1	0.32	−12.8	0.007	0.000	1.2	0.69
	7.5	32.5	60	32.3	0.20	−21.7	0.009	0.000	0.9	0.30
F7	7.5	42.5	50	42.6	0.20	−20.0	0.005	0.012	3.4	14.80
F8	8.75	36.25	55	25.1	0.26	−25.7	0.006	0.005	4.4	14.70
F9	10	30	60	37.1	0.25	−25.5	0.008	0.008	3.3	2.04
	10	30	60	25.0	0.32	−14.9	0.008	0.008	3.0	15.21
F10	10	40	50	21.3	0.22	−14.2	0.008	0.005	2.8	0.26
F11	10	50	40	16.0	0.13	−14.7	0.007	0.036	0.6	0.65
	10	50	40	15.8	0.19	−13.8	0.007	0.032	0.6	0.56

Figure 1. Screening of oils (A), surfactants (B) and cosurfactants (C), in addition to selection of the optimum Smix ratio (D).

Figure 2. Contour diagrams for the effect of formulation variables on the globule size (A), optical clarity (B), Q1 (C), Q24 (D), ER (E) and desirability (F).

Figure 3. Rheological (A) and morphological (B) characteristics of the optimized ME gel formula.

Figure 4. Ex vivo (A) and in vivo (B) permeation profiles of optimized ME gel in comparison with the drug hydrogel and the oral drug solution.

Table 2. Pharmacokinetic parameters of the optimized ME gel formula in comparison with the drug hydrogel and oral solution (A) and SAS analysis of C_max, AUC_0–24 h and AUC_0–∞ (B).

(A)
	Treatment (mean ± SD)
Pharmacokinetics parameters	Optimized ME gel	Drug hydrogel	Oral drug solution
Cmax (ng/mL)	122.00 ± 99.32	43.85 ± 20.61	24.68 ± 8.56
Tmax (h)	1.13 ± 0.80	1.50 ± 2.04	0.5 ± 0.00
AUC0–24 h (ng.h/mL)	270.02 ± 104.56	135.33 ± 71.77	59.67 ± 12.57
AUC0–∞ (ng.h/mL)	332.91 ± 139.92	145.28 ± 74.08	92.99 ± 21.05
Ke (l/h)	0.11 ± 0.04	0.22 ± 0.06	0.04 ± 0.00
t½ (h)	7.24 ± 2.34	3.37 ± 0.87	17.88 ± 1.48
MRT (h)	12.62 ± 5.15	8.61 ± 3.11	22.49 ± 4.20
(B)
Cmax
DF	1	4	1	1
Type III SS	0.31647282	0.27094836	2.76440032	2.22093451
Mean square	0.31647282	0.06773709	2.76440032	2.22093451
F value	0.75	0.16	6.53	5.24
Pr > F	0.4361	0.9482	0.063	0.0839
AUC0–24 h
DF	1	4	1	1
Type III SS	0.09975565	1.19820373	0.23013033	1.73642523
Mean square	0.09975565	0.29955093	0.23013033	1.73642523
F value	0.45	1.34	1.03	7.78
Pr > F	0.5403	0.3911	0.3673	0.0493
AUC0–∞
DF	1	4	1	1
Type III SS	0.08532882	1.35585856	0.42233766	2.41223985
Mean square	0.08532882	0.33896464	0.42233766	2.41223985
F value	0.6	2.38	2.97	16.97
Pr > F	0.4817	0.2103	0.1599	0.0146