Pharmaceutical composition and application thereof in preparing medicine for treating EGFRIs (epidermal growth factor receptors)-induced skin toxicity

Abstract

The invention relates to a pharmaceutical composition and application thereof in preparation of a medicine for treating EGFRIs-induced skin toxicity, the pharmaceutical composition comprises chlorogenic acid, ferulic acid and zinc salt, the mass ratio of chlorogenic acid to ferulic acid is 4: 1-1: 4, and the mass ratio of the total amount of chlorogenic acid and ferulic acid to zinc salt is 4: 1-1: 4. The pharmaceutical composition disclosed by the invention has the characteristics of definite curative effect and easiness in industrialization.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition for treating skin toxicity caused by EGFRIs, a preparation method thereof, and an application of the pharmaceutical composition in preparing a therapeutic drug for skin toxicity caused by EGFRIs. Background Art

[0002] In cancer treatment, epidermal growth factor receptor inhibitors (EGFRIs) are widely used in the clinical treatment of cancer patients with EGFR activating mutations, especially non-small cell lung cancer, breast cancer, colorectal cancer, etc. However, with the use of EGFRIs, patients have experienced a variety of adverse reactions, among which skin adverse reactions (including papulopustular rash, dry and itchy skin, paronychia, abnormal hair regeneration, etc.) are the most common adverse reactions, with an incidence rate of up to 79-88%. In the early stages of skin toxicity, it seriously affects the patient's daily life and mood. If the toxicity is not treated promptly and effectively, it will gradually worsen with the continued use of EGFRIs. Severe skin toxicity will force the dose of EGFRIs to be reduced or even stopped, and treatment interruption will aggravate the deterioration of cancer.

[0003] At present, the expert consensus on the treatment of EGFRIs adverse reactions recommends the topical use of antibiotics, steroids and emollients, or oral antibiotics, immunomodulators, etc. for adjuvant treatment, but these methods have poor clinical efficacy, recurrent attacks and long-term use bring side effects, causing secondary physical and mental damage to patients. Therefore, it is urgent to develop drugs that are effective in treating EGFRIs-induced skin toxicity and easy to industrialize for clinical use. Summary of the invention

[0004] In view of the deficiencies of the prior art, the present invention provides a pharmaceutical composition for treating skin toxicity caused by EGFRIs, a preparation method thereof, and an application thereof in preparing a therapeutic drug for treating skin toxicity caused by EGFRIs. The pharmaceutical composition can effectively treat skin toxicity caused by EGFRIs, has a definite therapeutic effect, and can better meet clinical needs.

[0005] To achieve the above object, the present invention adopts the following technical solution:

[0006] A pharmaceutical composition comprising the following components:

[0007] Chlorogenic acid, ferulic acid and zinc salt, wherein the mass ratio of the chlorogenic acid to the ferulic acid is 4:1-1:4, and the mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 4:1-1:4.

[0008] Chlorogenic acid has the following structural formula: .

[0009] Ferulic acid has the following structural formula: .

[0010] Preferably, the mass ratio of the chlorogenic acid to the ferulic acid is 2:1 to 1:3. Most preferably, the mass ratio of the chlorogenic acid to the ferulic acid is 1.5:1.

[0011] Preferably, the mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 3:1 to 1:3. Most preferably, the mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 3:1.

[0012] Preferably, the zinc salt is one or more of zinc acetate, zinc sulfate, zinc nitrate, calcium zinc gluconate or zinc oxide, preferably zinc acetate.

[0013] The second objective of the present invention is to provide the use of the pharmaceutical composition in the preparation of therapeutic drugs for EGFRIs-induced skin toxicity.

[0014] Preferably, the therapeutic drug is an external-use drug.

[0015] The EGFRIs include erlotinib, imatinib, erlotinib, sorafenib, rituximab, trastuzumab, cetuximab, bevacizumab or panitumumab.

[0016] The skin toxicity caused by EGFRIs is papulopustular rash, dry and itchy skin, desquamation, periungual inflammation or abnormal hair regeneration.

[0017] The beneficial effects of the pharmaceutical composition of the present invention are as follows:

[0018] The present invention finds that chlorogenic acid and ferulic acid have the effect of reversing the inhibitory effect of EGFRIs on the activity of human skin keratinocytes (HaCa-T cells), and can reduce the apoptosis of HaCa-T cells caused by EGFRIs. Zinc acetate can enhance the effect of chlorogenic acid and ferulic acid in reversing the inhibitory effect of EGFRIs on the activity of HaCa-T cells. The composition of chlorogenic acid, ferulic acid and zinc acetate is effective in treating skin toxic reactions such as papulopustular rash, dry and itchy skin, desquamation, periungual inflammation, abnormal hair regeneration and the like caused by EGFRIs, with an effective rate of up to 66.67%, providing a pharmaceutical composition for the clinical treatment of such skin toxic reactions. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a comparison chart of the effects of chlorogenic acid on the activity of HaCa-T cells in Example 1 (n=6, X±SD, * P <0.05, ** P <0.01).

[0020] Figure 2 This is a comparison chart of the effects of ferulic acid on the activity of HaCa-T cells in Example 1 (n=6, X±SD, * P <0.05, ** P <0.01).

[0021] Figure 3 This is a comparison chart of the effect of zinc acetate on the activity of HaCa-T cells in Example 1 (n=6, X±SD, * P <0.05, ** P <0.01).

[0022] Figure 4 This is a comparison of the effects of different concentrations of chlorogenic acid in reversing the inhibitory effects of erlotinib hydrochloride on HaCa-T cell activity in Example 2 (n=6, X±SD, * P <0.05, ** P <0.01).

[0023] Figure 5 This is a comparison of the effects of different concentrations of ferulic acid in reversing the inhibitory effects of erlotinib hydrochloride on HaCa-T cell activity in Example 2 (n=6, X±SD, * P <0.05, ** P <0.01).

[0024] Figure 6 This is a comparison chart of the effects of different ratios of chlorogenic acid and ferulic acid in Example 2 on reversing the inhibitory effects of erlotinib hydrochloride on HaCa-T cell activity when the chlorogenic acid concentrations were 2, 4, and 8 μg / mL, respectively (n=6, X±SD, *P<0.05, **P<0.01).

[0025] Figure 7 This is a comparison chart of the effects of ferulic acid (4 μg / mL) combined with different concentrations of chlorogenic acid in reversing the inhibition of erlotinib hydrochloride on HaCa-T cell activity in Example 2 (n=6, X±SD, * P <0.05, ** P <0.01).

[0026] Figure 8 This is a comparison of the inhibitory effects of chlorogenic acid and ferulic acid in different ratios on erlotinib hydrochloride-induced HaCa-T cell apoptosis in Example 3 (n=3, X±SD, * P <0.05, ** P <0.01).

[0027] Fig. 9 This is a comparison chart of the effects of different concentrations of zinc acetate on reversing the activity of erlotinib hydrochloride on HaCa-T cells in Example 4 (n=6, X±SD, * P <0.05, ** P <0.01).

[0028] Fig.10This is a comparison chart of the effects of the chlorogenic acid, ferulic acid and zinc acetate compositions of different ratios and concentrations in reversing the inhibitory effects of erlotinib hydrochloride on HaCa-T cell activity in Example 4 (n=6, X±SD, * P <0.05, ** P <0.01).

[0029] Fig.11 This is a graph showing the alleviation of skin toxicity symptoms in model mice after treatment with the composition of the present invention in Example 5.

[0030] Fig.12 This is a comparison chart of the effects of the composition of the present invention on the body weight of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0031] Fig.13 This is a comparison chart of the effects of the composition of the present invention on the spleen index of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0032] Fig.14 This is a comparison chart of the effects of the composition of the present invention on the liver index of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0033] Fig.15 This is a comparison chart of the effects of the composition of the present invention on the thymus index of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0034] Fig.16 This is a comparison chart of the effects of the composition of the present invention on the skin moisture content of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0035] Fig.17 This is a comparison chart of the effects of the composition of the present invention on the skin elasticity of model mice after treatment in Example 5 (n=6, X±SD, * P <0.05, ** P <0.01).

[0036] Fig.18 The results of HE and Oil Red staining of the skin of model mice after treatment with the composition of the present invention in Example 5 (the scale bar in the figure is 100 μm). DETAILED DESCRIPTION

[0037] The sources of cells, animals, drugs, reagents, and instruments involved in the examples are as follows:

[0038] Experimental cells: HaCa-T cells were purchased from the Shanghai Cell Bank, Chinese Academy of Sciences.

[0039] Experimental animals: SPF-grade BALB / c female mice were purchased from Jiangsu Jicui Pharmaceutical Biotechnology Co., Ltd., with experimental animal license number (SCXK (Su) 2022-0009), and were raised in the Experimental Animal Center of Jiangsu Institute of Traditional Chinese Medicine under light / dark (12 h / 12 ​​h) and temperature (22±3)°C, with free access to food and water, and experimental animal use license (SYXK (Su) 2016-0018).

[0040] Drugs and reagents: chlorogenic acid, ferulic acid (HPLC ≥ 98%, Chengdu Pusi Biotechnology Co., Ltd.); erlotinib hydrochloride (Shanghai Aladdin Biochemical Technology Co., Ltd.); DMEM culture medium (Gibco); fetal bovine serum (Deary Tech); CCK8 (Nanjing Enjing Biotechnology Co., Ltd.); DMSO (Rohn's reagent); penicillin-streptomycin-amphotericin B solution (Jiangsu KeyGen Biotechnology Co., Ltd.); zinc acetate, zinc sulfate, zinc nitrate, calcium zinc gluconate, zinc oxide (Rohn's reagent).

[0041] Instruments: Mutiskan Go microplate reader, ST16R centrifuge, 311 CO2 incubator (Thermo Fisher); clean bench (Suantai Air Technology Co., Ltd.); cell counter (IC1000, Countstar); MS205DU 1 / 100,000 electronic balance (Mettler Toledo); OS20-Pro mechanical stirrer (SCILogex); water purifier (Millipore, TANKPE 060); THZ-82AHS gas bath constant temperature and constant speed oscillator (Jintan City, Jiangsu Jincheng Guosheng Experimental Instrument Factory).

[0042] All other sources are commercial unless otherwise specified.

[0043] Example 1: Effects of chlorogenic acid, ferulic acid and zinc acetate on HaCa-T cell activity

[0044] HaCa-T cells in the logarithmic growth phase were taken and 5×10 3 The cells were inoculated in 96-well plates at 100 μg / well, with 6 parallel wells in each group. The cells were cultured in high-glucose DMEM medium containing 10% fetal bovine serum in a 5% CO2, 37 ℃ incubator for 24 h. Then, different concentrations of chlorogenic acid and ferulic acid (1.5625, 3.125, 6.25, 12.5, 25, 50, 100, 200 μM) and zinc acetate (5, 15, 25, 35, 50, 75, 90 μM) were added and incubated at 37 ℃, 5% CO2 for 24 h.

[0045] After the incubation, 10 μL of CCK8 reagent was added to each well, and the incubation continued for 2 h. The absorbance at 450 nm was measured by a microplate reader, and the relative cell activity was calculated (relative cell activity = (absorbance of the dosing well - absorbance of the culture medium) / (absorbance of the blank group - absorbance of the culture medium)).

[0046] The results are as follows Figures 1 to 3 As shown: Chlorogenic acid and ferulic acid in the range of 1~100 μM and zinc acetate in the range of 75 μM had no significant effect on the activity of HaCa-T cells.

[0047] Example 2: Combinations of chlorogenic acid and ferulic acid in different ratios and concentrations reverse the inhibitory effect of erlotinib hydrochloride on HaCa-T cell activity

[0048] HaCa-T cells in the logarithmic growth phase were taken and 5×10 3 Cells were seeded in 96-well plates at 100 μM each and 8 μM erlotinib hydrochloride was added. Each group had 6 parallel wells. The cells were cultured in high-glucose DMEM medium containing 10% fetal bovine serum, and then different concentrations of chlorogenic acid and ferulic acid (1.5625, 3.125, 6.25, 12.5, 25, 50, 100, 200 μM) were added, and the compositions with the mass ratio of chlorogenic acid to ferulic acid were 4:1, 2:1, 1:1, 1:2, 1:4 (the final concentration of chlorogenic acid was 2, 4, 8 μg / mL), and the compositions with a ferulic acid concentration of 4 μg / mL and a series of chlorogenic acid concentrations (ratios of 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:4) were added. The cells were incubated at 37°C, 5% CO2 for 24 h.

[0049] After the incubation, 10 μL of CCK8 reagent was added to each well, and the incubation was continued for 1.5 h. The absorbance at 450 nm was measured by a microplate reader, and the relative cell activity was calculated (relative cell activity = (absorbance of the dosing well - absorbance of the culture medium) / (absorbance of the blank group - absorbance of the culture medium)).

[0050] The results are as follows Figures 4 to 7 The results showed that ferulic acid and chlorogenic acid at 12.5-100 μM could significantly reverse the inhibitory effect of HaCa-T cells induced by erlotinib hydrochloride (P < 0.05, P < 0.01); the ratio of ferulic acid to chlorogenic acid at 2:1-1:3 (the final concentration of chlorogenic acid was 4, 8 μg / mL) had a significant effect on reversing the inhibition of HaCa-T cells induced by erlotinib hydrochloride (P < 0.05).

[0051] In addition, from Figure 7It can be seen that the ratio of ferulic acid to chlorogenic acid in the range of 1:1 to 1:2 is significantly higher than that of ferulic acid alone and chlorogenic acid alone in reversing the inhibition of HaCa-T cells caused by erlotinib hydrochloride, which indicates that within this range, the combined use of ferulic acid and chlorogenic acid is better for reversing the inhibition of HaCa-T cells caused by erlotinib hydrochloride, and the synergistic effect is best when the ratio of ferulic acid to chlorogenic acid is 1:1.5.

[0052] Example 3: Effects of different ratios of chlorogenic acid and ferulic acid on the inhibition of apoptosis of HaCa-T cells induced by erlotinib hydrochloride

[0053] HaCa-T cells in the logarithmic growth phase were collected and the cell suspension was diluted to 2×10 5 / mL, inoculated in 6-well plates, 2 mL per well, incubated for 24 h. After cell adhesion, the cells were treated with drugs and divided into 8 groups: normal control group, model group (16 μM erlotinib hydrochloride treated for 2 h), ferulic acid and chlorogenic acid combination (1:0.5, 1:1.5, 1:2.5, 1:3.5, ferulic acid concentration was 5 μg / mL), 16 μM erlotinib hydrochloride and ferulic acid, chlorogenic acid combination co-treated for 2 h; after treatment, PBS was washed three times, 50 μL was taken and added to a 1.5 mL centrifuge tube, 50 μL of cell apoptosis detection reagent was added in a 1:1 ratio, incubated in the dark for 15 min, and the apoptosis of HaCa-T cells was determined by flow cytometry, and analyzed by flow cytometry.

[0054] The results are as follows Figure 8 The results showed that ferulic acid to chlorogenic acid ratios of 1:0.5 to 1:3.5 could reduce erlotinib hydrochloride-induced apoptosis of HaCa-T cells (P < 0.05, P < 0.01), and the effect was most significant when the ratio was 1:1.5 (P < 0.001).

[0055] Example 4: Combinations of chlorogenic acid, ferulic acid and zinc acetate in different ratios and concentrations reverse the inhibitory effect of erlotinib hydrochloride on HaCa-T cell activity

[0056] HaCa-T cells in the logarithmic growth phase were taken and 5×10 3 Cells were inoculated in 96-well plates at 100 μM per well and 8 μM erlotinib hydrochloride was added. Each group had 6 parallel wells. The cells were cultured in high-glucose DMEM medium containing 10% fetal bovine serum. Different concentrations of zinc acetate and a combination of chlorogenic acid, ferulic acid and zinc acetate were added, and the cells were incubated at 37°C and 5% CO2 for 24 h.

[0057] After the incubation, 10 μL of CCK8 reagent was added to each well, and the incubation was continued for 1.5 h. The absorbance at 450 nm was measured by a microplate reader, and the relative cell activity was calculated (relative cell activity = (absorbance of the dosing well - absorbance of the culture medium) / (absorbance of the blank group - absorbance of the culture medium)).

[0058] The results are as follows Figures 9-10 The results showed that zinc acetate at 15-35 μM could significantly reverse the inhibitory effect of erlotinib hydrochloride on HaCa-T cells (P < 0.05, P < 0.01). When the total concentration of the chlorogenic acid and ferulic acid combination was 5 and 10 μg / mL, the mass ratio of chlorogenic acid and ferulic acid to zinc acetate was 3:1-1:3, which could significantly improve the reversal of the inhibitory effect of chlorogenic acid and ferulic acid on the activity of HaCa-T cells by erlotinib hydrochloride (P < 0.05). There was no significant difference among the groups in the 3:1-1:3 ratio. Therefore, the mass ratio of chlorogenic acid and ferulic acid combination to zinc acetate was selected as 3:1.

[0059] Example 5: Pharmacodynamics of the pharmaceutical composition against skin toxicity induced by EGFRIs

[0060] BALB / c mice (about 20 g, female) were fed for 3 days to adapt to the environment and then randomly divided into 2 groups according to body weight. They were randomly divided into a blank group and an erlotinib hydrochloride group, with 10 mice in the blank group and 20 mice in the erlotinib hydrochloride group. Preparation of erlotinib hydrochloride suspension: Take 500 mg of erlotinib hydrochloride, add 0.25% sodium carboxymethyl cellulose, add pure water to 50 mL, ultrasonicate for 30 minutes, and shake well when administering. The day before administration, the back of BALB / c mice was depilated and erlotinib hydrochloride solution was administered by gavage at a dose of 150 mg / kg (i.e., 0.015 mL / g), once a day, and skin toxicity occurred after continuous administration (about 48 days).

[0061] After the establishment of the animal model of skin toxicity caused by EGFRIs, the rats in the erlotinib hydrochloride group were grouped again and randomly divided into 10 rats in the erlotinib hydrochloride group (model group) and 10 rats in the erlotinib hydrochloride + drug composition group (drug composition group). Preparation of the drug composition: Take 100 mg of ferulic acid, 150 mg of chlorogenic acid, and 85 mg of zinc acetate, add 0.25% sodium carboxymethyl cellulose, and then add pure water to 50 mL, ultrasonicate for 30 min, and shake well when administering. Each group of mice continued to be gavaged with 150 mg / kg of erlotinib hydrochloride once a day. On this basis, the mice in the drug composition group applied the drug composition to the onset site of mouse skin toxicity at a dose of 333.5 mg / kg, and the model group applied normal saline once a day; the drug was administered continuously for 14 days.

[0062] After the animal experiment, the skin toxicity of each group of mice was observed and the severity of skin redness, swelling, herpes, and rash was statistically analyzed ( Fig.11 ), and the weight change curves of mice in each group were statistically analyzed ( Fig.12 ), and the water content and skin elasticity of a part of the mouse back skin were measured ( Fig.16 , Fig.17 ), the thymus, spleen and liver of mice in different groups were weighed, the organ index was calculated, and the differences between the groups were compared ( Fig.13 , Fig.14 , Fig.15 ), HE and Oil Red staining of the skin was performed on the pathological sections to observe the efficacy of the drug composition ( Fig.18 ).

[0063] The results are shown in Tables 1 to 3: From the severity of the dryness, desquamation, redness, swelling, herpes and rash of the mouse skin, it can be seen that the model group mice lost hair around the eyes, shoulders, necks and backs, and had dryness, desquamation, cracking and herpes around the mouth and limbs, and their activity status became worse; the pharmaceutical composition has a therapeutic effect on skin toxicity, and can significantly reduce the incidence of redness, swelling, herpes and rash on the mouse skin. The mouse hair resumed growth, and the symptoms disappeared significantly. The skin toxicity reaction was effectively treated, and the effective rate reached 66.67%.

[0064] Table 1 Statistics of the severity of redness and swelling of the limbs of mice

[0065] Group Number none Mild Moderate Severe Incidence / % blank 10 10 0 0 0 0 Model Group 10 0 2 5 3 100% Pharmaceutical composition group 10 7 3 0 0 33.33%

[0066] Table 2 Statistics of severity of herpes in mice

[0067] Group Number none Mild Moderate Severe Incidence / % blank 10 10 0 0 0 0 Model Group 10 0 6 4 0 100% Pharmaceutical composition group 10 7 2 1 0 33.33%

[0068] Group Number none Mild Moderate Severe Incidence / % blank 10 10 0 0 0 0 Model Group 10 0 6 2 2 100% Pharmaceutical composition group 10 7 3 0 0 33.33%

[0069] Table 3 Statistics of the severity of skin rash in mice

[0070] During the course of treatment, the body weight of mice in the model group did not change significantly, while the body weight of mice in the drug combination group increased (P<0.05, P<0.001), indicating that the quality of life of mice can be improved after administration. The liver index and spleen index of mice in the model group increased significantly, and the thymus index decreased, indicating that erlotinib hydrochloride had a serious damage to the immune system of mice; after administration of the drug combination, it can be restored (P<0.01, P<0.001), indicating that the drug can reverse and protect the organ damage caused by erlotinib hydrochloride.

[0071] From the analysis of the results of skin water content and skin rebound, the water content of the mice in the model group was significantly reduced, indicating that erlotinib hydrochloride had serious damage to the skin barrier of mice and affected its moisturizing function; the skin water content increased significantly after administration of the drug composition solution (P<0.001); from the results of skin elasticity, the skin rebound time of the mice in the model group was significantly prolonged, indicating that erlotinib hydrochloride may have serious damage to the skin collagen and elastic fibers of mice and affect the skin elasticity function; the skin rebound time of the mice was significantly shortened after administration of the drug composition (P<0.001); it shows that local application of the drug composition can have a certain repair effect on the skin barrier.

[0072] From the HE results, it can be seen that compared with the blank group, the characteristics of skin inflammation were observed in the model group mice, namely, parakeratosis (retention of stratum corneum cell nuclei), significant thickening of the stratum corneum, changes in skin structure, and the skin toxicity of the mice was improved after administration of the drug composition. The results of oil red staining showed that compared with the blank group, the oil red-stained sebaceous glands in the model group were reduced, the swollen follicles were ruptured, and the oil secretion was significantly reduced. Compared with the model, the oil secretion of the mouse skin was significantly restored after administration of the drug composition, indicating that the drug composition can effectively improve the phenomenon of abnormal oil secretion of sebaceous glands caused by erlotinib hydrochloride.

Claims

1. A pharmaceutical composition, characterized in that The components include: Chlorogenic acid, ferulic acid and zinc salt, wherein the mass ratio of the chlorogenic acid to the ferulic acid is 4:1-1:4, and the mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 4:1-1:

4.

2. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the chlorogenic acid to the ferulic acid is 2:1 to 1:

3.

3. The pharmaceutical composition according to claim 2, characterized in that The mass ratio of the chlorogenic acid to the ferulic acid is 1.5:

1.

4. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 3:1 to 1:

3.

5. The pharmaceutical composition according to claim 1, characterized in that The mass ratio of the total amount of the chlorogenic acid and the ferulic acid to the zinc salt is 3:

1.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The zinc salt is one or more of zinc acetate, zinc sulfate, zinc nitrate, zinc gluconate or zinc oxide.

7. Use of the pharmaceutical composition according to any one of claims 1 to 6 in the preparation of a therapeutic drug for EGFRIs-induced skin toxicity.

8. The use according to claim 7, characterized in that: The therapeutic drug is an external-use drug.

9. The use according to claim 7, characterized in that: The EGFRIs include erlotinib, imatinib, erlotinib, sorafenib, rituximab, trastuzumab, cetuximab, bevacizumab or panitumumab.

10. The use according to claim 7, characterized in that: The skin toxicity caused by EGFRIs is papulopustular rash, dry and itchy skin, desquamation, periungual inflammation or abnormal hair regeneration.

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