JP4091639B2 - Preventive agent and / or treatment agent for skin disorder caused by tyrosine kinase inhibitor - Google Patents

Description

  The present invention relates to a drug and a pharmaceutical composition containing a salicylic acid non-steroidal anti-inflammatory agent as an active ingredient and use thereof for the purpose of preventing and / or treating skin disorders associated with treatment with an EGFR tyrosine kinase inhibitor.

Epidermal growth factor (EGF) is a cytokine that induces division of epidermis and epithelial cells, and binds to epidermal growth factor receptor (EGFR) constituting receptor tyrosine kinase on the cell membrane surface to activate EGFR. EGFR is overexpressed in many human epithelial malignant tumors and malignant gliomas, and it is becoming clear that it is involved in tumor maintenance and growth. Furthermore, it has been reported that tumors with EGFR expression or overexpression show higher metastasis and poor prognosis than tumors with no expression, and have recently attracted attention as drug targets for anticancer drugs. (See Non-Patent Documents 1, 2, and 3). Numerous EGFR tyrosine kinase inhibitors have been developed in an attempt to inhibit EGFR activation, among which gefitinib ( IRESSA (registered trademark) ) and erlotinib (Erlotinib; TARCEVA (registered trademark) ) have been clinically successful. Has been launched.

Gefitinib is the first EGFR tyrosine kinase inhibitor marketed and is also clinically used in Japan as a treatment for non-small cell lung cancer. Gefitinib is a clinically very useful anticancer agent, but side effects such as acute lung injury, interstitial pneumonia, and skin injury have been reported. Among them, the appearance rate of skin injury is as high as 50% or more. In fact, in a phase II clinical trial conducted in Japanese, it was reported that 67.2% had rash, 49.0% had pruritus, and 33.3% had dry skin (Non-Patent Document 1). reference). Although these skin disorders are not serious, when a skin disorder appears, it is instructed to take appropriate measures such as taking a rest or symptomatic treatment (see Non-Patent Document 4). Therefore, preventing the occurrence of these skin disorders or treating the skin disorders is very important for continuously performing cancer chemotherapy with gefitinib , There is a long-awaited treatment.

Skin damage caused by gefitinib is similar to that observed with other EGFR target reagents, and is reported to be caused by inhibition of EGFR signal transmission in the skin (see Non-Patent Documents 2 and 5). Thus, skin disorders found in gefitinib, other EGFR tyrosine kinase inhibitors, for example erlotinib (TARCEVA (TM)), CI1033, PKI166, GW2016 , EKB569, C225 ( cetuximab), ABX-EGF (panitumumab) , EMD-72000 (matuzumab) and MDX-447 (see Patent Documents 1 and 2) are also considered to be caused. Therefore, even in the EGFR tyrosine kinase inhibitors other than the above-mentioned gefitinib , a drug for clinically preventing or treating a skin disorder as a side effect is very useful.

Currently, gefitinib is clinically indicated for non-small cell lung cancer, but of course other cancers such as esophageal cancer, stomach cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, colon cancer, rectal cancer , Head and neck cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, skin cancer, malignant lymphoma, leukemia, brain tumor, among others, overexpression of EGFR is observed Theoretically, EGFR is involved in the tumor tumor convertibility of all tumors such as breast cancer, bladder cancer, lung cancer, gastric cancer, melanoma, and glioblastoma cells. (See Non-Patent Documents 3 and 6, Patent Documents 3 and 4). In addition, there is a report that an EGFR tyrosine kinase inhibitor is effective for diabetic vascular disorders (see Non-Patent Documents 7, 8, and 9). Indication of EGFR tyrosine kinase inhibitor to other diseases other than cancer There is also a possibility.

  On the other hand, salicylic acid non-steroidal anti-inflammatory agents are antipyretic analgesics that have been known for a long time. Its pharmacological action is to inhibit the production of prostaglandins, thereby exerting antipyretic and analgesic actions. Examples of salicylic acid non-steroidal anti-inflammatory agents include acetylsalicylic acid (aspirin), aspirin aluminum, sodium salicylate, choline salicylate, salicylamide, sazapyrine, diflunisal, ethenamide and the like. Most clinically used is acetylsalicylic acid.

  Examples of the use of salicylic acid-based non-steroidal anti-inflammatory agents for skin diseases include the use of acetylsalicylic acid for skin diseases by hemodialysis (see Patent Document 5), inflammatory skin diseases containing aspirin and synthetic corticosteroids. Although the use (refer patent document 6) is disclosed, these prior literatures do not disclose the use of a salicylic acid non-steroidal anti-inflammatory agent for skin disorders as a side effect of the anticancer agent. Furthermore, the prevention and alleviation effect of the skin damage by the EGFR tyrosine kinase inhibitor shown in the present invention is not disclosed.

JP 2005-529162 A, p7 JP-T 2005-53488, p3 JP-A-8-325299, p3 JP 2005-528368 gazette, p4 JP 2004-51522 A JP-A-8-208487 “Pharmaceutical Interview Form (Iressa® Tablets 250)” p1, AstraZeneca website (http://www.astrazeneca.co.jp/products/index2.html) Vallbohmer D et al. “Epidermal growth factor receptor as a target for chemotherapy” 2005, Suppl 1: S19 Sainsbury, J.R., et al., 1985, Lancet 1: 364 "Iressa (registered trademark) lock 250 package insert 14th edition" p2, AstraZeneca website (http://www.astrazeneca.co.jp/products/index2.html) Lee MW et al. “Cutaneous side effects in non-small cell lung cancer patients treated with Iressa (ZD1829), an inhibitor of epidermal growth factor” Acta Derm Venereol. 2004; 84 (1), p23 Pier Paolo Di Fiore et al. “Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells” Cell, 1987, Vol 51, p1063 Benter et al. “Diabetes-induced renal vascular dysfunction is normalized by inhibition of epidermal growth factor receptor tyrosine kinase” J. Vasc. Res., 2005, 42 (4), p284 Yousif MH et al. `` The role of tyrosine kinase-mediated pathways in diabetes-induced alterations in responsive of rat carotid artery '' Auton Autacoid Pharmacol., 2005, 25 (2), p69 Benter et al. “Epidermal growth factor receptor tyrosine kinase-mediated signaling contributes to diabetes-induced vascular dysfunction in the mesenteric bed” Br. J. Pharmacol., 2005, 145 (6), p829

  EGFR tyrosine kinase inhibitors are clinically very useful drugs as cancer chemotherapeutic agents. However, the incidence of side effects of skin disorders such as rashes exceeds 50%, and in such cases, treatments such as drug withdrawal or symptomatic treatment are instructed. Due to the appearance of such side effects of skin disorders, there is a fact that the administration plan has to be changed, and the anticancer action that the EGFR tyrosine kinase inhibitor potentially holds is not fully exerted. This is an important issue. It has become.

  The present invention has been made in view of the above-mentioned important problems with high medical needs, and an object thereof is a drug and a medicament for preventing and / or treating skin disorders that are side effects of EGFR tyrosine kinase inhibitors. It is to provide a composition.

As a result of intensive studies in view of the above-mentioned important issues with high medical needs, the present inventor has the effect of preventing skin disorders caused by EGFR tyrosine kinase inhibitors in salicylic acid derivatives that are non-steroidal anti-inflammatory drugs. I found. Furthermore, the present inventors have found that not only a preventive effect but also a mitigation effect. Based on these novel findings, the present inventor has a prophylactic agent comprising a salicylic acid non-steroidal anti-inflammatory agent as an active ingredient, characterized in that it prevents and / or treats skin disorders caused by EGFR tyrosine kinase inhibitors And inventions relating to treatment agents and pharmaceutical compositions have been completed.

  By providing the preventive agent, treatment agent and pharmaceutical composition of the present invention, the above-mentioned problems are solved. Specifically, the skin disorder is prevented by means of administering the prophylactic agent, treatment agent and pharmaceutical composition of the present invention to a patient who has not yet developed a skin disorder caused by an EGFR tyrosine kinase inhibitor. Furthermore, the recurrence of the skin disorder is prevented by means of administering the prophylactic agent, treatment agent and pharmaceutical composition of the present invention to a patient who has already developed the skin disorder but has recovered. Alternatively, the disorder is treated by means of administering the prophylactic agent, treatment agent and pharmaceutical composition of the present invention to a patient who has developed the skin disorder.

  It is possible to prevent and treat skin disorders caused by EGFR tyrosine kinase inhibitors using the preventive agent, treatment agent and pharmaceutical composition of the present invention. In addition, by avoiding the side effects, administration of the EGFR tyrosine kinase inhibitor can be continued, and a sufficient antitumor effect can be expected at an early stage. Providing the prophylactic agent, therapeutic agent and pharmaceutical composition of the present invention that brings about the potential anticancer effect of an EGFR tyrosine kinase inhibitor by preventing it as well as treating side effects greatly contributes to cancer therapy. It is something that can be done.

  A first embodiment of the present invention is to provide a prophylactic and / or therapeutic agent for a skin disorder caused by an EGFR tyrosine kinase inhibitor, comprising a salicylic acid non-steroidal anti-inflammatory agent as an active ingredient. That is, the first object of the present invention is to prevent skin disorders caused by EGFR tyrosine kinase inhibitors by using a pharmaceutical composition containing a salicylic acid non-steroidal anti-inflammatory agent as an active ingredient, and / or To treat patients with diseases that require treatment with an EGFR tyrosine kinase inhibitor, and to continue treatment with an EGFR tyrosine kinase inhibitor.

  A second embodiment of the present invention is to provide a pharmaceutical composition containing an EGFR tyrosine kinase inhibitor and a salicylic acid non-steroidal anti-inflammatory agent to a patient having a disease in need of treatment with an EGFR tyrosine kinase inhibitor. . That is, the second object of the present invention is to prevent skin disorders caused by an EGFR tyrosine kinase inhibitor by using a mixed preparation comprising an EGFR tyrosine kinase inhibitor and a salicylic acid non-steroidal anti-inflammatory agent as active ingredients, and / or Alternatively, to treat patients with diseases requiring treatment with an EGFR tyrosine kinase inhibitor, continue to be treated with an EGFR tyrosine kinase inhibitor.

Here, the EGFR tyrosine kinase inhibitor related to the present invention is not limited to one that directly acts on the tyrosine kinase site, but one that inhibits the binding of EGFR and its ligand, and the signal transduction transmitted from EGFR by the binding to the ligand. Inhibiting proteins, including proteins such as antibodies, peptides, and low molecular weight compounds. Specific examples include, but are not limited to, gefitinib ( IRESSA (registered trademark) ), erlotinib ( TARCEVA (registered trademark) ), CI1033, PKI166, GW2016, EKB569, C225, ABX-EGF, EMD-72000, MDX- 447. EGFR tyrosine kinase inhibitors according to the present invention may also include pharmaceutically acceptable salts, hydrates, solvates and equivalents thereof.

  The salicylic acid non-steroidal anti-inflammatory agent related to the present invention is a salicylic acid derivative anti-inflammatory agent. Specific examples include, but are not limited to, acetylsalicylic acid (aspirin), aspirin aluminum, sodium salicylate, choline salicylate, salicylamide, sazapyrine, diflunisal, and ethenamide. The salicylic acid non-steroidal anti-inflammatory agent according to the present invention may also include pharmaceutically acceptable salts, hydrates, solvates and equivalents thereof. Particularly preferably, the salicylic acid non-steroidal anti-inflammatory agent according to the present invention is acetylsalicylic acid (aspirin), or a pharmaceutically acceptable salt, hydrate, solvate and equivalent thereof.

  A disease requiring treatment with an EGFR tyrosine kinase inhibitor according to the present invention is a disease for which treatment with an EGFR tyrosine kinase inhibitor is effective. Currently, only cancer is clinically approved, but it may also include diseases that will be effective in the future. For example, there is a report that an EGFR tyrosine kinase inhibitor is effective for diabetic vascular disorders, and it can be included in diseases requiring treatment with the EGFR tyrosine kinase inhibitor of the present invention. In addition, non-small cell lung cancer is currently approved for clinical use, but of course other cancers such as esophageal cancer, stomach cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer , Colon cancer, rectal cancer, head and neck cancer, lung cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, skin cancer, malignant lymphoma, leukemia, brain tumor, more preferably, EGFR tyrosine kinase inhibitors are also effective against tumors in which EGFR is overexpressed, such as, but not limited to, breast cancer, bladder cancer, lung cancer, gastric cancer, melanoma, glioblastoma types, etc. Therefore, it is included in diseases requiring treatment with an EGFR tyrosine kinase inhibitor according to the present invention.

A skin disorder caused by an EGFR tyrosine kinase inhibitor according to the present invention is a skin disorder caused by inhibition of EGFR signal transduction in the skin and includes, but is not limited to, dermatitis, rash, pruritus, skin dryness, acne. Including.

A preferred first embodiment of the present invention is that the skin is caused by EGFR tyrosine kinase inhibitor gefitinib (IRESSA (registered trademark)) , and acetylsalicylic acid which is a salicylic acid non-steroidal anti-inflammatory agent is an active ingredient. It is a prophylactic and / or therapeutic agent for disorders. A further preferred first embodiment of the present invention is a prophylactic agent designed such that when gefitinib is orally administered at 1 mg-10 g / dose / day, acetylsalicylic acid is orally administered at 1 mg-10 g / dose / day And / or a treatment agent. The most preferred first embodiment of the present invention is a prophylactic agent designed such that when gefitinib is orally administered at 250 mg / dose / day, acetylsalicylic acid is orally administered at 80-100 mg / dose / day and / or Or it is a treatment agent.

A preferred second embodiment of the present invention is a pharmaceutical composition for use in cancer patients, comprising gefitinib (IRESSA®) as an EGFR tyrosine kinase inhibitor and acetylsalicylic acid as a salicylic non-steroidal anti-inflammatory agent as active ingredients It is a thing. A further preferred second embodiment of the present invention is a pharmaceutical composition designed such that gefitinib is orally administered at 1 mg-10 g / dose / day and acetylsalicylic acid is orally administered at 1 mg-10 g / dose / day. is there. The most preferred second embodiment of the invention is a pharmaceutical composition designed to be administered orally at gefitinib at 250 mg / dose / day and acetylsalicylic acid at 80-100 mg / dose / day.

  The term “prevention” in the context of the present invention means that mammals including humans who have never experienced a skin disorder caused by an EGFR tyrosine kinase inhibitor are prevented from causing the skin disorder, and an EGFR tyrosine kinase inhibitor. It means to prevent mammals including humans who have experienced skin damage caused by the above from newly causing the skin damage.

  The EGFR tyrosine kinase inhibitor according to the present invention, or a pharmaceutically acceptable salt thereof, is formulated into various dosage unit forms, each of which is also a salicylic acid non-steroidal anti-inflammatory agent formulated into various dosage forms, or They can also be administered separately or simultaneously with the pharmaceutically acceptable salt. Alternatively, both can be blended in advance, and these can be administered after being formulated into various dosage unit forms. When administered separately, it can be administered at any time before and after administration of the EGFR tyrosine kinase inhibitor.

  When the EGFR tyrosine kinase inhibitor and the salicylic acid non-steroidal anti-inflammatory agent according to the present invention are administered to mammals including humans, various pharmaceutical dosage forms can be used depending on the purpose of treatment. Specifically, oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, solutions, suspensions and emulsions; parenterals such as injections, suppositories, ointments and patches Can do. These administration agents can be formulated by a conventional formulation method generally known in this field using a pharmaceutically acceptable carrier or the like.

  In forming into a tablet form, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicate, etc .; water, ethanol, propanol, corn starch, Simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, potassium phosphate, polyvinylpyrrolidone, etc .; dried starch, sodium alginate, agar powder, laminaran powder Disintegrating agents such as sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, lactose; sucrose, stearic acid, kaka Disintegration inhibitors such as butter and hydrogenated oils; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Moisturizers such as glycerin and starch; Adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid A lubricant such as purified talc, stearate, boric acid powder or polyethylene glycol can be used.

  Furthermore, the tablet can be made into a tablet coated with a normal coating as necessary, for example, sugar-coated tablet, gelatin-encapsulated tablet, enteric-coated tablet, film-coated tablet, double tablet, multilayer tablet and the like.

  When forming into a pill form, as a carrier, for example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin, talc; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, etc. Disintegrants such as laminaran and agar can be used.

  Capsules are prepared by mixing with various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to a conventional method.

  When an oral liquid preparation is used, a liquid preparation, a syrup, an elixir or the like can be produced by a conventional method using a corrigent, a buffer, a stabilizer, a corrigent and the like. In this case, examples of the flavoring agent include sucrose, orange peel, citric acid, and tartaric acid, examples of the buffering agent include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  In molding into a suppository, for example, polyethylene glycol, cacao butter, higher alcohol, higher alcohol esters, gelatin, semi-synthetic glyceride and the like can be used as a carrier.

  In the case of injections, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. When forming into these forms, diluents such as water, aqueous lactic acid, ethyl alcohol, Propylene glycol, macrogol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of sodium chloride, glucose or glycerin may be included in the pharmaceutical preparation to prepare an isotonic solution, and usual solubilizing agents, buffers, soothing agents, etc. may be added. May be.

  Furthermore, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals may be blended in each of the above preparations as necessary. The amount of the EGFR tyrosine kinase inhibitor and the salicylic acid non-steroidal anti-inflammatory agent or pharmaceutically acceptable salt thereof contained in the preparation of the present invention is not particularly limited and can be appropriately selected. It is preferable to be about 0.01 to 70% by weight in the preparation.

  The administration method of the preventive agent, treatment agent and pharmaceutical composition of the present invention is not particularly limited, and is appropriately determined according to various preparation forms, patient age, sex and other conditions, and the degree of symptoms of the patient. For example, tablets, pills, powders, granules, capsules, solutions, suspensions and emulsions are administered orally. The injection is administered intravenously alone or mixed with a normal fluid such as glucose or amino acid, and further administered alone, if necessary, intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered rectally. Ointments and patches are administered transdermally.

The dosage of the salicylic acid-based non-steroidal anti-inflammatory agent according to the present invention can be appropriately selected depending on the administration method, patient age, sex, etc., severity of the disease, and dosage of the EGFR tyrosine kinase inhibitor . Usually, the dosage of a salicylic acid non-steroidal anti-inflammatory agent is 1 mg to 10 g / day, preferably 10 mg to 1 g / day. Similarly, the dose of the EGFR tyrosine kinase inhibitor according to the present invention is appropriately selected depending on the administration method, the age, sex, etc. of the patient, and the severity of the disease. Usually, the dosage of the EGFR tyrosine kinase inhibitor is 1 mg to 10 g / day, preferably 10 mg to 1 g / day. Moreover, these preventive agents, treatment agents and pharmaceutical compositions of the present invention can be administered once a day or divided into about 2 to 4 times a day.

  The present invention can also include a therapeutic method for a disease requiring treatment with an EGFR tyrosine kinase inhibitor using the prophylactic agent, treatment agent and pharmaceutical composition of the present invention.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these.

During the period from 2000 to 2004, 40 patients with non-small cell lung cancer who were not eligible for radical treatment by surgery and who had not yet received gefitinib were included. The profile of the patient entered in Table 1 and the study design is shown in FIG. Gefitinib was orally administered at 250 mg once a day, and aspirin was orally administered at 100 mg once a day. Two weeks after the start of the study, side effects were determined in patients who were able to continue administration, and humoral factors were also analyzed. There were 27 gefitinib-administered groups and 12 aspirin combination groups (Table 1). The side effect was determined by a doctor based on the diagnostic criteria. As the humoral factors, the plasma concentrations of thromboxane B ₂ which is a stable metabolite of thromboxane A2 and soluble p-selectin which is an indicator of platelet activation are measured before and 1 week and 2 weeks after the start of the test. Using the kit (thromboxane B ₂ : Immunotech (Marselle, France), soluble p-selectin: BioSource International (CA, USA)), the measurement was performed by the ELISA method. Statistical processing was performed using t-test.

As a result, plasma thromboxane B ₂ and soluble p- selectin is increased with gefitinib alone. On the other hand, plasma thromboxane B ₂ are aspirin combination group had been suppressed, the suppression of soluble p- selectin was apparent (Figure 2A, 2B).
Moreover, there were few side effects in the aspirin combination group (Table 2). A comparison of the incidence of side effects between the gefitinib single administration group and the aspirin combination group (gefitinib single administration group vs aspirin combination group) is as follows: all side effects: 77.8% vs 58.3%, skin disorders: 74.1% vs 33.3%, Diarrhea: 18.5% vs 0% (Table 2). There was no obvious difference between the two groups in terms of effect (37.0 vs 33.3%) (Table 1).

  From the results (Table 2) in which the expression of gefitinib-induced skin damage was reduced in the aspirin combination group, it was shown that aspirin exerts a preventive effect on EGFR tyrosine kinase inhibitor-induced skin damage. Therefore, aspirin is useful as a preventive agent for skin disorders in patients who are administered EGFR tyrosine kinase inhibitors.

In addition, gefitinib administration resulted in increased plasma concentrations of thromboxane B ₂ and soluble p-selectin (FIGS. 2A, 2B), suggesting that skin damage caused by EGFR tyrosine kinase inhibitors may be mediated by platelet activation Sex was suggested. This result is the use of platelet activation inhibitors as preventive agents or treatment agent of EGFR tyrosine kinase inhibitors induced skin disorders, and for the use of platelet activation marker as a diagnostic marker for EGFR tyrosine kinase inhibitor induced skin disorders It becomes the basis of a new invention. In particular, use of thromboxane production or action inhibitor as a preventive agent or treatment agent, or soluble p-selectin production or action inhibitor, and further use of thromboxane B ₂ or soluble p-selectin as a diagnostic marker. Will be the basis of a new invention.

  Further, in the above test, skin damage occurred in an example of the aspirin combination group when aspirin administration was temporarily suspended due to nasal bleeding. After that, when aspirin administration was resumed, the skin disorder improved and healed. From these results, it was shown that aspirin exerts a treatment effect on skin disorders caused by EGFR tyrosine kinase inhibitors. Therefore, aspirin is useful as a skin disorder treatment agent for patients receiving EGFR tyrosine kinase inhibitors.

  Since the preventive agent, treatment agent and pharmaceutical composition of the present invention are effective for skin disorders caused by EGFR tyrosine kinase inhibitors, in the treatment of diseases requiring treatment with EGFR tyrosine kinase inhibitors, particularly cancers, It can be used industrially as a medicine.

It is the figure which showed the clinical research design. It illustrates the effects on plasma levels of thromboxane B ₂ and soluble P- selectin agents.

Explanation of symbols

TxB ₂ : Thromboxane B ₂
sP-selectin: Soluble P-selectin
*: P <0.05
**: p <0.01
***: p <0.001
NS: No significant difference

Claims (7)

An agent for preventing or treating skin disorders caused by an epidermal growth factor receptor (hereinafter referred to as EGFR) tyrosine kinase inhibitor, comprising 80-100 mg of acetylsalicylic acid (aspirin) as an active ingredient . The prophylactic agent according to claim 1, wherein the EGFR tyrosine kinase inhibitor is selected from the group consisting of gefitinib , erlotinib , CI1033, PKI166, GW2016, EKB569, C225, ABX-EGF, EMD-72000, and MDX-447. Treatment agent . The preventive agent or treatment agent according to claim 1 or 2, wherein the skin disorder is selected from the group consisting of dermatitis, rash, pruritus, dry skin, and acne. The prophylactic or therapeutic agent according to any one of claims 1 to 3 , which is administered to a patient having cancer. The prophylactic or therapeutic agent according to claim 4 , wherein the cancer is selected from the group consisting of breast cancer, bladder cancer, lung cancer, gastric cancer, melanoma, and glioblastoma type. The prophylactic or therapeutic agent according to claim 4, wherein the cancer is non-small cell lung cancer. The prophylactic or therapeutic agent according to any one of claims 1 to 6, wherein gefitinib is orally administered at 250 mg / dose / day.

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