Ionic liquid-iontophoresis mediates transdermal delivery of sparingly soluble drugs

Abstract

Low solubility restricted transdermal penetration of drugs. We aimed to develop a novel ionic liquid-iontophoresis (IL-IS) technology and assess their efficacy and primary factors in facilitating transdermal drug delivery. Five choline-based ILs with different chain length were synthesized and validated, and the impact of IL and/or IS technology on transdermal penetration of model drugs were investigated. The results indicated that five groups of ILs synthesized in this study exhibited minimal level of toxicity, and the longer the chain of acid ligands of ILs, the greater the cytotoxicity. The longer chain of acid ligand was demonstrated superior solubilizing capabilities compared to the shorter chain. Cinnamic acid-choline-based IL ([Cho] [Cin]) significantly improved permeation of all three model drugs, and permeation quantity was linearly positively associated with the concentration of ILs. The 10 h cumulative permeation of aripiprazole applied with ILs alone was enhanced by about 14-fold when paired with IS, and the penetration was linearly positively associated with the concentration and current strength of the ILs. In vivo results indicated that IL and/or IS technology primarily facilitated drug penetration into the skin, with potential involvement of endocytosis in this process. This study demonstrated that [Cho] [Cin] exhibited a significant enhancement in the transdermal delivery of three sparingly soluble drugs. It further enhanced the transdermal permeation of weak base drug following with the combining IL and IS technology. These findings highlighted that the IL-IS technology holded promise for facilitating the transdermal delivery of sparingly soluble and weak base drugs.

Keywords: Ionic liquids; iontophoresis; permeation enhancer; sparingly soluble; transdermal delivery.

Graphical abstract

Figure 1.

(A) Structure of choline cation and organic acid anion; (B) in vitro cytotoxicity of the ILs with regard to HaCaT cells. Data are presented as the mean ± SD (n = 3). Statistically significant differences between IL group and SDS group are shown by the asterisks (***p < 0.001).

Figure 2.

Structure and solubilities of model drug in different concentrations of ILs; (A,B) apremilast; (C,D) aripiprazole; (E,F) indomethacin. Data are presented as the mean ± SD (n = 3).

Figure 3.

Effect of ILs type and concentration on the 24 h permeation/retention of model drugs when using IL alone. Data are presented as the mean ± SD (n = 4–6). Statistically significant differences of permeation/retention between IL group and control group are shown by the asterisks (*p < 0.05; **p < 0.01; ***p < 0.001). (A) Permeation profiles of apremilast under different IL types. (B) Permeation profiles of aripiprazole under different IL types. (C) Permeation profiles of indomethacin under different ILs types. (D) Permeation profiles of apremilast under different ILs concentrations. (E) the permeation/retention amounts of apremilast under different IL types. (F) The permeation/retention amounts of aripiprazole under different IL types. (G) The permeation/retention amounts of indomethacin under different IL types. (H) The permeation/retention amounts of apremilast under IL concentrations.

Figure 4.

Effect of current direction on the 24 h permeation/retention and current intensity on the 10 h permeation/retention of model drugs when using IL-IS. Data are presented as the mean ± SD (n = 4–6). Statistically significant differences of permeation/retention between positive current group and negative current group are shown by the asterisks (*p < 0.05; **p < 0.01). (A) Permeation profiles of apremilast at different current directions. (B) Permeation profiles of aripiprazole at different current directions. (C) Permeation profiles of indomethacin at different current directions. (D) The permeation/retention amounts of apremilast at different current directions. (E) The permeation/retention amounts of aripiprazole at different current directions. (F) The permeation/retention amounts of indomethacin at different current directions. (G) Permeation profiles of apremilast at different current intensities. (H) Permeation profiles of aripiprazole at different current intensities. (I) Permeation profiles of indomethacin at different current intensities. (J) The permeation/retention amounts of apremilast at different current intensities. (K) The permeation/retention amounts of aripiprazole at different current intensities. (L) The permeation/retention amounts of indomethacin at different current intensities.

Figure 5.

Other effects on the 10 h permeation of model drugs when using IL-IS. Data are presented as the mean ± SD (n = 6). (A) Permeation profiles of apremilast at different penetration enhancement strategies. (B) Permeation profiles of aripiprazole at different penetration enhancement strategies. (C) Permeation profiles of indomethacin at different penetration enhancement strategies. (D) Permeation profiles of aripiprazole at different pH values. (E) Permeation profiles of aripiprazole at different IL types. (F) Permeation profiles of aripiprazole at different IL concentrations. (G) Permeation profiles of butenafine at different penetration enhancement strategies. (H) Permeation profiles of terazosin at different penetration enhancement strategies.

Figure 6.

SEM, TEM images, and histopathological evaluation of skin samples for different methods treated. (A) SEM of skin applicated control gel, IL gel, IS and IL-IS for 24 h. (B) TEM of skin applicated control gel, IL gel, IS and IL-IS for 24 h. (C) Histopathological evaluation of skin applicated control gel, IL gel, IS and IL-IS for 7 days.

Figure 7.

CLSM diagrams of the cross section and surface of the skin. (A) CLSM images of rhodamine B transported through skin treated by control gel, IL gel, is, IL-IS, control gel with endocytosis inhibitors, IL gel with endocytosis inhibitors, is with endocytosis inhibitors, and IL-IS with endocytosis inhibitors; (B) CLSM images of rhodamine B transported surface of the skin treated by control gel, IL gel, is, IL-IS, control gel with endocytosis inhibitors, IL gel with endocytosis inhibitors, is with endocytosis inhibitors, and IL-IS with endocytosis inhibitors.