JP4983989B2 - Preventive and therapeutic agents for hand-foot syndrome - Google Patents

Description

  The present invention relates to a prophylactic and therapeutic agent for hand-foot syndrome containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof.

  Hand-foot syndrome is a skin disease that occurs as a side effect of anticancer drug treatment, and is one of the dose limiting factors of anticancer drugs. Common sites of hand-foot syndrome are the extremities of the extremities, especially the palms, soles, and nails. In mild cases (hand-foot syndrome criteria standard 1), there is no particular restriction on daily life, but when it becomes severe, swelling and redness appear with pain (same criteria grade 2). In addition, keratinization and desquamation are prominent especially on the palms and soles, and skin cracks may occur due to hypersensitivity. Under such conditions, it becomes difficult to grasp objects due to pain, and walking is difficult. (Judgment standard grade 3).

  The onset mechanism of hand-foot syndrome is currently unknown. For example, inhibition of the proliferation ability of skin basal cells, leakage of anticancer drugs from blood vessels (US Pat. No. 6060083, see Patent Document 1), secretion of anticancer drugs from eccrine sweat glands (Annals of Oncology), 16 Vol. 12, pp. 1210-1211 (2005); see Non-patent Document 1), etc., have been shown to be one of the causes, but the causal relationship between anticancer drugs and their onset remains unclear. is there.

Thus, since the onset mechanism of hand-foot syndrome is unknown, there has been no established prevention method or treatment method. Current treatments for hand-foot syndrome rely on symptomatic treatment based on empirical treatment. For example, when the limbs are resting and swelling is strong, the limbs are raised and the limbs are cooled; Topical treatment using topical preparations such as urea ointment, heparin-like substance preparation or vitamin-containing ointment for the purpose of treatment; topical treatment using topical steroids with anti-inflammatory action; prednisolone or dexamethasone or pyridoxine hydrochloride as systemic therapy (Vitamin B ₆ ) (Investigational New Drugs, Vol. 8, pp. 57-63 (1990); Non-Patent Document 2); Cleaning against nail symptoms, gauze protection, Taping, nail arthroplasty, artificial nails, cryosurgery, etc. are performed.

In addition to the above, for example, the use of topical DMSO for the treatment of hand-foot syndrome induced by liposomal doxorubicin (see US Pat. No. 6060083; see Patent Document 1), induced by fluorouracil or a precursor thereof. Of dihydropyrimidine dehydrogenase, thymidine phosphorylase and / or uridine phosphorylase enzyme inhibitors for the treatment of severe hand-foot syndrome (see WO 2009/100367; see Patent Document 2) and induced by chemotherapy and / or radiation therapy Use of a cyclin-dependent kinase II inhibitor to prevent and / or reduce the severity of epithelial cytotoxic side effects including limb syndrome (see WO 2000/052013; see Patent Document 3) Proposed To have.
However, these effects are not satisfactory.

In addition, because there is no treatment method, the causative drug must be withdrawn. However, for example, in the Japanese phase II clinical trial of capecitabine, the time to recovery of hand-foot syndrome due to drug withdrawal is, for example, an average of 2 to 3 months for patients who showed the highest criteria grade 3 There is also a report (Hand-foot Syndrome Atlas, supervised by Tetsuya Taguchi, 2007, Chugai Pharmaceutical; see Non-patent Document 3), and it takes time to recover even if means such as drug withdrawal is used.
Therefore, there is a demand for a drug that is more effective and superior in immediate effect.

  On the other hand, with regard to hand-foot syndrome, there are several reports showing the relationship between the onset and sweat. For example, JP 2010-18564 A (Patent Document 4) discloses an anticancer agent comprising an adhesive base and at least one compound selected from the group consisting of oils, polyhydric alcohols, and hydrophilic polymer compounds. A skin patch under treatment is disclosed, and the skin patch prevents the storage of sweat or sebum containing an anticancer agent in the skin and also absorbs sweat or sebum containing an anticancer agent. It is described that it has shown effectiveness in hand-foot syndrome. However, Patent Document 4 is a document that pays attention to the fact that removing an anticancer agent contained in sweat or sebum using a skin patch of a specific composition is effective for hand-foot syndrome. Furthermore, the document does not identify the anticancer agent that caused the onset of hand-foot syndrome, nor does it describe which of the blood vessels or the eccrine sweat gland is important as the secretion route of anticancer agents to sweat and sebum. .

  On the other hand, in Anals of Oncology, Vol. 16, pp. 1210-1211 (2005) (Non-patent Document 1), doxorubicin, an anticancer drug, was administered to sweat of patients who developed hand-foot syndrome. Describes that the drug was detected and that the patient had hyperhidrosis, suggesting an association between limb syndrome and hyperhidrosis. However, Non-Patent Document 1 does not verify how the presence of drugs in sweat leads to the development of hand-foot syndrome. In addition, since this document is intended to associate hand-foot syndrome with sweat, although the document proposes the use of antiperspirants such as iontophoresis and aluminum chloride to suppress the development of hand-foot syndrome, Even after 5 years since the publication of this document, there have been no reports of successful cases where the use of such antiperspirants has prevented the development of hand-foot syndrome.

In recent years, findings have been reported that question the causal relationship between drug secretion in sweat and hand-foot syndrome (Pharmacotherapy, 30, 52-56 (2010); Non-patent document 4). The document states that this drug is not detected in the sweat of patients with hand-foot syndrome due to administration of the anticancer agent sorafenib, and that the secretion of the drug in sweat is not related to the hand-foot syndrome caused by sorafenib. Has been. The document concludes that further elucidation of the mechanism of hand-foot syndrome is necessary in the future.
As described above, development of a method for preventing and / or treating hand-foot syndrome is indispensable for continuing anticancer treatment and is indispensable, but no effective means has yet been obtained.

On the other hand, imidafenacin (Stebra (registered trademark), Uritos (registered trademark)) is an anticholinergic drug, and is an automatic gastrointestinal motility such as irritable bowel syndrome, diverticulum disease, functional diarrhea, esophageal laxity, cardia spasm It is reported to be useful for treatment of disorders; treatment of biliary tract, urethral spasm, urinary incontinence, etc .; treatment of chronic airway obstructive disease (Japanese Patent Laid-Open No. 7-215943; Patent Document 5).
However, there are no reports of imidafenacin applied to the prevention and / or treatment of hand-foot syndrome.

US Pat. No. 6060083 Specification International Publication No. 2009/100367 Pamphlet International Publication No. 2000/052013 Pamphlet JP 2010-18564 A JP-A-7-215943

Anals of Oncology, 16, 1210-1211 (2005) Investigational New Drugs, 8, 57-63 (1990) Hand-foot Syndrome Atlas, supervised by Tetsuya Taguchi, 2007, Chugai Pharmaceutical Pharmacotherapy, 30, 52-56 (2010)

Hand-foot syndrome is a serious side effect caused by the administration of anticancer drugs, and the reduction or alleviation of anticancer drugs is one effective means for alleviating and alleviating it, but this is the original purpose It means that the effect of cancer treatment is diminished and that cancer treatment is suspended or stopped, and it cannot be said that it is suitable as a countermeasure for side effects in cancer treatment. In order to continue appropriate cancer treatment in the current situation where the effects of known drugs are not satisfactory as treatments for hand-foot syndrome, and we have to rely on weight reduction, withdrawal or discontinuation of anticancer drugs There is a need for effective prevention and / or treatment of new hand-foot syndrome.
Therefore, the subject of this invention is providing the safe chemical | medical agent which has the outstanding prevention and / or treatment effect with respect to hand-foot syndrome.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have surprisingly found that imidafenacin has an excellent preventive and / or therapeutic effect on hand-foot syndrome and completed the present invention. The effect is surprising that one skilled in the art can hardly predict. Specifically, as shown in the examples of the present specification, when imidafenacin was administered to a patient who developed severe hand-foot syndrome due to anticancer drug treatment, the symptom was observed in only a few days to several weeks after the start of the administration. It is surprising that significant relaxation is observed.

  Imidafenacin is an anticholinergic agent, and anticholinergic agents are known to have antiperspirant action. Since sweat is secreted by the release of acetylcholine from sympathetic nerves to sweat glands, it is said that anticholinergic drugs can suppress sweating. On the other hand, the recommended degree of anticholinergic agent as an antiperspirant in the primary local hyperhidrosis clinical practice guidelines issued by the Japanese Dermatological Association (Journal of Japanese Dermatological Association, 120 (8), 1607-1625, 2010) Is C1 for which there is no sufficient basis. Furthermore, there are no reports showing that imidafenacin has an antiperspirant effect.

  As described at the beginning, Non-Patent Document 1 suggests the use of an antiperspirant effective for the treatment of hyperhidrosis such as iontophoresis and aluminum chloride in order to suppress the onset of hand-foot syndrome. However, considering the seriousness of the hand-foot syndrome (particularly in the case of hand-foot syndrome criteria grade 3), it is unlikely that the use of antiperspirants will alleviate such serious symptoms. It was. Furthermore, according to the primary local hyperhidrosis clinical practice guideline, aluminum chloride has irritant dermatitis as a side effect, which may further exacerbate skin disorders when used in patients with hand-foot syndrome with skin disorders. . In addition, since iontophoresis requires time until the effect is shown, immediate effect cannot be expected. Therefore, although Non-Patent Document 1 suggested the use of an antiperspirant to suppress the onset of hand-foot syndrome, its effectiveness was questioned, so it was not actually looked at. As you can see, the treatment of hand-foot syndrome is currently dependent on symptomatic treatment.

On the other hand, Non-Patent Document 1 does not suggest any use of imidafenacin as an antiperspirant. In addition, anti-cholinergic drugs that have not been established as antiperspirant in the treatment of hyperhidrosis as much as iontophoresis and aluminum chloride, and are not well-founded in antiperspirant effect. There is no reason to actively use imidafenacin, which is completely unknown.
Moreover, those skilled in the art have predicted that the use of imidafenacin can provide a significant alleviation of the symptoms within just a few days to weeks of administration, even for patients who develop severe hand-foot syndrome. Not what you get.

  Treatment with imidafenacin for hand-foot syndrome, which is a side effect of anticancer drug treatment, does not require reduction, withdrawal or discontinuation of the anticancer drug, so the effect of cancer treatment, which is the original purpose, is reduced, cancer treatment is suspended or It is groundbreaking in that it can cope with side effects in cancer treatment without discontinuation.

That is, the present invention provides [1] a prophylactic and / or therapeutic agent for hand-foot syndrome containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof; [2] prevention and / or treatment of a hand-foot syndrome containing imidafenacin. Or [3] agent of [1] or [2], wherein the hand-foot syndrome is a hand-foot syndrome caused by administration of an anticancer agent; [4] agent of [3], wherein the anticancer agent is an antimetabolite or a molecular target drug [5] The agent of [4], wherein the antimetabolite is capecitabine and the molecular target drug is sunitinib malate or sorafenib tosylate; [6] The agent of [4], wherein the anticancer agent is an antimetabolite; 7] Agent of [4] wherein the anticancer drug is a molecular target drug; [8] Agent of [6] wherein the antimetabolite is capecitabine; [9] The molecular target drug is sunitinib malate or sorafenib tosylate [10] an agent of [7]; [10] a prophylactic and / or therapeutic agent for hand-foot syndrome containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof, and a moisturizer, antibiotic, topical steroid, steroid [11] a limb containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof; a pharmaceutical comprising a combination of one or more selected from the group consisting of an internal medicine, a nonsteroidal anti-inflammatory analgesic and a vitamin B ₆ preparation; [12] imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof, and a moisturizer, antibiotic, topical steroid, oral steroid, combine one or more selected from the group consisting of non-steroidal anti-inflammatory agent and vitamin B ₆ preparation [13] An agent for preventing and / or treating hand-foot syndrome comprising combining imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof and an anticancer agent; [14] The agent according to [1], wherein the prevention is prevention of recurrence; [15] prevention of limb syndrome, comprising administering to a mammal an effective amount of imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof; It relates to / or a treatment method.

  The present invention provides a preventive and / or therapeutic agent for hand-foot syndrome containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof. Until now, in order to cope with hand-foot syndrome, it has been necessary to reduce the dose of anticancer drugs, stop taking drugs, or discontinue administration, but if the agent of the present invention is used, it becomes possible to continue appropriate cancer treatment, It leads to early recovery. In addition, improvement of the limb syndrome improves the patient's quality of life (QOL).

The effect of imidafenacin on hand-foot syndrome caused by capecitabine administration is shown. In the figure, Cap represents capecitabine, LTZ represents letrozole, IMD represents imidafenacin, and HFS represents limb syndrome. Figure 2 shows the effect of imidafenacin on limb syndrome caused by sunitinib malate administration. In the figure, SU is sunitinib malate, IMD is imidafenacin, U ointment is urea ointment, H ointment is heparin analog ointment, C ointment is clobetasol propionate ester ointment, and HFS indicates hand-foot syndrome. Figure 2 shows the effect of imidafenacin on limb syndrome due to sorafenib tosylate administration. In the figure, SO is sorafenib tosylate, IMD is imidafenacin, G ointment is gentamicin sulfate ointment, B ointment is vitamin A oil ointment, H cream is heparin analog cream, and HFS is hand-foot syndrome. Figure 2 shows the effect of imidafenacin on limb syndrome due to sorafenib tosylate administration. In the figure, SO represents sorafenib tosylate, IMD represents imidafenacin, U ointment represents urea ointment, and HFS represents hand-foot syndrome.

  In the present invention, imidafenacin is 4- (2-methyl-1H-imidazol-1-yl) -2,2-diphenylbutanamide. Imidafenacin can be produced by a known method, for example, a method described in JP-A-7-215943. Also, imidafenacin may be a commercially available product (Stablar (registered trademark), Uritos (registered trademark)).

  In the present invention, the salt of imidafenacin is preferably a pharmaceutically acceptable salt. The pharmaceutically acceptable salt is preferably non-toxic and water-soluble. Suitable salts of imidafenacin include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or formate, propionate, malonic acid Salt, succinate, maleate, fumarate, oxalate, acetate, lactate, malate, tartrate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzene Examples include organic acid salts such as sulfonate, aspartate, glutamate, toluenesulfonate, isethionate, glucuronate, and gluconate.

In the present invention, examples of suitable solvates of imidafenacin include solvates such as water and alcohol solvents (for example, ethanol). The solvate is preferably low in toxicity and water-soluble. Further, the solvate of imidafenacin includes a solvate of the above salt.
Imidafenacin can be converted to the salt or the solvate by a known method.

In the present invention, a prodrug of imidafenacin refers to a compound that is converted into imidafenacin by a reaction with an enzyme, gastric acid or the like in a living body. A prodrug of imidafenacin can be produced by a known method. Further, the prodrug of imidafenacin may be either a hydrate or a non-hydrate. In addition, the prodrug of imidafenacin may be changed to imidafenacin under physiological conditions as described in “Development of Drugs”, Vol. 7, “Molecular Design”, pages 163 to 198, published in Yodogawa Shoten 1990. . Furthermore, imidafenacin may be labeled with a radioisotope (for example, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.), and any atom contained in imidafenacin has a corresponding stable isotope (for example, Deuterium ( ² H), heavy carbon ( ¹³ C), heavy nitrogen ( ¹⁵ N), heavy oxygen ( ¹⁷ O, ¹⁸ O), etc.) may be substituted.

  The present invention provides an effective amount of imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof to a mammal (eg, a human or non-human animal (eg, monkey, sheep, cow, horse, dog, cat, rabbit). , Rat, mouse, etc.), preferably a human (patient) to prevent and / or treat hand-foot syndrome (hereinafter sometimes abbreviated as the method of the present invention), imidafenacin used in the method , A salt thereof, a solvate thereof, or a prodrug thereof, a prophylactic and / or therapeutic agent for hand-foot syndrome (hereinafter sometimes abbreviated as an agent of the present invention), and such a prophylactic and / or therapeutic agent The use of imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof for the production of

  In the present invention, the limb syndrome to be prevented and / or treated is caused by administration of an anticancer agent, sickle cell disease, or other factors. Preferred is a limb syndrome caused by administration of an anticancer agent. Hand-foot syndrome is also known as palm / plantar redness perception deficiency syndrome, limb erythema, chemotherapy drug-induced limb erythema, palm / plantar erythema, limb skin reaction, and the like. In the present invention, the term limb syndrome includes all these synonyms.

  In the present invention, the anticancer drug means a drug that induces hand-foot syndrome among drugs used in cancer chemotherapy. Examples of the anticancer agent include alkylating agents, antimetabolites, microtubule inhibitors, antibiotic anticancer agents, topoisomerase inhibitors, platinum preparations, biological preparations, folic acid antimetabolites, molecular target drugs, and the like.

  Examples of the alkylating agent include cyclophosphamide (endoxan (registered trademark)), ifosfamide (ifomide (registered trademark)), nitrosourea, dacarbazine (dacarbazine (registered trademark)), temozolomide (Temodar (registered trademark)), Nimustine (Nidran (registered trademark)), Busulfan (Busulex (registered trademark)), Melphalan (Alkeran (registered trademark)), Procarbazine (Procarbazine hydrochloride (registered trademark)), Ranimustine (Cymellin (registered trademark)), Thiotepa (Tespamamine) (Registered trademark)).

  Antimetabolites include, for example, floxuridine (FUDR (registered trademark)), enositabine (sanrabin (registered trademark)), carmofur (miflor (registered trademark)), capecitabine (xeloda (registered trademark)), tegafur (ftofurol ( Registered trademark)), tegafur uracil (YUFT (registered trademark)), tegafur gimeracil oteracil potassium (TS1 (registered trademark)), gemcitabine (GEMSAR (registered trademark)), cytarabine (cytosar-U (registered trademark)) ), Cytarabine ocphosphate (staraside (registered trademark)), nelarabine (alanonzi (registered trademark)), fluorouracil (5-FU), fludarabine (fludara (registered trademark)), pemetrexed (Arimta (registered trademark)), Pentostatin (cohorin ( Recording TM)), methotrexate, cladribine (Leustatin (R)), doxifluridine (Furtulon (Registered Trademark)), hydroxycarbamide (Hydrea (R)), mercaptopurine (Roikerin (registered trademark)) and the like.

Examples of the microtubule inhibitor include vinorelbine (Navelvin (registered trademark)), vinblastine (Exzar (registered trademark)), vincristine (oncobin (registered trademark)), vindesine (fildesine (registered trademark)), docetaxel (taxotere (registered trademark)) Trademark)), paclitaxel (Taxol (registered trademark)) and the like.
Antibiotic anticancer agents include, for example, mitomycin C (mitomycin (registered trademark)), doxorubicin (adriacin (registered trademark)), epirubicin (epirubicin hydrochloride (registered trademark)), daunorubicin (daunomycin (registered trademark)), bleomycin (bleo (Registered trademark)), actinomycin D (cosmegen (registered trademark)), aclarubicin (acracinone (registered trademark)), idarubicin (idadamine (registered trademark)), pirarubicin (pinorbin (registered trademark)), peplomycin (pepreo (registered trademark)) )), Mitoxantrone (Novantrone (registered trademark)), amrubicin (calced (registered trademark)), dinostatin stimamarer (Smanx (registered trademark)), liposomal doxorubicin (doxyl (registered trademark)), etc. Is .

Examples of the topoisomerase inhibitor include irinotecan (campto (registered trademark)), nogitecan (highcamtin (registered trademark)), etoposide (bepsid (registered trademark)), sobuzoxane (perazoline (registered trademark)), and the like.
Examples of the platinum preparation include cisplatin (IACOAL (registered trademark)), nedaplatin (Akpra (registered trademark)), oxaliplatin (Elplat (registered trademark)), carboplatin (carboplatin (registered trademark)), and the like.

Examples of the biologic include interferon α, β and γ, interleukin, ubenimex (bestatin (registered trademark)), dry BCG (immunobladder (registered trademark)), and the like.
Examples of the folic acid antimetabolite include folinate and levofolinate.

Examples of molecular targeted drugs include rituximab (Rituxan (registered trademark)), alemtuzumab, trastuzumab (Herceptin (registered trademark)), cetuximab (Arbitux (registered trademark)), panitumumab (Vectivix (registered trademark)), imatinib (Gleevec ( Registered trademark)), dasatinib (Sprisel (registered trademark)), nilotinib (Tastigna (registered trademark)), gefitinib (Iressa (registered trademark)), erlotinib (Tarceva (registered trademark)), everolimus (Affinitol (registered trademark)), Temsirolimus (Tricel (registered trademark)), Bevacizumab (Avastin (registered trademark)), Sunitinib malate (Sutent (registered trademark)), Sorafenib tosylate (Nexavar (registered trademark)), Bortezomib (Velcade (registered trademark)) Gemtuzumab ozogamicin (Mylotag®), Ibritumomab Tiuxetane (Zevalin®), Tamibarotene (Amnolake®), Tretinoin (Vesanoid®), Lapatinib Tosylate Hydrate (Tykerb) (Registered trademark)), thalidomide (sared (registered trademark)), lenalidomide (revramid (registered trademark)) and the like. In addition to the molecular target drugs specified here, human epidermal growth factor receptor 2 inhibitor, epidermal growth factor receptor inhibitor, Bcr-Abl tyrosine kinase inhibitor, epidermal growth factor tyrosine kinase inhibitor, mTOR inhibition Agents, inhibitors targeting vascularization such as vascular endothelial growth factor receptor 2 inhibitor (α-VEGFR-2 antibody), various kinase inhibitors such as MAP kinase inhibitor, inhibitors targeting cytokines, proteasome Molecular targeting drugs such as inhibitors and antibody-anticancer agent conjugates can also be included. These inhibitors also include antibodies.
Moreover, the anticancer agent in the present invention includes not only those found so far but also those found in the future.

Preferred alkylating agents are cyclophosphamide and melphalan.
Antimetabolites are preferably floxuridine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, cytarabine, fluorouracil, methotrexate, doxyfluridine, hydroxycarbamide, particularly preferably capecitabine.
Preferred microtubule inhibitors are vincristine, docetaxel, and paclitaxel.

Antibiotic anticancer agents are preferably doxorubicin, daunorubicin, idarubicin, and liposomal doxorubicin.
A preferred topoisomerase inhibitor is etoposide.
Preferred platinum preparations are cisplatin and oxaliplatin.
Interleukin 2 is preferable as a biologic.
The molecular target drug is preferably trastuzumab, sunitinib malate, sorafenib tosylate, or lapatinib tosylate hydrate, and particularly preferably sunitinib malate or sorafenib tosylate.
In the present invention, preferred anticancer agents to be prevented and / or treated are antimetabolite agents and molecular targeted drugs.

  Combination therapy combining two or more anticancer drugs also induces limb syndrome. Examples of combination therapy for inducing hand-foot syndrome include combination therapy including one or more anticancer agents selected from the above-mentioned anticancer agents. Specifically, capecitabine and letrozole (Femara (registered trademark)), capecitabine and lapatinib tosylate hydrate, capecitabine and trastuzumab, capecitabine and traxuzuplatin, capecitabine and docetaxel, capecitabine and cyclophosphamide, etc. .

  When imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof is used for prevention and / or treatment of hand-foot syndrome, the administration route may be oral administration or parenteral administration. Parenteral administration may be systemic administration such as intravenous administration, or local administration such as transdermal administration. Preferably, it is oral administration or transdermal administration capable of topical administration.

  When imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof is administered to a mammal (for example, a human or non-human animal, preferably a human (patient)) by the above-mentioned administration method, each administration A pharmaceutical composition according to the form is used.

  Examples of the pharmaceutical composition used for oral administration include solid preparations for internal use such as tablets, pills, capsules (hard capsules, soft capsules), powders, granules, and the like, for example, solutions, suspensions, emulsions, Examples include liquids for internal use such as syrups and elixirs. The tablets include sublingual tablets, intraoral adhesive tablets, intraoral quick disintegrating tablets, orally disintegrating tablets and the like.

  The solid preparation for internal use is imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof as it is or an excipient (eg, lactose, lactose hydrate, mannitol, D-sorbitol, glucose, crystalline cellulose, Crystalline cellulose, partially pregelatinized starch, starch, etc.), binder (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, gelatin, polyvinyl alcohol, polyvinyl alcohol partial saponified product, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc.) , Disintegrating agents (for example, calcium cellulose glycolate, low-substituted hydroxypropylcellulose, croscarmellose sodium, methylcellulose, crospovidone, etc.), lubricants For example, magnesium stearate, calcium stearate, talc, hardened oil and the like), stabilizers, solubilizers (e.g., mixed glutamate, with aspartic acid, etc.) or the like, can be formulated according to a conventional method. If necessary, it is coated with a coating agent (for example, sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, titanium oxide, iron sesquioxide, carnauba wax, etc.) Alternatively, it may be coated with two or more layers. In the case of capsules, for example, proteins such as gelatin and collagen, such as starch, amylose, polygalacturonic acid, agar, carrageenan, gum arabic, gellan gum, xanthan gum, pectin, alginic acid and other polysaccharides such as polylactic acid In addition, a biodegradable plastic such as polyhydroxybutyric acid and polyglutamic acid, for example, a capsule film mainly composed of hardened fats and oils such as triglycerides and diglycerides of medium chain fatty acids may be filled.

  The liquid for internal use is obtained by dissolving, suspending, or emulsifying imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof in a commonly used diluent (eg, purified water, ethanol, or a mixture thereof). Can be formulated. Further, for example, a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance, a preservative, a buffering agent and the like can be added to this liquid agent.

Pharmaceutical compositions used for intra-arterial, intravenous, or local injection are either solutions, suspensions, emulsions, or solid injections that are dissolved or suspended in the solvent at the time of use. May be. These pharmaceutical compositions are produced by dissolving, suspending, or emulsifying imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof in a solvent. Examples of the solvent include distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, this pharmaceutical composition comprises a stabilizer, buffer, pH adjuster, solubilizer, solubilizer, suspending agent, emulsifier, surfactant, antioxidant, antifoaming agent, isotonic agent, painless. Additives such as those described in, for example, “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association), etc., such as Yakuhin Nippo Co., Ltd., may be included. In addition, in addition to these additives, electrolytes (for example, sodium chloride, potassium chloride, calcium chloride, sodium lactate, sodium dihydrogen phosphate, sodium carbonate, magnesium carbonate, etc.) are used in the case of infusion preparations for infusion administration. Sugars (eg, glucose, fructose, sorbitol, mannitol, dextran, etc.), protein amino acids (eg, glycine, aspartic acid, lysine, etc.), vitamins (eg, vitamin B ₁ , vitamin C, etc.), etc. Components used for infusion can be used. These are sterilized in the final step or prepared by aseptic manipulation. In addition, an aseptic solid preparation, for example, a freeze-dried product can be produced and used after being sterilized or dissolved in aseptic distilled water for injection or other solvents.

  The pharmaceutical composition for local injection may be a microsphere injection. Regarding the microsphere production method, usage method, and the like, it may be referred to, as necessary, by Jun Koishi, “Development and application of micro / nano-based capsules and fine particles”, CMC Publishing Co., Ltd. (2003). Regarding the sustained release of a general physiologically active substance, Kohei Miyao, “Practice of Drug Delivery System”, Medicinal Journal, Inc. (1986) may be referred to as necessary. The above-mentioned pharmaceutical composition as a microsphere injection can be injected intramuscularly, preferably subcutaneously, to locally release imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof. Become. Such microsphere injections can be administered intravenously or intraarterially as desired.

  Examples of the pharmaceutical composition used for transdermal administration include liquid sprays, lotions, ointments, creams, gels, sols, aerosols, poultices, plasters, tapes and the like. These compositions include imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof, and an oily base generally used for external use [eg, vegetable oil (eg, cottonseed oil, sesame oil, olive oil, etc.), Waxes (eg, carnauba wax, beeswax, etc.), higher hydrocarbons (eg, white petrolatum, liquid paraffin, plastibase, etc.), fatty acids (eg, stearic acid, palmitic acid, etc.), and esters thereof, higher alcohols (eg, , Cetanol, etc.), silicones (eg, silicon fluid, silicone rubber, etc.)], water-soluble bases [eg, solutions of polyvinyl alcohol, carboxyvinyl polymer, cellulose derivatives, etc., or polymer hydrogels, polyethylene glycol (local Macrogol), polyethylene glycol-poly Lopylene glycol copolymer, propylene glycol, 1,3-butylene glycol, ethanol, glycerin, etc.], pressure-sensitive adhesives used in tapes [for example, synthetic rubber-based pressure-sensitive adhesives (for example, methacrylic acid ester copolymers, natural rubber Adhesive, synthetic isoprene, etc.), silicone polymer adhesive, etc.], film base [eg, polyethylene, polypropylene, polyethylene-vinyl acetate copolymer, PET, aluminum laminate, etc.], gel base [eg, dry agar , Gelatin, aluminum hydroxide, silicic acid, etc.], or an oily base and a water soluble base, a surfactant [eg, anionic surfactant (eg, fatty acid, saponin, fatty acid sarcoside, alcohol sulfate, alcohol phosphate) Esters), cationic surfactants (eg quaternary ammonium) , Heterocyclic amines, etc.), amphoteric surfactants (eg, alkylbetaines, lysolecithin, etc.), nonionic surfactants (eg, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, etc.)] Etc. to which an emulsion base and the like are added is used. Further, if necessary, commonly used additives such as surfactants [for example, anionic surfactants (for example, fatty acids, saponins, fatty acid sarcosides, alcohol sulfates, alcohol phosphates, etc.), cations Surfactant (eg, quaternary ammonium salt, heterocyclic amine, etc.), amphoteric surfactant (eg, alkylbetaine, lysolecithin, etc.), nonionic surfactant (eg, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid) Esters, sucrose fatty acid esters, etc.]], thickeners [eg, cellulose derivatives (eg, carboxymethyl cellulose, etc.), polycarboxylic acids (eg, polyacrylic acid, methoxymethylene maleic anhydride copolymers, etc.), nonionic Water-soluble polymers (eg, polyvinylpyrrolidone, poly Nil alcohol, etc.)], stabilizers [eg, antioxidants (eg, ascorbic acid, sodium pyrosulfite, etc.), chelating agents (eg, EDTA, etc.)], pH adjusters [eg, phosphate buffers, etc. Sodium hydroxide, etc.], preservatives [eg, parabens, alkyl quaternary ammonium salts (eg, benzalkonium chloride, benzethonium chloride, etc.)], absorption enhancers [eg, fatty acids and esters thereof (eg, Oleic acid, isopropyl myristate, etc.), phospholipids (eg, phosphatidylcholine, etc.), terpenes (eg, limonene, etc.), azacycloalkanes (eg, Azone (trade name, Nelson Research) etc.) etc.] It can also be added. These preparations for transdermal administration containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof are prepared using the above-mentioned various bases, adhesives, or other additives that are added as necessary. It can be produced by a conventional method.

  Liquid sprays, lotions, sols, or aerosols can be obtained by imidafenacin, its salts, its solvates, or their prodrugs in a solvent such as water, propylene glycol, 1,3-butylene glycol, ethanol, glycerin, etc. In addition, it can be produced by dissolving or dispersing. Moreover, the said additive can also be added if desired.

  An ointment or cream is an imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof, a solvent commonly used in the art such as the water-soluble base, the oil-based base and / or water, or vegetable oil. And a surfactant is added if necessary, and an emulsification treatment is performed. Moreover, the said additive can also be added if desired.

  The poultice, plaster, or tape is a solution containing imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof and the above-mentioned pressure-sensitive adhesive (may contain the above-mentioned additives if necessary). Can be produced by applying a cross-linking treatment and a drying operation as necessary.

  The gel is prepared by pouring imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof and a solution containing the gel base (may contain the additive if necessary) into a mold. Depending on the case, it can be produced by performing a crosslinking treatment or a drying operation.

  Dosage of imidafenacin, its salt, its solvate, or their prodrugs can reduce the amount of imidafenacin, its salt, its solvate, or their prodrugs to limb syndrome without significant toxicity in the body. Any dosage is acceptable as long as it is effective, but it is usually used in the range of about 0.01 mg to about 10 mg. Note that, by changing the administration method as described above, the dose required to obtain the desired effect also changes, so when administering imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof, A suitable dose may be selected according to the administration method.

  As a guideline for the dose of imidafenacin, for example, when administered orally, the dose per dose is preferably about 0.025 mg to about 0.8 mg, more preferably about 0.05 mg to about 0.00. 4 mg, more preferably about 0.1 mg to about 0.2 mg, and particularly preferably about 0.1 mg or about 0.2 mg. In addition, for example, in the case of transdermal administration, the dose per dose is preferably about 0.05 mg to about 5 mg, more preferably about 0.1 mg to about 2 mg, and further preferably about 0.00. 2 mg to about 1 mg. In addition, when using the salt of imidafenacin, its solvate, or those prodrugs, the dosage shown above is suitable as the amount of imidafenacin.

  When imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof is used as a prophylactic and / or therapeutic agent for hand-foot syndrome, the dosing period is any period as long as it is effective. Good. If desired, it may be administered intermittently with an appropriate drug holiday.

Specific administration periods in the agent of the present invention include, for example, 1 day to 5 years, 1 day to 1 year, 1 day to 6 months, 1 day to 2 months, and the like.
Examples of the number of doses per day during these dosing periods include, for example, 1 to 10 times for oral and intravenous administration forms. The number of administrations per day is preferably 1 to 3 times, more preferably 1 to 2 times, and further preferably 2 times in the oral administration form. In the transdermal administration mode, the administration frequency is, for example, twice a day, once a day, or once every 2 to 7 days, once a day, or 2 to 4 One time during the day is preferred.

In the present invention, the agent of the present invention may be administered for preventive purposes before the onset or recurrence of hand-foot syndrome, or may be administered for therapeutic purposes after onset of hand-foot syndrome.
In the present invention, the agent of the present invention may be administered, for example, at the same time as the start of the administration of the anticancer agent that induces hand-foot syndrome, either before the start of the administration of the anticancer agent or after the start of the administration of the anticancer agent. For example, an anticancer agent or the like and the agent of the present invention can be used in combination in chemotherapy, and in this case, the dose of the anticancer agent or the like may be an amount effective for treatment usually used for cancer chemotherapy.

  In the present invention, the preventive and / or therapeutic effects of imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof on hand-foot syndrome are, for example, those of hand-foot syndrome shown in Table 1, Table 2, or Table 3 below. It can be evaluated using a criterion. Table 1 is a criterion for hand-foot syndrome proposed by Blum et al., And is described in J. Clin. Oncol., 17, 485-493 (1999). Yes. Grade 0 is not specifically mentioned, but it is understood as grade 0 when there is no symptom. Table 2 shows the 2nd edition of the Common Toxicity Criteria (National Cancer Institute-Common Toxicity Criteria Version 2.0 (NCI-CTC v2.0)), and Table 3 shows the 3rd edition of the Common Terms for Adverse Events (National Cancer Institute-Common Terminology Criteria). for Adverse Events Version 3.0 (NCI-CTCAE v3.0)). In Table 3, grade 0 is not particularly mentioned, but it is understood as grade 0 when there is no symptom.

該当する症状のグレードが両基準（臨床領域、機能領域）で一致しない場合は、より適切と判断できるグレードを採択する。

If the grade of the corresponding symptom does not match between the two criteria (clinical area, functional area), the grade that can be judged to be more appropriate is adopted.

  In any of the judgment criteria of Tables 1, 2, and 3, when the hand-foot syndrome grade is 2 or more, it may be necessary to reduce the dose of the anticancer drug, stop the drug, or discontinue the administration. Therefore, it is necessary to suppress limb syndrome at grade 1 or lower in order to continue appropriate cancer treatment. In order to maintain or improve the patient's quality of life (QOL), it is important to suppress hand-foot syndrome to grade 1 or lower.

  In the present invention, treatment means relieving symptoms of hand-foot syndrome. Specifically, for example, the patient's subjective symptoms are improved, or one or more grades are lowered from the stage before administration of imidafenacin, and preferably the grade is 1 or less.

  In the present invention, prevention means preventing the onset of hand-foot syndrome, or maintaining a mild symptom, such as grade 1, even if it develops. Prevention also includes prevention of recurrent hand-foot syndrome (relapse prevention).

  In the present invention, imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof may be used alone, or other drugs used for the treatment of hand-foot syndrome, other measures for hand-foot syndrome, And / or may be used in combination with drugs other than anti-cancer drugs used in cancer treatment.

  When imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof is used in combination with another drug, it may be administered in the form of a combination containing both components in one preparation, or separately. It may be in the form of administration as a pharmaceutical preparation. Administration as separate formulations includes simultaneous administration and administration by time lag.

Examples of other drugs used for the treatment of hand-foot syndrome include moisturizers, antibiotics, topical steroids, oral steroids, non-steroidal anti-inflammatory analgesics, vitamin B ₆ preparations, and the like.

  Examples of the humectant include urea-containing preparations (for example, urea (Urepar (registered trademark), keratinamine (registered trademark), pastalon (registered trademark), etc.), heparin-like substance-containing preparations (for example, heparin-like substance (Hirudoid (registered trademark) Trademark), hirudoid soft (registered trademark), etc., vitamin-containing ointments (for example, vitamin A oil (Zane (registered trademark)), tocopherol containing vitamin E, vitamin A oil (YUBERA (registered trademark)), etc., containing guaiazulene Examples thereof include ointments (for example, sodium azulene sulfonate hydrate (azulene)), white petrolatum and the like.

Examples of antibiotics include gentamicin sulfate (gentacin (registered trademark)), fradiomycin sulfate, sodium fusidate, and the like.
Examples of steroid external preparations include clobetasol propionate (dermovate (registered trademark)), diflorazone acetate (difural (registered trademark), mometasone furan carboxylate (furmeta (registered trademark)), betamethasone butyrate propionate (anteveate). (Registered trademark)), fluocinonide (topsim (registered trademark)), betamethasone dipropionate (linderon DP (registered trademark)), difluprednate (mizer (registered trademark)), amsinonide (visdarm (registered trademark)), Yoshi Diflucortron herbate (Texmethen (registered trademark)), Hydrocortisone butyrate propionate (Pandel (registered trademark)), Deprodon propionate (Ekler (registered trademark)), Dexamethasone propionate (Mesaderm (registered trademark)) )), Dexamethasone valerate (Boara (registered trademark)), harsinonide (Adcortin (registered trademark)), betamethasone valerate (betonebate (registered trademark)), beclomethasone propionate (propaderum (registered trademark)), fluocino And ronacetonide (full coat (registered trademark)).

  Examples of oral steroids include prednisolone, methylprednisolone, dexamethasone, betamethasone and the like.

Examples of non-steroidal anti-inflammatory analgesics include acetylsalicylic acid, ibuprofen, loxoprofen sodium, acetaminophen, diclofenac sodium, celecoxib and the like.
Examples of the vitamin B ₆ preparation include pyridoxine hydrochloride, pyridoxal phosphate (pyridoxal phosphate ester hydrate (pidoxal (registered trademark))) and the like.

  In the present invention, other methods of dealing with hand-foot syndrome include, for example, soaking hands and feet in cold water, avoiding excessive temperature, pressure and friction, applying a soft pad to the affected area, and cleaning for nail symptoms , Gauze protection, taping, nail arthroplasty, artificial nails, cryosurgery and the like.

  Examples of drugs other than anticancer drugs used in cancer treatment include drugs used for the treatment of cancer pain and drugs that reduce the side effects of anticancer drugs.

Examples of the drug used for the treatment of cancer pain include non-steroidal anti-inflammatory analgesics, morphine, fentanyl, oxycodone, codeine phosphate, and the like.
Drugs that reduce the side effects of anticancer drugs include, for example, antiemetics, appetite promoters, drugs useful for the treatment of anemia, drugs useful for the treatment of neutropenia, and useful for peripheral neuropathy caused by cancer chemotherapy And other drugs.
Antiemetics include, for example, neurokinin 1 receptor antagonists (eg aprepitant, fosaprepitant dimeglumine, etc.), 5HT ₃ receptor antagonists (eg granisetron hydrochloride, ondansetron hydrochloride, azasetron hydrochloride, Palonosetron hydrochloride, etc.), antidopaminergic drugs (eg, metoclopramide, etc.), steroid drugs (eg, dexamethasone, methylprednisolone, betamethasone, etc.), benzodiazepines, and the like.

Appetite promoting agents include, for example, limonade hydrochloride, ghrelin-like agonists (anamorelin hydrochloride, etc.) and the like.
Examples of drugs useful for the treatment of anemia include erythropoietin preparations (epoetin alfa and the like).
Examples of drugs useful for the treatment of neutropenia include human granulocyte colony stimulating factor (G-CSF).
Examples of drugs useful for peripheral neuropathy caused by cancer chemotherapy include PGE ₁ preparations (Limaprost, Alphadex, etc.) and the like.

  The aforementioned agents used in combination with imidafenacin, a salt thereof, a solvate thereof, or a prodrug thereof are exemplary and not limited thereto. The administration method of these drugs is not particularly limited, and may be oral administration or parenteral administration. These drugs may be administered in combination of any two or more. These drugs include not only those that have been found to date based on the above-described mechanism, but also those that will be found in the future.

[toxicity]
The toxicity of imidafenacin, its salts, its solvates, or their prodrugs is sufficiently low and safe enough for use as a pharmaceutical.

  Hereinafter, although an example explains the present invention in detail, the present invention is not limited to these. In cases 1 to 4, Stabra (registered trademark) tablets or Uritos (registered trademark) tablets were used as imidafenacin.

Example 1: Effect of imidafenacin on hand-foot syndrome caused by capecitabine administration (case 1)
In the combination therapy of capecitabine (Method B: oral administration of 2400 mg / day for 2 weeks, followed by a week off, repeated administration as a course) and letrozole 2.5 mg / day, We investigated the effect of imidafenacin on recurrent breast cancer patients (female) who developed hand-foot syndrome.
The degree of hand-foot syndrome was evaluated according to the criteria shown in Table 1 above, and the evaluation results are shown in FIG.
From the end of the third course of capecitabine in which hand-foot syndrome was grade 3, 0.1 mg of imidafenacin was orally administered to the patient twice a day.
As a result, imidafenacin improved symptom of hand-foot syndrome to grade 1 in a short period of 14 days from the start of administration. In addition, since Grade 1 was maintained without any worsening of the limb syndrome associated with the start of the next course, cancer treatment was performed without changing cancer chemotherapy (decrease in anticancer drugs, withdrawal of drugs other than scheduled, or discontinuation of administration). I was able to continue.
From these results, it was revealed that imidafenacin has a therapeutic effect and a preventive effect on hand-foot syndrome caused by capecitabine or a combination therapy of capecitabine and letrozole.

Example 2: Effect of imidafenacin on hand-foot syndrome caused by sunitinib malate administration (case 2)
Patients with kidney cancer (male) who developed hand-foot syndrome in the administration of sunitinib malate (50 mg / day as sunitinib, orally administered for 4 weeks, then withdrawn for 2 weeks. Repeat this as a course) We investigated the effect of imidafenacin on the aging of the animal.
The degree of hand-foot syndrome was evaluated according to the criteria shown in Table 1 above, and the evaluation results are shown in FIG.
The patient was orally administered with 0.1 mg of imidafenacin twice a day after the completion of the second course of medication with hand-foot syndrome of grade 3.
As a result, imidafenacin improved symptom of hand-foot syndrome to grade 1 in a short period of 4 days from the start of administration. Later, with the dermatology visit, the moisturizer urea ointment, heparin analog ointment, and clobetasol propionate ointment, which has anti-inflammatory action, were prescribed, so when I started using it together with imidafenacin, 8 days after the combination, complete cure of hand-foot syndrome was observed. Furthermore, as a result of continuing these treatments, the hand-foot syndrome that deteriorated to grade 3 by administration of sunitib malate for 4 weeks in the second course remained at grade 1 in the third course.
From these results, it was revealed that imidafenacin has a therapeutic effect and a preventive effect on limb syndrome caused by sunitinib malate.

Example 3: Effect of imidafenacin on hand-foot syndrome caused by sorafenib tosylate administration (case 3)
The effect of imidafenacin on renal cancer patients (male) who developed hand-foot syndrome in the administration of sorafenib tosylate (800 mg / day as sorafenib) was examined.
The degree of hand-foot syndrome was evaluated according to the criteria shown in Table 1 above, and the evaluation results are shown in FIG.
Immediately after initiating dosing with sorafenib tosylate, patients were prescribed gentamicin sulfate ointment, an antibiotic, followed by vitamin A oil ointment, a moisturizer, because Grade 3 hand-foot syndrome developed. However, even after the addition of vitamin A oil ointment for 35 days, the symptoms of hand-foot syndrome remained unchanged.
Therefore, from this time point, in addition to gentamicin sulfate ointment and vitamin A oil ointment, the patient started oral administration of imidafenacin 0.1 mg twice a day.
As a result, the symptoms of hand-foot syndrome improved to grade 1 35 days after the start of imidafenacin administration (at the next visit). In gentamicin sulfate ointment and vitamin A oil ointment, the additional prescription of imidafenacin showed an improvement effect against hand-foot syndrome caused by sorafenib tosylate, which did not improve, so this effect is due to imidafenacin Obviously. Furthermore, with the improvement of symptoms of hand-foot syndrome, the concomitant drug was switched from gentamicin sulfate ointment and vitamin A oil ointment to a heparin-like substance cream as a moisturizing agent, and oral administration of imidafenacin was continued. As a result, after 22 days, complete cure of hand-foot syndrome was confirmed. In addition, continued administration of imidafenacin and moisturizer after complete cure prevented recurrence of limb syndrome.
From these results, it was clarified that imidafenacin has a therapeutic effect and a preventive effect on limb syndrome caused by sorafenib tosylate.

Example 4: Effect of imidafenacin on limb syndrome caused by sorafenib tosylate administration (case 4)
We investigated the effect of imidafenacin on renal cancer patients (female) who developed hand-foot syndrome in the administration of sorafenib tosylate.
The degree of hand-foot syndrome was evaluated according to the criteria shown in Table 1 above, and the evaluation results are shown in FIG.
The patient started taking sorafenib tosylate (800 mg / day as sorafenib). Grade 21 hand-foot syndrome developed 21 days after the start of the medication, so the patient was withdrawn. On the 28th day after the start of the drug withdrawal, since the hand-foot syndrome recovered to Grade 1, treatment was resumed by a method of gradually increasing the dose of sorafenib tosylate (starting from 200 mg / day as sorafenib). Later, limb syndrome developed again, and limb syndrome worsened to grade 3 at a dose of 800 mg / day as sorafenib. Therefore, a prescription of urea ointment, which is a moisturizing agent, was carried out, and then the dose of sorafenib tosylate was reduced (400 mg / day as sorafenib), but no improvement in symptoms was observed even on the 50th day after the dose reduction.
From this point, in addition to the urea ointment, the patient began oral administration of imidafenacin 0.1 mg twice daily.
As a result, administration of imidafenacin gradually improved limb syndrome, and limb syndrome improved to grade 1 after 42 days from the start of administration. The addition of imidafenacin showed an improving effect on hand-foot syndrome caused by sorafenib tosylate, which did not improve with the reduction in urea ointment and sorafenib tosylate, so this effect was due to imidafenacin Obviously. In addition, the symptoms of hand-foot syndrome were maintained at grade 1 thereafter.
From these results, it was clarified that imidafenacin has a therapeutic effect and a preventive effect on limb syndrome caused by sorafenib tosylate.

  The preventive and / or therapeutic agent for hand-foot syndrome containing imidafenacin, a salt, a solvate, or a prodrug thereof disclosed in the present invention can be safely administered to patients with hand-foot syndrome, and Since it shows an excellent preventive and / or therapeutic effect, it is very useful as a medicine. Until now, in order to cope with hand-foot syndrome, it has been necessary to reduce or discontinue or discontinue administration of anticancer agents, but if the agent of the present invention is used, it becomes possible to continue appropriate cancer treatment, and further, hand-foot syndrome. As a result of the improvement, the quality of life (QOL) of the patient is also improved.

Claims (11)

Imidafenacin, a salt thereof or a prophylactic and / or therapeutic agent for foot syndrome containing the solvate thereof.   A prophylactic and / or therapeutic agent for hand-foot syndrome containing imidafenacin.   The preventive and / or therapeutic agent according to claim 1 or 2, wherein the limb syndrome is a limb syndrome caused by administration of an anticancer agent.   The preventive and / or therapeutic agent according to claim 3, wherein the anticancer agent is an antimetabolite or a molecular target drug.   The preventive and / or therapeutic agent according to claim 4, wherein the antimetabolite is capecitabine and the molecular target drug is sunitinib malate or sorafenib tosylate.   The preventive and / or therapeutic agent according to claim 4, wherein the anticancer agent is an antimetabolite.   The preventive and / or therapeutic agent according to claim 4, wherein the anticancer agent is a molecular target drug.   The preventive and / or therapeutic agent according to claim 6, wherein the antimetabolite is capecitabine.   The preventive and / or therapeutic agent according to claim 7, wherein the molecular target drug is sunitinib malate or sorafenib tosylate. Imidafenacin, comprising a salt thereof, or a prophylactic and / or therapeutic agent for foot syndrome containing the solvate thereof, humectants, antibiotics, topical steroids, steroid oral medicine, non-steroidal anti-inflammatory agent and vitamin B ₆ preparation A medicament for preventing and / or treating hand-foot syndrome, comprising a combination of one or more selected from the group. Imidafenacin, a salt thereof, or a prophylactic and / or therapeutic agent for foot syndrome containing the solvate thereof, comprising a combination of anti-cancer drugs, prevention of hand-foot syndrome and / or therapeutic medicament for the.

Images