The enantioselective enhancing effect and mechanistic insights of chiral enhancers in transdermal drug delivery

Abstract

Overlook of chiral consideration in transdermal drug delivery increases administrated dose and risk of side effects, decreasing therapeutical effects. To improve the transdermal delivery efficiency of eutomer, this work focused on investigating the law and mechanism of enantioselective enhancing effects of chiral permeation enhancers on drug enantiomers. Chiral nonsteroidal anti-inflammatory drugs and terpene permeation enhancers were selected as model drug and enhancers. The results indicated that the L-isomer of permeation enhancers increased the skin absorption of S-enantiomer of drug and D-isomer improve the permeation of R-enantiomer, in which the enhancement effect (ER) of L-menthol on S-enantiomer (ER = 3.23) was higher than that on R-enantiomer (ER = 1.49). According to the pharmacokinetics results, L-menthol tended to enhance the permeation of S-enantiomer better than R-enantiomer (2.56 fold), and showed excellent in vitro/in vivo correlations. The mechanism study showed that L-isomer of permeation enhancers improved the permeation of S-enantiomer by increasing the retention, but the D-isomer by improving partition for better permeation. Enantioselective mechanism indicated that the weaker chiral H-bond interaction between drug-chiral enhancers was caused by the enantiomeric conformation. Additionally, stronger chiral enhancers-skin interaction between L-isomer and S-conformation of ceramide produced better enhancing effects. In conclusion, enantioselective interaction of chiral drug-chiral enhancers and chiral enhancers-chiral skin played a critical role in transdermal drug delivery, rational utilization of which contributed to improving the uptake of eutomer and inhibiting distomers to decrease a half of dose and side effects, increasing transdermal therapeutical efficiency.

Keywords: Chiral ceramide; Conformation-dependence; Enantiomers; Terpene.

Graphical abstract

Fig. 1

In vitro permeation profiles of drug enantiomers with (A) L-isomer and (B) D-isomer of CCPEs (n = 3), *P < 0.05, **P < 0.01.

Fig. 2

In vitro release profiles of drug enantiomers with (A) L-isomer and (B) D-isomer of CCPEs (n = 3), *P < 0.05, **P < 0.01.

Fig. 3

Retention amount of (A) FP enantiomers and (B) CCPEs in skin (n = 3) *P < 0.05, **P < 0.01.

Fig. 4

(A) The percentage of the FP enantiomers in skin and permeation, (B) The percentage of CCPEs in the unabsorbed, skin retention and skin permeation.

Fig. 5

Transdermal Arrhenius plots of FP enantiomers with or without L- and D-MEN (n = 3).

Fig. 6

The optimized formulation patch of FP enantiomers (A) in vitro release profiles, (B) in vitro skin permeation profiles, and (C) in vivo permeation profiles (n = 6).

Fig. 7

¹³C NMR spectra of FP enantiomers with (A) L-MEN, (B) L-LIM, (C) LIN.

Fig. 8

Minimum energy complexes of FP enantiomers with (A) L-MEN, (B) LIM, and (V) L-LIN.

Fig. 9

CD spectra of chiral MEN with FP enantiomers (A) R-FP (B) S-FP.

Fig. 10

Characterization of skin with chiral drug and CCPEs. (A-B) ATR-FTIR profiles in the SC after treating with FP enantiomers and CCOEs, (B&E) SAXS profiles in the SC treated with FP enantiomers and CCPEs, (C&F) DSC curve of SC following by addition of FP enantiomers and CCPEs.

Fig. 11

(A) AFM of Topography maps of skin samples under the treatment of FP and MEN enantiomers. (B) The snapshots of the simulated systems at the end stage of the MD.

Fig. 12

Schematic illustration of mechanistic insight of enantioselective permeation enhancing effects.