Novel reverse electrodialysis-driven iontophoretic system for topical and transdermal delivery of poorly permeable therapeutic agents

Figures & data

Figure 1. Schematic diagram of RED system.

Table 1. Mass detector parameters used for the analysis of vitamin C, lopinavir, ketoprofen, and valsartan (IS).

	Analytes
Parameter	Vitamin C	Lopinavir	Ketoprofen	IS
m/z value of precursor ion	175.0	629.7	255.1	436.2
m/z value of product ion	114.9	447.3	209.1	291.2
Fragment voltage (V)	113	126	110	98
Collision energy (eV)	10	12	11	14
Cell accelerator voltage (V)	1	1	1	5
Gas temperature (°C)	300	300	350	–^a
Gas flow (L/min)	9	11	11	–
Nebulizer pressure (psi)	25	30	15	–
Capillary voltage (V)	5000	3000	5000	–

^a Same as lopinavir or ketoprofen.

Figure 3. The amount of vitamin C deposited in the stratum corneum and epidermis/dermis of hairless mouse skin at 6 h after the application of vitamin C-soaked gauze dressing without the RED system (control) and vitamin C-loaded RED system (RED) on the mouse skin fixed in the diffusion cells. The rectangular bars and their error bars represent the means and standard deviations (n = 3–4). The asterisk (*) represents a value significantly different from that of the stratum corneum, and the pound sign (#) represents a value significantly different from that of the control group (p < .05).

Figure 4. In vitro hairless mouse skin permeation profiles of lopinavir after the application of lopinavir-soaked gauze dressing without the RED system (control) and lopinavir-loaded RED system (RED) on the mouse skin fixed in the diffusion cells (A) and the arterial plasma concentration versus time profiles of lopinavir after the transdermal application of lopinavir-soaked gauze dressing without the RED system (control) and lopinavir-loaded RED system (RED) in rats (B). Bullet symbols and their error bars represent the means and standard deviations (n = 3–4). The asterisk (*) represents a value of the RED group significantly different from that of the control group (p < .05).

Table 2. In vitro skin permeation parameters of lopinavir after the application of lopinavir-soaked gauze dressing without the RED system (control) and lopinavir-loaded RED system (RED) on the hairless mouse skin fixed in the diffusion cells (n = 3–4).

Parameter	Control	RED
Flux (μg/h/cm^2)	ND^b	ND
Q10 h^a (μg/cm^2)	280 ± 132	1470 ± 534*
Lag time (h)	ND	ND

^a Cumulative amount permeated over 10 h.

^b Not determined.

* Significantly different from the control group (p < .05).

Table 3. Pharmacokinetic parameters of lopinavir after the transdermal application of lopinavir-soaked gauze dressing without the RED system (control) and lopinavir-loaded RED system (RED) in rats (n = 3–4).

Parameter	Control	RED
Cmax (μg/mL)	20.2 ± 8.7	54.1 ± 8.0*
Tmax (h)	9 (6–12)	4 (4)*
Css (μg/mL)	11.1 ± 5.0	24.5 ± 5.4*
AUClast (μg·h/mL)	267 ± 119	589 ± 129*

* Significantly different from the control group (p < .05).

Figure 5. In vitro hairless mouse skin permeation profiles of ketoprofen after the application of ketoprofen-soaked gauze dressing without the RED system (control), ketoprofen-loaded RED system (RED), and Ketotop^® patch without the RED system (Ketotop^®) on the mouse skin fixed in the diffusion cells (A) and the arterial plasma concentration versus time profiles of ketoprofen after the transdermal application of ketoprofen-soaked gauze dressing without the RED system (control), ketoprofen-loaded RED system (RED), and Ketotop^® patch without the RED system (Ketotop^®) in rats (B). Bullet symbols and their error bars represent the means and standard deviations (n = 3–4). The asterisk (*) represents a value of the RED group significantly different from that of the control group (p < .05), and the pound sign (#) represents a value of the Ketotop^® group significantly different from that of the control group (p < .05).

Table 4. In vitro skin permeation parameters of ketoprofen after the application of ketoprofen-soaked gauze dressing without the RED system (control), ketoprofen-loaded RED system (RED), and Ketotop^® patch without the RED system (Ketotop^®) on the hairless mouse skin fixed in the diffusion cells (n = 3–4).

Parameter	Control	RED	Ketotop^®
Flux (μg/h/cm^2)	4.17 ± 0.62	19.5 ± 4.9*	17.7 ± 1.9*
Q10 h^a (μg/cm^2)	42.4 ± 5.2	183 ± 40*	174 ± 26*
Lag time (h)	0.459 ± 0.371	1.14 ± 0.18	0.375 ± 0.255

^a Cumulative amount permeated over 10 h.

* Significantly different from the control group (p < .05).

Table 5. Pharmacokinetic parameters of ketoprofen after the transdermal application of ketoprofen-soaked gauze dressing without the RED system (control), ketoprofen-loaded RED system (RED), and Ketotop^® patch without the RED system (Ketotop^®) in rats (n = 3–4).

Parameter	Control	RED	Ketotop^®
Cmax (μg/mL)	1.16 ± 0.13	2.55 ± 0.72*	2.32 ± 0.43*
Tmax (h)	9 (9–12)	6 (6–9)	9 (9–12)
Css (μg/mL)	0.748 ± 0.074	1.57 ± 0.36*	1.61 ± 0.24*
AUClast (μg·h/mL)	18.0 ± 1.77	37.8 ± 8.7*	38.8 ± 5.8*

* Significantly different from the control group (p < .05).

Figure 6. Erythema indices of skin at 0, 1, and 24 h (A) and its photographs at 24 h (B) after the transdermal application of saline solution, saline-soaked gauze dressing without the RED system (Saline gauze without RED), ketoprofen-soaked gauze dressing without the RED system (Ketoprofen gauze without RED), ketoprofen-loaded RED system, and Ketotop^® patch without the RED system (Ketotop^®) in rats. The rectangular bars and their error bars represent the means and standard deviations (n = 3–4).