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. 2009;10(3):967-76.
doi: 10.1208/s12249-009-9283-5. Epub 2009 Jul 28.

The enhancing effect of ion-pairing on the skin permeation of glipizide

Zhe Tan  1 , Jingying Zhang, Jian Wu, Liang Fang, Zhonggui He
Affiliations

The enhancing effect of ion-pairing on the skin permeation of glipizide

Zhe Tan et al. AAPS PharmSciTech. 2009.

Abstract

The purpose of the present study was to investigate the permeation of glipizide (GP) and observe the effect of an interaction with amines as counter ions, including diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, N-(2-hydroxylethyl) piperidine. Permeation experiments were performed in vitro, using rat abdominal skin as a barrier. The lipophilic donor system consisting of isopropyl myristate (IPM) and ethanol (EtOH; EI system, 8:2) produced a marked enhancement of GP flux through rat skin. All the amines investigated in this study had performed an enhancing effect on GP flux, and triethylamine had the most potent enhancing effect on GP in the vehicle IPM:EtOH = 8:2(w/w). In the presence of counter ions, the solubility of GP in the donor solution (IPM:EtOH = 8:2) was increased and the log K (o/w) of GP was decreased, which may due to higher solubility of the GP in the IPM:EtOH = 8:2(w/w). (13)C NMR spectroscopy was used to identify the ion-pairing formation between GP and the respective counter ion. It was surprising that all the four enhancers examined, such as isopropyl myristate, propylene glycol, N-methyl-2-pyrrolidone, azone, and oleic acid, had no enhancing effect on the percutaneous permeation of GP. This study showed that the formation of ion-pairs between GP and counter ions is a useful method to promote the skin permeation of GP.

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Figures

Fig. 1
Fig. 1
Chemical structures of GP and amines. a Glipizide, b DA, c TEA, d EA, e DEA, f TEA, g HEPP
Fig. 2
Fig. 2
Effect of IPM and EtOH with different ratios on the permeation of GP through rat abdominal skin
Fig. 3
Fig. 3
Effect of different counter ions on the permeation of GP in IPM:EtOH = 8:2 through rat abdominal skin
Fig. 4
Fig. 4
The relationship between the LogQ 12 and the molecular weight (MV) of the amines
Fig. 5
Fig. 5
The relationship between the cumulative amount (Q 12) and the pK a of the amines
Fig. 6
Fig. 6
The NMR spectra of GP and amines. a GP, b GP-EA, c GP-DEA, d GP-TEA
Fig. 7
Fig. 7
The NMR spectra of GP and amines. e GP-DA, f GP-TA, g GP-HEPP
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