Pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction

Abstract

The present invention provides a pharmaceutical composition for preventing or treating a hand-foot syndrome or hand-foot skin reaction, comprising a specific peptide derivative or a mixture of specific peptide derivatives as an active ingredient.

Description

Pharmaceutical composition for the prevention or treatment of hand-foot syndrome or hand-foot skin reaction

[0001] The present invention relates to a pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction, which comprises a specific peptide derivative or a mixture of specific peptide derivatives as an active ingredient.

[0002] Skin toxicity caused by anticancer drugs is a significant issue in the treatment of cancer patients. While it rarely manifests as a life-threatening, severe side effect, it is a significant side effect that can impact cancer treatment by causing numerous symptoms and diminishing the patient's quality of life, ultimately leading to a reduction, delay, or discontinuation of the anticancer drug dose.

[0003] Hand-foot skin reactions (HFS) caused by chemotherapy can be classified into cytotoxic chemotherapy-induced hand-foot syndrome (HFS) and multikinase inhibitor-induced hand-foot skin reaction (HFSR). Chemotherapy-induced HFS (also called palmar-plantar erythrodysesthesia, PPE) is mainly caused by drugs such as fluoropyrimidines, pegylated liposomal doxorubicin, cytarabine, and docetaxel, and its incidence is reported to be 50-70% (Nagore E, et al., Am J Clin Dermatol. 2000 Jul-Aug;1(4):225-34; Miller KK, et al., J Am Acad Dermatol. 2014 Oct;71(4):787-94). The mechanism is explained by the cyclooxygenase-2 (COX-2) inflammatory response, sweat gland secretion and local stimulation of anticancer drugs and metabolites, enzymes involved in anticancer drug metabolism, and transport related to absorption (Miller KK, et al., J Am Acad Dermatol. 2014 Oct;71(4):787-94; Lou Y, et al., Chem Res Toxicol. 2016 Oct 17;29(10):1591-1601). Hand-foot syndrome (HFS) is characterized by tingling and tenderness that progresses to symmetrical redness, swelling, and pain mainly on the palms and soles [dysesthesia, erythema, scaling].

[0004] Multitarget therapy-induced hand-foot skin reaction (HFSR) occurs with multitarget inhibitors based on vascular endothelial growth factor (VEGF), such as sorafenib, sunitinib, regorafenib, axitinib, and cedirafenib, and its frequency is reported to be 20-40% (Miller KK, et al., J Am Acad Dermatol. 2014 Oct;71(4):787-94; Lou Y, et al., Chem Res Toxicol. 2016 Oct 17;29(10):1591-1601; Anderson R, et al., Oncologist. 2009 Mar;14(3):291-302; McLellan B, et al., Ann Oncol. 2015 Oct;26(10):2017-26). The mechanism has been explained by inhibition of platelet-driven growth factor receptor (PDGFR), inhibition of healing mechanisms due to inhibition of other targets, sweat gland secretion and local irritation by anticancer drugs (Miller KK, et al., J Am Acad Dermatol. 2014 Oct;71(4):787-94; Lacouture ME, et al., Ann Oncol. 2008 Nov;19(11):1955-61). In DFDR, initial stinging and burning may progress to bilateral hyperkeratotic, callus-like lesions on an asymmetric erythematous base. It usually occurs on the palms and soles of the feet, as well as in areas subject to friction or pressure (dysesthesia, erythema, pain, blisters, hyperkeratosis at pressure points).

[0005] Numerous studies have been conducted to prevent or treat hand-foot syndrome (HFS) induced by anticancer and multi-target therapy agents, including pyridoxine, urea / lactic acid-based topical creams, and celecoxib. A recent meta-analysis reported that the COX-2 inhibitor celecoxib was effective in preventing Grade 2 or higher HFS caused by capecitabine. However, no drug has yet demonstrated clear efficacy through large-scale phase 3 trials, and current treatment options for HFS are still conservative.

[0006] The present inventors conducted various studies to develop agents capable of preventing or treating hand-foot skin reactions, such as hand-foot syndrome and / or hand-foot skin reaction. Surprisingly, the present inventors discovered that a specific peptide derivative or a mixture of specific peptide derivatives reduced the incidence of grade 2 or higher HFS and also exhibited superior HF-QoL scores.

[0007] Accordingly, the present invention aims to provide a pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction, which comprises the specific peptide derivative or a mixture of specific peptide derivatives as an active ingredient.

[0008] According to one aspect of the present invention, a pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction is provided, comprising as an active ingredient a peptide derivative of the following chemical formula 1; a peptide derivative of the following chemical formula 2; or a mixture of a peptide derivative of the following chemical formula 1 and a peptide derivative of the following chemical formula 2.

[0009] <Chemical Formula 1>

[0010]

[0011] <Chemical Formula 2>

[0012]

[0013] The pharmaceutical composition of the present invention may contain, as an active ingredient, a mixture of a peptide derivative of chemical formula 1 and a peptide derivative of chemical formula 2, preferably a mixture of a peptide derivative of chemical formula 1 and a peptide derivative of chemical formula 2 in a weight ratio of 1:0.5 to 1.5. In one embodiment, the pharmaceutical composition of the present invention may have a cream-type formulation.

[0014] The present invention has revealed that when a peptide derivative of chemical formula 1; a peptide derivative of chemical formula 2; or a mixture of a peptide derivative of chemical formula 1 and a peptide derivative of chemical formula 2 is applied to patients with hand-foot skin reaction, the incidence of HFS of grade 2 or higher is reduced and an excellent HF-QoL score is also exhibited. Therefore, the pharmaceutical composition of the present invention can be usefully used for the prevention or treatment of hand-foot syndrome or hand-foot skin reaction.

[0015] Figure 1a shows the symptoms of hand-foot syndrome according to each grade.

[0016] Figure 1b shows the symptoms of hand-foot skin reaction according to each grade.

[0017] Figure 2 is a schematic diagram of the research method of this test.

[0018] Figure 3 shows the results of evaluating changes in quality of life (QoL) during treatment according to this trial.

[0019] Figure 4 shows the results of evaluating changes in QoL in the hand during treatment according to this test.

[0020] Figure 5 shows the changes in HSF of a representative hand during treatment according to this test.

[0021] Figure 6 shows the results of evaluating changes in QoL in the foot during treatment according to this test.

[0022] Figure 7 shows the changes in HSF of a representative foot during treatment according to this test.

[0023] Figure 8 shows the results of evaluating changes in QoL in ADL (activities of daily living) during treatment according to this test.

[0024] This study was conducted as a single-center, prospective, randomized, open-label, placebo-controlled trial. Patients who developed grade 1 HFS according to the National Cancer Institute Common Terminology Criteria for Adverse Events or World Health Organization (WHO) criteria after treatment with cytotoxic chemotherapy or multiple kinase inhibitors were included. Patients were randomly assigned to receive either the study drug (a cream formulation containing the peptide derivative of formula 1 and the peptide derivative of formula 2, also referred to as "tripeptide cream" hereinafter) or a placebo (a cream formulation consisting of the same ingredients as the study drug except that it did not contain the peptide derivative of formula 1 and the peptide derivative of formula 2, also referred to as "placebo cream" hereinafter), and were followed up at 3-week intervals for up to 9 weeks. The primary endpoint is the development of grade ≥2 HFS. Secondary endpoints include QoL scores assessed using the Hand-Foot Skin Reaction and Quality of Life (HF-QoL) questionnaire and the frequency of dose reductions or discontinuations of anticancer drugs associated with HFS.

[0025] From April 2019 to July 2022, 68 patients were randomized, and 60 patients (31 in the study drug group and 29 in the placebo group) completed the study. The incidence of Grade 2 or higher HFS was significantly lower in the study drug group than in the placebo group (25.8% vs. 51.7%, P=0.039). Compared to the placebo group, which did not reach statistical significance, the study drug group showed a better HF-QoL score at week 9 (26.0 vs. 29.9, P=0.574) and a trend toward a lower frequency of chemotherapy discontinuation, interruption, or dose reduction (51.6% vs. 58.6%, P=0.586). Therefore, these results demonstrate that the study drug significantly reduces the incidence of Grade 2 or higher HFS in patients with chemotherapy-related HFS. Therefore, the trial drug may be an effective treatment for HFS associated with anticancer agents.

[0026] The present invention provides a pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction, comprising as an active ingredient a peptide derivative of the following chemical formula 1; a peptide derivative of the following chemical formula 2; or a mixture of a peptide derivative of the following chemical formula 1 and a peptide derivative of the following chemical formula 2.

[0027] <Chemical Formula 1>

[0028]

[0029] <Chemical Formula 2>

[0030]

[0031] The peptide derivative of the above chemical formula 1 may also be expressed as "palmitoyl-Lue-Gly-Asp-amide" and is known as CAS No. 2137461-15-3. The peptide derivative of the above chemical formula 2 may also be expressed as "palmitoyl-Ala-Gln-Lys-amide" and is known as CAS No. 2170645-13-1. In the peptide derivatives of the above chemical formulas 1 and 2, the amino acids constituting the peptide moieties (i.e., the Lue-Gly-Asp and Ala-Gln-Lys moieties, respectively) may independently be in the form of L-amino acids or D-amino acids.

[0032] The peptide derivatives of the above chemical formulae 1 and 2 can be prepared by various methods, and for example, can be prepared according to known methods such as CAS No. 2137461-15-3, CAS No. 2170645-13-1, etc. For example, in the peptide derivatives of the chemical formulae 1 and 2, each peptide moiety can be synthesized using an automatic peptide synthesizer (ASP48S, Peptron, Daejeon, Korea) using the FMOC solid-phase peptide synthesis method. Palmitoylation at the N-terminus can be carried out by coupling palmitic acid to the N-terminus of the peptide moiety on Link Amide MBHA Resin using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU) and 1-hydroxybenzotriazole (HOBt) as coupling agents in the presence of diisopropylethylamine (DIEA) in dimethylformamide (DMF). Amidation at the C-terminus can be carried out using Rink Amide MBHA Resin. The obtained peptide derivatives of formulae 1 and 2 can be purified and analyzed by reverse-phase HPLC (Prominence LC-20AB, Shimadzu, Japan) using, for example, a Vydac Everest C18 column (250 mm x 22 mm, 10 μm). Elution in chromatography can be performed with a water-acetonitrile linear gradient (3-40% (v / v) acetonitrile) containing 0.1% (v / v) trifluoroacetic acid, and the molecular weight of the obtained product can be confirmed using LC / MS (HP 1100 Series LC / MSD, Hewlett-Packard, Roseville, USA).

[0033] In one embodiment, the pharmaceutical composition of the present invention may comprise a mixture of a peptide derivative of formula 1 and a peptide derivative of formula 2 as active ingredients. In another embodiment, the pharmaceutical composition of the present invention may comprise a mixture of a peptide derivative of formula 1 and a peptide derivative of formula 2 as active ingredients in a weight ratio of 1:0.5 to 1.5, preferably a weight ratio of about 1:1.

[0034] The pharmaceutical composition according to the present invention may include a pharmaceutically acceptable carrier or additive, and may be formulated in a parenteral dosage form, such as for transdermal administration, subcutaneous administration, or intramuscular administration. In one embodiment, the pharmaceutical composition of the present invention may have a cream-type formulation that, in addition to the above-described active ingredient, includes a pharmaceutically acceptable carrier or additive. The pharmaceutically acceptable carrier or excipient includes, but is not limited to, purified water, glycerin, niacinamide, hydrogenated polydecene, caprylic / capric triglyceride, shea butter, squalane, dimethicone, 1,2-hexanediol, cetearyl olivate, polyglyceryl-3 methylglucose distearate, glyceryl stearate, tromethamine, sorbitan olivate, acrylates / C10-30 alkyl acrylate crosspolymer, hydroxyacetophenone, panthenol, xanthan gum, disodium EDTA, palmitoyl SH-tripeptide-4amide, palmitoyl-tripeptide-53amide, and the like.

[0035] The pharmaceutical composition of the present invention can be administered to a patient in an amount suitable for preventing, improving, or treating hand-foot syndrome or hand-foot skin reaction. For example, the effective ingredient in the pharmaceutical composition of the present invention can be administered at a dosage of about 30 to 90 mg / kg per day, but the dosage can generally vary depending on the age, weight, and symptoms of each patient. Therefore, in the pharmaceutical composition of the present invention, the content of the effective ingredient can be contained in an amount sufficient to achieve the effect of preventing, improving, or treating the hand-foot syndrome or hand-foot skin reaction, for example, in an amount of about 0.001 to 0.02 wt% based on the total weight of the composition, and preferably in an amount of about 0.003 to 0.006 wt%.

[0036] Hereinafter, the present invention will be described in more detail through examples and test examples. However, these examples and test examples are intended to illustrate the present invention, and the present invention is not limited to these examples and test examples.

[0037] Example

[0038] In the examples below, the test drug is commercially available Ultimate Relief TM Cream (Ultimate Relief TM Cream, (Supad Elixir Co., Ltd.) Ultimate Relief TM The cream contains peptide derivatives of the above chemical formulas 1 and 2 as main ingredients. The placebo contains Ultimate Relief except for the peptide derivatives of the above chemical formulas 1 and 2 as main ingredients. TM It is the same cream as the cream and was provided by Supad Elixir Co., Ltd.

[0039] 1. Test method

[0040] (1) Selection of subjects

[0041] (1-1) Selection criteria for subjects

[0042] <1> Patients diagnosed with histologically or cytologically confirmed cancer and receiving treatment with chemotherapy and multi-targeted therapy

[0043] <2> Patients who developed grade 1 hand-foot skin adverse reactions according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) or Worth Health Organization (WHO) criteria were included.

[0044] <3> 19 years of age or older

[0045] <4> Activity level Eastern Clinical Oncology Group (ECOG) 0 to 2

[0046] <5> Expected survival period of 12 weeks or more according to the investigator's judgment

[0047] <6> Patients with adequate bone marrow, renal, and hepatic function, including:

[0048] ① Hematology: Absolute neutrophil count ≥ 1,000 / mm 3 , platelets ≥ 75,000 / mm 3 , hemoglobin ≥ 8.0 g / dL

[0049] ② Kidney: Serum creatinine ≤ 1.5 mg / dL or creatinine clearance ≥ 50 mL / min

[0050] ③ Liver: Serum bilirubin < 2.5 x upper limit of normal, AST and ALT < 2.5 x upper limit of normal (however, if liver metastasis is present, < 5 x upper limit of normal)

[0051] <7> Those who gave written consent to this study

[0052] (2) Exclusion criteria for subjects

[0053] <1> Patients with skin diseases

[0054] <2> Patients who experienced NCI-CTCAE or WHO grade 2 or higher hand / foot skin adverse reactions

[0055] <3> Patients with side effects other than hand-foot skin reactions that require dose reduction or discontinuation of anticancer drugs or multi-target therapy

[0056] <4> Those taking or needing medications that may affect the evaluation of this study (e.g., steroid preparations, nonsteroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitors, pyridoxine, antibiotics, etc.)

[0057] <5> Acute, active infection requiring antibiotics

[0058] <6> pregnant or breastfeeding women

[0059] <7> Those who do not understand or agree to the written consent for this study

[0060] (3) Number of subjects targeted and basis thereof

[0061] Based on the researcher's judgment, 30 patients were allocated to each group for placebo and test drug, resulting in a total of 60 patients. Taking into account a 10% loss to follow-up, a total of 66 patients were enrolled.

[0062] (4) Research method

[0063] Patients who developed Grade 1 skin reactions were followed up for up to 9 weeks at 3-week intervals (± 1 week) after receiving placebo and control medication. The study methods are summarized in Figure 2.

[0064] (5) Treatment method

[0065] In cases of Grade 1 or higher, placebo and test drug were applied to the hands and feet where hand and foot skin adverse reactions occurred, 1 to 1.5 g (approximately 1 small teaspoon, applied to each hand and foot) twice a day along with general conservative treatment. In cases of Grade 2 or higher hand and foot skin adverse reactions, the placebo and test drug were administered in combination with the following treatment recommended in the guidelines.

[0066] [Table 1]

[0067] Current management of hand-foot skin adverse events

[0068]

[0069] (6) Observation items, clinical examination items, and observation examination methods

[0070] (6-1) Grade of adverse effects on hands and feet skin

[0071] Adverse reactions to hand and foot skin were classified into grades based on the NCI-CTCAE and WHO (Table 2).

[0072] [Table 2]

[0073] NCI-CTCAE and WHO classifications

[0074]

[0075] (6-2) Quality of life

[0076] Quality of life was measured using the Korean version of the Hand-foot skin reaction and quality of life (HF-QoL-K) questionnaire (Anderson RT, et al. Oncologist. 2015 Jul;20(7):831-8; Nam SH, et al., J Korean Med Sci. 2016 Dec;31(12):1969-1975). The HF-QoL-K consists of 20 symptom-related questions and 18 questions regarding the degree of interference with daily life.

[0077] (6-3) Dosage and discontinuation of anticancer drugs and multi-target therapy

[0078] Through a medical record survey, we investigated the frequency and dose intensity of dose reduction and discontinuation of anticancer drugs and multi-target therapy drugs related to hand and foot skin side effects.

[0079] (7) Predicted side effects and precautions for use

[0080] Currently, no adverse reactions have been reported with the use of the cream or peptides. The cream is used in the same way as general cosmetics. Take the prescribed amount (1-1.5 g, 1 teaspoon) of cream and apply evenly to both hands and feet. After use, be sure to close the cap and store out of reach of children. Avoid storing in places with high or low temperatures and direct sunlight. When using, be careful not to contact the eyes or eye mucosa. If contact occurs, immediately rinse with water. If an allergic reaction (itching, spots, swelling, or irritation) occurs, immediately discontinue use.

[0081] (8) Criteria for subject withdrawal and exclusion from the study

[0082] Enrollment of a research subject signifies the commencement of the study after meeting the above-mentioned selection and exclusion criteria. Enrolled subjects may discontinue the study at any point during the study period. Subjects who fall under the following circumstances were excluded from the study.

[0083] <1> If the research subject withdraws consent

[0084] <2> If you do not follow the researcher's instructions

[0085] <3> If follow-up observation of the observation examination is not followed or has never been performed

[0086] <4> If a serious illness unrelated to participation in the study occurs

[0087] <5> If the research subject dies before the follow-up examination after the start of the study

[0088] <6> When it is difficult to proceed with the research further at the researcher's discretion

[0089] (9) Effectiveness evaluation criteria, evaluation methods, and interpretation methods

[0090] (9-1) Effectiveness evaluation criteria and evaluation methods

[0091] <1> Incidence of Grade 2 or higher adverse reactions to hand and foot skin

[0092] <2> Time until the occurrence of grade 2 or higher skin adverse reactions

[0093] <3> Frequency of dose reduction of anticancer drugs and multi-targeted therapies

[0094] <4> Frequency of dose interruptions of anticancer and multitargeted therapies

[0095] <5> Dose intensity of anticancer drugs and multi-targeted therapies

[0096] <6> quality of life

[0097] (9-2) Interpretation method (statistical analysis method)

[0098] The incidence of grade 2 or 3 hand-foot skin adverse reactions and the frequency of dose reductions and discontinuations of chemotherapy between the two groups were compared using Fisher's exact test. The time to the occurrence of grade 2 or 3 hand-foot skin adverse reactions was compared using the Kaplan-Meier method and the log-rank test. The dose intensities of chemotherapy and multitargeted therapy were compared using t-tests. A p value <0.05 was considered statistically significant. All statistical analyses were performed using SPSS for Windows software, version 18.0 (SPSS Inc., Chicago, IL).

[0099] (10) Safety evaluation criteria, evaluation methods, and reporting methods including side effects

[0100] (10-1) Safety evaluation criteria and evaluation methods

[0101] A summary and analysis of adverse reactions (AEs) were conducted on treatment-emergent adverse events (TEAEs). TEAEs are adverse reactions that were absent before drug administration but developed after drug administration, or were present at baseline but worsened in severity after drug administration. The incidence of treatment-emergent TEAEs, adverse drug reactions (ADRs), and serious adverse events (SAEs) is presented as frequency and percentage, and the severity of AEs is classified according to the NCI-CTCAE.

[0102] (10-2) Safety reporting method

[0103] Each time the researcher met with the subject patient, they checked for adverse reactions through specific questions and tests. Furthermore, information on all adverse reactions was recorded immediately upon recognition, including the date of onset, severity, treatment, outcome, and the researcher's opinion regarding the relationship between the adverse reaction and the study drug.

[0104] All serious adverse reactions occurring from the date of enrollment up to 30 days after the last dose, regardless of whether they were related to the treatment drug, were recorded on the attached adverse reaction record sheet and reported to the principal investigator within 24 hours. Adverse reactions with the potential to develop into serious adverse reactions were monitored until resolved or stabilized, and if they progressed to severe status, they were recorded as serious adverse reactions. Serious adverse reactions thought to be related to the study drug or possibly (probably or possibly) were also reported using the same procedure, even if they occurred more than 30 days after the last dose.

[0105] (11) Consent of research subjects

[0106] All subjects were asked to sign a consent form of their own free will only if they had been given a detailed explanation of the purpose, method, and expected effects of this clinical trial and agreed to participate in the clinical trial.

[0107] (12) Compensation for victims

[0108] The drug used in this study is internationally approved for use as a cosmetic ingredient and product ingredient. It is intended for topical application to the hands and feet, and poses minimal or no risk to the patient. However, since the subjects were cancer patients undergoing cancer treatment, any adverse effects or complications that arose were treated to the best of medical standards.

[0109] (13) Treatment and care standards for research subjects after clinical trials

[0110] The subjects of this study are cancer patients who are actively undergoing cancer-related treatment. After the clinical trial, the treatment and care standards for the subjects will follow the current standard cancer treatment and will be determined by the clinician's judgment.

[0111] (14) Measures to protect the safety of research subjects

[0112] Standard safety measures were applied to patients receiving chemotherapy, and all subjects received pre-treatment education on side effects and how to manage them. If new safety information arose during the clinical trial, subjects were immediately notified, and the clinical trial staff were instructed to take appropriate and prompt action.

[0113] Subjects' medical information was considered confidential. Confidentiality was ensured through the use of identification codes, which prevented the identification of individuals. All information obtained during this study was kept confidential to the extent possible and used solely for research purposes. Subject numbers were kept separately by the researcher, and subjects' identities were kept confidential even when the results were published.

[0114] (15) Other matters necessary to safely conduct research

[0115] (15-1) Ethical aspects

[0116] This study was conducted in accordance with the ethical principles required by the Declaration of Helsinki and Good Clinical Practice (GCP), which require absolute protection of individuals.

[0117] (15-2) Data Management

[0118] The data obtained in this study were recorded directly in the case record sheet. All data entered in the case record sheet must be truthful and consistent with the source documents. Source documents include all observations, records of research activities, and all reports and records necessary for the evaluation and reconstruction of the study. Therefore, source documents include all records of all treatments implemented according to the study protocol or similar records. The investigators were to retain all documents related to the implementation of this study for three years from the completion date of the clinical trial.

[0119] 2. Test results

[0120] (1) Subject characteristics (Demographic features)

[0121] The subjects' demographic features are as shown in Table 3 below.

[0122] [Table 3]

[0123]

[0124] * One patient in the placebo arm received cetuximab as a target agent.

[0125] (2) Primary Endpoint

[0126] The occurrence of grade 2 or higher skin side effects during treatment is as shown in Table 4 below.

[0127] [Table 4]

[0128]

[0129] (3) Changes in quality of life

[0130] Changes in quality of life (QoL) during treatment are shown in Table 5 and Figure 3.

[0131] [Table 5]

[0132]

[0133] The QoL changes in the hand during treatment are as shown in Figure 4, and the representative changes in HSF of the hand during treatment are as shown in Figure 5. The QoL changes in the foot during treatment are as shown in Figure 6, and the representative changes in HSF of the foot during treatment are as shown in Figure 7. The QoL changes in ADL (activities of daily living) during treatment are as shown in Figure 8.

[0134] Additionally, the Chemotherapy / TKI dose intensity is as shown in Table 6 below.

[0135] [Table 6]

[0136]

[0137] (4) Summary

[0138] The above results can be summarized as follows.

[0139] - The incidence of grade 2 PPE was higher in the placebo group than in the test drug group.

[0140] - During the treatment period, 25.8% of patients in the study drug group developed PPE of grade 2 or higher, while 51.7% of patients in the placebo group developed PPE of grade 2 or higher (P=0.039).

[0141] - In the group administered the test drug, a trend of symptom improvement was observed initially, and the effect continued throughout the treatment period.

[0142] - The test drug can be used to alleviate symptoms and prevent worsening of chemotherapy-related PPE.

Claims

1. A pharmaceutical composition for preventing or treating hand-foot syndrome or hand-foot skin reaction, comprising as an active ingredient a peptide derivative of the following chemical formula 1; a peptide derivative of the following chemical formula 2; or a mixture of a peptide derivative of the following chemical formula 1 and a peptide derivative of the following chemical formula 2. <Chemical Formula 1> <Chemical Formula 2> 2. A pharmaceutical composition characterized in that it comprises a mixture of a peptide derivative of chemical formula 1 and a peptide derivative of chemical formula 2 as an active ingredient in claim 1.

3. A pharmaceutical composition characterized in that it comprises a mixture of the peptide derivative of chemical formula 1 and the peptide derivative of chemical formula 2 in a weight ratio of 1:0.5 to 1.5 as an active ingredient in the second paragraph.

4. A pharmaceutical composition having a cream-type formulation according to any one of claims 1 to 3.

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