Research Article

Analgesic and Anti-inflammatory Effects of Xueshan Jinluohan Coating Agent and Its Transdermal Mechanism

226 views

⸱

DOI:

10.3791/70480

⸱

April 30th, 2026

 ,  ,  ,  ,  ,  ,  ,  , 
1Qingdao Academy of Chinese Medicinal Sciences, Shandong University of Traditional Chinese Medicine, 2State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, 3Tibet Rhodiola Pharmaceutical Holding Co. Ltd, 4State Key Laboratory of Southwestern Chinese Medicine Resources, School of pharmacy, Chengdu University of Traditional Chinese Medicine, 5Laboratory of Epigenetics and Immunology, West China Institute of Women and Children's Health, NHC Key Laboratory of Chronobiology, Department of Obstetric and Pediatric, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University

* These authors contributed equally

In This Article

Summary

This study presents an integrated approach to evaluate the analgesic and anti-inflammatory effects of Xueshan Jinluohan Pain-Relieving Coating Agent. The effects were area- and time-dependent, and transdermal analysis identified benzoylaconine as the primary permeating component with diffusion-controlled release.

Abstract

Topical traditional Chinese medicine (TCM) preparations are widely used for the management of inflammatory and pain-related conditions because they provide local therapeutic effects while potentially reducing systemic adverse reactions. However, the pharmacodynamic characteristics and transdermal mechanisms underlying many clinically applied formulations remain insufficiently characterized. Xueshan Jinluohan Pain-Relieving Coating Agent (XJCA), a Tibetan medicine formulation, is commonly prescribed for inflammatory pain, yet the influence of application area, duration of action, and the relative contributions of local versus systemic effects have not been systematically evaluated. This study establishes an integrated in vivo–in vitro methodological framework to investigate these parameters. Multiple complementary animal models were employed to assess central and peripheral analgesic activity and acute inflammatory responses, enabling evaluation of area-, time-, and local-versus-systemic-dependent effects. In parallel, a Franz diffusion cell system coupled with ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) was used to characterize the percutaneous absorption kinetics of two principal alkaloids, benzoylaconine and aconitine. XJCA demonstrated significant area- and time-dependent analgesic and anti-inflammatory effects, and larger application areas were associated with greater systemic contribution to analgesic efficacy. Transdermal kinetic analysis revealed that benzoylaconine exhibited a substantially higher steady-state flux and followed diffusion-controlled release consistent with the Higuchi model, whereas aconitine showed lower permeability and a more complex release profile. These findings link transdermal delivery behavior with observed pharmacodynamic outcomes and provide a structured framework for evaluating and optimizing topical TCM formulations.

Introduction

Inflammation and pain are interrelated physiological and pathological responses that play a key role in the body’s defense against injury and infection1. However, persistent or excessive inflammation and pain, such as osteoarthritis, rheumatoid arthritis, or post-traumatic pain, can lead to tissue damage that can seriously impair the physical functioning and mental health of patients2,3. Currently, clinical treatments for inflammation and pain mainly rely on non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., diclofenac, ibuprofen) and opioids. While NSAIDs are widely used for their anti-inflammatory and analgesic effects, oral administration often causes gastrointestinal irritation, renal damage, and cardiovascular risks4. Opioids, though potent analgesics, are associated with addiction, respiratory depression, and other severe side effects5,6. Consequently, there is a growing clinical need for safer alternatives. Topical preparations, which deliver drugs directly to the site of action, offer a strategic solution to mitigate these systemic side effects7. However, their efficacy is highly dependent on the drug's ability to overcome the skin barrier, a factor that can limit the translatability of preclinical findings, particularly for larger molecules or those with poor lipophilicity8,9. Therefore, developing safe and effective alternative therapies, especially topical preparations with local action and minimal systemic exposure, has become a research focus in pharmacology.

Topical TCM preparations have a long history of application in treating inflammation and pain. Their advantages include direct action on the lesion site, reduced systemic side effects, and prolonged drug release10,11. XJCA is a clinically used TCM film-forming gel composed of multiple herbal ingredients. It is widely used in China for alleviating pain and inflammation caused by osteoarthritis, soft tissue injuries, and neuralgia12,13,14. However, the scientific evidence for its efficacy is limited, and key pharmacodynamic characteristics, such as the relationship between application area and efficacy, the time course of action, and the difference between local and systemic effects, remain unclear. These gaps hinder the rational clinical application of XJCA.

Transdermal absorption is a key factor influencing the therapeutic effect of topical preparations. As the primary barrier, the skin restricts the penetration of drugs into the systemic circulation or local tissues15,16. For XJCA, understanding the transdermal absorption characteristics of its active ingredients is crucial to clarify its pharmacodynamic effects and optimize the dosage form. Previous studies on TCM preparations have shown that alkaloids (e.g., aconitine derivatives) are important active components with anti-inflammatory and analgesic effects17,18. Benzoylaconine and aconitine are two main alkaloids in XJCA19,20, and their content and transdermal behavior may directly affect the XJCA’s efficacy. However, there is no report on the transdermal absorption of these two components in XJCA, nor on their kinetic characteristics and release mechanisms.

To fill this research gap, this study aims to develop and validate a systematic methodological framework for assessing topical TCM formulations, using XJCA as a case study. The goal was to demonstrate an integrated evaluation approach that includes: (1) in vivo pharmacodynamic model(s) designed to dissect effects of application site, length of treatment and local vs systemic drug delivery on efficacy; and (2) an in vitro transdermal kinetic evaluation using Franz diffusion cells and UPLC-MS/MS to measure percutaneous absorption and release of key active alkaloids. We hypothesized that the in vivo efficacy of XJCA, particularly its area- and time-dependence, is primarily driven by the transdermal kinetics of its key components. By linking in vivo efficacy parameters to corresponding in vitro kinetic data, this approach provides a mechanistic understanding of how transdermal delivery informs the pharmacodynamics of topical TCM preparations.

Access restricted. Please log in or start a trial to view this content.

Protocol

This study was conducted in accordance with the Guidelines for Ethical Review of Welfare of Laboratory Animals (GB/T 35892-2018) and the Guiding Opinions on the Humane Treatment of Laboratory Animals. All animal procedures were approved by the Experimental Animal Ethics Committee of Chengdu University of Traditional Chinese Medicine (Approval No. TCM-09-315).

Experimental animals and housing
Specific pathogen-free (SPF) Kunming mice (20~25 g, male/female = 1:1) and SPF Sprague-Dawley (SD) rats (180~200 g) were used. Animals were housed under controlled conditions: a 12 h light/dark cycle, a temperature of 23 ± 2 °C, and a humidity of 60% ± 5%, with free access to food and water. To comprehensively evaluate the analgesic and anti-inflammatory profile of XJCA, a battery of in vivo mouse models was employed. The hot plate test assessed centrally mediated pain threshold; the formalin test distinguished between neurogenic (Phase I) and inflammatory pain (Phase II); the xylene-induced ear edema test evaluated acute anti-inflammatory activity; and the acetic acid-induced writhing test modeled visceral inflammatory pain. Note that XJCA is a ready-to-use film-forming gel. No additional preparation is required prior to application.

Effect of application area on analgesic and anti-inflammatory efficacy
SPF Kunming mice were randomly divided into 4 groups (male/female = 1:1): normal control group (NC), XJCA small-area (1×1 cm, 1 cm2) group (XJCASAAG), XJCA medium-area (1×2 cm, 2 cm2) group (XJCAMAAG), and XJCA large-area (1.5×2 cm, 3 cm2) group (XJCALAAG). XJCA was applied at 0.015 g/cm2 (0.15 mL per mouse) for 7 consecutive days. The NC group received normal saline in the same manner. At 120 min after the last administration, analgesic efficacy was evaluated using the hot-plate and formalin tests.

For the hot plate test, mice were pre-screened by placing them on a constant-temperature hot plate maintained at 55 ± 0.5 °C. Paw withdrawal latency (PWL) was recorded, and only mice with baseline PWL between 5 and 30 s were selected (n = 40, male/female = 1:1). After 7 days of treatment, PWL was measured at 30 min intervals 3 times, and the average value was recorded. A cutoff time of 60 s was applied to prevent tissue damage.

In the formalin test (n = 40, male/female = 1:1), after 7 days of treatment, 1% formalin (1 mL/kg) was subcutaneously injected into the right hind paw. Immediately after injection, mice were placed in individual observation chambers. Pain-related behaviors (licking, lifting, and escaping) were recorded during Phase I (0–10 min, neurogenic pain) and Phase II (15–30 min, inflammatory pain). Successful injection was confirmed by visible swelling of the paw.

Time-dependent analgesic and anti-inflammatory efficacy evaluation
One hundred twenty SPF Kunming mice were randomly divided into three groups (n = 10 per time point, male/female = 1:1): a model control (MC) group, an XJCALAAG (1.5×2 cm, 3 cm2) group, and a Diclofenac Diethylamine Emulgel (DDE) positive control group. The XJCA (0.015 g/cm2, 0.15 mL/mouse) and DDE (0.016 g/cm2, 0.15 mL/mouse) were applied for 7 consecutive days, while the MC group received normal saline. At 2, 4, 6, and 8 h after the last administration, both the xylene-induced ear edema test and the acetic acid-induced writhing test were conducted.

In the xylene-induced ear edema test, 30 µL of xylene was applied to both sides of the right ear (the MC group received normal saline), and after 60 min, mice were anesthetized with pentobarbital sodium (30 mg/kg, i.p.) and sacrificed; ear discs (8 mm diameter) were then punched and weighed. The ear edema degree was calculated as the right ear disc weight minus the left ear disc weight, and the edema inhibition rate was determined as [(MC group edema degree – treatment group edema degree) / MC group edema degree] × 100%. A circular ear punch (8 mm diameter) was taken from the same position on both left and right auricles, and the ear tissue was weighed using an electronic balance.

In the acetic acid-induced writhing test, 0.6% acetic acid solution (0.1 mL /10 g) was injected intraperitoneally, and writhing response times (hindlimb extension, abdominal contraction, and trunk twist) were recorded within 20 min. Immediately after acetic acid injection, mice were placed in individual observation cages. Writhing inhibition rate was calculated according to the following formula: [(writhing times in the MC group – writhing times in the treatment group)/writhing times in the MC group]×100%.

Comparison of local vs. systemic analgesic efficacy
To dissociate locally restricted analgesia from effects arising from transdermal absorption and systemic distribution, we conceptualized two administration regimens with clear operational definitions. Local effect refers to the action of the drug at a site localized to tissues immediately beneath or adjacent to the application site, with little contribution from the circulating drug. Systemic effect, on the other hand, refers to analgesia mediated by a drug that has entered the blood and acts at central or peripheral sites remote from the application site. We directly tested the hypothesis that increasing the area of application leads to greater systemic uptake of the drug and, hence, produces analgesic effects greater than those due to local action alone, by keeping the dose per unit area constant while varying the total treated area. This design enables quantification of how the spatial scale of exposure determines systemic bioavailability and the resultant contribution of systemically mediated effects.

Thirty SPF Kunming mice (with PWL of 5~30 s in the hot plate test) were randomly divided into 3 groups (n = 10 per group, male/female = 1:1): NC group, topical medication group (TMG), and systemic medication group (SMG). XJCA was administered at a fixed dose of 0.015 g/cm2, with a volume of 0.15 mL, for 7 consecutive days.

For the TMG, the formulation was applied to a localized area of the hindlimb skin. For the SMG, to simulate increased systemic absorption, the formulation was applied to a combined area including both hindlimbs and the back skin, while maintaining the same dose per unit area (0.015 g/cm2). This design ensured that the total amount of XJCA applied to the SMG group was proportionally higher than that of the TMG group, facilitating greater potential for transdermal absorption into the systemic circulation. At 120 min after the last administration, PWL was measured by the hot plate test (3 times at 30 min intervals, average value recorded). By comparing TMG (local effect predominant) and SMG (local + systemic effect), we could dissect the contribution of systemic drug distribution to overall analgesia.

In vitro transdermal absorption study
The study utilized Franz diffusion cells with an effective diffusion area of 1.76625 cm2. The Franz diffusion cell is the gold standard for assessing percutaneous absorption. The system consists of a donor compartment (containing the test formulation), a receptor compartment (filled with physiological buffer), and excised skin mounted between them. Drug molecules diffuse through the skin into the receptor solution, and samples are collected over time to quantify permeation kinetics. Abdominal skin excised from SD rats anesthetized with pentobarbital sodium (30 mg/kg, i.p.) was carefully prepared by removing subcutaneous fat, rinsed with normal saline, and soaked in normal saline for 24 h. It is vital to protect the integrity of the stratum corneum. Do not stretch, fold, or touch the surface of the epidermis. The skin's permeability is greatly affected by its hydration status. The hydration time yields reproducible results.

The prepared skin was mounted between the donor and receptor compartments, with the stratum corneum facing the donor compartment. The donor side received 200 µL of XJCA (equivalent to 0.06 g of crude drug), while the receptor compartment was filled with 15 mL of receiving solution (30% ethanol:70% PBS, degassed by sonication for 15 min), maintained at 32 ± 0.5 °C under continuous magnetic stirring at 350 r·min⁻1. The receiving solution should be degassed by sonication for 15 min before use to prevent bubble formation during the experiment.

One mL samples were collected from the receptor compartment at 2, 4, 6, 8, 10, 12, 20, and 24 h, each time replenished with an equal volume of pre-warmed (32 °C) fresh receiving solution.

Note: The replacement solution must be at the same temperature to avoid temperature fluctuations that could affect diffusion kinetics. The collected samples were filtered through 0.22 µm microporous membranes and subsequently analyzed by UPLC-MS/MS within 24 h. Due to aconitine's instability, samples should be analyzed within 24 h of collection, or stabilizers should be added. If immediate analysis is not possible, aliquot the samples and store them at -80 °C, but validate their stability under these conditions before proceeding.

UPLC-MS/MS conditions
Chromatographic analysis was performed by using an Agilent ZORBAX SB-C18 column (2.1 × 100 mm, 1.8 µm) maintained at 40 °C, with a flow rate of 0.3 mL/min and an injection volume of 2 µL. The mobile phase consisted of acetonitrile (A) and 0.1 mol/L ammonium acetate solution containing 0.5 mL/L glacial acetic acid (B), using the following gradient program: 0–5 min (26%–45% A), 5–7 min (45%–74% A), 7–10.1 min (74%–90% A), 10.1–12 min (90% A), 12–12.1 min (90%–26% A), and 12.1–15 min (26% A).

Mass spectrometric detection was carried out with an electrospray ionization (ESI) source in positive ion mode under the following settings: drying gas temperature 500 °C, drying gas flow 5 L/min, nebulizer pressure 50 psi, sheath gas temperature 500 °C, sheath gas flow 11 L/min, capillary voltage 5500 V, and data acquisition in multiple reaction monitoring (MRM) mode. The MRM transitions and parameters were set as follows: aconitine (m/z 646.6→586.4, dwell time 100 ms, DP 102.930 V, CE 49.810 V) and benzoylaconine (m/z 604.4→105.1, dwell time 100 ms, DP 105.120 V, CE 74.270 V).

Method validation and data analysis
Method validation was conducted by assessing specificity, linearity, precision, stability, and repeatability. Specificity was verified by analyzing blank receiving solution, standard solution, and sample solution to confirm the absence of interference from endogenous substances. For linearity, standard curves were constructed by plotting peak area against concentration using the least squares regression method. Precision was evaluated through both intra-day (6 replicates) and inter-day (2 replicates over 3 days) assays using a 50 ng/mL standard solution, expressed as the relative standard deviation (RSD) of peak areas. Stability was assessed by determining the peak area RSD of sample solutions at 0, 2, 4, 6, 8, 12, 16, 18, and 24 h. Repeatability was confirmed by measuring the peak area RSD from six parallel sample preparations. The standard stock solutions were prepared by accurately weighing 2.5 mg each of benzoylaconine and aconitine, then dissolving them in an isopropanol:dichloromethane (1:1) mixture to achieve a final concentration of 25 µg/mL. For the test solution, an appropriate amount of the sample was transferred to a centrifuge tube and subjected to high-speed centrifugation at 12,000 x g for 5 min, after which the supernatant was collected for analysis.

The cumulative permeation amount (Qn, ng/cm2) at each time point was calculated using the following formula:

Qn = [(Cn × V + ΣCi × Vi) / A]

Where:
Qn: Cumulative permeation amount at the nth sampling time (ng/cm2).
Cn: Concentration of the drug in the receiving solution at the nth sampling time (ng/mL).
Ci: Concentration of the drug in the receiving solution at the ith sampling time (ng/mL).
V: Volume of the receiving solution (15 mL).
Vi: Sampling volume at each time point (1 mL).
A: Effective diffusion area of the Franz diffusion cell (1.76625 cm2).

The cumulative permeation amount-time (Q-t) curve was plotted with Qn as the ordinate and time (t, h) as the abscissa. The linear part of the Q-t curve was subjected to linear regression, and the slope of the regression equation was taken as the steady-state transdermal flux (Js, ng/cm2/h).

The Q-t curve was fitted to the zero-order model (Q = kt + b), first-order model (ln(Qmax - Q) = -kt + lnQmax), and Higuchi model (Q = kt1/2 + b), where Qmax is the maximum cumulative permeation amount, k is the rate constant, and b is the intercept. The fit was evaluated using the correlation coefficient (R2), with a higher R2 indicating a better fit.

Statistical analysis
The individual-animal raw data for all in vivo behavioral tests and the raw UPLC-MS/MS chromatographic data for the in vitro permeation study are provided as Supplementary Files 1 and 2, respectively. All experimental data were presented as mean ± standard deviation (x̄ ± SD). The statistical analysis was performed using GraphPad Prism 9.0. One-way analysis of variance (ANOVA) followed by Dunnett’s multiple-comparison test was used to compare group differences. p < 0.05 was considered statistically significant.

Access restricted. Please log in or start a trial to view this content.

Results

Dependence of analgesic and anti-inflammatory efficacy on application area
XJCA exhibited a positive correlation between application area and analgesic/anti-inflammatory efficacy in mouse models, following 7 consecutive days of administration at a fixed dose of 0.03 g/cm2. In the hot plate test, the NC group exhibited the shortest mean PWL, indicating the strongest pain response. In contrast, XJCA-treated groups showed an area-dependent prolongation of PWL: XJCASAAG, XJCAMAAG, and XJCALAAG...

Access restricted. Please log in or start a trial to view this content.

Discussion

Inflammation and pain are complex pathological processes involving multiple signaling pathways. Topical preparations have been increasingly favored because they can accurately act on lesions and minimize systemic adverse reactions21,22. This study successfully established and validated a systematic methodological framework for evaluating topical TCM formulations, using XJCA as a demonstration case. The integrated approach, combining strategically designed in vivo...

Access restricted. Please log in or start a trial to view this content.

Disclosures

The authors have no conflicts of interest to declare.

Acknowledgements

This study was supported by the Taishan Scholars Program of Shandong Province (tsqn20250730), the University (Sichuan University)-Enterprise (Tibet Rhodiola Pharmaceutical Holding Co., Ltd.) Cooperation Project (24H0764, 24H1043) and the Bian Que Scholar Programme of Shandong University of Traditional Chinese Medicine.

Access restricted. Please log in or start a trial to view this content.

Materials

List of materials used in this article
NameCompanyCatalog NumberComments
0.22 μm microporous membrane filtersMilliporeSigma, Burlington, MA, USAGSWP04700
Acetic acidCNW Technologies GmbHN3800060Chromatography grade
AcetonitrileMerck KGaAI1241129242Mass spectrometry grade
AconitineChengdu Lemeitian Pharmaceutical Technology Co., Ltd.DSTDW00060220 mg, ≥98% purity
Agilent ZORBAX SB-C18 columnAgilent2.1 × 100 mm, 1.8 μm
Ammonium acetateGENERAL-REAGENTP1492146Analytical grade
BenzoylaconineChengdu Lemeitian Pharmaceutical Technology Co., Ltd.DSTDB00550220 mg, ≥98% purity
DichloromethaneCINC Chemical Co., Ltd.P3048495Analytical grade
Diclofenac Diethylamine Emulgel (DDE)Novartis Pharma Beijing Co., Ltd.H20020176
Formalin solutionSinopharm Chemical Reagent Co., Ltd.10010061
Franz diffusion cellsShenzhen Ruituo Analytical Instruments Co., Ltd.RT806
GraphPad Prism 9.0 softwareGraphPad Software, Inc.Version 9.0
IsopropanolGENERAL-REAGENT0530240601DChromatography grade
Normal salineSinopharm Chemical Reagent Co., Ltd.SY15931
Pentobarbital sodiumSigma-Aldrich, St. Louis, MO, USAP3761
Purified waterGuangzhou Watson's Food and Beverage Co., Ltd.Batch No. 20240717C
SPF Kunming miceChengdu Enswell Biotechnology Co., Ltd.License: SYXK (Sichuan) 2019-049
SPF Sprague-Dawley ratsBeijing Speifu Biotechnology Co., Ltd.License: SYXK (Beijing) 2024-0010
UPLC-MS/MS systemAgilent Technologies, Santa Clara, CA, USAAgilent 1260 Infinity
Xueshan Jinluohan Pain-Relieving Coating Agent (XJCA)Tibet Pharmaceutical Co., Ltd.Z20010095
XyleneSinopharm Chemical Reagent Co., Ltd.10023418

References

  1. Kang, S. Y., Ryu, Y. Editorial: Chronic inflammation and related diseases: From mechanisms to therapies. Int J Mol Sci. 24 (13), (2023).
  2. Liu, Y., et al. The analgesic effects of Yu-Xue-Bi tablet (YXB) on mice with inflammatory pain by regulating LXA4-FPR2-TRPA1 pathway. Chin Med. 19 (1), 104(2024).
  3. Lara, C. O., Burgos, C. F., Moraga-Cid, G., Carrasco, M. A., Yévenes, G. E. Pentameric ligand-gated ion channels as pharmacological targets against chronic pain. Front Pharmacol. 11, 167(2020).
  4. Yang, E. L., et al. Abietane-type diterpenoids from Nepeta bracteata Benth and their anti-inflammatory activity. Front Chem. 10, 944972(2022).
  5. Allen, H. N., Hestehave, S., Duran, P., Nelson, T. S., Khanna, R. Uncoupling the CRMP2-Ca(V)2.2 interaction reduces pain-like behavior in a preclinical osteoarthritis model. bioRxiv. , (2024).
  6. Ochandarena, N. E., Niehaus, J. K., Tassou, A., Scherrer, G. Cell-type specific molecular architecture for mu opioid receptor function in pain and addiction circuits. Neuropharmacology. 238, 109597(2023).
  7. Singh, S., Awasthi, R. Berberine HCl and diacerein loaded dual delivery transferosomes: Formulation and optimization using Box–Behnken design. ADMET DMPK. 12 (3), 553-580 (2024).
  8. Madawi, E. A., et al. Polymeric nanoparticles as tunable nanocarriers for targeted delivery of drugs to skin tissues for treatment of topical skin diseases. Pharmaceutics. 15 (2), (2023).
  9. Li, L., et al. Evaluation of physical and chemical modifications to drug reservoirs for stimuli-responsive microneedles. Drug Deliv Transl Res. 15 (7), 2390-2414 (2025).
  10. Wang, Q., et al. Naturally derived anti-inflammatory compounds from Chinese medicinal plants. J Ethnopharmacol. 146 (1), 9-39 (2013).
  11. Kheoane, P. S., et al. Anti-inflammatory effects of orally and topically administered nanoformulations of Malva parviflora root extracts, and Prunus persica and Cupressus sempervirens exudates. Pharmacol Res Mod Chin Med. 17, 100685(2025).
  12. Zhenping, W., Yanxiu, L., Kun, G., Lei, Z. Clinical observation of Xueshan Jinluohan plastic for relieving pain in the treatment of 66 patients with osteoarthritis. J Clin Med Pract. , (2013).
  13. Kui, S., Guiming, L. Xueshan Jinluohan odynolysis plastics for postherpetic neuralgia: Observation of clinical efficacy. China Pharm. , (2007).
  14. Hai-Yan, W., Lei, Z., Ya-Fang, Z., Xue, J. Clinical observation on Xueshan Jinluohan analgesic film in treating 66 patients with rheumatoid arthritis with syndrome of blood stasis and obstructive arthralgia. Tianjin J Tradit Chin Med. , (2014).
  15. Zhao, L., et al. Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing. Front Pharmacol. 14, 1333986(2023).
  16. Kathe, K., Kathpalia, H. Film forming systems for topical and transdermal drug delivery. Asian J Pharm Sci. 12 (6), 487-497 (2017).
  17. Xue, M., et al. Illumination on chemical compounds from Qufeng Zhitong capsule and its potential pharmacological mechanism against rheumatoid arthritis based on UHPLC/Q-Orbitrap-MS combined with network pharmacology analysis. Int J Anal Chem. 2022, 7863435(2022).
  18. Zhao, P., et al. Aconitine and its derivatives: Bioactivities, structure-activity relationships and preliminary molecular mechanisms. Front Chem. 12, 1339364(2024).
  19. Ling-Li, L., Lan-Xia, W., Ling, N., Xi, Y. Determination of safflower glucoside I and gentiopicrin in Xueshan Jinluohan pain-relief liniment by HPLC. Chin Tradit Pat Med. 34 (3), 499-502 (2012).
  20. Xiang, G., Guo, S., Wu, C., Wang, S., Zhang, Y. Deciphering the mysteries of Aconitum pendulum: Unique identification of various processed products and characteristic chemical markers. Arab J Chem. 17 (2), 105585(2024).
  21. Yang, C., et al. Development and evaluation of a Chinese herbal gel for analgesic and anti-inflammatory effects. Pak J Pharm Sci. 36 (4 Suppl), 1261-1269 (2023).
  22. Zhang, W., et al. Nicotine in inflammatory diseases: Anti-inflammatory and pro-inflammatory effects. Front Immunol. 13, 826889(2022).
  23. Zhan, M. X., et al. Ulinastatin exhibits antinociception in rat models of acute somatic and visceral pain through inhibiting the local and central inflammation. J Pain Res. 14, 1201-1214 (2021).
  24. Liu, C., et al. Investigation of the permeation enhancer strategy on benzoylaconine transdermal patch: The relationship between transdermal enhancement strength and physicochemical properties of permeation enhancer. Eur J Pharm Sci. 138, 105009(2019).
  25. Jiang, Z., Liu, S., Li, Y., Yuan, S. Study on the absorption mechanism of glucocorticoids in the stratum corneum. Colloids Surf B Biointerfaces. 256 (Pt 1), 114984(2025).
  26. Fabbrocini, G., et al. Skin needling to enhance depigmenting serum penetration in the treatment of melasma. Plast Surg Int. 2011, 158241(2011).
  27. Costa, R., Costa Lima, S. A., Gameiro, P., Reis, S. On the development of a cutaneous flavonoid delivery system: Advances and limitations. Antioxidants (Basel). 10 (9), (2021).
  28. Li, Z., et al. Analgesic and neuroprotective effects of Baimai ointment on diabetic peripheral neuropathy. J Ethnopharmacol. 292, 115122(2022).
  29. Lei, Y., et al. Formulation and evaluation of a drug-in-adhesive patch for transdermal delivery of colchicine. Pharmaceutics. 14 (10), (2022).
  30. Sirisha Mulukuri, N. V. L., et al. Statistical modeling, optimization and characterization of andrographolide loaded emulgel for its therapeutic application on skin cancer through enhancing its skin permeability. Saudi Pharm J. 32 (6), 102068(2024).
  31. Cohen, E., Lee, Y. C. A mechanism-based approach to the management of osteoarthritis pain. Curr Osteoporos Rep. 13 (6), 399-406 (2015).
  32. Boehnke, K. F., Gagnier, J. J., Matallana, L., Williams, D. A. Cannabidiol product dosing and decision-making in a national survey of individuals with fibromyalgia. J Pain. 23 (1), 45-45 (2022).
  33. Pan, S. Y., et al. New perspectives on Chinese herbal medicine (Zhong-Yao) research and development. Evid Based Complement Alternat Med. 2011, 403709(2011).
  34. Sana, E., et al. Topical delivery of curcumin-loaded transfersomes gel ameliorated rheumatoid arthritis by inhibiting NF-κB pathway. Nanomedicine (Lond). 16 (10), 819-837 (2021).
  35. Ya-Nan, H., et al. New understanding of aconitine hydrolysis pathway: Isolation, identification and toxicity evaluation based on intermediate products. Arab J Chem. 15 (11), 104255(2022).
  36. Shakeel, F., et al. Investigating antiarthritic potential of nanostructured clove oil (Syzygium aromaticum) in FCA-induced arthritic rats: Pharmaceutical action and delivery strategies. Molecules. 26 (23), (2021).
  37. Zhou, C., et al. Benzoylaconine modulates LPS-induced responses through inhibition of toll-like receptor-mediated NF-κB and MAPK signaling in RAW264.7 cells. Inflammation. 44 (5), 2018-2032 (2021).
  38. Jin, X., et al. Aconitine – a promising candidate for treating cold and mechanical allodynia in cancer-induced bone pain. Biomed Pharmacother. 161, 114284(2023).
  39. Tao, H., et al. Pharmacokinetics and pharmacology of aminoalcohol-diterpenoid alkaloids from Aconitum species. J Ethnopharmacol. 301, 115726(2023).
  40. Teaima, M. H., et al. Enhanced transdermal delivery of bisoprolol hemifumarate via combined effect of iontophoresis and chemical enhancers: Ex vivo permeation/in vivo pharmacokinetic studies. Pharmaceutics. 13 (5), (2021).
  41. Liu, X., et al. The inhibition of PPARα protein degradation alleviates the cardiotoxicity of Tiebangchui by regulating fatty acid metabolism. J Ethnopharmacol. 348, 119838(2025).
  42. Abdella, S., Afinjuomo, F., Song, Y., Upton, R., Garg, S. Mucoadhesive buccal film of estradiol for hormonal replacement therapy: Development and in vivo performance prediction. Pharmaceutics. 14 (3), (2022).

Access restricted. Please log in or start a trial to view this content.

Reprints and Permissions

Request permission to reuse the text or figures of this JoVE article

Request Permission

Tags

Analgesic EffectsTopical TCMPercutaneous AbsorptionFranz Diffusion CellUPLC MS MSBenzoylaconineAconitine

Related Articles