A traditional Chinese medicine composition for treating hand-foot skin reaction and a preparation method thereof

Abstract

The application provides a traditional Chinese medicine composition for treating hand-foot skin reaction and a preparation method thereof, and belongs to the technical field of traditional Chinese medicines; the traditional Chinese medicine composition is composed of the following components: angelica, honeysuckle, giant knotweed, baizhi, licorice, comfrey, frankincense, myrrh and dragon's blood, and has the effects of clearing heat and resolving toxins, promoting blood circulation and promoting tissue regeneration. The application shows good curative effect in the clinical application in treating hand-foot skin reaction caused by chemotherapy drugs and targeted drugs.

Description

Technical Field

[0001] This invention belongs to the field of traditional Chinese medicine technology, and in particular relates to a traditional Chinese medicine composition for treating hand and foot skin reactions and its preparation method. Background Technology

[0002] Chemotherapy and targeted therapy are important methods in anti-tumor treatment. The most common skin side effect is hand-foot skin reaction (HFSR), the incidence of which is closely related to the type of drug, frequency of administration, and route of administration. Symptoms mainly include sensitivity, tingling, burning, erythema, swelling, thickening, roughness, cracking, and desquamation of the hands and feet, accompanied by severe pain. The severity varies slightly depending on the type of drug and is dose-limiting toxicity. Common drugs that cause HFSR include cytotoxic chemotherapy drugs such as capecitabine, fluorouracil, liposomal doxorubicin, and docetaxel, as well as multi-kinase inhibitors such as regorafenib, sorafenib, and sunitinib. HFSR can also be caused by EGFR inhibitors (erlotinib, gefitinib) and BRAF inhibitors (vemurafenib, dabrafenib).

[0003] Hand and foot skin reactions have a significant impact on patients. On the one hand, lesions on the hands and feet are difficult to conceal with clothing. On the other hand, the hands and feet are closely related to daily life, seriously affecting patients' emotions (86.11%), social entertainment (73.41%), lifestyle habits (73.58%), disease treatment (48.03%), and intimate relationships (45.97%). This increases patients' psychological burden and sleep disorders. Furthermore, when patients experience grade II or higher adverse skin reactions, 80.09% of doctors will adjust the treatment plan by reducing or discontinuing the medication, which has a significant negative impact on patients' anti-tumor treatment, quality of life, and physical and mental health.

[0004] The pathogenesis of HFSR remains unclear, but it is believed to be related to factors such as keratinocyte dysfunction, crosstalk between vascular endothelial cells and keratinocytes, and sweat gland excretion. Current research indicates that oral medications such as celecoxib, dexamethasone, pyridoxine, and vitamin B6, as well as topical medications such as moisturizing creams, hydrocolloid excipients, and clobetasol ointment, have some effect on the prevention and treatment of HFSR, but these effects are controversial. Urea ointment shows relatively good efficacy, exhibiting a significant preventive effect against HFSR, reducing its incidence (56% vs 73.6%, P<0.01) and prolonging the median time to onset. However, its overall efficacy in treating HFSR remains low, and it does not significantly improve comorbid symptoms such as pain and itching. Reduction or discontinuation of targeted therapies remains the most effective treatment for HFSR. To date, there are no high-level evidence-based recommendations for the prevention and treatment of HFSR, making the research and development of drugs for its prevention and treatment significant clinical importance and application prospects. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a traditional Chinese medicine composition for treating hand and foot skin reactions and its preparation method, which can be well applied in the treatment of hand and foot skin reactions and has good efficacy.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0007] This invention provides a traditional Chinese medicine composition for treating hand and foot skin reactions, comprising the following components in parts by weight:

[0008] Angelica sinensis 50-150 parts, honeysuckle 50-150 parts, Polygonum cuspidatum 100-200 parts, Angelica dahurica 40-80 parts, licorice 20-60 parts, Lithospermum erythrorhizon 50-150 parts, frankincense 10-50 parts, myrrh 10-50 parts, and dragon's blood 5-15 parts.

[0009] The present invention also provides a traditional Chinese medicine preparation for treating hand and foot skin reactions, comprising the aforementioned traditional Chinese medicine composition and excipients;

[0010] The excipients are petrolatum and ethylparaben solution;

[0011] Alternatively, it could be sesame oil and beeswax.

[0012] The present invention also provides a method for preparing the aforementioned traditional Chinese medicine preparation. When the excipients are petrolatum and ethylparaben solution, the preparation method is as follows:

[0013] A. Mix Angelica sinensis, Lonicera japonica, Polygonum cuspidatum, Angelica dahurica, Glycyrrhiza uralensis, and Lithospermum erythrorhizon with 5 to 10 times their weight of ethanol solution with a volume concentration of 50 to 80%, reflux extract 1 to 3 times, each time for 40 to 80 minutes, combine the extracts, and concentrate the extract to a fluid extract with a relative density of 1.14 to 1.20.

[0014] B. After freezing frankincense and dragon's blood, mix, pulverize and sieve to obtain frankincense-dragon's blood powder; pulverize myrrh separately and sieve to obtain myrrh powder.

[0015] Alternatively, frankincense and myrrh can be pulverized and sieved, then 10 to 14 times their weight of ethanol with a volume concentration of 80 to 100% can be added for percolation. The percolate can be collected and concentrated to a relative density of 1.00 to 1.15 to obtain frankincense-myrrh percolate concentrate. Bloodskin can be pulverized and sieved to obtain bloodskin powder.

[0016] C. Add the fluid extract described in step A to 1500-2200 parts of melted petroleum jelly and homogenize to obtain a matrix;

[0017] D. Mix the frankincense-dragon's blood powder, myrrh powder, ethylparaben solution and the matrix described in step B with the matrix described in step C, and cool to obtain the final product;

[0018] Alternatively, the frankincense-myrrh percolation concentrate, dragon's blood powder, ethylparaben solution, and matrix described in step B can be mixed and cooled to obtain the final product.

[0019] Preferably, the sieving is performed through a 100-200 mesh sieve.

[0020] Preferably, the temperature of the petroleum jelly is 45–60°C.

[0021] Preferably, the total amount of frankincense-dragon's blood powder and myrrh powder is in a mass ratio of 15 to 25:1 to the ethylparaben solution, and the concentration of the ethylparaben solution is 1 to 3%.

[0022] Preferably, the concentration temperature in step B is 50–60°C.

[0023] This invention also provides a method for preparing the aforementioned traditional Chinese medicine preparation. When the excipients are sesame oil and beeswax, the preparation method is as follows:

[0024] a. Soak angelica, honeysuckle, Japanese knotweed, angelica dahurica, and licorice in 1500-2500 parts of sesame oil for 2-5 days;

[0025] b. After soaking, heat to 100-160℃ and maintain for 20-60 minutes, filter, and collect the liquid phase component; add alkanet root to the liquid phase component, heat to 140-180℃, fry for 10-30 minutes, filter out the residue, and obtain the filtered oil;

[0026] c. Keep the oil temperature at 110-135℃, add 300-700 parts of beeswax, stir for 3-8 minutes until the beeswax is completely melted, and then cool to 40-55℃;

[0027] d. Add the crushed and sieved frankincense, dragon's blood, and myrrh powder, and stir well to obtain the final product.

[0028] The present invention also provides the use of the traditional Chinese medicine composition in the preparation of a medicament for treating hand and foot skin reactions.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] The present invention provides a traditional Chinese medicine composition for treating hand-foot skin reaction, which is an exploratory improvement based on Yuhong Shengji Ointment, a famous classical prescription for sores. It removes mercurous chloride, a mercury-containing toxic substance, adds Flos Lonicerae and Rhizoma Polygoni Cuspidati that clear heat, cool blood, resolve dampness and detoxify, and adds Olibanum and Myrrha that relieve pain. The composition has the effects of clearing heat and detoxifying, activating blood circulation and promoting tissue regeneration. In this prescription, the monarch drugs Radix Angelicae Sinensis and Flos Lonicerae can invigorate blood circulation to relieve pain, clear heat and detoxify; the minister drugs Rhizoma Polygoni Cuspidati, Olibanum and Myrrha can cool blood and detoxify, disperse blood stasis to relieve pain, reduce swelling and promote tissue regeneration; the adjuvant drugs Radix Angelicae Dahuricae, Sanguis Draxonis and Radix Arnebiae / Lithospermi can dispel wind to relieve pain, promote tissue regeneration and heal sores, assist in alleviating swelling and pruritus, and assist in repair; the guide drug Radix Glycyrrhizae can clear heat and detoxify, and harmonize all the drugs. Modern pharmacological studies also show that multiple drugs in this prescription have effects such as antioxidation, anti-inflammation and bacteriostasis, activating blood circulation to relieve pain, and anti-tumor. Brief Description of the Drawings

[0031] Figure 1 is a flow chart of case inclusion;

[0032] Figure 2 shows the drug treatment status of the patient;

[0033] Figure 3 shows the change of NCI grade at each evaluation node (the unit of the vertical axis is case);

[0034] Figure 4 shows the change of NRS pain grade before and after treatment;

[0035] Figure 5 is a comparison diagram of the therapeutic effect of HFSR caused by taking apatinib;

[0036] Figure 6 is a comparison diagram of the therapeutic effect of HFSR caused by taking tegafur, gimeracil and oteracil potassium;

[0037] Figure 7 is a comparison diagram of the therapeutic effect of HFSR caused by taking liposomal doxorubicin plus anlotinib. Detailed Description of the Embodiments

[0038] The present invention provides a traditional Chinese medicine composition for treating hand-foot skin reaction, which comprises the following components in parts by mass:

[0039] 50 to 150 parts of Radix Angelicae Sinensis, preferably 70 to 120 parts, more preferably 100 parts;

[0040] 50 to 150 parts of Flos Lonicerae, preferably 70 to 120 parts, more preferably 100 parts;

[0041] 100 to 200 parts of Rhizoma Polygoni Cuspidati, preferably 130 to 170 parts, more preferably 150 parts;

[0042] 40 to 80 parts of Radix Angelicae Dahuricae, preferably 50 to 70 parts, more preferably 60 parts;

[0043] Licorice 20-60 parts, preferably 30-50 parts, more preferably 40 parts;

[0044] The amount of gromwell root is 50-150 parts, preferably 70-120 parts, and even more preferably 100 parts;

[0045] Frankincense 10-50 parts, preferably 20-40 parts, more preferably 30 parts;

[0046] Myrrh: 10-50 parts, preferably 20-40 parts, more preferably 30 parts;

[0047] 5-15 parts of dragon's blood, preferably 7-12 parts, and more preferably 10 parts;

[0048] The present invention also provides a traditional Chinese medicine preparation for treating hand and foot skin reactions, comprising the aforementioned traditional Chinese medicine composition and excipients;

[0049] The excipients are petrolatum and ethylparaben solution;

[0050] Alternatively, it could be sesame oil and beeswax.

[0051] The present invention also provides a method for preparing the aforementioned traditional Chinese medicine preparation. When the excipients are petrolatum and ethylparaben solution, the preparation method is as follows:

[0052] A. Mix Angelica sinensis, Lonicera japonica, Polygonum cuspidatum, Angelica dahurica, Glycyrrhiza uralensis, and Lithospermum erythrorhizon with 5 to 10 times their weight of ethanol solution with a volume concentration of 50 to 80%, reflux extract 1 to 3 times, each time for 40 to 80 minutes, combine the extracts, and concentrate the extract to a fluid extract with a relative density of 1.14 to 1.20.

[0053] B. After freezing frankincense and dragon's blood, mix, pulverize and sieve to obtain frankincense-dragon's blood powder; pulverize myrrh separately and sieve to obtain myrrh powder.

[0054] Alternatively, frankincense and myrrh can be pulverized and sieved, then 10 to 14 times their weight of ethanol with a volume concentration of 80 to 100% can be added for percolation. The percolate can be collected and concentrated to a relative density of 1.00 to 1.15 to obtain frankincense-myrrh percolate concentrate. Bloodskin can be pulverized and sieved to obtain bloodskin powder.

[0055] C. Add the fluid extract described in step A to 1500-2200 parts of melted petroleum jelly and homogenize to obtain a matrix;

[0056] D. Mix the frankincense-dragon's blood powder, myrrh powder, ethylparaben solution and the matrix described in step B with the matrix described in step C, and cool to obtain the final product;

[0057] Alternatively, the frankincense-myrrh percolation concentrate, dragon's blood powder, ethylparaben solution, and matrix described in step B can be mixed and cooled to obtain the final product.

[0058] In this invention, the amount of ethanol used in step A is preferably 5 to 10 times the total amount of Angelica sinensis, Lonicera japonica, Polygonum cuspidatum, Angelica dahurica, Glycyrrhiza uralensis, and Lithospermum erythrorhizon, more preferably 6 to 8 times, and even more preferably 7 times; the volume concentration of ethanol is preferably 50 to 80%, more preferably 60 to 70%, and even more preferably 65%; the number of reflux extractions is preferably 1 to 3 times, more preferably 2 times; the reflux extraction time for each extraction is preferably 40 to 80 minutes, more preferably 50 to 70 minutes, and even more preferably 60 minutes; the density of the fluid extract is preferably 1.14 to 1.20, more preferably 1.15 to 1.18, and even more preferably 1.17.

[0059] In this invention, frankincense and dragon's blood are frozen and then mixed and pulverized in step B. Freezing and pulverizing frankincense and dragon's blood reduces the difficulty of pulverization, ensures that the effective components of the medicine are not destroyed, and significantly improves the extraction efficiency of the effective components, thus improving the therapeutic effect. Pulverizing frankincense and dragon's blood together reduces the cross-linking degree between the pulverized materials. Myrrh is pulverized separately because myrrh pulverized material is flocculent and easily agglomerates with other medicinal materials, making it difficult to sieve; therefore, it needs to be pulverized separately. The preferred sieve mesh size is 100-200 mesh, more preferably 130-170 mesh, and even more preferably 150 mesh. In this invention, the amount of ethanol used in step B is preferably 10-14 times the total mass of frankincense and myrrh, more preferably 11-13 times, and even more preferably 12 times. The volume concentration of ethanol is preferably 80-100%, more preferably 85-95%, and even more preferably 90%. The concentration temperature is preferably 50-60°C, more preferably 52-58°C, and even more preferably 55°C.

[0060] In this invention, the temperature at which the petroleum jelly is melted is preferably 45-60°C, more preferably 50-58°C, and even more preferably 55°C; the amount of petroleum jelly used is preferably 1500-2200 parts, more preferably 1700-2000 parts, and even more preferably 1900 parts.

[0061] In this invention, the content of ethylparaben in the ethylparaben solution is preferably 1-4%, more preferably 1.5-3%, and even more preferably 2%; the mass ratio of the total amount of frankincense-dragon's blood powder and myrrh powder to the ethylparaben solution is preferably 15-25:1, more preferably 17-22:1, and even more preferably 20:1.

[0062] This invention also provides a method for preparing a traditional Chinese medicine preparation. When the excipients are sesame oil and beeswax, the preparation method is as follows:

[0063] a. Soak angelica, honeysuckle, Japanese knotweed, angelica dahurica, and licorice in 1500-2500 parts of sesame oil for 2-5 days;

[0064] b. After soaking, heat to 100-160℃ and maintain for 20-60 minutes, filter, and collect the liquid phase component; add alkanet root to the liquid phase component, heat to 140-180℃, fry for 10-30 minutes, filter out the residue, and obtain the filtered oil;

[0065] c. Keep the oil temperature at 110-135℃, add 300-700 parts of beeswax, stir for 3-8 minutes until the beeswax is completely melted, and then cool to 40-55℃;

[0066] d. Add the crushed and sieved frankincense, dragon's blood, and myrrh powder, and stir well to obtain the final product.

[0067] In this invention, the amount of sesame oil used is preferably 1500-2500 parts, more preferably 1700-2200 parts, and even more preferably 2000 parts; the soaking time is preferably 2-5 days, more preferably 2.5-4 days, and even more preferably 3 days.

[0068] In this invention, the soaking process requires stirring, and the stirring interval is preferably 12-36 hours, more preferably 20-30 hours, and even more preferably 24 hours; after soaking, the heating temperature is preferably 100-160℃, more preferably 110-140℃, and even more preferably 120℃; the heating time is preferably 20-60 minutes, more preferably 30-50 minutes, and even more preferably 40 minutes; after adding alkanet root, the frying temperature is preferably 140-180℃, more preferably 150-170℃, and even more preferably 160℃; the frying time is preferably 10-30 minutes, more preferably 12-20 minutes, and even more preferably 15 minutes.

[0069] In this invention, after adding beeswax, the heating temperature is preferably 110-135°C, more preferably 115-125°C, and even more preferably 120°C; the heating time is preferably 4-12 min, more preferably 6-10 min, and even more preferably 8 min; the cooling temperature is preferably 40-55°C, more preferably 45-52°C, and even more preferably 50°C.

[0070] This invention provides the application of the traditional Chinese medicine composition in the preparation of a medicament for treating hand and foot skin reactions.

[0071] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0072] Example 1

[0073] A traditional Chinese medicine ointment for treating hand and foot skin reactions, by weight, is made of the following components: 1900 parts petroleum jelly, 100 parts angelica sinensis, 100 parts honeysuckle, 150 parts Japanese knotweed, 60 parts angelica dahurica, 40 parts licorice, 100 parts gromwell root, 30 parts frankincense, 30 parts myrrh, and 10 parts dragon's blood.

[0074] The preparation method, with specific steps as follows:

[0075] Step 1: Add 7 times the mass of 65% ethanol to Angelica sinensis, honeysuckle, Polygonum cuspidatum, Angelica dahurica, licorice, and Lithospermum erythrorhizon and reflux extract twice, each time for 1 hour. Combine the extracts, recover the ethanol, and concentrate to a fluid extract with a relative density of 1.17 for later use.

[0076] Step 2: Freeze the frankincense and dragon's blood, then mix and grind them together. Grind the myrrh separately, sieve, and set aside for later use.

[0077] Step 3: Add the fluid extract to molten petroleum jelly (at 55°C) and homogenize to obtain the matrix;

[0078] Step 4: Add frankincense-dragon's blood powder, myrrh powder and 2% ethylparaben solution (the total amount of frankincense-dragon's blood powder and myrrh powder to the ethylparaben solution is in a mass ratio of 20:1), stir well and cool to obtain the final product.

[0079] Example 2

[0080] A traditional Chinese medicine ointment for treating hand and foot skin reactions, by weight, is made of the following components: 1500 parts petroleum jelly, 60 parts angelica sinensis, 60 parts honeysuckle, 100 parts polygonum cuspidatum, 40 parts angelica dahurica, 30 parts licorice, 150 parts gromwell root, 20 parts frankincense, 20 parts myrrh, and 10 parts dragon's blood.

[0081] The preparation method, with specific steps as follows:

[0082] Step 1: Add 7 times the mass of 65% ethanol to Angelica sinensis, honeysuckle, Polygonum cuspidatum, Angelica dahurica, licorice, and Lithospermum erythrorhizon and reflux extract twice, each time for 1 hour. Combine the extracts, recover the ethanol, and concentrate to a fluid extract with a relative density of 1.17 for later use.

[0083] Step 2: After crushing frankincense and myrrh, sieve them, add 12 times the mass of 90% ethanol for percolation, collect the percolate, concentrate it to a relative density of 1.00-1.15 to obtain frankincense-myrrh percolate concentrate, and crush dragon's blood and sieve it to obtain dragon's blood powder.

[0084] Step 3: Add the fluid extract to molten petroleum jelly (at 55°C) and homogenize to obtain the matrix;

[0085] Step 4: Mix the frankincense-myrrh percolation concentrate, dragon's blood powder, ethylparaben solution and matrix, and cool to obtain the final product.

[0086] Example 3

[0087] A traditional Chinese medicine ointment for treating hand and foot skin reactions, by weight, is made of the following components: 2000 parts sesame oil, 400 parts beeswax, 100 parts angelica, 100 parts honeysuckle, 150 parts Japanese knotweed, 60 parts angelica dahurica, 40 parts licorice, 100 parts gromwell root, 30 parts frankincense, 30 parts myrrh, and 10 parts dragon's blood.

[0088] The preparation method, with specific steps as follows:

[0089] Step 1: Soak angelica, honeysuckle, Japanese knotweed, angelica dahurica, and licorice in sesame oil for three days, stirring once every 24 hours;

[0090] Step 2: After soaking, heat to 130℃ and maintain for 30 minutes, filter, and collect the liquid phase component; add alkanet root to the liquid phase component, heat to 160℃, fry for 10-30 minutes, filter out the residue, and obtain the filtered oil;

[0091] Step 3: When the oil temperature drops to 120℃, add beeswax to the filtrate, heat over a low flame for 5 minutes until the beeswax is completely melted, and then cool to 40-55℃.

[0092] Step 4: Add the crushed and sieved frankincense, dragon's blood, and myrrh powders, and stir well to obtain the final product.

[0093] Example 4

[0094] A traditional Chinese medicine ointment for treating hand and foot skin reactions, by weight, is made from the following components: 2200 parts petrolatum, 150 parts angelica sinensis, 150 parts honeysuckle, 150 parts polygonum cuspidatum, 80 parts angelica dahurica, 50 parts licorice, 150 parts gromwell root, 25 parts frankincense, 25 parts myrrh, and 10 parts dragon's blood. The preparation process is the same as in Example 1.

[0095] clinical trials

[0096] 1. Clinical Data

[0097] 1.1 Study Subjects: Patients with malignant tumors who developed hand and foot skin reactions after treatment with anti-tumor drugs (targeted drugs, chemotherapy drugs) were selected from the outpatient or inpatient departments of multiple centers such as Jiangsu Provincial Hospital of Integrated Traditional and Western Medicine and Lishui District Hospital of Traditional Chinese Medicine.

[0098] 1.2 Case Criteria

[0099] 1.2.1 Inclusion criteria: 1) Pathologically confirmed malignant tumor; 2) Hand and foot skin reaction, and its occurrence is significantly correlated with antitumor drugs (such as anlotinib, fruquintinib, regorafenib, capecitabine, etc.); 3) Karnofsky Performance Status (KPS) score > 60; 4) Age 18-85 years, gender not limited; 5) Prospective survival ≥ 3 months; 6) Conscious and able to judge and evaluate their own pain; 7) No local skin infection.

[0100] 1.2.2 Exclusion criteria: 1) Hand and foot skin infections and ulcers caused by immune system diseases, severe infections, severe diabetes, etc.; 2) People with a history of severe skin diseases or currently suffering from other severe skin diseases; 3) Pregnant women and breastfeeding women; 4) People who are participating in other similar hand and foot skin reaction research projects.

[0101] 1.2.3 Withdrawal criteria: 1) The patient withdraws the informed consent form; 2) The patient experiences an adverse event (AE) that the investigator deems necessary to terminate the trial treatment; 3) The investigator believes that, from the patient's best interests, the best option is to terminate the trial treatment; 4) The investigator believes that the patient intentionally or unintentionally fails to comply with the study-related regulations; 5) Other circumstances that the investigator deems necessary to withdraw from the study.

[0102] 1.3 Treatment Methods

[0103] 1.3.1 Drugs

[0104] The drug prepared using Example 1 was prepared in a formulation room that meets GMP standards.

[0105] 1.3.2 Administration method: Apply evenly to the skin of the palms and soles, including between the fingers and joints, three times a day.

[0106] 1.3.3 Duration of medication: 4 weeks.

[0107] 1.3.4 Concomitant medication during the observation period

[0108] During the observation period, patients should not take other medications for treating HFSR. If the patient experiences pain or infection, symptomatic medication can be administered.

[0109] 1.4 Observation Indicators:

[0110] 1.4.1 Key Observation Indicators

[0111] HFSR severity grading: Patient grading was recorded before and after treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Cure: Complete symptom relief or grade reduction to 0; Effective: Grade reduction of ≥1 level, but not down to 0; Ineffective: No change in grade or even worsening. Overall response rate = (Cure + Effective) / Total number of cases * 100%. Assessments were performed before treatment, and at 2 and 4 weeks after treatment.

[0112] 1.4.2 Secondary observation indicators

[0113] 1) The HFSR-specific quality of life scale (HFSR-14) was used for assessment before treatment and at 2 and 4 weeks after treatment; 2) Pain relief rate: assessed using a combination of the WHO pain efficacy evaluation criteria and the NRS method, at 2 and 4 weeks after treatment; 3) Antitumor drug completion rate: assessed on day 28 of treatment, considered complete if no dose reduction or discontinuation occurred during the study; 4) The HFSR common symptom scale was used for assessment before treatment and at 2 and 4 weeks after treatment; 5) Adverse reaction assessment: assessed using the NCI-CTC skin toxicity criteria, observing for any rash, allergies, or other subjective discomfort after application of this invention, at 2 and 4 weeks after treatment.

[0114] 1.5 Statistical Methods

[0115] All data were analyzed using SPSS 26.0 software. Continuous data were expressed as mean ± standard deviation (x ± s), and categorical data were expressed as N (%). Chi-square test was used for comparison of categorical data, paired t-test for comparison of continuous data, and rank-sum test for ordinal data. A 95% confidence interval was chosen for all statistical analyses. P < 0.05 was considered statistically significant, and P > 0.05 was considered not statistically significant.

[0116] 2. Research Results

[0117] In the early stages of this invention, a multicenter, small-sample clinical study was conducted on the treatment of hand-foot skin reactions with the traditional Chinese medicine preparation of this invention (ethics approval: 2023LWKYZ041; registration on the National Clinical Trial Platform: ChiCTR2300071320). The study ultimately included and analyzed 58 patients.

[0118] Statistics show that half of the enrolled patients had a history of treatment for hand-foot skin reactions, such as moisturizers, ointments, silicone oils, aloe vera creams, and repair creams, but the treatment effect was not good. The traditional Chinese medicine preparation of this invention has a definite curative effect on HFSR and is expected to become an effective intervention for HFSR.

[0119] 2.1 Case Completion Status

[0120] This invention screened 65 patients, with 3 excluded due to not meeting the inclusion / exclusion criteria, leaving 62 included in the study. Four patients dropped out, resulting in a total dropout rate of 6.45%, less than 20%. Details of the dropped out cases are shown in Table 1. Finally, 58 patients were included in the statistical analysis. All patients signed informed consent forms. The case inclusion flowchart is shown below. Figure 1 .

[0121] Table 1. List of cases of shedding

[0122]

[0123] 2.2 Baseline Analysis

[0124] Table 2 General patient information

[0125]

[0126] The general information of the enrolled patients is shown in Table 2: The mean age of the 58 patients included in the analysis was 63.1 years, with the oldest patient being 89 years old and the youngest being 9 years old. Patients over 60 years old accounted for 56.9%; there were 36 male patients and 22 female patients, with a male-to-female ratio of 1.64:1; in terms of education level, 87.9% of the patients had junior high school or lower education, with only a small number of patients (12.1%) having a university education; in terms of treatment history, 46.6% of the patients had a history of HFSR / HFSR treatment, including the application of moisturizers, emollients, ointments, and repair creams, but the treatment effect was not good; the study involved a variety of cancer types, as shown in Table 3, with colorectal cancer being the most common, accounting for 48.3% of the total, followed by lung cancer, liver cancer, breast cancer, gastric cancer, uterine cancer, esophageal cancer, and prostate cancer.

[0127] Table 3 Patient Illness Status

[0128]

[0129] The enrolled patients were those who developed HFSR / HFSR after receiving antitumor therapy. Statistical analysis is shown in Table 4. Figure 2 Chemotherapy drugs were used in 25 cases, accounting for 43.1% of the total; targeted drugs were used in 33 cases, accounting for 56.9%, of which 1 case was caused by the combination of anlotinib and vormetinib, and 1 case was caused by the combination of anlotinib and afatinib.

[0130] Table 4 Patient's Drug Treatment Status

[0131]

[0132] 2.3 Evaluation of therapeutic effect

[0133] 2.3.1 HFSR / HFSR Classification

[0134] At baseline, 50 patients (86.2%) had moderate to severe HFSR / HFSR; 25 patients (43.1%) had moderate to severe HFSR / HFSR by treatment day 14; and 13 patients (22.4%) had moderate to severe HFSR / HFSR by treatment day 28, showing an overall downward trend. Changes in NCI grading at each assessment point before and after treatment are compared, as shown in Table 5. Figure 3The results showed that as the treatment time increased, the proportion of moderate to severe patients decreased, and there were significant differences between the baseline and D14 and D28 (P<0.01). Further comparison of the data between the D14 and D28 groups also showed statistical significance (P<0.01).

[0135] Table 5. Changes in NCI rating at each assessment node (examples)

[0136]

[0137] The efficacy before and after treatment was compared, as shown in Tables 6 and 7: the effective rate of treatment D14 was significantly higher than that of treatment D7 (79.3% vs 46.6%, P<0.05), and there was also a significant difference in efficacy grade between treatments D7 and D14 (P<0.05). There was no statistically significant difference in effective rate or efficacy grade between treatments D14 and D28 (P>0.05).

[0138] Table 6 Comparison of treatment efficacy for D7 and D14

[0139]

[0140] Table 7 Comparison of treatment efficacy for D14 and D28

[0141]

[0142] In addition, subgroup analysis was performed according to the NCI classification, as shown in Tables 8 to 10: In terms of cure rate, the cure rate of grade II patients was significantly higher than that of grade I and III patients (P<0.05); in terms of efficacy rate, the efficacy rate of grade III patients was higher than that of grade I and II patients at D7 and D14, and the difference was statistically significant (P<0.05), but the difference was not statistically significant at D28 (P>0.05).

[0143] Table 8 Comparison of treatment efficacy for D7 at different NCI levels

[0144]

[0145]

[0146] Table 9 Comparison of treatment efficacy for D14 at different NCI levels

[0147]

[0148] Table 10 Comparison of treatment efficacy for D28 at different NCI levels

[0149]

[0150] Subgroup analysis based on the drug treatment regimens, as shown in Table 11, revealed the following: at day 14, the effective rate of the targeted drug group was 78.8%, and the effective rate of the chemotherapy drug group was 80%, with no statistically significant difference (P>0.05); at day 28, the effective rate of the targeted drug group was 81.8%, and the effective rate of the chemotherapy drug group was 87.5%, with no statistically significant difference (P>0.05).

[0151] Table 11 Comparison of efficacy at each assessment point of HFSR / HFSR

[0152]

[0153] The results above show that the external application of the traditional Chinese medicine preparation of the present invention can effectively reduce the severity of HFSR / HFSR and NCI classification, especially can rapidly relieve the symptoms of patients with grade III and cure the symptoms of patients with grade II.

[0154] 2.3.2 Pain

[0155] Of the 48 patients (82.8% of the total) who presented with pain at baseline, 41 had moderate to severe pain. Figure 4 It can be seen that the number of patients with no pain is on the rise, while the number of patients with moderate to severe pain is on the decline.

[0156] Comparing the changes in pain NRS grade and NRS score before and after treatment, as shown in Tables 12 to 14, it can be concluded that there were significant differences between the baseline and D14 and D28 (P<0.05), and further comparison of the data between the D14 and D28 groups also showed statistical significance (P<0.05).

[0157] Table 12 Changes in NRS pain grading before and after treatment (cases)

[0158]

[0159] Table 13 Comparison of baseline and treatment D14 NRS scores

[0160]

[0161] Table 14 Comparison of NRS scores on treatment days 14 and 28.

[0162]

[0163] The pain relief rates of 48 patients with pain symptoms at baseline were compared, as shown in Table 15. The results showed that the pain relief rate on day 14 was 77.1% and the pain relief rate on day 28 was 91.7%, which were higher than those on day 14 and the difference was statistically significant (P<0.05).

[0164] Table 15 Comparison of pain relief on treatment days 14 and 28.

[0165]

[0166] 2.3.3 HFSR-14 Quality of Life

[0167] Comparing the patients' quality of life before and after treatment, as shown in Tables 16 and 17, it was found that the patients' quality of life scores steadily improved with the extension of treatment time, and the improvement on D28 was more significant than that on D14 (P<0.05).

[0168] Table 16 Comparison of baseline and treatment D14 HFSR-14 scores

[0169]

[0170] Table 17 Comparison of HFSR-14 scores between treatment D14 and D28

[0171]

[0172] The results of pain and HFSR-14 quality of life show that the topical application of the traditional Chinese medicine preparation of the present invention can effectively relieve patients' pain and improve their quality of life. In addition, long-term continuous use on the basis of effectiveness is beneficial to further relieve pain and improve quality of life.

[0173] 2.3.4 Common Symptoms

[0174] The scores of common HFSR / HFSR symptoms before and after treatment were compared, as shown in Table 18. The results showed that on day 28 after treatment, there were significant improvements in numbness, tingling, pain, hypoesthesia, erythema, desquamation, pigmentation, swelling, and ulceration compared to baseline (P<0.05), while there was no statistically significant difference in the improvement of burning sensation (P>0.05).

[0175] Table 18 Comparison of common symptom scores before and after treatment

[0176]

[0177]

[0178] As can be seen from the above results, the traditional Chinese medicine preparation of the present invention can effectively relieve clinical symptoms such as numbness, tingling, pain, dulled sensation, erythema, desquamation, pigmentation, swelling, and ulceration in the hands and feet of patients when applied externally.

[0179] 2.4.5 Completion rate of antitumor drugs

[0180] Of the 58 patients included in the analysis, only 2 required dose reduction or discontinuation of medication due to HFSR / HFSR, resulting in an antitumor drug completion rate of 96.6%. This demonstrates that the topical application of the traditional Chinese medicine preparation of this invention can ensure the completion rate of antitumor treatment, thereby improving the treatment effect for patients.

[0181] 3.6 Adverse Reactions

[0182] According to the Chinese Pharmacopoeia, all components of the drug in this invention are non-toxic. Furthermore, the treatment method is external application. Statistical analysis showed that only one patient in the study experienced itching; the remaining patients did not exhibit any treatment-related toxic reactions such as rash, blisters, or skin redness, indicating good safety. These results demonstrate that the traditional Chinese medicine preparation of this invention is safe and reliable for external use, with no particularly serious adverse reactions occurring.

[0183] 4. Analysis and Explanation of Research Results

[0184] 4.1 Analysis of Case Completion Status

[0185] The study included 62 patients, reaching the planned sample size of 60. Analysis of 4 dropout patients revealed that 2 were elderly patients with advanced cancer, in poor general condition, and exhibited poor adherence to the ointment application, discontinuing treatment without authorization; these could be considered intentional or unintentional non-compliance with study guidelines. One patient died due to unforeseen circumstances, resulting in treatment interruption; neither of these cases was related to the herbal preparation of this invention. One patient experienced itching after applying the ointment, which subsided upon discontinuation, suggesting a possible connection to the experimental ointment.

[0186] 4.2 Analysis of baseline data

[0187] After excluding data dropouts, data from 58 patients were included in the analysis. A large proportion of patients were over 60 years old, and most had an educational level of junior high school or below. Since this study incorporated subjective observation indicators such as the quality of life scale, common symptom scale, and pain score, lower educational levels may bias the results. Therefore, researchers need to provide professional guidance to patients during follow-up statistical analysis to assist them in completing the scales.

[0188] 4.3 Analysis of the efficacy of NCI classification

[0189] Regarding the efficacy of NCI grading, the efficacy of D14 was improved compared to D7, and the difference was statistically significant (P<0.05), but there was no significant difference in efficacy compared to D28 (P>0.05). Therefore, in order to shorten the research cycle, the treatment time can be set to 2 weeks in future studies.

[0190] Subgroup analysis: Subgroup analysis based on drug treatment regimens showed no significant difference in efficacy between targeted therapy-related HFSR and chemotherapy-related HFSR at any assessment point (P>0.05). Therefore, we can conclude that the traditional Chinese medicine preparation of this invention has good efficacy for both. Subgroup analysis based on baseline NCI classification: The cure rate of grade II patients was significantly higher than that of grade I and III patients (P<0.05). At the assessments on treatment days 7 and 14, the response rates of grade III patients were significantly higher than those of grade I and II patients, indicating that the average time for grade III patients to achieve effective symptom relief was shorter than that of grade I and II patients. This is consistent with the significant decrease in grade III patients at day 7 in the figure. At day 28, there was no significant difference in the response rates among the three groups. Considering that grade I patients only have mild skin changes and sensory abnormalities that do not affect daily life, their perception of symptom improvement is weaker than that of grade III patients. The efficacy can only be assessed by achieving the cure criteria. Future studies could include only grade II and above patients to make the results more representative.

[0191] 4.4 Analysis of changes in pain, quality of life, and common symptoms

[0192] Regarding changes in pain and quality of life, the improvement on D14 was better than that on D7 (P<0.05), and the improvement on D28 was better than that on D14 (P<0.05), indicating that long-term continuous use of the traditional Chinese medicine preparation of the present invention is beneficial for HFSR / HFSR patients to further alleviate pain and improve quality of life. In addition, apart from burning sensation, the traditional Chinese medicine preparation of the present invention has a good effect on improving common symptoms of HFSR / HFSR patients such as numbness, tingling, pain, sensory dullness, erythema, desquamation, pigmentation, swelling, and ulceration (P<0.05).

[0193] 4.5 Analysis of the completion rate and safety of anti-tumor drugs

[0194] The completion rate of antitumor drugs during the entire treatment process was 96.6%, and only one patient experienced the adverse reaction of itching. This indicates that the topical application of the traditional Chinese medicine preparation of the present invention is safe and reliable for the treatment of HFSR / HFSR, and can reduce the occurrence of patients interrupting treatment, changing medications, or being forced to reduce dosage due to intolerance to HFSR / HFSR, thereby further improving the antitumor treatment effect for patients.

[0195] 5. Typical Cases

[0196] (1) Patient Qin, male, 55 years old, gastric adenocarcinoma. Six months after surgery, liver metastasis was found. He was subsequently treated with "sintilimab + purpura + tegafur" and "oxaliplatin + raltitrexed". After a follow-up examination, his disease progression was observed, and he was switched to third-line treatment with "apatinib 250mg qd". After two cycles of treatment, he developed HFSR. When the patient presented, his hands were red, swollen, cracked, and desquamated, accompanied by severe pain and swelling, which affected his ability to dress, make a half-clenched fist, and other actions, seriously affecting his daily life. His NCI classification was III. At the time of enrollment, he was still taking apatinib orally. He was given the traditional Chinese medicine preparation of this invention, and was instructed to apply it to the affected area three times a day. He was followed up weekly.

[0197] One week later, all symptoms had improved.

[0198] Two weeks later, the patient's HFSR symptoms improved significantly, especially the desquamation and fissures, which were almost completely healed. There was no swelling or pain, only slight pigmentation. The NCI grade was 0, and the condition no longer affected daily life. The patient successfully completed subsequent apatinib treatment at the original dose (treatment results can be found in...). Figure 5 ).

[0199] (2) Patient Zhao, male, 76 years old, post-esophageal cancer surgery. His current treatment regimen is "tegafur 40mg twice daily for 1-14 days," which has been completed for 7 cycles. 140 days after the first dose, he developed HFSR (High-Frequency Syndrome). At the time of consultation, he presented with erythema, blisters, and pigmentation on both feet, accompanied by severe pain, an NRS score of 8, affecting his standing and walking; his NCI classification was III. Upon enrollment, he continued tegafur treatment and was given the traditional Chinese medicine preparation of this invention, instructed to apply it to the affected area three times daily, with weekly follow-ups.

[0200] One week later, a follow-up visit showed that the blisters had subsided, the pain had decreased, and the NRS score was 3. Standing was not affected, but long-distance walking was limited; the NCI classification was Grade II. Two weeks later, a follow-up visit showed that the erythema on both hands had disappeared, with some pigmentation and mild desquamation; there was no pain, and the movement of both feet was not affected; the NCI classification was Grade I (treatment results are available in [link to treatment report]). Figure 6 ).

[0201] (3) Patient Gao, female, 50 years old. She underwent surgery for uterine leiomyomas on July 24, 2023. Postoperatively, she was treated with "liposomal doxorubicin + anlotinib 4mg qd". After 2 cycles, she developed hand and foot skin reactions. At the time of consultation, she presented with erythema and desquamation on both hands, accompanied by severe pain, with an NRS score of 8, affecting her ability to hold chopsticks, dress and undress, etc.; and erythema and desquamation on both feet, accompanied by swelling and pain, with an NRS score of 8, affecting her ability to stand and walk; her NCI grade was III. At enrollment, she continued to be treated with anlotinib and was given the traditional Chinese medicine preparation of this invention, instructed to apply it to the affected area 3 times a day, and followed up weekly.

[0202] Two weeks later, at the follow-up visit, the erythema on both hands had subsided, with slight desquamation, no pain, and no impact on hand movements; both feet showed mild desquamation, and the pain had subsided. The NCI classification was Grade I (treatment results are available in the table below). Figure 7 ).

[0203] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A traditional Chinese medicine composition for treating hand-foot skin reactions, characterized in that, It is made from the following components in parts by mass: Angelica sinensis 50-150 parts, honeysuckle 50-150 parts, Polygonum cuspidatum 100-200 parts, Angelica dahurica 40-80 parts, licorice 20-60 parts, Lithospermum erythrorhizon 50-150 parts, frankincense 10-50 parts, myrrh 10-50 parts, dragon's blood 5-15 parts.

2. A traditional Chinese medicine preparation for treating hand-foot skin reactions, characterized in that, The traditional Chinese medicine composition and excipient combination as described in claim 1; The excipients are petrolatum and ethylparaben solution; Alternatively, it could be sesame oil and beeswax.

3. The method for preparing the traditional Chinese medicine preparation according to claim 2, characterized in that, When the excipients are petrolatum and ethylparaben solution, the preparation method is as follows: A. Mix Angelica sinensis, Lonicera japonica, Polygonum cuspidatum, Angelica dahurica, Glycyrrhiza uralensis, and Lithospermum erythrorhizon with 5-10 times their weight of 50-80% ethanol solution, reflux and extract 1-3 times, each time for 40-80 minutes, combine the extracts, and concentrate the extract to a fluid extract with a relative density of 1.14-1.

20. B. After freezing frankincense and dragon's blood, mix, pulverize and sieve to obtain frankincense-dragon's blood powder; myrrh is pulverized separately and sieved to obtain myrrh powder. Alternatively, frankincense and myrrh can be pulverized and sieved, then 10-14 times their weight of ethanol with a volume concentration of 80-100% can be added for percolation. The percolate can be collected and concentrated to a relative density of 1.00-1.15 to obtain frankincense-myrrh percolate concentrate. Bloodskin can be pulverized and sieved to obtain bloodskin powder. C. Add the fluid extract described in step A to 1500-2200 parts of melted petroleum jelly and homogenize to obtain a matrix; D. Mix the frankincense-dragon's blood powder, myrrh powder, ethylparaben solution and the matrix described in step B with the matrix described in step C, and cool to obtain the final product; Alternatively, the frankincense-myrrh percolation concentrate, dragon's blood powder, ethylparaben solution, and matrix described in step B can be mixed and cooled to obtain the final product.

4. The preparation method according to claim 3, characterized in that, The sieving process involves passing through a 100-200 mesh sieve.

5. The preparation method according to claim 3, characterized in that, The temperature of the petroleum jelly is 45~60℃.

6. The preparation method according to claim 3, characterized in that, The total amount of frankincense-dragon's blood powder and myrrh powder is in a mass ratio of 15~25:1 to the ethylparaben solution, and the concentration of the ethylparaben solution is 1~3%.

7. The preparation method according to claim 3, characterized in that, The concentration temperature in step B is 50~60℃.

8. A method for preparing the traditional Chinese medicine preparation according to claim 2, characterized in that, When the excipients are sesame oil and beeswax, the preparation method is as follows: a. Soak angelica, honeysuckle, Japanese knotweed, angelica dahurica, and licorice in 1500-2500 parts of sesame oil for 2-5 days; b. After soaking, heat to 100~160℃, maintain for 20~60 minutes, filter, and collect the liquid phase components; Add alkanet root to the liquid phase component, heat to 140~180℃, fry for 10~30 minutes, filter out the residue, and obtain filtered oil; c. Keep the oil temperature at 110~135℃, add 300~700 parts of beeswax, stir for 3~8 minutes until the beeswax is completely melted, and then cool to 40~55℃; d. Add the crushed and sieved frankincense, dragon's blood, and myrrh powder, and stir well to obtain the final product.

9. The use of the traditional Chinese medicine composition according to claim 1 in the preparation of a medicament for treating hand and foot skin reactions.

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