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In vitro skin retention and drug permeation study of Tongluo-Qutong rubber plaster by UPLC/UV/MS/MS

Abstract

Tongluo-Qutong rubber plaster (TQRP), a typical Chinese patent medicine that contains 13 different herbal remedies, is widely used in clinical practice for the treatment of cervical spondylosis and osteoarthritis. However, due to a lack of in vitro transdermal studies, the active ingredients of TQRP have not been fully elucidated. This presents a huge obstacle for quality evaluation, pharmacokinetic studies and clinical safety assessment of TQRP. In this work, a UPLC/UV/MS/MS method was established and validated to evaluate five analytes in TQRP. The validation demonstrated linearity (r > 0.99), specificity (no co-eluting peaks at the retention times of the analytes), and precision (RSD < 15%) within acceptable parameters. A skin permeation study was performed to determine the concentrations of drugs delivered to the dermis. The 24-hour cumulative permeation of ferulic acid, aleo-emodin, emodin and piperine were 303.68, 709.31, 671.06 and 25561.01 ng/cm2, respectively. According to the fitting data of the TQRP active components, skin permeation was mainly due to a combination of passive diffusion and drug release after matrix erosion.

Keywords:
Tongluo-Qutong rubber plaster; Skin permeation; UPLC/UV/MS/MS; Piperine

INTRODUCTION

In recent years, traditional Chinese medicine (TCM) has played an important role in the treatment of joint pain (Lao et al., 2015Lao L, Hochberg M, Lee DY, Gilpin AM, Fong HH, Langenberg P, et al. Huo-Luo-Xiao-Ling (HLXL)-Dan, a traditional Chinese medicine, for patients with osteoarthritis of the knee: A multi-site, randomized, double-blind, placebo-controlled phase II clinical trial. Osteoarthritis Cartilage. 2015;23(12):2102-8.). It has been reported that TCM showed clear effects in acute gouty arthritis and protection of cartilage matrix (Shi et al., 2016Shi L, Zhao F, Zhu F, Liang Y, Yang F, Zhang G, et al. Traditional Chinese Medicine Formula “Xiaofeng granules” suppressed gouty arthritis animal models and inhibited the proteoglycan degradation on chondrocytes induced by monosodium urate. J Ethnopharmacol . 2016;191: 254-63.). In the treatment of rheumatoid arthritis, unlike western medicines that contain non-steroidal anti-inflammatory drugs (NSAIDS) and biological agents (such as anti- tumor necrosis factor-a) (Hennekens et al., 2014Hennekens CH, Borzak S, Bjorkman DJ. Cardiovascular risks of cyclooxygenase-2 inhibitors and traditional anti- inflammatory drugs: necessary but not sufficient for clinical decision making. Expert Rev Cardiovasc Ther. 2014;12(3):291-3.), the widely used natural plant products in TCM can exert synergistic therapeutic effects through multiple components, targets and actions, thus reducing the incidence of serious adverse side effects and toxicity (Wu et al., 2015Wu Y, Wang F, Ai Y, Ma W, Bian Q, Lee DY, et al. Simultaneous determination of seven coumarins by UPLC- MS/MS: Application to a comparative pharmacokinetic study in normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan or single-herb extract. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;991:108-17.).

Tongluo-Qutong rubber plaster (TQRP), a typical Chinese patent medicine, is recorded in the Pharmacopoeia of The People’s Republic of China 2015 edition (Committee, 2015Committee, N. P. Pharmacopoeia of The People’s Republic of China. Beijing: Chemical Industry Press; 2015.) and was authorized for clinical use in China in 2000 (National Drug Approval No. Z20000065). In the theory of traditional Chinese medicine, it has the functions of promoting blood circulation, clearing cold and dehumidifying, reducing swelling and relieving pain. TQRP contains 13 different TCM (Angelicae Sinensis Radix, Chuanxiong Rhizoma, Carthami Flos, Kaempferiae Rhizoma, Zanthoxyli Pericarpium, Piperis Fructus, Caryophylli Flos, Cinnamomi Cortex, Piperis Longi Fructus, Zingiberis Rhizoma, Rhei Radix et Rhizoma, Borneolum Syntheticum and Camphor) that have been widely used in clinical practice for the treatment of cervical spondylosis and osteoarthritis. Until now, studies on the finished TQRP preparation have been limited to determination of the content of a single indicator component, and simple pharmacodynamic evaluation. In the Chinese Pharmacopoeia, only the lowest levels of borneol and camphor detected by gas chromatography are specified, which is insufficient as a quality control standard. Active TQRP components with anti-inflammatory and analgesic effects have previously been studied, such as ferulic acid from Angelicae Sinensis Radix, aleo-emodin and emodin from Rhei Radix et Rhizoma, piperine from Piperis Fructus and cinnamic acid from Cinnamomi Cortex (Bae et al., 2010Bae GS, Kim MS, Jung WS, Seo SW, Yun SW, Kim SG, et al. Inhibition of lipopolysaccharide-induced inflammatory responses by piperine. Eur J Pharmacol. 2010;642(1-3):154-62.; Kong et al., 2014Kong X, Wan H, Su X, Zhang C, Yang Y, Li X, et al. Rheum palmatum L. and Coptis chinensis Franch., exert antipyretic effect on yeast-induced pyrexia rats involving regulation of TRPV1 and TRPM8 expression. J Ethnopharmacol. 2014;153(1):160-8.; McCarty, Assanga, 2018McCarty MF, Assanga SBI. Ferulic acid may target MyD88- mediated pro-inflammatory signaling - Implications for the health protection afforded by whole grains, anthocyanins, and coffee. Med Hypotheses. 2018;118:114-20.; Silveira et al., 2018Silveira GR, Campelo KA, Lima GRS, Carvalho LP, Samarao SS, Vieira-da-Motta O, et al. In vitro anti-toxoplasma gondii and antimicrobial of amides derived from cinnamic acid. Molecules. 2018;23(4):774.; Vazquez et al., 1996Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol . 1996;55(1):69-75.). Although these components are believed to be pharmacologically active agents in TQRP, their skin permeation or transdermal absorption have not been determined. Furthermore, because of the lack of in vitro or in vivo permeation data, the active ingredients of TQRP have not been fully elucidated, which presents a huge obstacle for quality evaluation, pharmacokinetic studies and clinical safety assessment of TQRP.

Therefore, based on these considerations, the present work established a UPLC/UV/MS/MS method to investigate and quantify the in vitro transdermal permeation of TQRP components. Skin retention of materials in the plaster was also examined. To the best of our knowledge, this is the first time that the transdermal activity of TQRP active ingredients has been studied.

MATERIAL AND METHODS

Material

Tongluo-Qutong rubber plaster (TQRP, batch number:161206) was provided by Henan Lingrui Pharmaceutical Co., Ltd (Henan, China). Ferulic acid (99.0% purity, batch No. 110773-201614), aleo-emodin (98.5% purity, batch No. 111595-201306), emodin (98.7% purity, batch No. 110756-201512), cinnamic acid (98.8% purity, batch No. 110786-201604) and piperine (98.9% purity, batch No. 110775-201706) were all purchased from the National Institute for the Control of Pharmaceutical and Biological Products (Beijing, China). Acetonitrile and methanol of HPLC grade were obtained from Fisher Scientific Co. (Fair Lawn, NJ, USA). Formic acid was supplied by Tokyo Chemical Industry Co., Ltd. (Shanghai, China). All reagents were of analytical grade. Purified Milli-Q water (Millipore, Billerica, MA, USA) was used for all experiments.

Balb/c nude mice (weighing 25 ± 5 g; Vital River Experimental Animal Tech. Co. Ltd; Tianjin, China; License: SCXK 2016-0006) were housed at room temperature with free access to drinking water. The protocol and any amendments or procedures involving the care or use of animals in this study were in accordance with the regulations for animal experimentation issued by the State Committee of Science and Technology of China and approved by the Tianjin University of Traditional Chinese Medicine Institutional Animal Care and Use Committee (Document number TCM-LAEC 2018020).

UPLC/UV/MS/MS instrumentation

All samples were analyzed using a UPLC/UV/MS/ MS system consisting of an Agilent series 1290 UPLC system and an Agilent 6460 triple quadrupole mass spectrometer (Agilent Technologies, Santa Clara, CA, USA). The chromatographic separation of analytes was performed on an Acquity UPLC®HSS T3 C18 column (100 × 2.1 mm, 1.8 μm, Waters, CA, USA) at a column temperature of 40°C. Chromatographic separation was achieved by gradient elution using a mobile phase comprised of 0.1% formic acid in water (A) and acetonitrile (B). The UPLC gradient schedule was set as follows: 20%→70% B at 0.0-15.0 min; 70%→90% B at 15.0-16.0 min; 90%→90% B at 16.0-19.0 min; 90%→20% B at 19.0-20.0 min; 20%→20% B at 20.0-23.0 min. Efficient separation and symmetrical peaks were obtained at a flow rate of 0.3 mL/min. The sample injection volume was set at 5 μL. The concentration of piperine exceeded the upper limit of the linear range by mass spectrometry in a preliminary experiment, so UV detection at 265 nM was employed to determine this analyte. The detection of other analytes was in multiple reaction monitoring mode (MRM) using electrospray negative ionization (ESI). The ESI configuration was set as follows: gas temperature 350°C; gas flow rate 11 L/min; nebulizer 20 psi; capillary 4000 V (Agilent Technologies). Data acquisition and processing were performed using the Agilent Mass Hunter Workstation.

Preparation of standard solutions

The stock solutions of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine were prepared in methanol and diluted with saline/ethanol (70:30, v/v). All solutions were kept at 4°C and brought to room temperature before use.

Method validation

Validation of the method was conducted according to the China Food and Drug Administration (CFDA) guidelines, including specificity, linearity, accuracy, precision, and stability during sample storage and processing.

Interfering peaks at the elution times of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine were evaluated for specificity. To evaluate linearity, calibration curves were constructed using standard solutions of 15- 3000 ng/mL for ferulic acid, 40-8000 ng/mL for aleo- emodin, 5-1000 ng/mL for emodin, 250-50000 ng/mL for cinnamic acid and 2500-500000 ng/mL for piperine. Linear regression was subsequently carried out using 1/x as a weighting factor (except for piperine). The lower limit of quantification (LLOQ) was used to determine the sensitivity of the method with a signal-to-noise ratio of 10:1. Relative error (RE) and relative standard deviation (RSD) on the same day and on three consecutive days were analyzed to assess intra- and inter-day accuracy and precision, respectively.

Reflux sample extraction

Three different solvents (50%, 70%, and 90% ethanol) were evaluated for extraction of TQRP index components using the reflux heating method. Two pieces of TQRP (70 cm2 for each plaster) were cut into small pieces and placed in a 250 mL round-bottomed flask and extracted with solvent under a reflux condenser for 2 h. After cooling and filtration, the solution was passed through a 0.45 μm filter. The TQRP extracts were analyzed and quantified using the validated UPLC/UV/MS/MS method. The extracts were stored at 4°C until analysis.

Preparation of skin samples

The nude mice were sacrificed by cervical dislocation, and non-injured skin was peeled off. Subcutaneous fat and blood vessels were carefully removed with a blade, and the skin washed repeatedly with normal saline. The clean skin was wrapped in aluminum foil and stored at -20°C. Samples were defrosted before conducting experiments at room temperature (used within 3 days).

Skin permeation study

The skin permeation study was performed in Franz diffusion cells with a diffusion area of 3.14 cm2 and a receptor compartment of 7 mL. Skin samples were thawed at room temperature prior to mounting in the diffusion cells with the dermal side facing the receptor chamber. TQRP was placed directly on the mouse skin in the donor compartment. The concentrations of ferulic acid, aleo- emodin, emodin, cinnamic acid and piperine in TQRP were obtained from reflux samples in our preliminary study. The receptor solution was physiological saline containing 30% (v/v) ethanol and kept at 37 ± 1 °C under magnetic stirring during the entire experiment. An aliquot (2 mL) of receptor solution was collected at different time points (1, 2, 3, 4, 6, 8, 10, 12, and 24 h) and replaced with an equal volume of fresh receptor solution. After centrifugation (12,000 rpm for 10 min), the receptor samples were assayed by UPLC/ UV/MS/MS to determine the cumulative amounts of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine that had permeated through the skin.

Skin retention study

At the end of the permeation experiment (24 h), the skin was removed from the equipment. The formulation was removed from the surface of the skin, which was then washed repeatedly with pure water. Cleaned epidermis membrane was cut into small pieces and added to normal saline containing 30% (v/v) ethanol. The suspension was sonicated for 30 min, cooled, and then filtered. The skin sample extracts were assayed by UPLC/UV/MS/MS to determine the concentrations of ferulic acid, aleo- emodin, emodin, cinnamic acid and piperine retained in the skin. All values were the average of five parallel experiments.

Data calculation

Individual permeation profiles were obtained for all the conditions under study by fitting the empirical diffusion equation derived from Fick’s Second Law of Diffusion (see Equation 1) to the accumulated amounts of ferulic acid, aleo-emodin, emodin and piperine (ng/ cm2) against time (hours).

Q n = C n V + i = 1 n - 1 C i V i A

Where Q n is the cumulative amount of drug permeated per area unit, C n is the concentration of drug in the donor vehicle at the nth sampling, C i is the concentration of drug in the donor vehicle at the ith sampling, V is the volume of receptor cell, V i is the replaced volume and A is the area of drug permeation.

In order to study the four analytes transdermal kinetic from the TQRP, four mathematical models were used to analyze the experimental data. The applied mathematical models based on each diffusion, erosion and degradation mechanism are summarized below. Zero- order kinetic model for drug delivery is represented by the following equation

Q = k 0 t

Where, Q is the cumulative amount of drug permeated per area unit at time t, k 0 is the zero-order kinetic dissolution constant and t is the release time.

First-order kinetic model, presented as follows, can also be used to describe the drug release

l n Q = - k 1 t

Where, Q is the cumulative amount of drug permeated per area unit at time t, k 1 is the first-order kinetic constant and t is the release time.

Higuchi kinetic model is based on the Higuchi equation and describes the Fickian diffusion of the drug (Higuchi, 1963Higuchi T. Mechanism of sustained-action. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52:1145-9.).

Q = k h t 1 / 2

Where, Q is the cumulative amount of drug permeated per area unit at time t, k h is a Higuchi kinetic constant and t is the release time.

Ritger-Peppas kinetic model is represented by the following equation

Q = k p t n

Where, Q is the cumulative amount of drug permeated per area unit at time t, k p is a Ritger-Peppas kinetic constant, t is the release time and n is the diffusion exponent related to the drug release mechanism.

RESULTS AND DISCUSSION

LC-MS/MS instrumentation and chromatographic conditions

In this study, a UPLC/UV/MS/MS method was developed and validated for the determination of five major active ingredients (shown in Figure 1) of TQRP, using UV to determine the concentration of piperine and tandem mass spectrometry to analyze the other four components. UV detection was used to determine piperine rather than tandem mass spectrometry because the concentration of piperine was significantly higher than other analytes. In addition, the MRM positive ion mode for piperine ionization severely affected the response of the other analytes in negative ion mode detection. Therefore, high-performance liquid chromatography with UV detection was appropriately applied to analyze piperine in TQRP, and the analytical conditions were set as previously reported (Alomrani et al., 2018Alomrani AH, Alhazza FI, AlGhamdi KM, El Maghraby GM. Effect of neat and binary vehicle systems on the solubility and cutaneous delivery of piperine. Saudi Pharm J. 2018;26(2):162-8.).

FIGURE 1
Chemical structures of five analytes (A) FA, (B) AE, (C) EMO, (D) CA, and (E)PIP

The selection of mobile phase was based on chromatographic peak shape and retention time.

Accordingly, acetonitrile was found to be superior to methanol with lower column pressure and lower background noise. The addition of 0.1% formic acid was used to obtain a higher response (Wang et al., 2017Wang S, Li D, Pi J, Li W, Zhang B, Qi D, et al. Pharmacokinetic and ocular microdialysis study of oral ginkgo biloba extract in rabbits by UPLC-MS/MS determination. J Pharm Pharmacol. 2017;69(11):1540-51.). The wavelength was set at 265 nm for piperine determination. Precursor-to-product ion transitions at m/z 193.1→114.1, 268.8→239.1, 269.04→224.9 and 147.04→102.9 were used for quantification of ferulic acid, aleo-emodin, emodin and cinnamic acid, respectively, in MRM mode.

Method validation

The typical chromatograms of blank receptor solution, standard solution and receptor solution from the tested skin are shown in Figures 2 and 3. No endogenous interference was observed at the retention time of the analytes in the blank receptor solution, which proved the specificity of the method. Regression equations, linear ranges and correlation coefficients are listed in Table I. All calibration curves showed good linearity, with correlation coefficients > 0.99. The LLOQ values of ferulic acid, aleo-emodin, emodin, cinnamic acid, and piperine were 15, 40, 5, 250, and 2,500 ng/mL, respectively. Precision and accuracy data for the five analytes are summarized in Table II. Intra- and inter-day precision were < 5%, and accuracy was within 8.24%. The results indicated that the UPLC/UV/MS/MS method was accurate, sensitive and reproducible.

FIGURE 2
Chromatograms of skin permeation samples by MS/MS detector (a-blank receptor solution; bstandard solution; c-receptor sample; d-skin sample; 1-FA; 2-AE; 3-EMO; 4-CA)

FIGURE 3
Chromatograms of PIP skin permeation samples by UV detector (1-blank receptor solution; 2-standard solution; 3-receptor sample; 4-skin sample; Peak A-PIP)

TABLE I
Linearity for assay of FA, AE, EMO, CA and PIP in standard solution

TABLE II
Precision and accuracy (Mean±SD, n=6)

The stabilities of ferulic acid, aleo-emodin, emodin, cinnamic acid, and piperine in the standard solution under the described conditions are listed in Table III. The results demonstrated that all analytes were stable in stock solution during storage at room temperature for 4 h and at 4°C for 30 days. The stability data satisfy the requirements for a routine skin permeation/retention study.

TABLE III
Stability of five analytes in stock solution (Mean±SD, n=6)

Skin permeation study

As shown in Table IV, the five active ingredients of TQRP were effectively extracted by all three solvents. The concentrations of ferulic acid and piperine were highest in 50% ethanol, the concentration of cinnamic acid was highest in 70% ethanol and the concentrations of aleo-emodin and emodin were highest in 90% ethanol, due to the different hydrophilicities of each index component. The total concentrations of the five analytes in the three extraction solvents (50%, 70%, and 90% ethanol) were 48888.46, 49143.40, and 47382.30 ng/ cm2, respectively. Since 70% ethanol is the recommended solvent for extraction of TQRP in the Pharmacopoeia (Committee, 2015Committee, N. P. Pharmacopoeia of The People’s Republic of China. Beijing: Chemical Industry Press; 2015.), this solvent was chosen as the extraction solvent to measure the drug content of TQRP and calculate cumulative penetration in the subsequent skin permeation test.

TABLE IV
The contents of five analytes in the sample solution of a different concentration of the solvent (ng/cm², Mean±SD, n=3)

The in vitro drug permeation test was conducted using the analytical method to determine whether all five components could permeate skin. The hairless mouse species was used because of similarities to human skin in the absence of hair (Nam et al., 2011Nam SH, Xu YJ, Nam H, Jin GW, Jeong Y, An S, et al. Ion pairs of risedronate for transdermal delivery and enhanced permeation rate on hairless mouse skin. Int J Pharm. 2011;419(1-2):114-20.). A preliminary experiment was conducted before the main experiment to optimize the receptor solution. Saline/ ethanol (70:30, v/v) was used as the receptor solution. The cumulative permeation of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine through the skin over time was profiled. It can be seen from Figure 4 that the amounts of the permeated agents increased over time during the 24-hour experiment. In the nude mouse skin permeation study, the 24-hour cumulative permeation amounts of ferulic acid, aleo-emodin, emodin and piperine per unit area were 303.68, 709.31, 671.06, and 25561.01 ng/cm2, respectively. The concentration of cinnamic acid in the samples was below the limit of quantitation, so the cumulative permeation of cinnamic acid could not be accurately measured.

FIGURE 4
Amounts of four analytes accumulated in the receptor compartment at different time points (mean ± SD, n=5).

Additionally, the mechanisms for transdermal permeation of the four analytes from TQRP were studied by fitting the experimental data to zero-order, first-order, Ritger-Peppas and Higuchi mathematical models. The results are presented in Table V. The correlation coefficients in the Ritger-Peppas equation for ferulic acid, aleo-emodin, emodin and piperine were all greater than 0.98, indicating a good linear relationship. This suggested that the drugs were mainly released by matrix erosion, since the permeability coefficient in the Ritger-Peppas equation was greater than 0.89 (Peppas, 2014Peppas NA. Commentary on an exponential model for the analysis of drug deliv ery: Original research article: a simple equation for description of solute release: I II. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs, 1987. J Control Release 2014;190:31-2.; Siepmann, Peppas, 2001Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48(2-3):139-57.). On other hand, the correlation coefficients of the zero-order kinetic fitting equation for emodin and piperine were better than those of the Ritger-Peppas equation, indicating a passive diffusion mechanism for skin permeation of emodin and piperine. According to the fitting data, skin permeation of active components from TQRP was a combination of passive diffusion and drug release after matrix erosion.

TABLE V
Fitting results of drug release model of four analytes

Skin retention study

The concentrations of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine from TQRP retained in the skin were also determined. The ratios of total released drug retained and passing through the skin are presented in Table VI. The release ratios of ferulic acid, aleo-emodin, emodin, cinnamic acid and piperine were 41.22%, 38.66%, 41.68%, 8.34%, and 70.10%, respectively. The release ratio of cinnamic acid was lower than those of the other analytes, indicating lower permeation (not detected in our experiments) and higher retention on the skin (Spagnol et al., 2017Spagnol CM, Di Filippo LD, Isaac VLB, Correa MA, Salgado HRN. Caffeic acid in dermatological formulations: In vitro release profile and skin absorption. Comb Chem High Throughput Screen. 2017;20(8):675-81.). This result suggests that cinnamic acid may be a promising topical agent to provide a local effect due to its antioxidant and anti-inflammatory activity. Ferulic acid, aleo-emodin, emodin and piperine, the release ratios of which were 38.66%-70.10%, were revealed as the most effective components of TQRP, providing a foundation for future in vivo studies.

TABLE 6
Skin concentrations per unit area and release ratio of five analytes

The natural volatile oil components contained in the plaster, such as eugenol and cinnamaldehyde, may act as transdermal enhancers. Chen suggested that the volatile oil component of the plaster promotes transdermal absorption of the indicator component (Chen et al., 2014Chen Y, Quan P, Liu X, Wang M, Fang L. Novel chemical permeation enhancers for transdermal drug delivery. Asian J Pharm Sci. 2014;9:51-64.). Moreover, piperine has been explored as a bioenhancer for transdermal delivery and shown to augment drug permeation 2-8-fold (Jantarat et al., 2018Jantarat C, Sirathanarun P, Boonmee S, Meechoosin W, Wangpittaya H. Effect of piperine on skin permeation of curcumin from a bacterially derived cellulose-composite double-layer membrane for transdermal curcumin delivery. Sci Pharm. 2018;86(3):39.). It can be considered that permeability of the other analytes may be improved by the synergistic effect of volatile oils and piperine.

CONCLUSIONS

Five pharmacologically active ingredients of TQRP were determined using a UPLC/UV/MS/MS analytical method. In the skin permeation study, the 24- hour cumulative permeation amounts of ferulic acid, aleo-emodin, emodin and piperine per unit area were 303.68, 709.31, 671.06, and 25561.01 ng/cm2, respectively. According to the fitting data, skin permeation of the active components from TQRP resulted mainly from a combination of passive diffusion and drug release after matrix erosion. A total of 38.66%-70.10% of the four active agents in TQRP reached the skin tissue where they could exert their pharmacological effects. To the best of our knowledge, this is the first transdermal study of traditional Chinese medicine rubber plaster.

REFERENCES

  • Alomrani AH, Alhazza FI, AlGhamdi KM, El Maghraby GM. Effect of neat and binary vehicle systems on the solubility and cutaneous delivery of piperine. Saudi Pharm J. 2018;26(2):162-8.
  • Bae GS, Kim MS, Jung WS, Seo SW, Yun SW, Kim SG, et al. Inhibition of lipopolysaccharide-induced inflammatory responses by piperine. Eur J Pharmacol. 2010;642(1-3):154-62.
  • Chen Y, Quan P, Liu X, Wang M, Fang L. Novel chemical permeation enhancers for transdermal drug delivery. Asian J Pharm Sci. 2014;9:51-64.
  • Committee, N. P. Pharmacopoeia of The People’s Republic of China. Beijing: Chemical Industry Press; 2015.
  • Hennekens CH, Borzak S, Bjorkman DJ. Cardiovascular risks of cyclooxygenase-2 inhibitors and traditional anti- inflammatory drugs: necessary but not sufficient for clinical decision making. Expert Rev Cardiovasc Ther. 2014;12(3):291-3.
  • Higuchi T. Mechanism of sustained-action. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci. 1963;52:1145-9.
  • Jantarat C, Sirathanarun P, Boonmee S, Meechoosin W, Wangpittaya H. Effect of piperine on skin permeation of curcumin from a bacterially derived cellulose-composite double-layer membrane for transdermal curcumin delivery. Sci Pharm. 2018;86(3):39.
  • Kong X, Wan H, Su X, Zhang C, Yang Y, Li X, et al. Rheum palmatum L. and Coptis chinensis Franch., exert antipyretic effect on yeast-induced pyrexia rats involving regulation of TRPV1 and TRPM8 expression. J Ethnopharmacol. 2014;153(1):160-8.
  • Lao L, Hochberg M, Lee DY, Gilpin AM, Fong HH, Langenberg P, et al. Huo-Luo-Xiao-Ling (HLXL)-Dan, a traditional Chinese medicine, for patients with osteoarthritis of the knee: A multi-site, randomized, double-blind, placebo-controlled phase II clinical trial. Osteoarthritis Cartilage. 2015;23(12):2102-8.
  • McCarty MF, Assanga SBI. Ferulic acid may target MyD88- mediated pro-inflammatory signaling - Implications for the health protection afforded by whole grains, anthocyanins, and coffee. Med Hypotheses. 2018;118:114-20.
  • Nam SH, Xu YJ, Nam H, Jin GW, Jeong Y, An S, et al. Ion pairs of risedronate for transdermal delivery and enhanced permeation rate on hairless mouse skin. Int J Pharm. 2011;419(1-2):114-20.
  • Peppas NA. Commentary on an exponential model for the analysis of drug deliv ery: Original research article: a simple equation for description of solute release: I II. Fickian and non-Fickian release from non-swellable devices in the form of slabs, spheres, cylinders or discs, 1987. J Control Release 2014;190:31-2.
  • Shi L, Zhao F, Zhu F, Liang Y, Yang F, Zhang G, et al. Traditional Chinese Medicine Formula “Xiaofeng granules” suppressed gouty arthritis animal models and inhibited the proteoglycan degradation on chondrocytes induced by monosodium urate. J Ethnopharmacol . 2016;191: 254-63.
  • Siepmann J, Peppas NA. Modeling of drug release from delivery systems based on hydroxypropyl methylcellulose (HPMC). Adv Drug Deliv Rev. 2001;48(2-3):139-57.
  • Silveira GR, Campelo KA, Lima GRS, Carvalho LP, Samarao SS, Vieira-da-Motta O, et al. In vitro anti-toxoplasma gondii and antimicrobial of amides derived from cinnamic acid. Molecules. 2018;23(4):774.
  • Spagnol CM, Di Filippo LD, Isaac VLB, Correa MA, Salgado HRN. Caffeic acid in dermatological formulations: In vitro release profile and skin absorption. Comb Chem High Throughput Screen. 2017;20(8):675-81.
  • Vazquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol . 1996;55(1):69-75.
  • Wang S, Li D, Pi J, Li W, Zhang B, Qi D, et al. Pharmacokinetic and ocular microdialysis study of oral ginkgo biloba extract in rabbits by UPLC-MS/MS determination. J Pharm Pharmacol. 2017;69(11):1540-51.
  • Wu Y, Wang F, Ai Y, Ma W, Bian Q, Lee DY, et al. Simultaneous determination of seven coumarins by UPLC- MS/MS: Application to a comparative pharmacokinetic study in normal and arthritic rats after oral administration of Huo Luo Xiao Ling Dan or single-herb extract. J Chromatogr B Analyt Technol Biomed Life Sci. 2015;991:108-17.

Publication Dates

  • Publication in this collection
    20 Apr 2022
  • Date of issue
    2022

History

  • Received
    05 Jan 2019
  • Accepted
    11 Apr 2019
Universidade de São Paulo, Faculdade de Ciências Farmacêuticas Av. Prof. Lineu Prestes, n. 580, 05508-000 S. Paulo/SP Brasil, Tel.: (55 11) 3091-3824 - São Paulo - SP - Brazil
E-mail: bjps@usp.br