Medicine for treating chemotherapy-induced peripheral neuropathy

Abstract

The present invention provides a pharmaceutical composition for treating an acute-phase peripheral neuropathy induced by a chemotherapeutic agent, the pharmaceutical composition comprising an alkalizing agent. By administering this pharmaceutical composition, it is possible to treat an acute-phase peripheral neuropathy induced by a chemotherapeutic agent, in particular, a chemotherapeutic agent for cancer. The present invention also provides an anticancer pharmaceutical composition that contains an alkalizing agent and a chemotherapeutic agent for cancer and that is designed to suppress an acute-phase peripheral neuropathy induced by the chemotherapeutic agent or to suppress worsening of symptoms caused by the peripheral neuropathy. By administering this pharmaceutical composition, it is possible to provide a cancer treatment in which an acute-phase peripheral neuropathy or worsening of symptoms caused by the peripheral neuropathy is suppressed.

Description

Medicaments for the treatment of chemotherapy-induced peripheral neuropathy

[0001] The present invention relates to a novel pharmaceutical composition comprising an alkalizing agent. More specifically, the present invention relates to a pharmaceutical composition comprising an alkalizing agent for treating acute peripheral neuropathy induced by a chemotherapy drug.

[0002] Cancer chemotherapy can cause, for example, hypoesthesia or dysesthesia in the limbs. These symptoms are caused by peripheral neuropathy and tend to be more severe in the more peripheral parts of the limbs. The symptoms of anticancer drug-induced peripheral neuropathy (sometimes abbreviated as CIPN herein) can interfere with daily life due to unpleasant abnormal sensations, and in severe cases, can make it impossible to walk or put on or take off clothes. CIPN is rarely a transient condition that quickly resolves upon discontinuation of anticancer drugs; improvement can take months or even years, and it is not uncommon for some form of disability to remain for the rest of one's life.

[0003] Although CIPN has long been known as an adverse event, its detailed mechanism remains largely unknown, and no effective treatment has yet been established. Various drugs have been used for treatment, but these have not been sufficiently effective. CIPN is a significant adverse event that hinders the continuation of cancer chemotherapy. Its prevention and treatment could contribute not only to improving the outcomes of cancer treatment but also to improving patients' quality of life. However, the only effective treatment is to discontinue the chemotherapy agent that causes CIPN (Non-Patent Document 1).

[0004] Symptomatic classification of CIPN includes sensory neuropathy, motor neuropathy (numbness), tingling, or pain. Intense pain is also sometimes described as shooting pain or burning pain. Regarding the relationship between these, motor neuropathy and tingling do not necessarily mean intense pain, but it has been reported that almost all patients who experience intense pain also experience motor neuropathy or tingling. The motor neuropathy of CIPN manifests as muscle atrophy and weakness, or flaccid paralysis, predominantly in the distal limbs. Furthermore, tendon reflexes in the limbs are reduced or absent, becoming more pronounced the more distal the limbs are. The autonomic neuropathy of CIPN causes disorders of blood pressure, intestinal motility, or involuntary muscle function, and symptoms may include urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0005] Calcium or magnesium may be administered to prevent CIPN in the hopes of preventing neurotoxicity, but clear evidence of their effectiveness has not been obtained. Medications for numbness or pain include Goshajinkigan, vitamin B12 preparations, nonsteroidal anti-inflammatory drugs, pregabalin, gabapentin, and opioids, but the efficacy of none of these drugs is clear, and there is insufficient evidence to recommend their administration (Non-Patent Document 1). The only medication for which moderate evidence of its effectiveness has been obtained in the guidelines is duloxetine (Non-Patent Document 2). However, it is known that duloxetine often leads to early discontinuation due to adverse events after administration (Non-Patent Document 3).

[0006] On the other hand, some citric acid preparations or alkalizing agents such as sodium bicarbonate are known to be effective for treating hyperuricemia and gout, which are typical lifestyle-related diseases. It is also known that administration of alkalizing agents can suppress the formation of urinary stones by shifting acidic urine to alkaline urine. It is also known that administration of alkalizing agents to early-stage CKD patients can inhibit the progression of renal damage and reduce the blood concentration of uremic substances (Patent Documents 1 and 2). Furthermore, citric acid preparations are known to suppress renal fibrosis in diabetic nephropathy (Patent Document 3). However, it is not known that alkalizing agents are effective in treating chemotherapy-induced peripheral neuropathy.

[0007] International Publication No. WO 2018 / 193648 International Publication No. WO 2018 / 193752 International Publication No. WO 2020 / 080451

[0008] Guidelines for the Management of Peripheral Neuropathy Associated with Cancer Chemotherapy Neuropathic Pain Pharmacotherapy Guidelines Revised 2nd Edition Examination of Risk Factors for Adverse Events Caused by Duloxetine in Cancer Patients

[0009] One object of the present invention is to provide a pharmaceutical useful for treating acute peripheral neuropathy induced by a chemotherapy drug. Another object of the present invention is to provide an anti-cancer combination preparation comprising an alkalizing agent and a cancer chemotherapy drug, which is designed to suppress the deterioration of acute peripheral neuropathy. Another object of the present invention is to provide an anti-cancer pharmaceutical composition comprising an alkalizing agent and a cancer chemotherapy drug, which is designed to suppress the deterioration of acute peripheral neuropathy. Another object of the present invention is to provide an anti-cancer pharmaceutical kit comprising an alkalizing agent and a cancer chemotherapy drug, which is designed to suppress the deterioration of acute peripheral neuropathy. Another object of the present invention is to provide a method for treating acute peripheral neuropathy induced by a chemotherapy drug. Another object of the present invention is to provide a method for treating cancer, in which the deterioration of acute peripheral neuropathy is suppressed.

[0010] The present inventors have conducted extensive research to achieve the above-mentioned object and have found that a specific alkalizing agent is useful for treating acute peripheral neuropathy induced by chemotherapy drugs, thereby completing the present invention.

[0011] That is, the present invention has the following aspects: (1) A pharmaceutical composition for treating acute peripheral neuropathy induced by a chemotherapy drug, comprising an alkalinizing agent. (2) The pharmaceutical composition according to (1), wherein the acute peripheral neuropathy induced by a chemotherapy drug is pain, sensory disorder, motor disorder, autonomic neuropathy, or a complication thereof, caused by peripheral neuropathy. (3) The pharmaceutical composition according to (1) or (2), wherein the acute peripheral neuropathy induced by a chemotherapy drug is peripheral neuropathic pain. (4) The pharmaceutical composition according to (3), wherein the peripheral neuropathic pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling. (5) The pharmaceutical composition according to (1) or (2), wherein the acute peripheral neuropathy induced by a chemotherapy drug is sensory disorder caused by peripheral neuropathy. (6) The pharmaceutical composition according to (5), wherein the sensory disturbance caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia. (7) The pharmaceutical composition according to (6), wherein the hyperesthesia is allodynia and the dysesthesia is dysesthesia or paresthesia. (8) The pharmaceutical composition according to (1) or (2), wherein the acute-phase peripheral neuropathy induced by a chemotherapy drug is autonomic neuropathy caused by peripheral neuropathy. (9) The pharmaceutical composition according to (8), wherein the symptoms caused by autonomic neuropathy are dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. (10) The pharmaceutical composition according to any one of (1) to (9), wherein the acute-phase peripheral neuropathy induced by a chemotherapy drug is peripheral neuropathy in which symptoms appear in the limbs. (11) The pharmaceutical composition according to any one of (1) to (10), which is designed to be administered after the onset of acute-phase peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy. (12) The pharmaceutical composition according to any one of (1) to (11), which is designed to suppress the worsening of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration.

[0012] (13) The pharmaceutical composition according to any one of (1) to (12), wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. (14) The pharmaceutical composition according to any one of (1) to (13), wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. (15) The pharmaceutical composition according to any one of (1) to (14), wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. (16) The pharmaceutical composition according to any one of (1) to (13), wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0013] (17) The pharmaceutical composition according to any one of (1) to (16), wherein the pharmaceutical composition is in the form of a tablet. (18) The pharmaceutical composition according to any one of (1) to (12), wherein the alkalinizing agent is sodium bicarbonate. (19) The pharmaceutical composition according to any one of (1) to (18), wherein the chemotherapeutic agent is a cancer chemotherapeutic agent. (20) The pharmaceutical composition according to (19), wherein the cancer chemotherapeutic agent is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug. (21) The pharmaceutical composition according to (20), wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. (22) The pharmaceutical composition according to (20), wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. (23) The pharmaceutical composition according to (20), wherein the immunotherapeutic drug is at least one anticancer drug selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. (24) The pharmaceutical composition according to (20), wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. (25) The pharmaceutical composition according to (19), wherein the cancer chemotherapeutic drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib. (26) The pharmaceutical composition according to (25), wherein the cancer chemotherapeutic drug is paclitaxel or oxaliplatin. (27) The pharmaceutical composition according to (26), wherein the cancer chemotherapeutic drug is paclitaxel.

[0014] (28) A combined preparation for simultaneous, separate, or sequential administration in the treatment of cancer, the combined preparation comprising at least two separate preparations of an alkalizing agent and a cancer chemotherapeutic drug, wherein the alkalizing agent is designed to be administered after the onset of acute peripheral neuropathy induced by the chemotherapeutic drug or symptoms caused by the peripheral neuropathy. (29) The combined preparation according to (28), designed to suppress the worsening of acute peripheral neuropathy induced by the chemotherapeutic drug or symptoms caused by the peripheral neuropathy from the time of administration of the alkalizing agent. (30) An anti-cancer pharmaceutical composition comprising an alkalizing agent and a first cancer chemotherapeutic drug, wherein the anti-cancer pharmaceutical composition is designed to be administered after the onset of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy. (31) The anti-cancer pharmaceutical composition according to (30), which is designed to suppress the worsening of acute-phase peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy from the time of administration. (32) An anti-cancer pharmaceutical kit comprising an alkalizing agent in a first compartment and a cancer chemotherapeutic drug in a second compartment, the alkalizing agent being designed to be administered after the onset of acute-phase peripheral neuropathy induced by the chemotherapeutic drug or symptoms caused by the peripheral neuropathy. (33) The anti-cancer pharmaceutical kit according to (32), which is designed to suppress the worsening of acute-phase peripheral neuropathy induced by the chemotherapeutic drug or symptoms caused by the peripheral neuropathy from the time of administration of the alkalizing agent.

[0015] The pharmaceutical composition, combined preparation, and pharmaceutical kit provided by the present invention enable the treatment of acute peripheral neuropathy induced by a chemotherapeutic drug.Furthermore, the pharmaceutical composition, combined preparation, and pharmaceutical kit provided by the present invention enable the treatment of acute peripheral neuropathy induced by a chemotherapeutic drug, particularly a cancer chemotherapeutic drug, or cancer in which the worsening of symptoms caused by the peripheral neuropathy is suppressed.

[0016]

[0023] For a reference example, this figure shows the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model, showing the relationship between the number of days since the start of oxaliplatin administration and the pain score for mechanical allodynia and cold dysestesia. For a reference example, this figure shows the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model, showing the pain score for each test group regarding mechanical allodynia on day 10 from the start of oxaliplatin administration, the pain score for each test group regarding cold dysestesia on day 3 from the start of oxaliplatin administration, and the body weight of each test group on day 10 from the start of oxaliplatin administration. For a reference example, this figure shows the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the relationship between the number of days since the start of paclitaxel administration and body weight, and the relationship between the number of days since the start of paclitaxel administration and the pain score for mechanical allodynia.

[0023] For a reference example, this is a diagram showing the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the pain scores for each test group regarding mechanical allodynia on day 14 from the start of paclitaxel administration, and the body weights of each test group on day 14 from the start of paclitaxel administration.

[0024] For a reference example, this is a diagram showing the effect of an alkalizing agent in a bortezomib-induced mouse neuropathic pain model, showing the relationship between the number of days since the start of bortezomib administration and body weights, and the relationship between the number of days since the start of bortezomib administration and the pain scores regarding mechanical allodynia.

[0025] For a reference example, this is a diagram showing the effect of an alkalizing agent in a bortezomib-induced mouse neuropathic pain model, showing the pain scores for each test group regarding mechanical allodynia on day 12 from the start of bortezomib administration, and the body weights of each test group on day 12 from the start of bortezomib administration. For a reference example, this is a graph showing the effect of an alkalinizing agent in a vincristine-induced mouse neuropathic pain model, showing the relationship between the number of days since the start of vincristine administration and body weight, and the relationship between the number of days since the start of vincristine administration and pain scores related to mechanical allodynia.

[0023] For a reference example, this figure shows the effect of an alkalizing agent in a vincristine-induced mouse neuropathic pain model, showing the pain scores of each test group regarding mechanical allodynia on day 14 from the start of vincristine administration, and the body weight of each test group on day 14 from the start of vincristine administration. For a reference example, this figure shows the effect of an alkalizing agent in a paclitaxel-induced rat neuropathic pain model, showing the relationship between the number of days from the start of paclitaxel administration and the 50% withdrawal threshold. For a reference example, this figure shows the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the pain scores of each test group regarding mechanical allodynia on day 13 from the start of paclitaxel administration.

[0023] For a reference example, this figure shows the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the spontaneous firing frequency for each neuron in each test group on day 14 from the start of paclitaxel administration, and the vFF-induced firing frequency for each neuron in each test group on day 14 from the start of paclitaxel administration. For a reference example, this figure shows the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the spontaneous firing frequency for each individual in each test group on day 14 from the start of paclitaxel administration, and the vFF-induced firing frequency for each individual in each test group on day 14 from the start of paclitaxel administration. For a reference example, this figure shows the effect of an alkalizing agent in an oxaliplatin-induced mouse neuropathic pain model, showing the relationship between the number of days since the start of oxaliplatin administration and body weight, and the relationship between the number of days since the start of oxaliplatin administration and pain scores related to mechanical allodynia.

[0023] Figure 1 shows the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model for a reference example, showing the pain score for each test group related to mechanical allodynia on day 10 from the start of oxaliplatin administration, and the body weight of each test group on day 10 from the start of oxaliplatin administration. Figure 2 shows the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model for a reference example, showing the relationship between the number of days from the start of paclitaxel administration and body weight, and the relationship between the number of days from the start of paclitaxel administration and the pain score related to mechanical allodynia.

[0023] For a reference example, this is a graph showing the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the pain score for each test group regarding mechanical allodynia on day 14 from the start of paclitaxel administration and the body weight for each test group on day 14 from the start of paclitaxel administration.

[0024] For the present invention, this is a graph showing the effect of initiating administration of an alkalinizing agent after the onset of mechanical allodynia in a paclitaxel-induced mouse neuropathic pain model, showing the relationship between the number of days from the start of paclitaxel administration and the pain score regarding mechanical allodynia.

[0017] 1. Pharmaceutical Composition <Pharmaceutical Composition for Treating Acute Peripheral Neuropathy Induced by a Chemotherapeutic Agent> The pharmaceutical composition for treating acute peripheral neuropathy induced by a chemotherapeutic agent provided by the present invention may contain an alkalizing agent as an active ingredient. "Containing an alkalizing agent as an active ingredient" means that the alkalizing agent is the main ingredient in the pharmaceutical composition, or that the alkalizing agent functions as a substantial active ingredient in the treatment of acute peripheral neuropathy induced by a chemotherapeutic agent, and is contained in an effective amount for the treatment.

[0018] Alkalizing agents are agents that can be used to reduce the HCO3 content of mammalian (especially human) body fluids, such as blood or urine. -An alkalinizing agent is an agent capable of increasing concentration or pH. Examples of alkalinizing agents include pharmaceutically acceptable salts of citric acid, their hydrates, or mixtures thereof, and sodium bicarbonate (baking soda). Examples of pharmaceutically acceptable salts of citric acid include alkali metal citrate salts. Examples of alkali metal citrate salts include potassium citrate and sodium citrate, which may be stable hydrates such as potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), respectively. Examples of preferred alkalinizing agents contained in the pharmaceutical compositions provided by the present invention include sodium citrate, potassium citrate or its hydrates, or mixtures thereof, such as a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O). The mixing ratio of potassium citrate monohydrate (C6H5K3O7.H2O) and sodium citrate dihydrate (C6H5Na3O7.2H2O) can be appropriately determined by those skilled in the art. For example, the molar ratio of potassium citrate monohydrate to sodium citrate dihydrate can be 1 part potassium citrate monohydrate to 0.01 to 100 parts sodium citrate dihydrate. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) to sodium citrate (e.g., sodium citrate dihydrate) can be appropriately determined by those skilled in the art, and may be, for example, 0.85:1.15 to 1.15:0.85, 0.90:1.10 to 1.10:0.90, 0.95:1.05 to 1.05:0.95, or 0.99:1.01 to 1.01:0.99, with 1:1 being preferred.

[0019] Another example of an active ingredient contained in the pharmaceutical composition of the present invention is sodium citrate or a hydrate thereof, such as sodium citrate dihydrate (C6H5Na3O7·2H2O). Another example of an active ingredient contained in the pharmaceutical composition of the present invention is potassium citrate or a hydrate thereof, such as potassium citrate monohydrate (C6H5K3O7·H2O). In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may comprise a mixture of sodium citrate or a hydrate thereof and citric acid (e.g., anhydrous citric acid), or a mixture of potassium citrate or a hydrate thereof and citric acid (e.g., anhydrous citric acid). In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate or a hydrate thereof, sodium citrate or a hydrate thereof, and citric acid (e.g., anhydrous citric acid). In this case, the mixing ratio (molar ratio) of citric acid (e.g., anhydrous citric acid), potassium citrate, and sodium citrate can be appropriately determined by those skilled in the art and may be, for example, 1:1.7-2.3:1.7-2.3, 1:1.9-2.1:1.9-2.1, or 1:1.95-2.05:1.95-2.05, with 1:2:2 being preferred. In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may be a mixture of potassium citrate monohydrate (C6H5K3O7·H2O), sodium citrate dihydrate (C6H5Na3O7·2H2O), and anhydrous citric acid. In this case, the mixing ratio (molar ratio) of anhydrous citric acid, potassium citrate monohydrate (C6H5K3O7.H2O), and sodium citrate dihydrate (C6H5Na3O7.2H2O) can be appropriately set by a person skilled in the art, and may be, for example, 1:1.7-2.3:1.7-2.3, 1:1.9-2.1:1.9-2.1, or 1:1.95-2.05:1.95-2.05, with 1:2:2 being preferred.In one embodiment, the alkalinizing agent contained in the pharmaceutical composition of the present invention may consist solely of a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. When referring to the weight of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (e.g., potassium citrate monohydrate (C6H5K3O7.H2O) and sodium citrate dihydrate (C6H5Na3O7.2H2O)) herein, the weight may be the dry weight.

[0020] In one embodiment, the treatment of acute chemotherapeutic drug-induced peripheral neuropathy can be treatment of acute organic damage to peripheral nerves induced by a chemotherapeutic drug. In another embodiment, the treatment of acute chemotherapeutic drug-induced peripheral neuropathy can be treatment of symptoms caused by acute chemotherapeutic drug-induced peripheral neuropathy, such as pain, sensory disturbance, motor disturbance, autonomic neuropathy, or complications thereof. In one embodiment, the "acute chemotherapeutic drug-induced peripheral neuropathy" can be pain, sensory disturbance, motor disturbance, autonomic neuropathy, or complications thereof caused by acute chemotherapeutic drug-induced peripheral neuropathy. In another embodiment, the "acute chemotherapeutic drug-induced peripheral neuropathy" can be acute chemotherapeutic drug-induced peripheral neuropathic pain. In yet another embodiment, the "acute peripheral neuropathic pain" can be electric shock pain, burning pain, pain (excluding electric shock pain and burning pain), or tingling.

[0021] In one embodiment, the "chemotherapeutic drug-induced acute phase peripheral neuropathy" can be a sensory disorder such as hypoesthesia, hyperesthesia, or dysesthesia caused by acute phase peripheral neuropathy induced by a chemotherapy drug. The hyperesthesia concept includes allodynia, including mechanical allodynia caused by mechanical stimuli. The dysesthesia concept includes dysesthesia and paresthesia, including cold dysesthesia caused by cold stimuli. One aspect of sensory and / or motor disorders is "numbness." Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for treating numbness caused by acute phase peripheral neuropathy induced by a chemotherapy drug.

[0022] In one embodiment, the "chemotherapeutic drug-induced acute phase peripheral neuropathy" may be autonomic neuropathy caused by acute phase peripheral neuropathy induced by a chemotherapy drug. Typical symptoms caused by the autonomic neuropathy include dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. In one embodiment, the "chemotherapeutic drug-induced acute phase peripheral neuropathy" may manifest in the limbs of mammals (particularly humans), and may manifest in the peripheral limbs in particular.

[0023] In one embodiment, acute peripheral neuropathy induced by a chemotherapy drug can be treated by administering a pharmaceutical composition comprising an alkalinizing agent as an active ingredient provided by the present invention. In one embodiment, pain, sensory disturbances, motor disturbances, autonomic neuropathy, or complications thereof caused by acute peripheral neuropathy induced by a chemotherapy drug can be treated by administering a pharmaceutical composition comprising an alkalinizing agent as an active ingredient provided by the present invention. Herein, pain caused by acute peripheral neuropathy may be referred to as acute peripheral neuropathic pain. The type and severity of acute peripheral neuropathic pain induced by a chemotherapy drug that can be treated with a pharmaceutical composition comprising an alkalinizing agent as an active ingredient provided by the present invention are not particularly limited, but typically, pain referred to as shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling can be treated. Herein, sensory disturbances caused by acute peripheral neuropathy induced by a chemotherapy drug are a concept that encompasses hypoesthesia, hyperesthesia, and dysesthesia. Furthermore, the concept of hyperesthesia includes allodynia, and the concept of dysesthesia includes dysesthesia and paresthesia. Therefore, by administering the pharmaceutical composition provided by the present invention, which contains an alkalizing agent as an active ingredient, sensory disorders such as hypoesthesia, hyperesthesia, and dysesthesia, including allodynia, dysesthesia, and paresthesia, caused by acute peripheral neuropathy induced by a chemotherapy drug, can be treated.

[0024] In one embodiment, administration of a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient can treat symptoms caused by acute autonomic neuropathy induced by a chemotherapy drug, such as dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. In one embodiment, administration of a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient can treat symptoms occurring in the limbs, particularly symptoms occurring in the peripheral limbs, in mammals (particularly humans).

[0025] As used herein, the term "chemotherapeutic drug" is not particularly limited as long as it can induce acute peripheral neuropathy, and may be, for example, a "cancer chemotherapeutic drug." Furthermore, the term "cancer chemotherapeutic drug" is not particularly limited as long as it can induce peripheral neuropathy. It is known in the art that the following cancer chemotherapeutic drugs tend to induce acute peripheral neuropathy: cytotoxic anticancer drugs such as paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. Molecularly targeted anticancer drugs such as bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. Immunotherapeutic drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. Other anticancer drugs such as cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. Here, the terms "cytotoxic anticancer drugs," "molecularly targeted anticancer drugs," "immunotherapeutic drugs," and "other anticancer drugs" are used for convenience in organizing the above-mentioned cancer chemotherapy drugs, and these terms do not limit the species belonging to each class.

[0026] Therefore, in the present specification, the term "chemotherapeutic drug-induced acute peripheral neuropathy" refers to, for example, cytotoxic anticancer drugs such as paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine; bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab; The acute peripheral neuropathy may be induced by at least one anticancer drug selected from the group consisting of molecularly targeted anticancer drugs such as ib, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib; immunotherapeutic drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab; and other anticancer drugs such as cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. In one embodiment, acute peripheral neuropathy induced by the above-mentioned cancer chemotherapeutic drugs, i.e., anticancer drugs, can be treated by administering a pharmaceutical composition provided by the present invention containing an alkalinizing agent as an active ingredient.

[0027] In another embodiment, acute peripheral neuropathy induced by at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib can be treated by administering a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient. In yet another embodiment, acute peripheral neuropathy induced by paclitaxel or oxaliplatin can be treated by administering a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient. In yet another embodiment, acute peripheral neuropathy induced by bortezomib or vincristine can be treated by administering a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient.

[0028] As used herein, "treatment" includes eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means therefor; it also includes "suppressing" the worsening of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means therefor; and it is a concept that includes "improvement." In one embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means therefor. In another embodiment, "treatment" refers to eliminating, curing, curing, or remission of "pathological" or "abnormal" symptoms, conditions, or diseases. In one embodiment, "treatment" includes administration of a pharmaceutical composition comprising an alkalinizing agent as an active ingredient, provided by the present invention, as part of the cancer chemotherapy drug, i.e., anti-cancer drug, treatment. In one embodiment, the term "treatment" refers to the disappearance, cure, cure, or remission of acute peripheral neuropathy induced by the administration of a cancer chemotherapeutic drug, i.e., an anticancer drug, or "pathological" or "abnormal" symptoms, conditions, or diseases caused by the peripheral neuropathy, by initiating administration of a pharmaceutical composition provided by the present invention containing an alkalinizing agent as an active ingredient after the onset of acute peripheral neuropathy induced by the cancer chemotherapeutic drug, i.e., an anticancer drug, or symptoms caused by the peripheral neuropathy, and may also include actions or means for achieving this; it may also include "suppressing" the worsening of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means for achieving this; and may also include a concept including "improvement." Here, "administration of the pharmaceutical composition of the present invention containing an alkalizing agent as an active ingredient is initiated after the onset of acute peripheral neuropathy induced by an anticancer drug or symptoms caused by the peripheral neuropathy" generally means that the pharmaceutical composition of the present invention containing an alkalizing agent as an active ingredient is not administered before the onset of acute peripheral neuropathy induced by an anticancer drug or symptoms caused by the peripheral neuropathy.In one embodiment, when administration of the pharmaceutical composition of the present invention containing an alkalizing agent as an active ingredient is initiated after the onset of acute peripheral neuropathy induced by the cancer chemotherapy drug, i.e., the anticancer drug, or symptoms caused by the peripheral neuropathy, administration may be initiated within 1 day, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, or 21 days after the onset of the peripheral neuropathy or symptoms caused by the peripheral neuropathy.

[0029] As used herein, "suppression" refers to stopping, slowing, or reducing the worsening or progression of a symptom, condition, or disease, and includes actions or means for doing so, and also refers to improving the symptom, condition, or disease, or includes actions or means for doing so. Here, "improvement" refers to bringing a "pathological" or "abnormal" symptom, condition, or disease closer to a "healthy" or "normal" state, or includes actions or means for doing so, and refers to bringing the condition to a "healthy" or "normal" state, or includes actions or means for doing so. Accordingly, in one embodiment, "improvement" refers to a numerical value that is an indicator of a "pathological" or "abnormal" symptom or condition decreasing or increasing in accordance with the "improvement," approaching a normal value, or becoming a normal value. The "worsening or progression of a symptom, condition, or disease" refers to the worsening or progression of a "pathological" or "abnormal" symptom, condition, or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition, or disease. In one embodiment, "suppression" refers to stopping, slowing, or reducing the worsening or progression of a symptom, condition, or disease, or an action or means therefor. In another embodiment, "suppression" refers to stopping, slowing, or reducing the worsening or progression of a symptom, condition, or disease. As used herein, "suppression" preferably includes stopping and improving the worsening or progression of a symptom, condition, or disease, and an action or means therefor. As used herein, "healthy" refers to a state free from acute or chronic disease or disorder, and "normal" refers to a state that a healthy subject normally experiences.

[0030] As used herein, "prevention" is a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means for achieving this. Therefore, "suppressing" "pathological" or "abnormal" symptoms, conditions, or diseases in a state where they do not develop (also referred to as manifestation) can be considered to include the concept of "prevention."

[0031] As used herein, the "acute phase" of acute peripheral neuropathy refers to the period from the onset of chemotherapy-induced peripheral neuropathy or symptoms attributable to the peripheral neuropathy to the peak, whereas chemotherapy-induced peripheral neuropathy or symptoms attributable to the peripheral neuropathy typically worsen over time after onset and reach their worst (also referred to as peak) after a certain period of time. The "onset" of peripheral neuropathy or symptoms attributable to the peripheral neuropathy refers, for example, to a progression from Grade 1 (no symptoms) to Grade 2 (moderate symptoms, limiting activities of daily living other than self-care) in the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (JCOG version), which grades the severity of adverse events (AEs) for peripheral sensory neuropathy. In another aspect, when peripheral neuropathy or symptoms caused by peripheral neuropathy are divided into acute, recovery, and chronic phases over time, the "acute phase" refers to the period up to the recovery phase. In another aspect, the "acute phase" refers to the period from when symptoms of peripheral neuropathy such as pain and numbness are observed in animal experiments until the pain or numbness reaches its peak. Therefore, the period during which the deterioration of peripheral neuropathy or symptoms caused by peripheral neuropathy progresses after the onset may be the "acute phase."

[0032] Here, the symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition provided by the present invention, or the administration of the pharmaceutical composition provided by the present invention is compared with the administration of a control or placebo. Thus, for example, "treatment of acute peripheral neuropathic pain induced by a chemotherapeutic agent" refers to the concept of eliminating, curing, curing, or ameliorating acute peripheral neuropathic pain induced by a chemotherapeutic agent, and actions or means therefor; inhibiting the worsening of acute peripheral neuropathic pain induced by a chemotherapeutic agent, and actions or means therefor; and ameliorating acute peripheral neuropathic pain induced by a chemotherapeutic agent. In another aspect, the concept includes the suppression of the worsening of acute peripheral neuropathic pain symptoms or conditions after administration of a pharmaceutical composition provided by the present invention, which contains an alkalizing agent as an active ingredient, compared to the symptoms or conditions before administration, or the suppression of the worsening of pain symptoms or conditions by administration of a pharmaceutical composition provided by the present invention, which contains an alkalizing agent as an active ingredient, compared to placebo administration or a control. For example, "prevention of chemotherapy-induced peripheral neuropathic pain" refers to a concept that includes preventing the onset of chemotherapy-induced peripheral neuropathic pain and actions or means therefor, as well as suppressing the onset of pain before the onset of the pain and actions or means therefor. In another aspect, when a pharmaceutical composition containing an alkalizing agent as an active ingredient provided by the present invention is administered before the onset of chemotherapy-induced peripheral neuropathic pain, even if the pain occurs, if the pain symptoms or condition are suppressed compared to placebo administration or a control, such a phenomenon can be included in the scope of prevention. The effect of "suppression" above can be evaluated based on the "pain score" described below, in the case of "pain," compared to placebo administration or a control. The concepts of treatment and prevention can be understood by replacing the above "pain" with the symptoms or conditions caused by acute chemotherapy-induced peripheral neuropathy, as already explained.For the evaluation of efficacy, appropriate indicators can be applied instead of the "pain score."

[0033] In this specification, the expression [A, B and / or C] means "at least one selected from the group consisting of A, B and C."

[0034] As used herein, "designed" or "being designed" means that specifications, aspects, applications, methods of use, etc. are designated or specified. Such designation or specification may stipulate the structure, composition, etc. of the object, or may designate or specify the specifications, aspects, applications, methods of use, etc. of the object by a specification, instruction manual, or other attached document.

[0035] The present inventors have discovered that when a pharmaceutical composition containing an alkalizing agent as an active ingredient provided by the present invention is administered to a subject prior to the administration of a chemotherapeutic agent, the onset of peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy can be prevented; however, once such symptoms have developed, the peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy tend to worsen even with continuous administration of the pharmaceutical composition containing the alkalizing agent. However, when a pharmaceutical composition containing the alkalizing agent is continuously administered to a subject after the onset of acute peripheral neuropathy induced by a chemotherapeutic agent or symptoms caused by the peripheral neuropathy, surprisingly, the worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy stops and begins to improve from the time of administration.

[0036] As described above, the pharmaceutical composition of the present invention, which contains an alkalizing agent as an active ingredient, can be administered to a subject after the onset of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy, thereby halting and ameliorating the worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy. Therefore, it is preferable to start administration as soon as possible after the onset of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy. In one aspect of the present invention, the pharmaceutical composition of the present invention, which contains an alkalizing agent as an active ingredient, can halt and ameliorate the worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy, even if its administration is started after the onset of peripheral neuropathy or symptoms caused by the peripheral neuropathy, and is therefore preferable from the viewpoint of being applicable according to the patient's symptoms.

[0037] When a pharmaceutical composition containing an alkalizing agent as an active ingredient provided by the present invention is administered to a subject after the onset of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy, the rate of worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy may typically be 0% based on the time of administration of the pharmaceutical composition. However, even if there is a slight temporary worsening, if the peripheral neuropathy or symptoms caused by the peripheral neuropathy are improved by continuing the administration of the pharmaceutical composition, i.e., the symptoms are only temporary, or if the period until the symptoms worsen can be postponed compared to when the pharmaceutical composition was not administered, even if the symptoms worsen despite continued administration of the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient, the object of the present invention can be achieved. One example of the slight worsening described above refers to a grade indicating the severity of adverse events (AEs) for peripheral sensory neuropathy in the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (JCOG Japanese translation), which indicates a condition in which moderate symptoms of Grade 2, or a condition in which limitations in activities of daily living other than self-care, have progressed, or a condition in which severe symptoms of Grade 3, or a condition in which limitations in activities of daily living have progressed, based on the severity of adverse events (AEs) for peripheral sensory neuropathy. Another example is when, in an animal experiment, the symptom score, based on the time of administration of the pharmaceutical composition, in an individual animal model is, for example, 40% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less, and the average score for a group of animals is 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less.

[0038] The pharmaceutical compositions provided by the present invention, which contain an alkalinizing agent as an active ingredient, can be administered to humans or other mammals orally or parenterally. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and topical administration.

[0039] The pharmaceutical composition of the present invention, which comprises an alkalinizing agent as an active ingredient, may be prepared by mixing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; or sodium bicarbonate, either as is or with a pharmaceutically acceptable carrier, for example, an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection, physiological saline), and, if necessary, other additives (e.g., pH adjuster, surfactant, solubilizer, preservative, emulsifier, isotonicity agent, stabilizer), and may be in the form of a tablet, capsule, suspension, injection, suppository, or other formulation. For example, to prepare a tablet, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; or sodium bicarbonate may be mixed with an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), etc. The tablet according to the present invention will be described in more detail below.

[0040] In one embodiment, the pharmaceutical composition of the present invention, which comprises an alkalinizing agent as an active ingredient, is a tablet. The tablet of the present invention may contain, in addition to the active ingredient (e.g., potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; or a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate), pharmaceutically acceptable additives conventionally used in the pharmaceutical field. Examples of such additives include excipients, binders, disintegrants, flow agents, flavoring agents, lubricants, pH adjusters, surfactants, stabilizers, and flavoring agents. The content of the active ingredient in the tablet of the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, of the tablet.

[0041] Examples of excipients that can be used in the tablets provided by the present invention include sugars such as lactose (e.g., lactose hydrate, anhydrous lactose), glucose, sucrose, fructose, maltose, etc., sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, D-mannitol, etc., starch (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, magnesium aluminometasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose, with crystalline cellulose being particularly preferred. The content of the excipient in the tablets provided by the present invention may be 1 to 95% by weight, preferably 1 to 80% by weight, more preferably 3 to 80% by weight, and even more preferably 3 to 20% by weight, of the tablet.

[0042] Examples of binders that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, dextrin, methyl cellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymer, polyethylene glycol, pregelatinized starch (e.g., partially pregelatinized starch), agar, and gelatin, with hydroxypropyl cellulose being particularly preferred. The content of the binder in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.1 to 10% by weight, and more preferably 0.3 to 3% by weight, based on the weight of the tablet.

[0043] Examples of disintegrants that can be used in the tablets provided by the present invention include croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, starch (e.g., wheat starch, corn starch, partially pregelatinized starch), and carmellose, with partially pregelatinized starch being particularly preferred. The content of the disintegrant in the tablets provided by the present invention may be 0.3 to 20% by weight, preferably 1 to 10% by weight, and more preferably 3 to 10% by weight, based on the weight of the tablet.

[0044] Examples of glidants that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminometasilicate. The content of the glidant in the tablets provided by the present invention may be 0.03 to 3 wt %, preferably 0.1 to 3 wt %, and more preferably 0.3 to 3 wt %, based on the weight of the tablet.

[0045] Examples of flavoring agents that can be used in the tablets provided by the present invention include acidulants such as citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid (however, these flavoring agents are not included in the active ingredients of the present invention), and sweeteners such as saccharin sodium, dipotassium glycyrrhizinate, aspartame (registered trademark), stevia, thaumatin, and sucralose. The content of the flavoring agent in the tablets provided by the present invention may be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, of the tablet.

[0046] Examples of lubricants that can be used in the tablets provided by the present invention include magnesium stearate, calcium stearate, talc, light anhydrous silicic acid, sucrose fatty acid esters, carnauba wax, macrogol, and sodium stearyl fumarate, with magnesium stearate being particularly preferred. The content of the lubricant in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 3% by weight, based on the weight of the tablet.

[0047] Examples of pH adjusters that can be used in the tablets provided by the present invention include citric acid, phosphates (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate), carbonates (e.g., magnesium carbonate, sodium carbonate), tartrates, fumarates, acetates, and amino acid salts (however, the above pH adjusters are not included in the active ingredients of the present invention). The content of the pH adjuster in the tablets provided by the present invention may be 0.1 to 30% by weight, preferably 0.3 to 10% by weight, and more preferably 1 to 5% by weight, of the tablet.

[0048] Examples of surfactants that can be used in the tablets provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyl stearate, macrogol, and poloxamer. The content of the surfactant in the tablets provided by the present invention may be 0.01 to 3 wt.%, preferably 0.03 to 1 wt.%, and more preferably 0.03 to 0.5 wt.%, based on the weight of the tablet. Examples of stabilizers that can be used in the tablets provided by the present invention include citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, sodium edetate, and tocopherol (however, these stabilizers are not included in the active ingredients of the present invention), with anhydrous citric acid being particularly preferred. The content of the stabilizer in the tablets provided by the present invention may be 0.01 to 30 wt.%, preferably 0.1 to 30 wt.%, and more preferably 1 to 20 wt.%, based on the weight of the tablet.

[0049] Examples of flavors that can be used in the tablet provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, as well as peppermint, spearmint, and menthol, and can be contained in the tablet in an appropriate amount (for example, 0.01 to 1% by weight, more preferably 0.01 to 0.1% by weight, based on the tablet). The total content of the active ingredient and pharmaceutically acceptable excipients in the tablet provided by the present invention does not exceed 100% by weight of the tablet.

[0050] The tablets provided by the present invention contain the above-mentioned ingredients and can be uncoated tablets without a coating layer, or film-coated tablets with a coating layer. The content of the coating layer can be determined appropriately by those skilled in the art, and may be, for example, 0.1 to 10% by weight of the uncoated tablet. In addition to the coating base, the coating layer can also contain plasticizers, colorants, glossing agents, etc. as appropriate. Examples of coating bases that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymer, and polyvinylpyrrolidone, with hydroxypropyl methylcellulose being particularly preferred. The content of the coating base in the tablets provided by the present invention can be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, of the tablet. Examples of coating plasticizers that can be used in the tablets provided by the present invention include triethyl citrate, medium-chain fatty acid triglycerides, triacetin, glycerin, propylene glycol, and polyethylene glycol (e.g., Macrogol 6000), with Macrogol 6000 being particularly preferred. The content of the coating plasticizer in the tablet provided by the present invention may be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, based on the tablet.

[0051] Examples of coating colorants that can be used in the tablets provided by the present invention include titanium oxide, yellow ferric oxide, ferric oxide, black ferric oxide, Food Blue No. 2, and Food Blue No. 2 aluminum lake. The content of the coating colorant in the tablets provided by the present invention may be 0.01 to 1 wt %, preferably 0.03 to 3 wt %, based on the weight of the tablet. Examples of coating polishing agents that can be used in the tablets provided by the present invention include carnauba wax. The content of the coating polishing agent in the tablets provided by the present invention may be 0.0001 to 0.1 wt %, preferably 0.001 to 0.01 wt %, based on the weight of the tablet.

[0052] The pharmaceutical composition of the present invention containing an alkalizing agent as an active ingredient can be prepared by a method known in the pharmaceutical field. For example, when preparing tablets, the preparation method may include a mixing step of mixing the active ingredient (e.g., potassium citrate or a hydrate thereof; sodium citrate or a hydrate thereof; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) with additives, a granulation step, a tableting step, and / or a coating step.

[0053] The mixing step may include a step of mixing the active ingredient with additives such as excipients, stabilizers, disintegrants, and / or binders. Furthermore, the method may further include a step of mixing the mixture containing the active ingredient and additives with a lubricant, flavoring agent, and / or fragrance prior to the tableting step. Mixing can be performed using a V-type mixer, W-type mixer, container mixer, tumbler mixer, stirrer mixer, or the like.

[0054] The granulation step can be carried out by a granulation method known in the pharmaceutical field. Examples of granulation methods include dry granulation, wet granulation, and fluidized bed granulation. In one embodiment, the mixture obtained in the mixing step or the granules obtained in the granulation step can be appropriately pulverized and / or sieved to obtain a mixture or granules having a desired particle size. Pulverization can be carried out using a pulverizer known in the pharmaceutical field, such as a ball mill, jet mill, or hammer mill. Sieving can be carried out using a 16-mesh sieve (opening size: 1000 μm) to 32-mesh sieve (opening size: 500 μm), etc.

[0055] The tableting step can be carried out by a tableting method known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and external lubrication tableting. For example, the mixture or granules obtained in the above step can be tableted using a tableting machine known in the pharmaceutical field, such as a single-punch tableting machine or a rotary tableting machine. When a single-punch tableting machine, a rotary tableting machine, or the like is used, a tableting pressure of 1 kN to 30 kN can be used.

[0056] The coating step can be carried out by a method known in the pharmaceutical field, for example, by spray coating the outside of the uncoated tablet with a coating liquid containing a coating base and appropriate additives such as a plasticizer, a colorant, and a glossing agent.

[0057] In one embodiment, the tablet provided by the present invention can be produced by mixing an active ingredient, an excipient (e.g., lactose, D-mannitol, crystalline cellulose, and / or glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, and / or polyvinylpyrrolidone (PVP)), a stabilizer (e.g., anhydrous citric acid), a disintegrant (e.g., starch (e.g., partially pregelatinized starch) and / or carboxymethylcellulose calcium (CMC-Ca)), and a lubricant (e.g., magnesium stearate), compressing the mixture to obtain a core tablet, and then forming a coating layer on the outer surface of the core tablet, the coating layer including a coating base (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and / or PVP), a plasticizer (e.g., triethyl citrate and / or macrogol 6000), a colorant (e.g., red iron oxide and / or titanium oxide), and a glossing agent (e.g., carnauba wax). In one embodiment, the hardness of the resulting tablets may be 10 to 200N, preferably 30 to 150N.

[0058] The amount of alkalizing agent in the pharmaceutical composition of the present invention containing an alkalizing agent as an active ingredient can be appropriately determined. In one embodiment, the amount of alkalizing agent in the pharmaceutical composition of the present invention may be determined so that the dose of the alkalizing agent in a human is an amount that improves acidic urine caused by gout or hyperuricemia when administered to the human, or an amount smaller or larger than that amount, for example, 100 to 800% by mass, 200 to 800% by mass, or 400 to 800% by mass of the daily dose approved in Japan for improving acidic urine caused by gout or hyperuricemia (e.g., when the alkalizing agent is a citric acid preparation: two tablets containing 231.5 mg of potassium citrate (C6H5K3O7.H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7.2H2O) are orally administered three times a day; when the alkalizing agent is sodium bicarbonate: 3 to 5 g are orally administered daily).

[0059] In one embodiment, the pharmaceutical composition of the present invention comprising an alkalinizing agent as an active ingredient is in the form of a tablet, and each tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, and more preferably 400 mg to 500 mg, of potassium citrate monohydrate or sodium citrate dihydrate as an active ingredient. In one embodiment, the pharmaceutical composition of the present invention comprising an alkalinizing agent as an active ingredient is in the form of a tablet, and each tablet may contain 10 mg to 300 mg of potassium citrate monohydrate and sodium citrate dihydrate, for a total of 20 mg to 600 mg, preferably 150 to 250 mg of each, for a total of 400 to 500 mg, and more preferably 190 to 240 mg of each, for a total of 400 to 450 mg. In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient is in the form of a tablet, and one tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, of sodium bicarbonate as the alkalinizing agent.

[0060] In one embodiment, the present invention provides a pharmaceutical composition comprising an alkalinizing agent as an active ingredient in the form of a tablet, which contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate as active ingredients, and may contain anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, macrogol 6000, titanium oxide, and carnauba wax as excipients.

[0061] In one embodiment, one dosage unit may be a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate. In this specification, "dosage unit" refers to a unit of a formulation, and "one dosage unit" refers to the smallest unit of a formulation. For example, in the case of tablets, a dosage unit is each tablet, and one dosage unit represents one tablet. In the case of an injection, a dosage unit is an injection contained in a sealed container such as an ampoule or vial, and one dosage unit represents an injection contained in a sealed container such as an ampoule or vial. In the case of a powder or jelly formulation, a dosage unit is a powder or jelly formulation sealed in a bag made of a single-layer or multi-layer film sheet such as polyethylene, or a sheet with an aluminum layer on the film sheet, and one dosage unit represents the powder or jelly formulation contained in one sealed bag. In the case of capsules (hard capsules, soft capsules, seamless capsules, etc.), the dosage unit is each capsule, and one dosage unit represents one capsule. When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the dosage units may be administered at a time, or one dosage unit may be divided and administered.

[0062] The dosage of the active ingredient is determined appropriately depending on the type of active ingredient, the administration method, the age, weight, sex, symptoms, drug sensitivity of the subject, the administration schedule of the chemotherapy drug, the degree of peripheral neuropathy induced by the chemotherapy drug, etc., but the dosage may be adjusted depending on the administration schedule of the chemotherapy drug, the degree of peripheral neuropathy induced by the chemotherapy drug, and the state of improvement of symptoms.

[0063] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate is orally administered to a human as an active ingredient, potassium citrate monohydrate and sodium citrate dihydrate may be administered at 1.5 to 6 g / day each for a total of 3 to 12 g / day, 1.5 to 9 g / day each for a total of 3 to 18 g / day, or 1.5 to 12 g / day each for a total of 3 to 24 g / day, preferably 3 to 12 g / day each for a total of 6 to 24 g / day, 3 to 9 g / day each for a total of 6 to 18 g / day, or 6 to 9 g / day each for a total of 12 to 18 g / day, and may be administered in divided doses 1 to 5 times a day, preferably 3 times a day.

[0064] In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate is orally administered to a human as an active ingredient, it may be administered at a dose of 3 to 24 g / day, 3 to 18 g / day, or 3 to 12 g / day, 1 to 5 times a day, preferably 3 times a day in divided doses. In one embodiment, when sodium bicarbonate is orally administered to a human as an active ingredient, it may be administered at a dose of 2.25 to 9 g / day, 1 to 5 times a day, preferably 3 times a day in divided doses.

[0065] In one embodiment, the pharmaceutical composition of the present invention, which contains an alkalizing agent as an active ingredient, can be administered to a subject suffering from acute peripheral neuropathy induced by a chemotherapy drug, for the purpose of treating the peripheral neuropathy. Such administration can be continued depending on the chemotherapy drug administration schedule, the degree of acute peripheral neuropathy induced by the chemotherapy drug, and the state of symptom improvement. In one embodiment, the pharmaceutical composition of the present invention, which contains an alkalizing agent as an active ingredient, can be administered for a long period of time, for example, 1 week, 2 weeks, 3 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 24 weeks, 40 weeks, 60 weeks, 80 weeks, 100 weeks, 120 weeks, 1 week or more, 2 weeks or more, 3 weeks or more, 6 weeks or more, 8 weeks or more, 10 weeks or more, 12 weeks or more, 24 weeks or more, 40 weeks or more, 60 weeks or more, 80 weeks or more, 100 weeks or more, 12 weeks or more, 14 weeks or more, 16 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more, 21 weeks or more, 22 weeks or more, 23 weeks or more, 24 weeks or more, 25 weeks or more, 26 weeks or more, 27 weeks or more, 28 weeks or more, 29 weeks or more, 30 weeks or more, 31 weeks or more, 32 weeks or more, 33 weeks or more, 34 weeks or more, 35 weeks or more, 36 weeks or more, 37 weeks or more, 38 weeks or more, 39 weeks or more, 40 weeks or more, 41 weeks or more, 42 weeks or more, 43 weeks or more, 44 weeks or more, 45 weeks or more, 46 weeks or more, 47 weeks or more, 48 weeks or more, 49 weeks or more The treatment is administered for 0 weeks or more, 6 weeks or more and 24 weeks or less, 12 weeks or more and 24 weeks or less, 6 weeks or more and 30 weeks or less, 12 weeks or more and 30 weeks or less, 6 weeks or more and 40 weeks or less, 12 weeks or more and 40 weeks or less, 6 weeks or more and 60 weeks or less, 12 weeks or more and 60 weeks or less, 6 weeks or more and 80 weeks or less, 12 weeks or more and 80 weeks or less, 6 weeks or more and 100 weeks or less, 12 weeks or more and 100 weeks or less, 6 weeks or more and 120 weeks or less, 12 weeks or more and 120 weeks or less, or 24 weeks or more and 120 weeks or less.

[0066] In one embodiment, the pharmaceutical composition provided by the present invention, which comprises an alkalinizing agent as an active ingredient, can be evaluated for its therapeutic effect on acute peripheral neuropathy induced by a chemotherapy drug, at the time point when the composition is administered continuously every day for two weeks after the administration of the chemotherapy drug.

[0067] <Anti-cancer pharmaceutical composition comprising an alkalizing agent and a first cancer chemotherapeutic agent, designed to suppress, from the time of administration, the worsening of acute peripheral neuropathy induced by a second cancer chemotherapeutic agent or symptoms caused by the peripheral neuropathy> In one embodiment, the present invention can provide an anti-cancer pharmaceutical composition designed to suppress, from the time of administration, the worsening of acute peripheral neuropathy induced by a second cancer chemotherapeutic agent or symptoms caused by the peripheral neuropathy, the anti-cancer pharmaceutical composition comprising, as active ingredients, an alkalizing agent and a first cancer chemotherapeutic agent. As described above, it is known that some cancer chemotherapeutic agents tend to induce peripheral neuropathy. Therefore, by combining an alkalinizing agent with a first anticancer drug that can induce peripheral neuropathy to form a combination drug, when peripheral neuropathy is induced by a second cancer chemotherapy drug, the combination drug can be applied to a subject who has developed the peripheral neuropathy or symptoms caused by the peripheral neuropathy, thereby providing an anticancer pharmaceutical composition that allows cancer treatment to be continued while suppressing the worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy.

[0068] In one aspect, the "anticancer pharmaceutical composition designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy" refers to an anticancer pharmaceutical composition designed to suppress the worsening, from the time of administration, of peripheral neuropathy induced by a second anticancer drug or symptoms caused by the peripheral neuropathy, compared to an "alkalinizing agent-free anticancer pharmaceutical composition" containing a second anticancer drug in an amount equal to the content of the first anticancer drug contained in the anticancer pharmaceutical composition provided by the present invention. In another aspect, the "anticancer pharmaceutical composition designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy" refers to an anticancer pharmaceutical composition designed to prevent the worsening, from the time of administration, of peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy. In another aspect, the "anticancer pharmaceutical composition designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapy drug or symptoms caused by the peripheral neuropathy" is an anticancer pharmaceutical composition designed to stop the worsening, from the time of administration, of acute peripheral neuropathy induced by a second anticancer drug or symptoms caused by the peripheral neuropathy, compared to an "anticancer pharmaceutical composition not containing an alkalizing agent" which contains a second anticancer drug in an amount equal to the content of the first anticancer drug contained in the anticancer pharmaceutical composition provided by the present invention. When the "anti-cancer pharmaceutical composition not containing an alkalizing agent" is administered to a subject, continued administration leads to the progression of worsening of acute peripheral neuropathy or symptoms caused by the peripheral neuropathy, whereas when the "anti-cancer pharmaceutical composition designed to suppress the worsening from the time of administration of acute peripheral neuropathy or symptoms caused by the peripheral neuropathy induced by a second cancer chemotherapy drug" is administered to a subject who has developed acute peripheral neuropathy or symptoms caused by the peripheral neuropathy, the worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy from the time of administration is halted, and by continuing the administration, the peripheral neuropathy or symptoms caused by the peripheral neuropathy can be improved.Here, the rate of worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy can be calculated based on an appropriate evaluation index, such as the "pain score" described below, with the time of administration of the pharmaceutical composition as the reference point. When the "anticancer pharmaceutical composition designed to suppress worsening from the time of administration of acute-phase peripheral neuropathy or symptoms caused by the peripheral neuropathy induced by a second cancer chemotherapy drug" of the present invention is administered after the onset of acute-phase peripheral neuropathy or symptoms caused by the peripheral neuropathy, the rate of worsening of the peripheral neuropathy or symptoms caused by the peripheral neuropathy may typically be 0% with the time of administration of the pharmaceutical composition as the reference point. However, even if there is a slight temporary worsening, if continued administration of the pharmaceutical composition improves the peripheral neuropathy or symptoms caused by the peripheral neuropathy, i.e., the improvement is temporary, or if the period until the symptoms worsen can be prolonged compared to when the pharmaceutical composition was not administered, even if the symptoms worsen despite continued administration of the pharmaceutical composition containing an alkalinizing agent as an active ingredient provided by the present invention., the object of the present invention can be achieved. One example of the slight worsening described above refers to a grade indicating the severity of adverse events (AEs) for peripheral sensory neuropathy in the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (JCOG Japanese translation), which indicates a condition in which moderate symptoms of Grade 2, or a condition in which limitations in activities of daily living other than self-care, have progressed, or a condition in which severe symptoms of Grade 3, or a condition in which limitations in activities of daily living have progressed, based on the severity of adverse events (AEs) for peripheral sensory neuropathy. Another example is when, in an animal experiment, the symptom score, based on the time of administration of the pharmaceutical composition, in an individual animal model is, for example, 40% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less, and the average score for a group of animals is 10% or less, 5% or less, 3% or less, 2% or less, or 1% or less.

[0069] In one embodiment, the anticancer pharmaceutical composition provided by the present invention is designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a chemotherapeutic drug for a second cancer or symptoms caused by the peripheral neuropathy. Examples of the chemotherapeutic drug for a first cancer (also referred to as an anticancer drug) contained as an active ingredient include cytotoxic anticancer drugs such as paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine; bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin; Examples of the anticancer drug include at least one anticancer drug selected from the group consisting of molecularly targeted anticancer drugs such as obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib; immunotherapeutic drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab; and other anticancer drugs such as cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. At least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib is preferred, with paclitaxel or oxaliplatin being particularly preferred, and paclitaxel being particularly preferred. The first anticancer drug and the second anticancer drug may be the same or different, but are preferably the same.

[0070] In one embodiment, the anticancer pharmaceutical composition provided by the present invention is designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapy drug or symptoms caused by the peripheral neuropathy. As the alkalinizing agent contained as an active ingredient, the aforementioned pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, and sodium bicarbonate can be used. In the anticancer pharmaceutical composition provided by the present invention, which is designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy, the blending ratio of the alkalinizing agent to the first cancer chemotherapeutic drug varies depending on the peripheral neuropathy-inducing ability of the first cancer chemotherapeutic drug to be blended, etc., but in one embodiment, when the alkalinizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof, the alkalinizing agent may be present in an amount of 10 to 10,000 parts by mass, preferably 20 to 6,000 parts by mass, and more preferably 30 to 5,500 parts by mass, per part by mass of the first anticancer drug.

[0071] In one embodiment, when the alkalizing agent is sodium citrate, potassium citrate, a hydrate thereof, or a mixture thereof, and the first anticancer drug is paclitaxel, the amount of the alkalizing agent can be 10 to 150 parts by mass, preferably 20 to 100 parts by mass, and more preferably 30 to 90 parts by mass, per part by mass of the first anticancer drug. In one embodiment, when the alkalizing agent is sodium citrate, potassium citrate, a hydrate thereof, or a mixture thereof, and the first anticancer drug is oxaliplatin, the amount of the alkalizing agent can be 10 to 150 parts by mass, preferably 30 to 120 parts by mass, and more preferably 50 to 85 parts by mass, per part by mass of the first anticancer drug. In one embodiment, when the alkalizing agent is sodium citrate, potassium citrate, a hydrate thereof, or a mixture thereof and the first anticancer drug is vincristine, the alkalizing agent may be present in an amount of 1,000 to 10,000 parts by mass, preferably 3,000 to 7,000 parts by mass, and more preferably 4,500 to 5,500 parts by mass per part by mass of the first anticancer drug. In one embodiment, when the alkalizing agent is sodium citrate, potassium citrate, a hydrate thereof, or a mixture thereof and the first anticancer drug is bortezomib, the alkalizing agent may be present in an amount of 1,000 to 10,000 parts by mass, preferably 3,000 to 7,000 parts by mass, and more preferably 5,000 to 6,000 parts by mass per part by mass of the first anticancer drug.

[0072] In one embodiment, the anticancer pharmaceutical composition provided by the present invention is designed to suppress the worsening of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by said peripheral neuropathy from the time of administration. The composition is designed to be administered to a subject, such as a human or other mammal, who has cancer and has developed acute peripheral neuropathy or symptoms caused by said peripheral neuropathy due to the administration of a second cancer chemotherapeutic drug. By applying the composition in this manner, cancer can be treated while suppressing the worsening of acute peripheral neuropathy or symptoms caused by said peripheral neuropathy from the time of administration. The cancer to be treated is determined by the type of first anticancer drug contained as an active ingredient in the anticancer pharmaceutical composition provided by the present invention. The first anticancer drugs exemplified above are known anticancer drugs themselves, and the cancers against which each anticancer drug is effective are also known. For example, when the first anticancer drug active ingredient is paclitaxel, it is known to be effective against non-small cell lung cancer, breast cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, angiosarcoma, germ cell tumors, etc. When the first anticancer drug active ingredient is oxaliplatin, it is known to be effective against colon cancer, gastric cancer, pancreatic cancer, or small intestine cancer. When the first anticancer drug active ingredient is vincristine, it is known to be effective against leukemia, malignant lymphoma, pediatric tumors, multiple myeloma, glioma, or pheochromocytoma. When the first anticancer drug active ingredient is bortezomib, it is known to be effective against multiple myeloma, mantle cell lymphoma, primary macroglobulinemia, or lymphoplasmacytic lymphoma. In one embodiment, the anticancer pharmaceutical composition provided by the present invention, which is designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by a second cancer chemotherapy drug or symptoms caused by said peripheral neuropathy, may be effective against cancers for which the first anticancer drug as an active ingredient is effective.

[0073] In one embodiment, the anticancer pharmaceutical composition provided by the present invention, which is designed to suppress the worsening of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by said peripheral neuropathy from the time of administration, is administered orally or parenterally to a subject, such as a human or other mammal, who has cancer and has developed acute peripheral neuropathy or symptoms caused by said peripheral neuropathy due to the administration of a second cancer chemotherapeutic drug. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intra-articular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, intrathecal administration, intraperitoneal administration, and topical administration. In one embodiment, when the first anticancer drug, which is the active ingredient of the anticancer pharmaceutical composition provided by the present invention, is a known anticancer drug, the anticancer pharmaceutical composition provided by the present invention can be administered to a subject in need of cancer treatment according to an established administration method and administration regimen for the first anticancer drug. The anticancer pharmaceutical composition provided by the present invention is designed to suppress the worsening of acute peripheral neuropathy induced by a second cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy from the time of administration. This suppresses the worsening of peripheral neuropathy or symptoms caused by the peripheral neuropathy from the time of administration, thereby enabling continuation of cancer treatment using the first anticancer drug even in subjects who have been unable to continue treatment with conventional anticancer drugs due to the onset of peripheral neuropathy or symptoms caused by the peripheral neuropathy, and improving the subject's quality of life, thereby enabling more effective cancer treatment than conventional cancer treatments. Furthermore, cancer can be treated by suppressing the worsening of acute peripheral neuropathy induced by a cancer chemotherapeutic drug or symptoms caused by the peripheral neuropathy, even without administering an alkalinizing agent before administration of the anticancer drug. In one embodiment, when the first anticancer drug, which is the active ingredient of the anticancer pharmaceutical composition provided by the present invention, is a known anticancer drug, the anticancer pharmaceutical composition provided by the present invention can be formulated in accordance with known formulations containing the first anticancer drug. In one embodiment, the formulation techniques described above for the pharmaceutical composition containing an alkalinizing agent as an active ingredient can be applied to the anti-cancer pharmaceutical composition provided by the present invention.

[0074] 2. Combination Preparations In one embodiment, the present invention provides a combination preparation for simultaneous, separate, or sequential administration in the treatment of cancer, the combination preparation comprising at least two separate formulations of an alkalizing agent and a cancer chemotherapeutic agent, wherein the alkalizing agent is designed to be administered after the onset of acute peripheral neuropathy induced by the chemotherapy agent or symptoms caused by the peripheral neuropathy. In one embodiment, the combination preparation may be a combination preparation designed to suppress the worsening of acute peripheral neuropathy induced by the chemotherapy agent or symptoms caused by the peripheral neuropathy from the time of administration of the alkalizing agent. The alkalizing agent and cancer chemotherapeutic agent in the combination preparation may be the alkalizing agent and cancer chemotherapeutic agent, respectively, previously disclosed, and the alkalizing agent formulation and cancer chemotherapeutic agent formulation may also be the formulations previously disclosed. The cancer to be treated with the combination preparation is determined by the type of cancer chemotherapeutic agent (also referred to as an anticancer drug) included in the combination preparation provided by the present invention. The anticancer drugs exemplified above are known anticancer drugs per se, and the cancers for which each anticancer drug is effective are also known.

[0075] The term "simultaneous administration" as used herein in connection with the combination preparation means that the alkalinizing agent formulation and the cancer chemotherapy drug formulation contained in the combination preparation are administered simultaneously at an appropriate time, and "simultaneous administration" as used herein means that the alkalinizing agent formulation and the cancer chemotherapy drug formulation are administered simultaneously at an appropriate time after the onset of acute peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy. The term "separately administration" as used herein in connection with the combination preparation means that the alkalinizing agent formulation and the cancer chemotherapy drug formulation contained in the combination preparation are administered at different times during the course of a common treatment schedule, and one requirement as used herein is that the alkalinizing agent formulation is administered after the onset of acute peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy. As used herein, the term "sequentially" in relation to the combination preparation means that the administration of one of the alkalizing agent preparation and the cancer chemotherapy drug preparation contained in the combination preparation is followed by the administration of the other preparation, and means that the other preparation can be administered immediately after the administration of one preparation, or within the time period during which the effectiveness of the one preparation is maintained after the administration of the other preparation, or within the time period during which the effectiveness of the one preparation is maintained after the repeated administration of one preparation for a certain period of time. However, as used herein, one requirement is that the alkalizing agent preparation be administered after the onset of acute peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy.

[0076] By applying the combination preparation, it is possible to provide a cancer treatment in which the onset of peripheral neuropathy induced by a cancer chemotherapy drug is suppressed. By applying the combination preparation provided by the present invention, the worsening of acute peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy can be suppressed from the time of administration of an alkalizing agent. This makes it possible to continue cancer treatment using the anticancer drug even in subjects who were unable to continue treatment with conventional anticancer drugs due to the onset of peripheral neuropathy, and this also improves the subject's quality of life, thereby enabling cancer treatment more effectively than conventional cancer treatments. Furthermore, it is possible to treat cancer by suppressing acute peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy, even without administering an alkalizing agent before administration of the anticancer drug. The content ratio of the alkalinizing agent and the cancer chemotherapy drug in the combination preparation provided by the present invention can be determined in accordance with the content ratio of the alkalinizing agent and the cancer chemotherapy drug in the anticancer pharmaceutical composition designed to suppress the worsening, from the time of administration, of acute peripheral neuropathy induced by the second cancer chemotherapy drug or symptoms caused by the peripheral neuropathy.

[0077] 3. Pharmaceutical Kit In one embodiment, the present invention provides an anti-cancer pharmaceutical kit comprising an alkalizing agent in a first compartment and a cancer chemotherapeutic agent in a second compartment, the alkalizing agent being designed to be administered after the onset of acute peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy. The alkalizing agent and cancer chemotherapeutic agent in the pharmaceutical kit may be the alkalizing agent and cancer chemotherapeutic agent previously disclosed, respectively. Furthermore, the alkalizing agent contained in the first compartment and the cancer chemotherapeutic agent contained in the second compartment are preferably formulated, and the formulations for the alkalizing agent and the cancer chemotherapeutic agent may be the formulations previously disclosed. The cancer to be treated in the pharmaceutical kit is determined by the type of cancer chemotherapeutic agent (also referred to as anticancer drug) contained in the pharmaceutical kit provided by the present invention. The anticancer drugs exemplified above are known anticancer drugs, and the cancers for which each anticancer drug is effective are also known. In one embodiment, the first compartment is further divided into two or more compartments depending on the number of administrations and dosage of the alkalinizing agent contained therein, and each compartment can contain an alkalinizing agent suitable for a single administration. In one embodiment, the second compartment is further divided into two or more compartments depending on the number of administrations and dosage of the cancer chemotherapy drug contained therein, and each compartment can contain a cancer chemotherapy drug suitable for a single administration.

[0078] The pharmaceutical kit is designed to administer an alkalizing agent to a subject, such as a human or other mammal, who has cancer and has developed acute peripheral neuropathy or symptoms caused by the peripheral neuropathy due to the administration of a cancer chemotherapy drug. By applying the kit in this manner, cancer can be treated while suppressing the deterioration of acute peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy that occurs after the administration of the alkalizing agent. By applying the pharmaceutical kit provided by the present invention, the deterioration of acute peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy that occurs after the administration of the alkalizing agent can be suppressed. This makes it possible to continue cancer treatment using the anticancer drug even in subjects who were unable to continue treatment with conventional anticancer drugs due to the onset of peripheral neuropathy or symptoms caused by the peripheral neuropathy, and this also improves the subject's quality of life, thereby enabling more effective cancer treatment than conventional cancer treatments. Furthermore, even without administering the alkalinizing agent before the administration of the anticancer drug, it is possible to treat cancer by suppressing acute peripheral neuropathy induced by a cancer chemotherapeutic drug or worsening of symptoms caused by the peripheral neuropathy. The content ratio of the alkalinizing agent to the cancer chemotherapeutic drug in the pharmaceutical kit provided by the present invention can be determined in accordance with the content ratio of the alkalinizing agent to the first cancer chemotherapeutic drug in the anticancer pharmaceutical composition containing the alkalinizing agent and the first cancer chemotherapeutic drug, which is designed to suppress, from the time of administration, acute peripheral neuropathy induced by the second cancer chemotherapeutic drug or worsening of symptoms caused by the peripheral neuropathy.

[0079] Examples of other embodiments of the present invention include the following. <1-1> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for use in the treatment of acute peripheral neuropathy induced by a chemotherapeutic agent. <1-2> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-1>, wherein the acute peripheral neuropathy induced by a chemotherapeutic agent is pain, sensory disorder, motor disorder, autonomic neuropathy, or a complication thereof caused by peripheral neuropathy. <1-3> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-1> or <1-2>, wherein the acute peripheral neuropathy induced by a chemotherapeutic agent is peripheral neuropathic pain. <1-4> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-3>, wherein the peripheral neuropathic pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling. <1-5> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-1> or <1-2>, wherein the acute phase peripheral neuropathy induced by a chemotherapy drug is a sensory disorder caused by peripheral neuropathy. <1-6> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-5>, wherein the sensory disorder caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia. <1-7> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-6>, wherein the hyperesthesia is allodynia and the dysesthesia is dysesthesia or paresthesia. <1-8> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to <1-1> or <1-2>, wherein the acute phase peripheral neuropathy induced by a chemotherapy drug is an autonomic neuropathy caused by peripheral neuropathy. <1-9> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for use according to <1-8>, wherein the symptom caused by autonomic nervous system disorder is dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.<1-10> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to any one of <1-1> to <1-9>, wherein the acute phase peripheral neuropathy induced by a chemotherapy drug is peripheral neuropathy in which symptoms appear in the limbs. <1-11> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to any one of <1-1> to <1-10>, which is designed to be administered after the onset of acute phase peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy. <1-12> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for the use according to any one of <1-1> to <1-11>, which is designed to suppress the worsening of acute phase peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration.

[0080] <1-13> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to any one of <1-1> to <1-12>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. <1-14> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to any one of <1-1> to <1-13>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. <1-15> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to any one of <1-1> to <1-14>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. <1-16> An alkalizing agent or a pharmaceutical composition containing an alkalizing agent, for use according to any one of <1-1> to <1-13>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0081] <1-17> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent, for the use according to any one of <1-1> to <1-16>, wherein the pharmaceutical composition is a tablet. <1-18> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent, for the use according to any one of <1-1> to <1-12>, wherein the alkalizing agent is sodium bicarbonate. <1-19> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent, for the use according to any one of <1-1> to <1-18>, wherein the chemotherapeutic drug is a cancer chemotherapeutic drug. <1-20> A pharmaceutical composition comprising an alkalizing agent or an alkalizing agent, for the use according to <1-19>, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or another anticancer drug. <1-21> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for use according to <1-20>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. <1-22> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-20>, wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. <1-23> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-20>, wherein the immunotherapeutic drug is at least one anticancer drug selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. <1-24> An alkalinizing agent or a pharmaceutical composition comprising an alkalinizing agent for use according to <1-20>, wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.<1-25> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-19>, wherein the cancer chemotherapeutic drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib. <1-26> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-25>, wherein the cancer chemotherapeutic drug is paclitaxel or oxaliplatin. <1-27> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-26>, wherein the cancer chemotherapeutic drug is paclitaxel.

[0082] <1-28> A combination preparation for use in the treatment of cancer in which the deterioration of acute-phase peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy is suppressed, the combination preparation comprising at least two separate preparations of an alkalizing agent and a cancer chemotherapy drug, to be administered simultaneously, separately, or sequentially. <1-29> The combination preparation for use according to <1-28>, designed to administer the alkalizing agent after the onset of acute-phase peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy. <1-30> The combination preparation for use according to <1-28> or <1-29>, designed to suppress the deterioration of acute-phase peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration of the alkalizing agent. <1-31> The combination preparation for use according to any one of <1-28> to <1-30>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is pain, sensory disorder, motor disorder, autonomic neuropathy, or a complication thereof caused by peripheral neuropathy. <1-32> The combination preparation for use according to any one of <1-28> to <1-30>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is peripheral neuropathic pain. <1-33> The combination preparation for use according to <1-32>, wherein the peripheral neuropathic pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling. <1-34> The combination preparation for use according to any one of <1-28> to <1-31>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is sensory disorder caused by peripheral neuropathy. <1-35> A combination preparation for use according to <1-34>, wherein the sensory disorder caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia. <1-36> A combination preparation for use according to <1-35>, wherein the hyperesthesia is allodynia, and the dysesthesia is dysesthesia or paresthesia.<1-37> The combination preparation for use according to any one of <1-28> to <1-31>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic agent is autonomic neuropathy caused by peripheral neuropathy. <1-38> The combination preparation for use according to <1-37>, wherein the symptoms caused by autonomic neuropathy are dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. <1-39> The combination preparation for use according to any one of <1-28> to <1-38>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic agent is peripheral neuropathy causing symptoms in the limbs.

[0083] <1-40> A combination preparation for use according to any one of <1-28> to <1-39>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. <1-41> A combination preparation for use according to any one of <1-28> to <1-40>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. <1-42> A combination preparation for use according to any one of <1-28> to <1-41>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. <1-43> A combination preparation for use according to any one of <1-28> to <1-40>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0084] <1-44> A combination preparation for use according to any one of <1-28> to <1-39>, wherein the alkalinizing agent is sodium bicarbonate. <1-45> A combination preparation for use according to any one of <1-28> to <1-44>, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or another anticancer drug. <1-46> A combination preparation for use according to <1-45>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. <1-47> The combination preparation for use according to <1-45>, wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. <1-48> The combination preparation for use according to <1-45>, wherein the immunotherapeutic drug is at least one anticancer drug selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. <1-49> A combination preparation for use according to <1-45>, wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. <1-50> A combination preparation for use according to any one of <1-28> to <1-44>, wherein the cancer chemotherapeutic drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib. <1-51> A combination preparation for use according to <1-50>, wherein the cancer chemotherapeutic drug is paclitaxel or oxaliplatin. <1-52> A combination preparation for use according to <1-51>, wherein the cancer chemotherapeutic drug is paclitaxel.

[0085] <1-53> An anti-cancer pharmaceutical composition comprising an alkalizing agent and a chemotherapeutic drug for a first cancer, for use in the treatment of a cancer in which acute peripheral neuropathy induced by a chemotherapeutic drug for a second cancer or worsening of symptoms caused by the peripheral neuropathy is suppressed. <1-54> The anti-cancer pharmaceutical composition for use according to <1-53>, designed to be administered after the onset of acute peripheral neuropathy induced by a chemotherapeutic drug for a second cancer or symptoms caused by the peripheral neuropathy. <1-55> The combined preparation for use according to <1-53> or <1-54>, designed to suppress worsening from the time of administration of acute peripheral neuropathy induced by a chemotherapeutic drug for a second cancer or symptoms caused by the peripheral neuropathy. <1-56> The anti-cancer pharmaceutical composition for use according to any one of <1-53> to <1-55>, wherein the acute peripheral neuropathy induced by a chemotherapeutic drug for a second cancer is pain, sensory disorder, motor disorder, autonomic neuropathy, or a complication thereof caused by peripheral neuropathy. <1-57> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-55>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug for the second cancer is peripheral neuropathic pain. <1-58> The anticancer pharmaceutical composition for use according to <1-57>, wherein the peripheral neuropathic pain is shooting pain, burning pain, pain (pain, excluding shooting pain and burning pain), or tingling. <1-59> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-56>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug for the second cancer is sensory disturbance caused by peripheral neuropathy. <1-60> The anticancer pharmaceutical composition for use according to <1-59>, wherein the sensory disturbance caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia. <1-61> The anticancer pharmaceutical composition for use according to <1-60>, wherein the hyperesthesia is allodynia and the dysesthesia is dysesthesia or paresthesia.<1-62> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-56>, wherein the acute-phase peripheral neuropathy induced by the chemotherapeutic drug for the second cancer is autonomic neuropathy caused by peripheral neuropathy. <1-63> The anticancer pharmaceutical composition for use according to <1-62>, wherein the symptoms caused by autonomic neuropathy are dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. <1-64> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-63>, wherein the acute-phase peripheral neuropathy induced by the chemotherapeutic drug for the second cancer is peripheral neuropathy in which symptoms appear in the limbs.

[0086] <1-65> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-64>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. <1-66> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-65>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. <1-67> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-66>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. <1-68> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-65>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0087] <1-69> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-64>, wherein the alkalinizing agent is sodium bicarbonate. <1-70> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-69>, wherein the first or second cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or another anticancer drug. <1-71> The anticancer pharmaceutical composition for use according to <1-70>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. <1-72> The anticancer pharmaceutical composition for use according to <1-70>, wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. <1-73> The anticancer pharmaceutical composition for use according to <1-70>, wherein the immunotherapeutic drug is at least one anticancer drug selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. <1-74> The anticancer pharmaceutical composition for use according to <1-70>, wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. <1-75> The anticancer pharmaceutical composition for use according to any one of <1-53> to <1-69>, wherein the first or second cancer chemotherapeutic drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib. <1-76> The anticancer pharmaceutical composition for use according to <1-75>, wherein the first or second cancer chemotherapeutic drug is paclitaxel or oxaliplatin. <1-77> The anticancer pharmaceutical composition for use according to <1-76>, wherein the first or second cancer chemotherapeutic drug is paclitaxel.

[0088] <1-78> A pharmaceutical kit for use in the treatment of cancer, in which the deterioration of acute-phase peripheral neuropathy induced by a cancer chemotherapy drug or symptoms caused by the peripheral neuropathy is suppressed, the pharmaceutical kit comprising an alkalizing agent in a first compartment and a cancer chemotherapy drug in a second compartment. <1-79> The pharmaceutical kit for use according to <1-78>, designed to administer the alkalizing agent after the onset of acute-phase peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy. <1-80> The pharmaceutical kit for use according to <1-78> or <1-79>, designed to suppress the deterioration of acute-phase peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration of the alkalizing agent. <1-81> A pharmaceutical kit for use according to any one of <1-78> to <1-80>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is pain, sensory disorder, motor disorder, autonomic neuropathy, or a complication thereof caused by peripheral neuropathy. <1-82> A pharmaceutical kit for use according to any one of <1-78> to <1-80>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is peripheral neuropathic pain. <1-83> A pharmaceutical kit for use according to <1-82>, wherein the peripheral neuropathic pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling. <1-84> A pharmaceutical kit for use according to any one of <1-78> to <1-81>, wherein the acute phase peripheral neuropathy induced by the chemotherapeutic drug is sensory disorder caused by peripheral neuropathy. <1-85> A pharmaceutical kit for use according to <1-84>, wherein the sensory disorder caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia. <1-86> A pharmaceutical kit for use according to <1-85>, wherein the hyperesthesia is allodynia, and the dysesthesia is dysesthesia or paresthesia.<1-87> A pharmaceutical kit for use according to any one of <1-78> to <1-81>, wherein the acute-phase peripheral neuropathy induced by the chemotherapeutic agent is autonomic neuropathy caused by peripheral neuropathy. <1-88> A pharmaceutical kit for use according to <1-87>, wherein the symptoms caused by autonomic neuropathy are dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus. <1-89> A pharmaceutical kit for use according to any one of <1-78> to <1-88>, wherein the acute-phase peripheral neuropathy induced by the chemotherapeutic agent is peripheral neuropathy in which symptoms appear in the limbs.

[0089] <1-90> A pharmaceutical kit for the use according to any one of <1-78> to <1-89>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof. <1-91> A pharmaceutical kit for the use according to any one of <1-78> to <1-90>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof. <1-92> A pharmaceutical kit for the use according to any one of <1-78> to <1-91>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof. <1-93> A pharmaceutical kit for the use according to any one of <1-78> to <1-90>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0090] <1-94> A pharmaceutical kit for use according to any one of <1-78> to <1-89>, wherein the alkalinizing agent is sodium bicarbonate. <1-95> A pharmaceutical kit for use according to any one of <1-78> to <1-94>, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or another anticancer drug. <1-96> A pharmaceutical kit for use according to <1-95>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine. <1-97> The pharmaceutical kit for use according to <1-95>, wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib. <1-98> The pharmaceutical kit for use according to <1-95>, wherein the immunotherapeutic drug is at least one anticancer drug selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab. <1-99> A pharmaceutical kit for use according to <1-95>, wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide. <1-100> A pharmaceutical kit for use according to any one of <1-78> to <1-94>, wherein the cancer chemotherapy drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib. <1-101> A pharmaceutical kit for use according to <1-100>, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin. <1-102> A pharmaceutical kit for use according to <1-101>, wherein the cancer chemotherapy drug is paclitaxel.

[0091] <2-1> A method for treating acute chemotherapeutic drug-induced peripheral neuropathy, comprising administering an effective amount of an alkalizing agent to a subject in need of treatment for acute chemotherapeutic drug-induced peripheral neuropathy. <2-2> The method for treatment according to <2-1>, comprising administering the effective amount of an alkalizing agent after the onset of acute chemotherapeutic drug-induced peripheral neuropathy or symptoms caused by the peripheral neuropathy. <2-3> The method for treatment according to <2-1> or <2-2>, in which the worsening of acute chemotherapeutic drug-induced peripheral neuropathy or symptoms caused by the peripheral neuropathy is suppressed from the time of administration of the alkalizing agent. <2-4> A method for treating cancer while suppressing the worsening of acute peripheral neuropathy induced by a chemotherapeutic agent, the method comprising administering effective amounts of an alkalizing agent and a cancer chemotherapeutic agent simultaneously, separately, or sequentially to a subject in need of cancer treatment, wherein the alkalizing agent is administered after the onset of acute peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy. <2-5> The method according to <2-4>, wherein the worsening of acute peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy is suppressed from the time of administration of the alkalizing agent.

[0092] <3-1> Use of an alkalizing agent for producing a pharmaceutical composition for treating acute peripheral neuropathy induced by a chemotherapy drug. <3-2> The use according to <3-1>, wherein the pharmaceutical composition is designed to be administered after the onset of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy. <3-3> The use according to <3-1> or <3-2>, wherein the pharmaceutical composition is designed to suppress the worsening of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration. <3-4> Use of an alkalizing agent and a cancer chemotherapy drug for producing a combined preparation to be administered simultaneously, separately, or sequentially in the treatment of cancer, wherein the combined preparation comprises at least two separate preparations of an alkalizing agent and a cancer chemotherapy drug, and is designed to be administered after the onset of acute peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy. <3-5> Use of an alkalinizing agent and a first cancer chemotherapeutic agent for the manufacture of an anti-cancer pharmaceutical composition comprising an alkalinizing agent and a first cancer chemotherapeutic agent, wherein the anti-cancer pharmaceutical composition is an anti-cancer pharmaceutical composition designed to be administered after acute peripheral neuropathy induced by a second cancer chemotherapeutic agent or the onset of symptoms caused by the peripheral neuropathy. <3-6> Use of an alkalinizing agent and a cancer chemotherapeutic agent for the manufacture of an anti-cancer pharmaceutical kit comprising an alkalinizing agent in a first compartment and a cancer chemotherapeutic agent in a second compartment, wherein the anti-cancer pharmaceutical kit is designed to be administered after acute peripheral neuropathy induced by the chemotherapeutic agent or the onset of symptoms caused by the peripheral neuropathy.

[0093] 4. Food Composition In one embodiment, the present invention may provide an alkalinizing agent or a food composition containing an alkalinizing agent for non-therapeutic use in the prevention of acute peripheral neuropathy induced by a chemotherapy drug or the worsening of symptoms caused by the peripheral neuropathy.

[0094] The alkalinizing agent may be any of those described in "1. Pharmaceutical Compositions" above. Examples of the alkalinizing agent include pharmaceutically acceptable salts of citric acid (e.g., alkali metal citrates, their hydrates, or mixtures thereof) or sodium bicarbonate, which are acceptable as foodstuffs. Preferably, the alkalinizing agent is a mixture of potassium citrate monohydrate (C6H5K3O7.H2O) and sodium citrate dihydrate (C6H5Na3O7.2H2O), or sodium citrate dihydrate.

[0095] The content of citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof; or sodium bicarbonate in the food composition provided by the present invention can be appropriately determined depending on the type of food. Examples of food compositions include foods for specified health uses, foods with functional claims, foods for hospital patients, and supplements. The form of these food compositions is not particularly limited as long as they contain an effective amount of an alkalizing agent to achieve the above-mentioned effect and are orally ingestible. They may be in the form of ordinary food or beverages, or may be provided as a formulation suitable for oral administration, such as tablets, capsules, or suspensions, which can be used in the pharmaceutical compositions. The composition and production method of these formulations can be directly applied to the composition and production method of the pharmaceutical formulation described in "1. Pharmaceutical Compositions" above, or any formulation technology known per se in the field of pharmaceutical formulation technology can be applied.

[0096] For example, in the case of a food for specified health uses, a food with functional claims, a food for hospital patients, or a supplement, a single serving of food may contain a total of 1 to 3 g (one-third of a serving) of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients. When a food for specified health uses, a food with functional claims, a food for hospital patients, or a supplement is provided as a tablet, for example, a 300 mg to 600 mg tablet may contain 70 to 80 wt% of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

[0097] When the food composition of the present invention is not formulated but is provided in the form of a conventional food or beverage, it can be prepared by those skilled in the art as appropriate depending on the type of food. For example, it can be prepared by blending citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof (e.g., potassium citrate and / or sodium citrate), or sodium bicarbonate with a food ingredient. Examples of the food or beverage form include liquid, milky, or paste-like foods such as beverages, soy sauce, milk, yogurt, and miso; semi-solid foods such as jellies and gummies; solid foods such as candy, gum, tofu, and supplements; and powdered foods. Examples of beverages include fruit juices, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, carbonated soft drinks, fruit extract drinks, vegetable extract juices, near-water, sports drinks, and diet drinks.

[0098] The beverage may contain additives, such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, colorants, emulsifiers, preservatives, seasonings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers, either alone or in combination. The food composition provided by the present invention can be used in the same manner as the pharmaceutical composition described above in "1. Pharmaceutical Composition," and can also be used for purposes other than the treatment or prevention of disease (also referred to as non-therapeutic uses). That is, the food composition can be applied to a subject to which the pharmaceutical composition is to be applied such that the amount of alkalinizing agent used in the food composition is the same as the amount of alkalinizing agent contained in the pharmaceutical composition, based on the amount of alkalinizing agent contained in the food composition. In one embodiment, the "food composition" of the present invention can be ingested by a subject (e.g., a human or other mammal) receiving chemotherapy for non-therapeutic purposes to suppress the worsening of peripheral neuropathy or symptoms caused by the peripheral neuropathy. In this case, whether the alkalinizing agent is a component of a pharmaceutical composition or a food composition, the pharmacological effect of the alkalinizing agent itself is basically the same, so the amount and method of application of the food composition can be adjusted appropriately based on the alkalinizing agent depending on the expected effect.

[0099] Food compositions that are applied to subjects (e.g., humans or other mammals) who do not have any "pathological" or "abnormal" symptoms, conditions, or diseases, i.e., subjects (e.g., humans or other mammals) who are in a "healthy" or "normal" state, in order to maintain or promote the "healthy" or "normal" state, are sometimes specifically referred to as "foods with functional claims."

[0100] The term "administration" described in "1. Pharmaceutical Composition" above can also be applied to the "food composition" of the present invention, and furthermore, with regard to the "food composition" of the present invention, the term "administration" can be read as "ingestion." Therefore, for example, the terms "administer," "administered," etc. can be read as "ingested," "taken," "ingested," etc., depending on the context.

[0101] The present invention will be further explained below with reference to Reference Examples and Examples, but the present invention is not limited to these.

[0102] Reference Example 1: Evaluation of an Alkalizing Agent in an Oxaliplatin-Induced Mouse Neuropathic Pain Model (Test Substance) The alkalinizing agent used was a mixture of 463 mg of potassium citrate monohydrate (C6H5K3O7·H2O), 390 mg of sodium citrate dihydrate (C6H5Na3O7·2H2O), and 147 mg of pharmaceutically acceptable additives (Uralyt U Powder, manufactured by Nippon Chemiphar Co., Ltd.) per gram of dry weight. The required amount of Uralyt U Powder (hereinafter simply referred to as "Uralyt") was weighed and dissolved in water for injection to achieve the desired concentration before use. Injectable water, the solvent for the alkalinizing agent, was used in the sham and control groups. (Animals) Six-week-old male C57BL / 6J mice (Japan SLC Co., Ltd.) were used. After allowing the animals to adapt for approximately one week, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: oxaliplatin (hereinafter also referred to as OXP)-induced peripheral neuropathy model mice were prepared using the following method. Grouping was performed based on the pain score evaluated the day before the start of the test (the day before administration of the test substance), specifically, by assigning animals to each group so that the pain score was averaged. Three groups were composed: Group 1: Sham group, Group 2: Control group, and Group 3: Alkalizing agent group. For 17 days from the day after grouping, the Sham and Control groups were orally administered with water for injection, and the Alkalizing agent group was orally administered with 1 g / kg of Uralit twice daily (by oral gavage). Note that administration was performed once daily on the final day of administration, with a 16.5-day dose administered over 17 days. Experimental animals were prepared by a single intraperitoneal administration of 3 mg / kg of OXP on the third day after administration of water for injection or Uralit. The required amount of OXP was weighed and dissolved in glucose injection (5%, Otsuka Pharmaceutical Factory, Inc.) to a concentration of 0.3 mg / mL. The OXP was prepared immediately before use. The sham group received glucose injection (5%) instead of OXP, which was its administration vehicle. (Measurement Time Points) Pain assessment was performed over time after OXP administration. Pain assessment included evaluation of mechanical allodynia and cold dysesthesias. The first day of OXP administration was counted as day 0, and pain assessments were performed 2 hours after administration of water for injection or Uralit on days 0, 1, 3, 6, 8, 10, and 14.Pain assessment was performed the day before the start of Uralyt administration and used as the pre-score. (Pain Assessment) Pain assessment was performed after transferring the animals to individual cages (W 110 × D 180 × H 150 mm) with a mesh bottom for pain scoring and allowing them to acclimate to the new environment for 30 minutes. To assess mechanical allodynia, the plantar surface of the hind paw was stimulated with a Von Frey hair (0.69 mN) and the reactivity to the stimulation was scored. To assess cold dysesthesias (OXP model only), acetone was applied to the plantar skin of the hind paw and the aversive response following the acetone stimulation was scored. (Scoring Method) (1) Mechanical Allodynia: A Von Frey hair was pressed perpendicularly against the center of the plantar surface of the hind paw and held for 1–3 seconds at a position where the filament was slightly bent. Stimuli of the same intensity were applied alternately to each hind paw three times, with a few seconds between each application. The average of all six stimulations (maximum score: 2) was used as the score. 0: No response or hind paw shifting to the side 1: Hind paw lifting 2: Hind paw flinching or licking at the stimulation site (2) Cold dycestedia acetone was applied to the skin of the plantar hind paw, and the hind paw response was observed for 10 seconds following the reaction immediately after application (not scored). Acetone was applied alternately to each hind paw three times with an interval of at least 20 seconds between applications, and the average of all six applications was used as a score (maximum score is 2). 0: No response or hind paw shifting to the side 1: Hind paw lifting 2: Hind paw flinching or licking at the stimulation site (Results) In OXP-induced peripheral neuropathy model mice, cold dycestedia peaked on Day 3 and mechanical allodynia peaked on Day 10 (Figure 1). Repeated administration of Uralit-U powder to a mouse model of OXP-induced peripheral neuropathy suppressed the onset of mechanical allodynia and cold dysesthesias (Figure 2). Based on the above, repeated oral administration of Uralit-U powder is considered to be highly effective against OXP-induced peripheral neuropathy.

[0103] Reference Example 2: Evaluation of Alkalizing Agents in a Paclitaxel-Induced Mouse Neuropathic Pain Model (Test Substance) The same test substance as in Reference Example 1 was used. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an approximately one-week acclimation period, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: paclitaxel-induced peripheral neuropathy model mice were prepared by a single intraperitoneal administration of 5 mg / kg of PTX in the same manner as in Reference Example 1, except that the chemotherapeutic agent inducing peripheral neuropathy was paclitaxel (hereinafter also referred to as PTX) and pain evaluation was performed up to 18 days after PTX administration. The required amount of PTX was weighed and dissolved in the following administration medium to a concentration of 0.5 mg / mL, and the resulting solution was prepared immediately before use. The administration vehicle was prepared freshly by adding 10% (v / v) Kolliphor and ethanol to physiological saline. (Measurement Time Point) Pain assessment was performed over time after PTX administration. Mechanical allodynia was assessed. The first day of PTX administration was counted as day 0, and pain assessment was performed 2 hours after administration of water for injection or Uralit on days 0, 1, 3, 5, 7, 10, 12, 14, and 18 of administration. Pain assessment was performed the day before the start of Uralit administration and used as the pre-value. (Pain Assessment) Pain was assessed using the same method as in Reference Example 1. (Results) Mechanical allodynia peaked on day 14 in PTX-induced peripheral neuropathy model mice (Figure 3). Repeated administration of Uralit to PTX-induced peripheral neuropathy model mice suppressed the onset of mechanical allodynia (Figure 4). From the above, it is believed that repeated oral administration of Uralit is highly effective against PTX-induced peripheral neuropathy.

[0104] Reference Example 3: Evaluation of Alkalizing Agents in a Bordezomib-Induced Mouse Neuropathic Pain Model (Test Substance) The same test substance as in Reference Example 1 was used. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an approximately one-week acclimation period, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: Bordezomib-induced peripheral neuropathy model mice were prepared by a single intravenous administration of 0.3 mg / kg of BTZ in the same manner as in Reference Example 1, except that the chemotherapeutic agent inducing peripheral neuropathy was bordezomib (hereinafter also referred to as BTZ) and pain evaluation was performed up to 15 days after BTZ administration. The required amount of BTZ was weighed and dissolved in physiological saline to a concentration of 0.6 mg / mL, and the solution was prepared immediately before use. (Measurement Time Points) Pain assessment was performed over time after BTZ administration. Mechanical allodynia was assessed for pain. The first day of BTZ administration was counted as day 0, and pain assessments were performed 2 hours after administration of injectable water or Uralit on days 0, 3, 6, 9, 12, and 15 of administration. Pain assessment was performed the day before the start of Uralit administration and used as the pre-value. (Pain Assessment) Pain was assessed using the same method as in Reference Example 1. (Results) In BTZ-induced peripheral neuropathy model mice, the onset of mechanical allodynia was observed, peaking on day 12 (Figure 5). Repeated administration of Uralit to BTZ-induced peripheral neuropathy model mice suppressed the onset of mechanical allodynia (Figure 6). From the above, repeated oral administration of Uralit is considered to be highly effective against BTZ-induced peripheral neuropathy.

[0105] Reference Example 4: Evaluation of Alkalizing Agents in a Vincristine-Induced Mouse Neuropathic Pain Model (Test Substance) The same test substance as in Reference Example 1 was used. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an approximately one-week acclimation period, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: vincristine-induced peripheral neuropathy model mice were prepared by a single intraperitoneal administration of 0.1 mg / kg VCN in the same manner as in Reference Example 1, except that the chemotherapeutic agent inducing peripheral neuropathy was vincristine (hereinafter also referred to as VCN) and pain assessment was conducted up to 18 days after VCN administration. The required amount of VCN was weighed and dissolved in physiological saline to a concentration of 0.01 mg / mL, and the solution was prepared immediately before use. (Measurement Time Points) Pain assessment was performed over time after VCN administration. Pain assessment was performed by evaluating mechanical allodynia. The first day of VCN administration was counted as day 0, and pain assessments were performed 2 hours after administration of injectable water or Uralit on days 0, 3, 7, 10, 14, and 18 of administration. Pain assessment was performed the day before the start of Uralit administration and used as the pre-value. (Pain Assessment) Pain was assessed using the same method as in Reference Example 1. (Results) In VCN-induced peripheral neuropathy model mice, the onset of mechanical allodynia was observed, peaking on day 14 (Figure 7). Repeated administration of Uralit to VCN-induced peripheral neuropathy model mice suppressed the onset of mechanical allodynia (Figure 8). From the above, it is believed that repeated oral administration of Uralit is highly effective against VCN-induced peripheral neuropathy.

[0106] Reference Example 5: Evaluation of Alkalizing Agents in a Paclitaxel-Induced Rat Neuropathic Pain Model (Test Substance) The same test substance as in Reference Example 1 was used. (Animals) Seven-week-old male SD rats (Jackson Laboratory Japan) were used. After an approximately one-week acclimatization period, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: rats with a PTX-induced peripheral neuropathy model were prepared using the following method. The animals were divided into groups based on the 50% withdrawal threshold evaluated the day before the start of the test (the day before administration of the test substance), specifically, by allocating them to each group so that the 50% withdrawal threshold and body weight were averaged. The groups were divided into three groups: Group 1: Sham group, Group 2: Control group, and Group 3: Alkalizing agent group. For 24 days, starting the day after grouping, the sham and control groups received repeated oral administration (gavage) of injectable water, and the alkalinizing agent group received 1 g / kg of Uralit twice daily. The final administration day was a single daily dose, with a 23.5-day dose administered over 24 days. Starting on the third day of injectable water or Uralit administration, experimental animals were prepared by intraperitoneally administering 2 mg / kg of PTX four times every other day (on days 3, 5, 7, and 9 after the start of injectable water or Uralit administration). PTX was prepared fresh by adding saline to 30 mg of taxol injection solution to a concentration of 2 mg / mL. The sham group received saline instead of PTX. (Measurement Time Points) Pain assessment was performed over time after PTX administration. Mechanical allodynia was assessed for pain. The first day of PTX administration was counted as day 0, and pain assessments were performed 3 hours after administration of injectable water or Uralit on days 7, 14, and 21 of administration. Pain assessment was performed the day before the start of Uralit administration (Day 3) and was used as the "Pre" value. (Pain Assessment) Pain assessment was performed by pressing a von Frey filament perpendicularly to the center of the rat's left hind paw, observing the avoidance response, and calculating the 50% withdrawal threshold according to the up-down method of Chaplan et al. (J. Neurosci. Methods. 1994; 53:55-63). (Results) In rats with PTX-induced peripheral neuropathy, mechanical allodynia developed, peaking on Day 21 (Figure 9).Repeated administration of Uralit to rats with PTX-induced peripheral neuropathy suppressed the onset of mechanical allodynia (Figure 9). Based on the above, repeated oral administration of Uralit is considered to be highly effective against peripheral neuropathy induced by repeated administration of PTX.

[0107] Reference Example 6: Evaluation of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model. This reference example confirmed the effect of administration of an alkalizing agent on spontaneous and mechanical stimulation-induced firing of spinal dorsal horn neurons in a paclitaxel-induced neuropathic pain model. (Test substance) The same test substance as in Reference Example 1 was used. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an approximately one-week acclimatization period, only healthy animals were subjected to the test. (Experimental Animal Preparation) Experimental animals: paclitaxel-induced peripheral neuropathy model mice were prepared by a single intraperitoneal administration of 5 mg / kg of PTX using the same method as in Reference Example 1, except that the chemotherapeutic agent inducing peripheral neuropathy was paclitaxel and pain assessment was performed up to 14 days after PTX administration. The required amount of PTX was weighed and dissolved in the following administration vehicle to a concentration of 0.5 mg / mL, and prepared immediately before use. The administration vehicle was prepared by adding 10% (v / v) Kolliphor and ethanol to physiological saline. (Evaluation) (1) Pain Evaluation by Mechanical Allodynia (Measurement Time Points) 3 days before and 13 days after PTX administration. (Pain Evaluation) Pain evaluation by mechanical allodynia was performed using the same method as in Reference Example 1. (Scoring Method) Scoring was performed using the same method as in Reference Example 1. (Results) In PTX-induced peripheral neuropathy model mice, the onset of mechanical allodynia was observed on Day 13, but repeated administration of uralit suppressed the onset of mechanical allodynia (Figure 10). (2) Electrophysiological Analysis (Preparation of Animals for Electrophysiological Experiments) 14 days after PTX administration, mice were deeply anesthetized with urethane (1.2-1.5 g / kg, i.p.), laminectomized at the thoracic and lumbar spinal cord level, and placed in a stereotaxic apparatus. The dura, arachnoid, and pia mater were sequentially peeled away under a stereomicroscope to expose the dorsal roots and secure space for electrode insertion. Krebs solution, saturated with 95% oxygen and 5% carbon dioxide and heated to 37°C, was then perfused over the spinal cord surface at a rate of 10-15 mL / min.Next, a tungsten electrode (FHC) was inserted into the superficial layer of the spinal dorsal horn (10-150 μm (Laminae I-II)) at the L4-L5 input site, and recording was performed. (Measurement Time Point) Measurements were performed on the prepared electrophysiological experimental animals at two points: before and after stimulation with the Von Frey Hair. (Electrophysiological Evaluation) Signals obtained from the measurements were amplified using an EX1 (Dagan Corporation), converted to digital data using a Digidata 1400A (Molecular Devices, LLC.), and recorded using the software Clampex ver. 10.2 (Molecular Devices, LLC.). Analysis was performed using the software Clampfit ver. 10.2 (Molecular Devices, LLC.). Firing was recorded without stimulation of the mice, and the frequency of spontaneous firing per unit time was evaluated. Subsequently, single neurons were identified using a paintbrush and hooked tweezers, and the receptive fields were also identified. A 0.69 mN von Frey filament (vFF) was applied to this area for 5 seconds, and the evoked firing was recorded as mechanical stimulation-induced firing, and the occurrence frequency per unit time was evaluated. (Results) Repeated administration of Uralit suppressed both the increase in spontaneous firing frequency and vFF-induced firing frequency observed in the spinal dorsal horn of PTX-induced peripheral neuropathy model mice (Figures 11 and 12). These results suggest that repeated oral administration of Uralit is highly effective against PTX-induced peripheral neuropathy.

[0108] Reference Example 7: Evaluation of an alkalizing agent in an oxaliplatin-induced mouse neuropathic pain model (Test substance) The alkalizing agent used was the test substance used in Reference Example 1, and sodium bicarbonate (also referred to herein as baking soda; manufactured by Tokyo Chemical Industry Co., Ltd.; purity: 99.0% or higher). The required amount of sodium bicarbonate was weighed and dissolved in water for injection to achieve the desired concentration, preparing it immediately before use. Water for injection, the solvent for the alkalizing agent, was used in the sham and control groups. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an acclimatization period of approximately one week, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: oxaliplatin-induced peripheral neuropathy model mice were prepared using the following method. The subjects were divided into groups based on the pain score evaluated on the day before the start of the study (the day before administration of the test substance), specifically, by allocating the subjects to each group so that the pain score was averaged. The four groups were: Group 1: Sham group, Group 2: Control group, Group 3: Alkalizing agent (Uralyt) group, and Group 4: Alkalizing agent (sodium bicarbonate) group. For 13 days from the day after grouping, the Sham and Control groups received injectable water, while the Alkalizing agent (Uralyt) group received 1 g / kg of Uralyt, and the Alkalizing agent (sodium bicarbonate) group received 0.75 g / kg of sodium bicarbonate, each administered orally twice daily (by oral gavage). The final day of administration was once daily, with a 12.5-day dose administered over 13 days. Experimental animals were prepared by a single intraperitoneal administration of 3 mg / kg of OXP on the third day after administration of water for injection, uralyt, or sodium bicarbonate. The required amount of OXP was weighed and dissolved in glucose injection (5%, Otsuka Pharmaceutical Factory, Inc.) to a concentration of 0.3 mg / mL, and prepared immediately before use. The sham group received the administration vehicle, glucose injection (5%), instead of OXP. (Measurement Time Points) Pain assessment was performed over time after OXP administration. Mechanical allodynia was assessed for pain. The first day of OXP administration was counted as day 0, and pain assessments were performed 2 hours after administration of water for injection, uralyt, or sodium bicarbonate on days 0, 3, 5, 7, and 10.Pain assessment was performed the day before the start of alkalizing agent administration and used as the "Pre" value. (Pain Assessment) Mechanical allodynia was assessed using the same method as in Reference Example 1. (Results) In OXP-induced peripheral neuropathy model mice, the onset of mechanical allodynia was observed, peaking on Day 10 (Figure 13). Repeated administration of Uralit U powder to OXP-induced peripheral neuropathy model mice inhibited the onset of mechanical allodynia (Figure 14). Repeated administration of sodium bicarbonate to OXP-induced peripheral neuropathy model mice inhibited the onset of mechanical allodynia, but the effect was smaller than in the Uralit-treated group (Figure 14). From the above, repeated oral administration of alkalizing agents (especially Uralit) is considered to be highly effective for OXP-induced peripheral neuropathy.

[0109] Reference Example 8: Evaluation of an Alkalizing Agent in a Paclitaxel-Induced Mouse Neuropathic Pain Model (Test Substance) The test substance used in Reference Example 1 and sodium bicarbonate (also referred to herein as baking soda; manufactured by Tokyo Chemical Industry Co., Ltd.; purity: 99.0% or higher) were used as the alkalizing agent. The required amount of sodium bicarbonate was weighed and dissolved in water for injection to achieve the desired concentration, preparing the solution immediately before use. Water for injection, the solvent for the alkalizing agent, was used in the sham and control groups. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After allowing the animals to adapt for approximately one week, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: mice with a paclitaxel-induced peripheral neuropathy model were prepared using the following method. The subjects were divided into groups based on the pain score evaluated on the day before the start of the study (the day before administration of the test substance), specifically, by allocating the subjects to each group so that the pain score was averaged. The four groups were: Group 1: Sham group, Group 2: Control group, Group 3: Alkalizing agent (Uralyt) group, and Group 4: Alkalizing agent (sodium bicarbonate) group. For 17 days from the day after grouping, the Sham and Control groups received injectable water, while the Alkalizing agent (Uralyt) group received 1 g / kg of Uralyt and the Alkalizing agent (sodium bicarbonate) group received 0.75 g / kg of sodium bicarbonate, each administered orally twice daily (by oral gavage). The final day of administration was once daily, with a 16.5-day dose administered over 17 days. Experimental animals: Paclitaxel-induced peripheral neuropathy model mice were prepared by a single intraperitoneal administration of 5 mg / kg of PTX on the third day after administration of water for injection, uralyt, or sodium bicarbonate. The required amount of PTX was weighed and dissolved in the following administration medium to a concentration of 0.5 mg / mL, and prepared immediately before use. The administration medium was prepared immediately after use by adding Kolliphor and ethanol to physiological saline to make 10% (v / v) concentrations. (Measurement Time Points) Pain was assessed over time after PTX administration. Mechanical allodynia was assessed for pain.The first day of PTX administration was counted as day 0, and pain assessments were performed 2 hours after administration of injectable water, ularit, or sodium bicarbonate on days 0, 1, 3, 5, 7, 10, 12, and 14. Pain assessment was performed the day before the start of alkalinizing agent administration and used as the "Pre" value. (Pain Assessment) Pain assessment for mechanical allodynia was performed using the same method as in Reference Example 1. (Results) In PTX-induced peripheral neuropathy model mice, mechanical allodynia peaked on day 14 (FIG. 15). Repeated administration of ularit to PTX-induced peripheral neuropathy model mice suppressed the onset of mechanical allodynia (FIG. 16). Repeated administration of sodium bicarbonate to PTX-induced peripheral neuropathy model mice suppressed the onset of mechanical allodynia, but the effect was smaller than in the ularit-treated group (FIG. 16). From the above, it is believed that repeated oral administration of alkalizing agents (especially Uralit) is very effective against PTX-induced peripheral neuropathy.

[0110] Example 1: Evaluation of an alkalizing agent on early peripheral neuropathy in a paclitaxel-induced mouse neuropathic pain model (Test substance) The test substance used in Reference Example 1 was used as the alkalizing agent. Injectable water, a solvent for the alkalizing agent, was used in the sham and control groups. (Animals) The same animals as in Reference Example 1 were used. Specifically, 6-week-old male C57BL / 6J mice (Japan SLC) were used. After an acclimation period of approximately one week, only healthy animals were subjected to the test. (Preparation of Experimental Animals) Experimental animals: mice with a paclitaxel-induced peripheral neuropathy model were prepared using the following method. Grouping was performed based on pain scores evaluated on the start of the test and on the fifth day after PTX administration, specifically by allocating animals to each group so that pain scores were averaged. On the first day of the study, the animals were assigned to a sham group or a PTX group. From day 5 after PTX administration, the PTX group was assigned to a control group or an alkalinizing agent (Uralit) group, resulting in three groups: Group 1 (Sham group), Group 2 (Control group), and Group 3 (Alkalinizing agent (Uralit) group). The study began the day after group assignment. The first day of the study was designated Day 0, and a single intraperitoneal administration of 5 mg / kg of PTX was administered to create experimental animals: paclitaxel-induced peripheral neuropathy model mice. The required amount of PTX was weighed and dissolved in the following administration medium to a concentration of 0.5 mg / mL. The administration medium was prepared fresh by adding 10% (v / v) Kolliphor and ethanol to physiological saline. (Measurement Time Points and Alkalinizing Agent Administration Conditions) Pain assessment was performed over time after PTX administration. Pain evaluation was performed to evaluate mechanical allodynia. The first day of PTX administration was counted as day 0, and pain evaluation was performed on days 0, 5, 7, 10, 12, 14, and 18 of administration. The time when a significant pain score was observed compared to day 0 was considered to be the time when early peripheral neuropathy occurred. From that day onwards, the sham group and the control group were orally administered with water for injection, and the alkalinizing agent (Uralit) group was orally administered with 1 g / kg of Uralit twice a day (forced oral administration). (Pain evaluation) Pain evaluation in mechanical allodynia was performed in the same manner as in Reference Example 1.(Results) Significant mechanical allodynia was observed on Day 5 in PTX-induced peripheral neuropathy model mice compared to Day 0. Therefore, from Day 5 onwards, the sham and control groups were given injectable water, and the alkalinising agent (Uralit) group was given 1 g / kg of Uralit twice daily by oral gavage. The control group experienced mechanical allodynia, peaking on Day 14 ( Figure 17 ). However, the alkalinising agent (Uralit) group showed a decreasing trend in mechanical allodynia scores from Day 5 onwards, which was significantly lower than the pain score in the control group. Administration of Uralit to early PTX-induced peripheral neuropathy significantly suppressed the onset of mechanical allodynia compared to the control group, demonstrating a decreasing trend ( Figure 17 ). Based on these findings, repeated oral administration of alkalinising agents (especially Uralit) is considered to be highly effective in treating early PTX-induced peripheral neuropathy.

[0111] The pharmaceutical composition, combined preparation, and pharmaceutical kit provided by the present invention enable the treatment of acute peripheral neuropathy induced by a chemotherapeutic drug.Furthermore, the pharmaceutical composition, combined preparation, and pharmaceutical kit provided by the present invention enable the treatment of cancer by suppressing acute peripheral neuropathy induced by a chemotherapeutic drug, particularly a cancer chemotherapeutic drug.

Claims

1. A pharmaceutical composition for treating acute peripheral neuropathy induced by a chemotherapy drug, comprising an alkalizing agent.

2. The pharmaceutical composition according to claim 1, wherein the acute peripheral neuropathy induced by a chemotherapy drug is pain, sensory disturbance, motor disturbance, autonomic neuropathy, or a complication thereof caused by peripheral neuropathy.

3. The pharmaceutical composition according to claim 1 or 2, wherein the acute peripheral neuropathy induced by a chemotherapy drug is peripheral neuropathic pain.

4. The pharmaceutical composition according to claim 3, wherein the peripheral neuropathic pain is electric shock pain, burning pain, pain (excluding electric shock pain and burning pain), or tingling sensation.

5. The pharmaceutical composition according to claim 1 or 2, wherein the acute peripheral neuropathy induced by a chemotherapy drug is sensory disturbance caused by peripheral neuropathy.

6. The pharmaceutical composition according to claim 5, wherein the sensory disturbance caused by peripheral neuropathy is hypoesthesia, hyperesthesia, or dysesthesia.

7. The pharmaceutical composition according to claim 6, wherein the hyperesthesia is allodynia and the dysesthesia is dysesthesia or paresthesia.

8. The pharmaceutical composition according to claim 1 or 2, wherein the acute peripheral neuropathy induced by a chemotherapy drug is autonomic neuropathy caused by peripheral neuropathy.

9. The pharmaceutical composition according to claim 8, wherein the symptoms caused by autonomic neuropathy are dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the acute peripheral neuropathy induced by a chemotherapy drug is peripheral neuropathy in which symptoms appear in the limbs.

11. A pharmaceutical composition according to any one of claims 1 to 10, designed to be administered after acute peripheral neuropathy induced by a chemotherapy drug or the onset of symptoms resulting from said peripheral neuropathy.

12. A pharmaceutical composition according to any one of claims 1 to 11, designed to suppress the worsening of acute peripheral neuropathy induced by a chemotherapy drug or symptoms caused by said peripheral neuropathy from the time of administration.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the alkalinizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

14. A pharmaceutical composition according to any one of claims 1 to 13, wherein the alkalinizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

15. The pharmaceutical composition of any one of claims 1 to 14, wherein the alkalinizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

16. The pharmaceutical composition according to any one of claims 1 to 13, wherein the alkalinizing agent is sodium citrate or a hydrate thereof.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the pharmaceutical composition is a tablet.

18. The pharmaceutical composition of any one of claims 1 to 12, wherein the alkalinizing agent is sodium bicarbonate.

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein the chemotherapeutic agent is a cancer chemotherapeutic agent.

20. The pharmaceutical composition according to claim 19, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug.

21. The pharmaceutical composition of claim 20, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine.

22. The pharmaceutical composition of claim 20, wherein the molecularly targeted anticancer drug is at least one anticancer drug selected from the group consisting of bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab emtansine, brentuximab vedotin, obinutuzumab, blinatumomab, lorlatinib, entrectinib, encorafenib, binimetinib, and pemigatinib.

23. The pharmaceutical composition of claim 20, wherein the immunotherapeutic agent is at least one anticancer agent selected from the group consisting of nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

24. The pharmaceutical composition of claim 20, wherein the other anticancer drug is at least one anticancer drug selected from the group consisting of cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

25. The pharmaceutical composition of claim 19, wherein the cancer chemotherapy drug is at least one anticancer drug selected from the group consisting of paclitaxel, vincristine, oxaliplatin, and bortezomib.

26. The pharmaceutical composition of claim 25, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

27. The pharmaceutical composition of claim 26, wherein the cancer chemotherapy drug is paclitaxel.

28. A combination preparation for simultaneous, separate, or sequential administration in the treatment of cancer, said combination preparation comprising at least two separate formulations of an alkalizing agent and a cancer chemotherapeutic agent, wherein the alkalizing agent is designed to be administered after the onset of acute peripheral neuropathy induced by the chemotherapeutic agent or symptoms attributable to the peripheral neuropathy.

29. The combination preparation according to claim 28, which is designed to suppress the worsening of acute peripheral neuropathy induced by the chemotherapy drug or symptoms caused by the peripheral neuropathy from the time of administration of an alkalinizing agent.

30. An anti-cancer pharmaceutical composition comprising an alkalinizing agent and a first cancer chemotherapeutic agent, wherein the anti-cancer pharmaceutical composition is designed to be administered after acute peripheral neuropathy induced by a second cancer chemotherapeutic agent or after the onset of symptoms caused by the peripheral neuropathy.

31. The anticancer pharmaceutical composition according to claim 30, which is designed to suppress the worsening of acute peripheral neuropathy induced by a second cancer chemotherapy drug or symptoms caused by said peripheral neuropathy from the time of administration.

32. An anti-cancer pharmaceutical kit comprising an alkalizing agent in a first compartment and a cancer chemotherapy drug in a second compartment, the alkalizing agent being designed to be administered after acute peripheral neuropathy induced by the chemotherapy drug or the onset of symptoms resulting from the peripheral neuropathy.

33. The anti-cancer pharmaceutical kit according to claim 32, which is designed to suppress the deterioration of acute peripheral neuropathy induced by the chemotherapeutic agent or symptoms caused by the peripheral neuropathy from the time of administration of the alkalinizing agent.

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