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1Traditional Medicine Research  2019, Vol. 4 Issue (1): 42-53    DOI: 10.12032/TMR201915098
Modernization of Traditional Medicine     
In vitro evaluation of transdermal permeation effects of Fu’s cupping therapy via six diffusion kinetics models
Wei-Jie Xie1,2, Yu-Mei Wu1, Shuai-Shuai Chen1, Jian Xu1, Fang-Fang Yang1, Yong-Ping Zhang1,*(), Xiao-Bo Sun2,*()
1School of Pharmacy, Guiyang University of Chinese Medicine, Guiyang, China.
2Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Highlights

The combination of cupping therapy and transdermal drug delivery can improve the transdermal rate of the drug.

Editor’s Summary

Traditional cuping therapy helps to the skin absorption. As a new physical transdermal drug delivery technology, Fu’s cupping therapy combines traditional cuping therapy and drug therapy, which is worthy of further research.

Abstract

In this study, six kinetics models of indomethacin hydrophilic gel patch transdermal in vitro release was established, including zero-level, first-order, Higuchi-level, Ritger-Peppas, Weibull and Hixcon-Crowell dynamic equations. The chemical permeation enhancers, including 3% and 5% Azone, and iontophoresis were used as the control. Transdermal diffusion tests were performed in vitro and indomethacin was quantified by high performance liquid chromatography system. The transdermal parameter of the Higuchi and Weibull dynamic equations, indicated that Fu’s cupping therapy (FCT) could significantly improve Higuchi and Weibull kinetic parameters in vitro transdermal, increased transdermal rate and permeability coefficient, reduced lagging time. Additionally, statistical analysis speculated the skin barrier function could be restored after 46 h treatment. Hence, as a new physical transdermal drug delivery technology, transdermal permeation effects produced by FCT are obvious, which has the characteristics of traditional Chinese medicine and has important clinical application value.



Key wordsIndomethacin      Diffusion kinetics models      Fu’s cupping therapy;      Transdermal permeation technology      Chemical penetration enhancers      Traditional Chinese medicine     
Published: 04 January 2019
Fund:  This work was supported by the Projects [NO. 20154030 and NO. (2017)5655] from the Science and Technology Department of Guizhou Province and the National Natural Science Foundation of China (No. 81873020). We express our sincere gratitude to the foundation.
Corresponding Authors: Zhang Yong-Ping,Sun Xiao-Bo     E-mail: zgygpg@126.com;sunxiaobo@163.com
Cite this article:

Wei-Jie Xie, Yu-Mei Wu, Shuai-Shuai Chen, Jian Xu, Fang-Fang Yang, Yong-Ping Zhang, Xiao-Bo Sun. In vitro evaluation of transdermal permeation effects of Fu’s cupping therapy via six diffusion kinetics models. 1Traditional Medicine Research, 2019, 4(1): 42-53. doi: 10.12032/TMR201915098

URL:

https://www.tmrjournals.com/tmr/EN/10.12032/TMR201915098     OR     https://www.tmrjournals.com/tmr/EN/Y2019/V4/I1/42

Figure 1 Quantitative HPLC chromatogram specificity investigation
A: Chromatograms of control substances of indomethacin; B: Chromatograms of test samples; C: Chromatograms of the negative samples. HPLC, High Performance Liquid Chromatography.
Number Original content (μg) Amount added
(μg)
Total amount
(μg)
Recovery rate
(%)
Mean
(%)
SD
YP1 28.41 28.42 57.74 103.2 1.56
YP2 28.45 28.42 56.63 99.2
YP3 28.50 28.42 56.75 99.4 101.2%
YP4 28.48 28.42 57.5 102.1
YP5 28.44 28.42 57.31 101.6
YP6 28.41 28.42 57.22 101.4
Table 1 Sample recovery test
Figure 2 Treatment of percutaneous permeation by cups
A. Cups with different sizes; B. Negative pressure generated by emptying of cup; C. Rat skin treated by cupping; D. Franz transdermal diffusion device. This images (A, B, C, D) were obtained from [9].
Group Zero-order First-order Higuchi Ritger-Peppas Hixcon-Crowell Weibull
3% Azone Y = 0.0106x + 0.0373, R2= 0.9574 Y = -0.0138x - 0.0221,
R2= 0.979
Y = 0.0432x - 0.0135, R2= 0.9945 Y = -0.1917x + 0.2339, R2 = 0.9606 Y = -0.0035x + 0.3209, R2= 0.9574 Y = 0.6648x - 7.8272, R2= 0.9973
5% Azone Y = 0.0134x + 0.0322, R2= 0.9751 Y = -0.0189x - 0.0016,
R2= 0.994
Y = 0.1075x - 0.1568, R2= 0.9985 Y = -0.2558x + 0.3327,R2= 0.9307 Y = -0.0045x + 0.3226, R2= 0.9751 Y = 0.726x - 7.8423,
R2= 0.9983
3% Azone and 5% mint oil Y = 0.002x - 0.0008,
R2= 0.9944
Y = -0.0021x + 0.0013, R2= 0.9956 Y = 0.0161x - 0.0285, R2= 0.9905 Y = -0.0284x + 0.0381,R2= 0.9212 Y = -0.0007x + 0.3336, R2= 0.9944 Y = 0.9291x - 10.51,
R2= 0.9988
Iontophoresis Y = 0.0108x - 0.0271,
R2= 0.9945
Y = -0.0133x + 0.0464, R2= 0.9912 Y = 0.0839x - 0.1694, R2= 0.9614 Y = -0.1714x + 0.259,
R2= 0.838
Y = -0.0036x + 0.3424, R2= 0.9945 Y = 1.2193x - 9.951,
R2= 0.9987
Blank Y = 0.0079x - 0.0315,
R2= 0.9919
Y = -0.009x + 0.0412,
R2= 0.9844
Y = 0.0606x - 0.1332, R2= 0.9422 Y = -0.1146x + 0.1813, R2= 0.8099 Y = -0.0026x + 0.3438, R2= 0.9919 Y = 1.3752x - 10.831, R2= 0.9995
FCTL Y = 0.0108x - 0.0285,
R2= 0.9978
Y = -0.0133x + 0.0476, R2= 0.9943 Y = 0.0839x - 0.171,
R2= 0.967
Y = -0.1712x + 0.2606, R2= 0.8443 Y = -0.0036x + 0.3428, R2= 0.9978 Y = 1.4174x - 10.975, R2= 0.9996
FCTM Y = 0.0136x + 0.0093, R2= 0.987 Y = -0.0188x + 0.0235, R2= 0.9977 Y = 0.1082x - 0.179,
R2= 0.9936
Y = -0.2505x + 0.3454, R2= 0.9033 Y = -0.0045x + 0.3302, R2= 0.987 Y = 0.891x - 8.4435,
R2= 0.9973
FCTH Y = 0.0207x + 0.088,
R2= 0.9503
Y = -0.0322x - 0.0476,
R2= 0.9831
Y = 0.1415x - 0.1321, R2= 0.9908 Y = -0.324x + 0.3067,
R2= 0.9506
Y = -0.0069x + 0.304,
R2= 0.9503
Y = 0.6344x - 7.1397, R2= 0.9924
Table 2 Equations of diffusion kinetics of each group
Group Tlag/h Js (μg·cm-2/h) P (cm/h)
Blank 4.831 0.061 8.22E-05
3%Azone 0.175 0.043 5.04E-04
5%Azone 2.128 0.108 1.95E-03
3% Azone and 5% mint oil 3.134 0.016 4.15E-04
Iontophoresis 4.077 0.084 8.78E-04
FCTL 4.154 0.084 1.18E-04
FCTM 2.737 0.108 1.16E-03
FCTH 0.872 0.142 1.50E-03
Table 3 Transdermal kinetic parameters of Higuchi equation analysis (n = 6)
Group τ m Lnt β β 1/m Td
Blank 0.820 1.375 -10.831 50576.824 0.727 2622.917
3%Azone 2.389 0.665 -7.827 2508.003 1.504 129846.797
5%Azone 2.107 0.726 -7.842 2546.028 1.377 49119.454
3% Azone and 5% mint oil 1.644 0.929 -10.510 36679.736 1.076 81757.950
Iontophoresis 0.354 1.219 -9.951 20973.920 0.820 3492.855
FCTL 0.598 1.248 -10.027 22625.420 0.801 3071.968
FCTM 1.418 0.891 -8.444 4644.995 1.122 13034.534
Table 4 Transdermal kinetic parameters of Weibull equation analysis (n = 6)
Groups
I J
Mean difference (I-J) Standard error P 95% Confidence interval
Lower limit Upper limit
5% Azone VS Blank 1.2537 0.362 0.002 0.515 1.993
Iontophoresis 0.6680 0.362 0.075 -0.071 1.407
FCTL 0.7640 0.362 0.0450 -0.175 1.302
FCTM -0.9285 0.362 0.016 -1.667 -0.190
FCTH -4.4213 0.362 < 0.001 -5.160 -3.682
Iontophoresis VS Blank 0.6900 0.362 0.066 -0.049 1.429
5% Azone -0.5640 0.362 0.130 -1.302 0.175
FCTL -0.1040 0.362 0.775 -0.843 0.635
FCTM -1.5963 0.362 < 0.001 -2.335 -0.857
FCTH -5.0892 0.362 < 0.001 -5.828 -4.350
Table 5 Multiple comparison of enhancing rate between groups at 12 h
Groups
I J
Mean difference (I-J) Standard error Significant 95% Confidence interval
Lower limit Upper limit
5% Azone VS Blank 0.9013* 0.266 0.002 0.359 1.444
Iontophoresis 0.4070 0.266 0.136 -0.135 0.949
FCTL 0.2800 0.266 0.300 -0.262 0.822
FCTM -0.9360* 0.266 0.001 -1.478 -0.394
FCTH -3.3185* 0.266 < 0.001 -3.861 -2.776
Iontophoresis VS Iontophoresis 0.4940 0.266 0.072 -0.048 1.037
5% Azone -0.4070 0.266 0.136 -0.949 0.135
FCTL -0.1270 0.266 0.636 -0.669 0.415
FCTM -1.3430* 0.266 < 0.001 -1.885 -0.801
FCTH -3.7255* 0.266 < 0.001 -4.268 -3.183
Table 6 Multiple comparisons of enhancing rate between groups at 16 h
Groups
I J
Mean difference (I-J) Standard error Significant 95% Confidence interval
Lower limit Upper limit
5% Azone VS Blank 0.4755 0.174 0.010 0.121 0.831
Iontophoresis -0.0800 0.174 0.651 -0.435 0.276
FCTL -0.0980 0.174 0.577 -0.453 0.257
FCTM -0.8697 0.174 < 0.001 -1.225 -0.515
FCTH -2.1773 0.174 < 0.001 -2.532 -1.822
Iontophoresis VS Blank 0.5550 0.174 0.003 0.200 0.910
5%Azone 0.0800 0.174 0.651 -0.276 0.435
FCTL -0.0190 0.174 0.916 -0.374 0.337
FCTM -0.7902 0.174 < 0.001 -1.145 -0.435
FCTH -2.0978 0.174 < 0.001 -2.453 -1.743
Table 7 Multiple comparisons of enhancing rate between groups of at 24 h
Groups
I J
Mean difference (I-J) Standard error Significant 95% Confidence interval
Lower limit Upper limit
5% Azone VS Blank 0.2370 0.140 0.103 -0.051 0.525
Iontophoresis -0.1970 0.140 0.173 -0.485 0.092
FCTL -0.2090 0.140 0.149 -0.497 0.080
FCTM -0.76967 0.140 < 0.001 -1.058 -0.481
Iontophoresis VS Blank 0.43350 0.140 0.005 0.145 0.722
5%Azone 0.1970 0.140 0.173 -0.092 0.485
FCTL -0.0120 0.140 0.932 -0.300 0.276
FCTM -0.5732 0.140 < 0.001 -0.861 -0.285
Table 8 Multiple comparisons of enhancing rate between groups at 30 h
Figure 3 ER-t curve and time of critical point (TCP) of each groups
Figure 4 SEM image of the effect of FCT treatment on animal skin microstructure
A, Blank group; B, FCT low-intensity group; C, FCT middle-intensity group; D, FCT high-intensity group; FCT, Fu’s cupping therapy.
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