Medicine for treating or preventing chemotherapy-induced peripheral nerve disorder

Abstract

The present invention provides a pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs, comprising an alkalizing agent. By administering this pharmaceutical composition, peripheral nerve disorders induced by chemotherapeutic drugs, particularly chemotherapeutic drugs for cancer, can be treated or prevented. Also provided is an anticancer pharmaceutical composition for inhibiting the expression of peripheral nerve disorders, the anticancer pharmaceutical composition comprising an alkalizing agent and a cancer chemotherapeutic agent. The administration of this pharmaceutical composition makes it possible to treat cancers in which the expression of peripheral nerve disorders can be suppressed.

Description

Technical Field

[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 or preventing peripheral nerve disorders induced by chemotherapeutic drugs.

[0002] This application claims priority based on Japanese Patent Application No. 2023-027461 filed in Japan on February 24, 2023, and Japanese Patent Application No. 2023-185444 filed in Japan on October 30, 2023, the contents of which are incorporated herein by reference. Background Art

[0003] Cancer chemotherapy sometimes causes numbness or paresthesia in the limbs, for example. These are symptoms caused by peripheral nerve disorders, and tend to become more severe towards the extremities. Symptoms of chemotherapy-induced peripheral neuropathy (CIPN) associated with anticancer drugs can sometimes interfere with daily life due to abnormal discomfort. In severe cases, it can sometimes lead to inability to walk or dress. CIPN is rarely a temporary disorder that recovers quickly after discontinuation of anticancer drugs. Improvement can take months or years, and it is not uncommon for the disorder to persist for life.

[0004] Although CIPN is known to be an adverse event, its detailed mechanism remains largely unknown, and effective treatment methods have yet to be established. Various drugs have been used for treatment, but sufficient results have not been achieved. CIPN is a significant adverse event that hinders the continued effectiveness of cancer chemotherapy. Preventing or treating CIPN can not only improve the effectiveness of cancer treatment but also improve the patient's quality of life (QOL). However, as a countermeasure, the actual situation is that the administration of the chemotherapeutic agent that causes CIPN has to be stopped (Non-Patent Document 1).

[0005] If CIPN is symptom-based, it manifests as sensory nerve disorder, motor nerve disorder (numbness), pinprick sensation (tingling), or pain (pain). In addition, intense pain is sometimes described as shooting pain or burning pain. Regarding their relationship, it is reported that motor nerve disorder and pinprick sensation do not necessarily present intense pain, but almost all patients who present intense pain are accompanied by motor nerve disorder or pinprick sensation. The motor nerve disorder of CIPN presents as muscle atrophy and muscle weakness, or flaccid paralysis, which mainly occurs in the distal part of the limbs. In addition, it is found that the tendon reflexes of the limbs decrease or disappear, and these symptoms are more obvious the closer to the distal end of the limbs. The autonomic nerve disorder of CIPN can cause blood pressure, intestinal motility or involuntary muscle disorders, and as symptoms, it sometimes manifests as urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation or paralytic ileus.

[0006] As a prevention of CIPN, calcium or magnesium is sometimes given in anticipation of a neurotoxicity-preventive effect, but there is no clear evidence for its effect. As a therapeutic drug for paralysis or pain, Niu Che Shen Qi Wan, vitamin B12 preparations, nonsteroidal anti-inflammatory analgesics, pregabalin, gabapentin and opioids are sometimes given, but their effectiveness is unclear and there is no sufficient evidence to recommend administration (non-patent literature 1). Duloxetine is the only drug with moderate effectiveness evidence in the guidelines (non-patent literature 2).

[0007] However, it is known that duloxetine also often leads to discontinuation of the drug due to adverse events in the early stage of drug administration (Non-Patent Document 3).

[0008] On the other hand, it is known that some citric acid preparations or alkalinizing agents such as sodium bicarbonate are effective for hyperuricemia or gout, which are typical lifestyle diseases. In addition, it is known that by administering an alkalinizing agent, acidic urine tends to be alkaline, thereby inhibiting the formation of urinary stones. In addition, it is known that by administering an alkalinizing agent to early CKD patients, the progression of renal damage can be inhibited and the blood concentration of uremic substances can be reduced (Patent Documents 1 and 2). In addition, citric acid preparations are known to inhibit renal fibrosis in diabetic nephropathy (Patent Document 3).

[0009] However, it is not known that alkalinizing agents are effective for preventing or treating chemotherapy-induced peripheral nerve disorders.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: International Publication No. 2018 / 193648

[0013] Patent Document 2: International Publication No. 2018 / 193752

[0014] Patent Document 3: International Publication No. 2020 / 080451

[0015] Non-patent literature

[0016] Non-Patent Literature 1: Guidelines for the Management of Peripheral Nervous System Disorders Accompanying Cancer Drug Therapy

[0017] Non-Patent Literature 2: Guidelines for Pharmacotherapy of Neuropathic Pain (Revised 2nd Edition)

[0018] Non-Patent Literature 3: Study on Risk Factors for Adverse Events Induced by Duloxetine in Cancer Patients Summary of the Invention

[0019] An object of the present invention is to provide a pharmaceutical for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs.

[0020] Another object of the present invention is to provide an anticancer combination preparation for suppressing the expression of peripheral nerve disorders, comprising an alkalizing agent and a cancer chemotherapeutic drug.

[0021] Another object of the present invention is to provide an anticancer pharmaceutical composition for suppressing the expression of peripheral nerve disorders, comprising an alkalizing agent and a cancer chemotherapeutic drug.

[0022] Another object of the present invention is to provide an anticancer drug kit for suppressing the expression of peripheral nerve disorders, comprising an alkalinizing agent and a cancer chemotherapeutic drug.

[0023] Another object of the present invention is to provide a method for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs.

[0024] Another object of the present invention is to provide a method for treating cancer by suppressing the expression of peripheral nerve dysfunction.

[0025] The present inventors have conducted intensive studies to achieve the above-mentioned objects and, as a result, have found that a specific alkalizing agent is useful for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs, thereby completing the present invention.

[0026] That is, the present invention has the following aspects.

[0027] (1) A pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs, comprising an alkalizing agent.

[0028] (2) The pharmaceutical composition according to (1), wherein the peripheral nerve disorder induced by the chemotherapeutic drug is pain, sensory disorder, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0029] (3) The pharmaceutical composition according to (1) or (2), wherein the peripheral neuropathy induced by a chemotherapeutic drug is peripheral neuropathy pain.

[0030] (4) The pharmaceutical composition according to (3), wherein the peripheral neuropathy pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling.

[0031] (5) The pharmaceutical composition according to (1) or (2), wherein the peripheral nerve disorder induced by the chemotherapeutic drug is a sensory disorder caused by the peripheral nerve disorder.

[0032] (6) The pharmaceutical composition according to (5), wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0033] (7) The pharmaceutical composition according to (6), wherein the hyperesthesia is allodynia, and the paresthesia is paresthesia or sensory perversion.

[0034] (8) The pharmaceutical composition according to (1) or (2), wherein the peripheral nerve disorder induced by a chemotherapeutic drug is an autonomic nerve disorder caused by the peripheral nerve disorder.

[0035] (9) The pharmaceutical composition according to (8), wherein the symptom caused by autonomic nervous system disorder is urination disorder, abnormal sweating, orthostatic hypotension, constipation or paralytic ileus.

[0036] (10) The pharmaceutical composition according to any one of (1) to (9), wherein the peripheral neuropathy induced by a chemotherapeutic drug is a peripheral neuropathy with symptoms appearing in the limbs.

[0037] (11) The pharmaceutical composition according to any one of (1) to (10), wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0038] (12) The pharmaceutical composition according to any one of (1) to (11), wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

[0039] (13) The pharmaceutical composition according to any one of (1) to (12), wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0040] (14) The pharmaceutical composition according to any one of (1) to (13), wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0041] (15) The pharmaceutical composition according to any one of (1) to (14), wherein the pharmaceutical composition is a tablet.

[0042] (16) The pharmaceutical composition according to any one of (1) to (10), wherein the alkalizing agent is sodium bicarbonate.

[0043] (17) The pharmaceutical composition according to any one of (1) to (16), wherein the chemotherapeutic drug is a cancer chemotherapeutic drug.

[0044] (18) The pharmaceutical composition according to (17), wherein the cancer chemotherapy drug is a cytotoxic anticancer drug, a molecular targeted anticancer drug, an immunotherapy drug, or other anticancer drug.

[0045] (19) The pharmaceutical composition according to (18), wherein the cytotoxic anticancer drug is at least one anticancer drug selected from paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin and nelarabine.

[0046] (20) The pharmaceutical composition according to (18), wherein the molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebacterinib, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemtansine.

[0047] (21) The pharmaceutical composition according to (18), wherein the immunotherapy drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0048] (22) The pharmaceutical composition according to (18), wherein the other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide and pomalidomide.

[0049] (23) The pharmaceutical composition according to (17), wherein the cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin and bortezomib.

[0050] (24) The pharmaceutical composition according to (23), wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

[0051] (25) A combined preparation for suppressing the expression of peripheral nerve disorders, which is administered simultaneously, separately or sequentially in the treatment of cancer.

[0052] The above-mentioned combined preparation comprises at least two independent preparations of an alkalinizing agent and a cancer chemotherapeutic drug.

[0053] (26) An anticancer pharmaceutical composition for suppressing the expression of peripheral nerve disorders, comprising an alkalinizing agent and a cancer chemotherapy drug.

[0054] (27) An anticancer drug kit for suppressing the expression of peripheral nerve disorders, comprising an alkalinizing agent in a first compartment and a cancer chemotherapy drug in a second compartment.

[0055] The pharmaceutical compositions, combined preparations, and drug kits provided herein can be used to treat or prevent peripheral nerve disorders induced by chemotherapeutic drugs. Furthermore, the pharmaceutical compositions, combined preparations, and drug kits provided herein can be used to treat cancers that suppress peripheral nerve disorders induced by chemotherapeutic drugs, particularly cancer chemotherapeutic drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 This is a graph showing the effects of alkalinizing agents in an oxaliplatin-induced mouse neuropathic pain model, and shows the relationship between the number of days from the start of oxaliplatin administration and the pain score for mechanical allodynia and cold allodynia.

[0057] Figure 2 This graph shows the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model, showing the pain scores of each subject group regarding mechanical allodynia on the 10th day from the start of oxaliplatin administration, the pain scores of each subject group regarding cold allodynia on the 3rd day from the start of oxaliplatin administration, and the body weight of each subject group on the 10th day from the start of oxaliplatin administration.

[0058] Figure 3 This is a graph showing the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, 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.

[0059] Figure 4 This graph shows the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 14th day from the start of paclitaxel administration, and the body weight of each test group on the 14th day from the start of paclitaxel administration.

[0060] Figure 5This is a graph showing the effect of an alkalinizing agent in a bortezomib-induced mouse neuropathic pain model, showing the relationship between the number of days from the start of bortezomib administration and body weight, and the relationship between the number of days from the start of bortezomib administration and the pain score related to mechanical allodynia.

[0061] Figure 6 This graph shows the effect of an alkalinizing agent in a bortezomib-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 12th day from the start of bortezomib administration, and the body weight of each test group on the 12th day from the start of bortezomib administration.

[0062] Figure 7 This graph shows the effects of alkalinizing agents in a vincristine-induced mouse neuropathic pain model, and shows the relationship between the number of days from the start of vincristine administration and body weight, and the relationship between the number of days from the start of vincristine administration and the pain score related to mechanical allodynia.

[0063] Figure 8 This graph shows the effect of an alkalinizing agent in a vincristine-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 14th day from the start of vincristine administration, and the body weight of each test group on the 14th day from the start of vincristine administration.

[0064] Figure 9 This is a graph showing the effect of an alkalinizing agent in a paclitaxel-induced neuropathic pain model in rats, and shows the relationship between the number of days from the start of paclitaxel administration and the 50% paw withdrawal threshold.

[0065] Figure 10 This is a graph showing the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 13th day from the start of paclitaxel administration.

[0066] Figure 11 This graph shows the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the spontaneous discharge frequency of each neuron in each test group on the 14th day from the start of paclitaxel administration, and the vFF (Von Frey filaments)-induced discharge frequency of each neuron in each test group on the 14th day from the start of paclitaxel administration.

[0067] Figure 12This graph shows the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, showing the spontaneous discharge frequency of each individual in each test group on the 14th day from the start of paclitaxel administration, and the vFF-induced discharge frequency of each individual in each test group on the 14th day from the start of paclitaxel administration.

[0068] Figure 13 This is a graph showing the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model, showing the relationship between the number of days from the start of oxaliplatin administration and body weight, and the relationship between the number of days from the start of oxaliplatin administration and the pain score related to mechanical allodynia.

[0069] Figure 14 This graph shows the effect of an alkalinizing agent in an oxaliplatin-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 10th day from the start of oxaliplatin administration, and the body weight of each test group on the 10th day from the start of oxaliplatin administration.

[0070] Figure 15 This is a graph showing the effect of an alkalinizing agent in a paclitaxel-induced mouse neuropathic pain model, 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.

[0071] Figure 16 This graph shows the effect of an alkalizing agent in a paclitaxel-induced mouse neuropathic pain model, and shows the pain score of each test group regarding mechanical allodynia on the 14th day from the start of paclitaxel administration, and the body weight of each test group on the 14th day from the start of paclitaxel administration. DETAILED DESCRIPTION

[0072] 1. Pharmaceutical compositions

[0073] <Pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs>

[0074] The pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs provided by the present invention may contain an alkalizing agent as an active ingredient.

[0075] “Containing an alkalizing agent as an active ingredient” means that the alkalizing agent is a main ingredient in the pharmaceutical composition, or that the alkalizing agent functions as a substantial active ingredient for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs, and the pharmaceutical composition contains an effective amount for the above-mentioned treatment or prevention.

[0076] Alkalizing agents are agents that have the effect of increasing the HCO3 content of mammalian (especially human) body fluids, such as blood or urine.- Examples of alkalizing agents include pharmaceutically acceptable salts of citric acid, hydrates thereof, or mixtures thereof, and sodium bicarbonate (baking soda). Examples of pharmaceutically acceptable salts of citric acid include alkali metal citrates. Examples of alkali metal citrates 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.

[0077] Examples of preferred alkalizing agents included in the pharmaceutical composition provided herein include sodium citrate, potassium citrate, or hydrates thereof, or mixtures thereof. For example, a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O) can be used. 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 0.01 to 100 parts of sodium citrate dihydrate per 1 part of potassium citrate monohydrate. The molar ratio of potassium citrate (e.g., potassium citrate monohydrate) to sodium citrate (e.g., sodium citrate dihydrate) can be appropriately set by those skilled in the art, for example, 0.85:1.15-1.15:0.85, 0.90:1.10-1.10:0.90, 0.95:1.05-1.05:0.95, or 0.99:1.01-1.01:0.99, preferably 1:1.

[0078] In addition, other examples of the active ingredient contained in the pharmaceutical composition provided by the present invention include sodium citrate or a hydrate thereof, for example, sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0079] In addition, other examples of the active ingredient contained in the pharmaceutical composition provided by the present invention include potassium citrate or a hydrate thereof, for example, potassium citrate monohydrate (C6H5K3O7·H2O).

[0080] In one embodiment, the alkalizing agent contained in the pharmaceutical composition of the present invention may include a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0081] In one embodiment, the alkalizing agent contained in the pharmaceutical composition of the present invention may include a mixture of sodium citrate or its hydrate and citric acid (eg, anhydrous citric acid), or a mixture of potassium citrate or its hydrate and citric acid (eg, anhydrous citric acid).

[0082] In one embodiment, the alkalizing agent included in the pharmaceutical composition of the present invention can be a mixture of potassium citrate or its hydrate, sodium citrate or its hydrate, 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 set by those skilled in the art, 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, preferably 1:2:2.

[0083] In one embodiment, the alkalizing agent included in the pharmaceutical composition of the present invention can 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 those skilled in the art, 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, preferably 1:2:2.

[0084] In one embodiment, the alkalizing agent contained in the pharmaceutical composition of the present invention may consist solely of a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

[0085] In this specification, when the weight of citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (for example, potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O)) is mentioned, the weight may be a dry weight.

[0086] In one embodiment, the treatment or prevention of peripheral nerve disorders induced by chemotherapeutic drugs may be the treatment or prevention of organic peripheral nerve disorders induced by chemotherapeutic drugs.

[0087] In another embodiment, the treatment or prevention of chemotherapeutic drug-induced peripheral nerve disorders can be the treatment or prevention of symptoms caused by chemotherapeutic drug-induced peripheral nerve disorders, such as pain, sensory impairment, movement disorder, autonomic nerve disorder, or complications thereof.

[0088] In one embodiment, the "peripheral nerve disorder induced by a chemotherapeutic drug" may be pain, sensory impairment, movement disorder, autonomic nerve disorder, or complications thereof caused by peripheral nerve disorder induced by a chemotherapeutic drug.

[0089] In another embodiment, the "peripheral neuropathy induced by a chemotherapeutic drug" may be peripheral neuropathy pain induced by a chemotherapeutic drug.

[0090] In another embodiment, the "peripheral nerve disorder pain" can be electric pain, burning pain, pain (excluding electric pain and burning pain), or a tingling sensation.

[0091] In one embodiment, the above-mentioned "peripheral neuropathy induced by chemotherapeutic drugs" may be sensory disorders such as insensitivity, hyperesthesia or paresthesia caused by peripheral neuropathy induced by chemotherapeutic drugs. The above-mentioned hyperesthesia is a concept that includes allodynia, and is a concept that includes mechanical allodynia caused by mechanical stimulation. In addition, the above-mentioned paresthesia is a concept that includes dysesthesia and paresthesia, and is a concept that includes cold dyssensuality caused by cold stimulation. In addition, one aspect of sensory impairment and / or movement disorder is "paralysis". Therefore, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for the treatment or prevention of paralysis caused by peripheral neuropathy induced by chemotherapeutic drugs.

[0092] In one embodiment, the "chemotherapeutic drug-induced peripheral nerve disorder" may be autonomic nervous system disorder caused by chemotherapeutic drug-induced peripheral nerve disorder. Typical symptoms of autonomic nervous system disorder include urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0093] In one embodiment, the aforementioned "peripheral nerve disorder induced by a chemotherapeutic drug" may manifest itself in mammals (particularly humans) as symptoms in the limbs, particularly in the distal extremities.

[0094] In one embodiment, peripheral nerve disorders induced by chemotherapeutic drugs can be treated or prevented by administering the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient.

[0095] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient can be administered to treat or prevent pain, sensory impairment, movement impairment, autonomic nervous system impairment, or their complications caused by chemotherapeutic drug-induced peripheral nerve disorders.

[0096] In this specification, pain caused by peripheral nerve disorder may be referred to as peripheral nerve disorder pain.

[0097] The type and degree of peripheral neuropathy pain induced by chemotherapeutic drugs that can be treated or prevented by the pharmaceutical composition provided by the present invention, which contains an alkalizing agent as an active ingredient, are not particularly limited. Typically, pain such as shooting pain, burning pain, pain (excluding electric pain and burning pain), or tingling pain can be treated or prevented.

[0098] In this specification, sensory disturbances caused by chemotherapeutic drug-induced peripheral nerve disorders are a concept that includes dysesthesia, hyperesthesia, and paresthesia. Furthermore, the aforementioned hyperesthesia is a concept that includes allodynia, and the aforementioned paresthesia is a concept that includes dysesthesia and paresthesia. Therefore, by administering the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient, sensory disturbances such as dysesthesia, hyperesthesia, and paresthesia, including allodynia, paresthesia, and paresthesia, caused by chemotherapeutic drug-induced peripheral nerve disorders, can be treated or prevented.

[0099] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient can be administered to treat or prevent symptoms caused by autonomic nervous system disorders induced by chemotherapeutic drugs, such as dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0100] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient can be administered to treat or prevent symptoms occurring in the limbs, particularly in the distal extremities, of mammals (particularly humans).

[0101] In this specification, the term "chemotherapeutic drug" is not particularly limited as long as it can induce peripheral nerve disorders, and may be, for example, a "chemotherapeutic drug for cancer." Furthermore, the term "chemotherapeutic drug for cancer" is not particularly limited as long as it can induce peripheral nerve disorders.

[0102] In the present technical field, it is known that the cancer chemotherapy drugs exemplified below have a tendency to induce peripheral nerve disorders.

[0103] Cytotoxic anticancer drugs such as Paclitaxel, Docetaxel, Cabazitaxel, Vinorelbine, Vincristine, Vinblastine, Vindesine, Eribulin, Oxaliplatin, Carboplatin, Cisplatin and Nelarabine.

[0104] Molecular targeted anticancer drugs such as Bortezomib, Ixazomib, Romidepsin, Gilteritinib, Trastuzumab emtansine, Brentuximab vedotin, Obinutuzumab, Blinatumomab, Lorlatinib, Entrectinib, Encorafenib, Binimetinib and Pemigatinib.

[0105] Immunotherapy drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0106] Other anticancer drugs include cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0107] Here, the expressions "cytotoxic anticancer drugs", "molecular targeted anticancer drugs", "immunotherapeutic drugs" and "other anticancer drugs" are used for the convenience of regulating the above-mentioned cancer chemotherapy drugs, and the expressions do not limit the types belonging to each category.

[0108] Therefore, in the present specification, "peripheral nerve disorders induced by chemotherapeutic drugs" may be, for example, peripheral nerve disorders induced by at least one anticancer drug selected from the group consisting of paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin and nelarabine; cytotoxic anticancer drugs such as bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab ... Molecularly targeted anticancer drugs such as anti-emtansine conjugates, vena cava, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib, and pemritinib; immunotherapeutic drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab; and other anticancer drugs such as cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0109] In one embodiment, peripheral nerve disorders induced by the above-exemplified cancer chemotherapy drugs, ie, anticancer drugs, can be treated or prevented by administering a pharmaceutical composition comprising an alkalizing agent as an active ingredient provided by the present invention.

[0110] In another embodiment, the pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient can be administered to treat or prevent peripheral nerve disorders induced by at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin, and bortezomib.

[0111] In another embodiment, peripheral nerve disorders induced by paclitaxel or oxaliplatin can be treated or prevented by administering the pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient.

[0112] In another embodiment, peripheral nerve disorders induced by bortezomib or vincristine can be treated or prevented by administering a pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient.

[0113] In this specification, "treatment" includes eliminating, completely curing, curing or alleviating "pathological" or "abnormal" symptoms, conditions or diseases, as well as actions or means used to achieve this purpose, including "suppressing" the worsening of "pathological" or "abnormal" symptoms, conditions or diseases, as well as actions or means used to achieve this purpose, or includes the concept of "improvement".

[0114] In one embodiment, "treatment" refers to the disappearance, complete cure, cure or alleviation of "pathological" or "abnormal" symptoms, conditions or diseases, as well as the actions or means used to achieve such a purpose. In another embodiment, "treatment" refers to the disappearance, complete cure, cure or alleviation of "pathological" or "abnormal" symptoms, conditions or diseases.

[0115] In one embodiment, "treatment" includes administering the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient as a part of the treatment of the above-mentioned cancer as a chemotherapeutic drug, ie, an anticancer drug.

[0116] In one embodiment, "treatment" may include the administration of the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient before the administration of the above-mentioned chemotherapeutic drug for cancer, i.e., anticancer drug, thereby causing the disappearance, complete cure, cure or alleviation of "pathological" or "abnormal" symptoms, conditions or diseases caused by the administration of the above-mentioned chemotherapeutic drug for cancer, i.e., anticancer drug, and actions or means for achieving such purpose, and may include "suppression" of the worsening of "pathological" or "abnormal" symptoms, conditions or diseases, and actions or means for achieving such purpose, or may include the concept of "improvement".

[0117] In one embodiment, when the administration of the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient is initiated before the administration of the above-mentioned cancer chemotherapy drug, i.e., anticancer drug, the administration can be initiated 10 days to 1 day before, 7 days to 1 day before, or 3 days to 1 day before the administration of the above-mentioned cancer chemotherapy drug, i.e., anticancer drug.

[0118] In this specification, "inhibit" is a concept that includes stopping, slowing down, or alleviating the deterioration or progression of a symptom, condition, or disease, as well as the actions or means used to achieve this purpose, or includes improving the above-mentioned symptom, condition, or disease, as well as the actions or means used to achieve this purpose. Here, "improve" is a concept that includes bringing a "morbid" or "abnormal" symptom, condition, or disease close to a "healthy" or "normal" state, or the actions or means used to achieve this purpose, or includes reaching a "healthy" or "normal" state, as well as the actions or means used to achieve this purpose. Therefore, in one embodiment, "improve" includes that the numerical value of an indicator of a "morbid" or "abnormal" symptom or condition becomes smaller or larger as the above-mentioned "improve", thereby approaching a normal value, or becoming a normal value. The above-mentioned "deterioration or progression of a symptom, condition, or disease" includes the deterioration or progression of a "morbid" or "abnormal" symptom, condition, or disease, as well as the deterioration or progression from a "healthy" or "normal" state to a "morbid" or "abnormal" symptom, condition, or disease. In one embodiment, "inhibit" refers to stopping, slowing down, or alleviating the worsening or progression of a symptom, state, or disease, or an act or means for achieving the same. In another embodiment, "inhibit" refers to stopping, slowing down, or alleviating the worsening or progression of a symptom, state, or disease.

[0119] In this specification, "healthy" means a state without acute or chronic diseases or disorders, and "normal" means a state in which a healthy subject behaves normally.

[0120] In this specification, "prevention" is a concept that includes avoiding the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, as well as the actions or means used to achieve this goal. Therefore, in a state where "pathological" or "abnormal" symptoms, conditions, or diseases do not occur (also referred to as manifestations), "suppression" of these can include the concept of "prevention."

[0121] Here, the above-mentioned symptoms, conditions, or diseases are compared before and after administration of the pharmaceutical composition provided by the present invention, or when the pharmaceutical composition provided by the present invention is administered, compared with when a control or placebo is administered.

[0122] Thus, for example, "treatment of peripheral neuropathy pain induced by chemotherapeutic drugs" encompasses the elimination, complete cure, treatment, or alleviation of peripheral neuropathy pain induced by chemotherapeutic drugs, as well as actions or means for achieving such ends, and encompasses the suppression of peripheral neuropathy pain induced by chemotherapeutic drugs, as well as actions or means for achieving such ends, or encompasses the concept of amelioration of peripheral neuropathy pain induced by chemotherapeutic drugs. Alternatively, the concept encompasses the suppression of symptoms or conditions of peripheral neuropathy pain induced by chemotherapeutic drugs after administration of the pharmaceutical composition comprising an alkalinizing agent as an active ingredient as compared to symptoms or conditions before administration of the pharmaceutical composition provided by the present invention, or the suppression of symptoms or conditions of pain by administration of the pharmaceutical composition comprising an alkalinizing agent as an active ingredient as compared to placebo or a control.

[0123] Furthermore, for example, the concept of "prevention of chemotherapeutic drug-induced peripheral neuropathy pain" encompasses avoiding the onset of chemotherapeutic drug-induced peripheral neuropathy pain, as well as actions or means for achieving this goal. It also encompasses suppressing the onset of such pain before it occurs, as well as actions or means for achieving this goal. Alternatively, if, when a pharmaceutical composition comprising an alkalinizing agent as an active ingredient provided by the present invention is administered before the onset of chemotherapeutic drug-induced peripheral neuropathy pain, even if such pain occurs, the symptoms or state of such pain are suppressed compared to administration of a placebo or a control, such phenomenon may be included within the scope of prevention.

[0124] Regarding the aforementioned "suppressive" effect on "pain", it can be evaluated based on the "pain score" described later, in comparison with placebo administration or a control.

[0125] By replacing the above-mentioned "pain" with the symptoms or conditions of peripheral nerve disorders induced by chemotherapy drugs as described above, the concepts of treatment and prevention can be understood. The evaluation of the effect can be performed using appropriate indicators instead of "pain score".

[0126] In this specification, the expression [A, B and / or C] means "at least one selected from A, B and C".

[0127] The pharmaceutical composition provided by the present invention, which contains an alkalizing agent as an active ingredient, is administered orally or parenterally to humans or other mammals. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, mucosal administration, transdermal administration, nasal administration, rectal administration, intramedullary administration, intraperitoneal administration, and topical administration.

[0128] The pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be prepared directly from citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof; or sodium bicarbonate, or mixed with a pharmaceutically acceptable carrier, such as an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a binder (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinyl pyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), a disintegrant (e.g., starch, carboxymethyl cellulose calcium (CMC-Ca)), a diluent (e.g., water for injection, physiological saline), and other additives as needed (e.g., pH adjusters, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents, stabilizers), and can be prepared in the form of tablets, capsules, suspensions, injections, suppositories, and the like. For example, when preparing tablets, citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof can be mixed; or sodium bicarbonate can 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, polyvinyl pyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), etc. to prepare the tablets.

[0129] The tablet according to the present invention will be described in more detail below.

[0130] In one embodiment, the pharmaceutical composition comprising an alkalizing agent as an active ingredient provided by the present invention is a tablet. The tablet provided by the present invention may also include pharmaceutically acceptable additives commonly used in the pharmaceutical field in addition to the active ingredient (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; or a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate). Examples of such additives include excipients, binders, disintegrants, glidants, flavoring agents, lubricants, pH regulators, surfactants, stabilizers, and spices.

[0131] The content of the active ingredient in the tablet provided by the present invention may be 10 to 95% by weight, preferably 30 to 90% by weight, and more preferably 60 to 85% by weight, relative to the weight of the tablet.

[0132] 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, and maltose; sugar alcohols such as erythritol, sorbitol, maltitol, xylitol, and D-mannitol; starches (e.g., corn starch, potato starch, rice starch, and wheat starch); crystalline cellulose, magnesium aluminum metasilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose; crystalline cellulose is particularly preferred.

[0133] The content of the excipient in the tablet 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 relative to the tablet.

[0134] Examples of binders that can be used in the tablets provided by the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, dextrin, methylcellulose, polyvinyl alcohol, sodium alginate, aminoalkyl methacrylate copolymers, polyethylene glycol, pregelatinized starch (e.g., partially pregelatinized starch), agar, and gelatin, with hydroxypropyl cellulose being particularly preferred.

[0135] The content of the binder in the tablet 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, relative to the weight of the tablet.

[0136] Examples of disintegrants that can be used in the tablets provided by the present invention include cross-linked sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, starch (e.g., wheat starch, corn starch, partially pregelatinized starch) and carboxymethyl cellulose, with partially pregelatinized starch being particularly preferred.

[0137] The content of the disintegrant in the tablet 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, relative to the weight of the tablet.

[0138] Examples of glidants that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminum metasilicate.

[0139] The content of the glidant in the tablet 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, relative to the weight of the tablet.

[0140] 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 (wherein the above flavoring agents are not included in the active ingredients of the present invention), and sweeteners such as saccharin sodium, dipotassium glycyrrhizate, aspartame (registered trademark), stevia, thaumatin, and sucralose.

[0141] The content of the flavoring agent in the tablet provided by the present invention can be 0.03 to 3% by weight, preferably 0.1 to 3% by weight, and more preferably 0.3 to 3% by weight, relative to the weight of the tablet.

[0142] 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, polyethylene glycol, and sodium stearyl fumarate, with magnesium stearate being particularly preferred.

[0143] The content of the lubricant in the tablet 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, relative to the weight of the tablet.

[0144] 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 (wherein the above pH adjusters are not included in the active ingredients of the present invention).

[0145] The content of the pH adjuster in the tablet 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, relative to the weight of the tablet.

[0146] Examples of surfactants that can be used in the tablets provided by the present invention include sodium lauryl sulfate, polysorbate, sucrose fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxyethylene stearate, polyethylene glycol, and poloxamer.

[0147] The content of the surfactant in the tablet provided by the present invention may be 0.01 to 3% by weight, preferably 0.03 to 1% by weight, and more preferably 0.03 to 0.5% by weight, relative to the weight of the tablet.

[0148] 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 (wherein the above stabilizers are not included in the active ingredients of the present invention), with anhydrous citric acid being particularly preferred.

[0149] The content of the stabilizer in the tablet provided by the present invention may be 0.01 to 30% by weight, preferably 0.1 to 30% by weight, and more preferably 1 to 20% by weight, relative to the weight of the tablet.

[0150] Examples of flavorings that can be used in the tablets provided by the present invention include citrus flavors such as lemon, orange, and grapefruit, peppermint, spearmint, and menthol, which can be contained in the tablets in an appropriate amount (e.g., 0.01 to 1% by weight, more preferably 0.01 to 0.1% by weight relative to the tablet).

[0151] The total content of the active ingredient and pharmaceutically acceptable additives in the tablet provided by the present invention is no more than 100% by weight relative to the tablet.

[0152] The tablets provided herein can be prepared as plain tablets containing the above-mentioned ingredients without a coating layer, or as film-coated tablets with a coating layer. The content of the coating layer can be appropriately determined by those skilled in the art, for example, 0.1 to 10% by weight relative to the plain tablet. In addition to the coating base, the coating layer may also contain a plasticizer, a colorant, a glossing agent, and the like.

[0153] Examples of coating bases that can be used in the tablets provided herein include hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, cellulose acetate phthalate, methacrylic acid copolymers, and polyvinyl pyrrolidone, with hydroxypropyl methylcellulose being particularly preferred. The content of the coating base in the tablets provided herein can be 0.01 to 10% by weight, preferably 0.3 to 3% by weight, relative to the weight of the tablet.

[0154] 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, glycerol, propylene glycol, and polyethylene glycol (e.g., polyethylene glycol 6000), with polyethylene glycol 6000 being particularly preferred. The content of the coating plasticizer in the tablets provided by the present invention can be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the weight of the tablet.

[0155] Examples of coating colorants that can be used in the tablets provided herein 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 herein can be 0.01 to 1% by weight, preferably 0.03 to 3% by weight, relative to the weight of the tablet.

[0156] An example of a coating glossing agent that can be used in the tablets provided by the present invention is carnauba wax. The content of the coating glossing agent in the tablets provided by the present invention can be 0.0001 to 0.1% by weight, preferably 0.001 to 0.01% by weight, relative to the tablet.

[0157] The pharmaceutical composition provided herein containing an alkalizing agent as an active ingredient can be manufactured by methods known in the pharmaceutical field. For example, when prepared as tablets, the manufacturing method may include a mixing step of mixing the active ingredient (e.g., potassium citrate or its hydrate; sodium citrate or its hydrate; a mixture of potassium citrate monohydrate and sodium citrate dihydrate; or sodium bicarbonate) with an additive, a granulation step, a tableting step, and / or a coating step.

[0158] The mixing process may include a process of mixing the active ingredient with additives such as excipients, stabilizers, disintegrants and / or binders. In addition, before the tableting process, the process of mixing the mixture comprising the active ingredient and additives with a lubricant, flavorings and / or spices may be further included. The mixing may be performed using a V-type mixer, a W-type mixer, a container blender, a drum mixer, a stirring mixer, etc.

[0159] The granulation step can be carried out by a granulation method known in the pharmaceutical field. Examples of the granulation method include dry granulation, wet granulation, and fluidized bed granulation.

[0160] As one embodiment, the mixture obtained in the mixing step or the granulated material obtained in the granulation step can be subjected to appropriate pulverization and / or screening to obtain a mixture or granulated material having a desired particle size. Pulverization can be performed using, for example, a pulverizer known in the pharmaceutical field, such as a ball mill, a jet mill, or a hammer mill. Sieving can be performed using a 16-mesh sieve (mesh size 1000 μm) to a 32-mesh sieve (mesh size 500 μm).

[0161] The tableting process can be performed using a tableting method known in the pharmaceutical field. Examples of tableting methods include direct tableting, dry tableting, wet tableting, and externally lubricated tableting. For example, the mixture or granulated material obtained in the above process can be tableted using a tableting machine known in the pharmaceutical field, such as a single-shot tablet press or a rotary tablet press. When using a single-shot tablet press or a rotary tablet press, a tableting pressure of 1 kN to 30 kN can be used.

[0162] The coating step can be performed using methods known in the pharmaceutical field, for example, by spraying a coating solution containing a coating base and a plasticizer, a colorant, a glossing agent, etc., onto the outside of the plain tablet.

[0163] In one embodiment, the tablets provided by the present invention can be manufactured by the following method: the active ingredient, excipients (such as lactose, D-mannitol, crystalline cellulose and / or glucose), binders (such as hydroxypropyl cellulose (HPC), gelatin and / or polyvinyl pyrrolidone (PVP)), stabilizers (such as anhydrous citric acid), disintegrants (such as starch (such as partially pregelatinized starch) and / or carboxymethyl cellulose calcium (CMC-Ca)) and lubricants (such as magnesium stearate) are mixed and tableted to obtain plain tablets; and a coating layer containing a coating base (such as hydroxypropyl cellulose, hydroxypropyl methylcellulose and / or PVP) and a plasticizer (such as triethyl citrate and / or polyethylene glycol 6000), a colorant (such as ferric oxide and / or titanium oxide), and a glossing agent (such as carnauba wax) is formed on the outside of the plain tablet.

[0164] In one embodiment, the hardness of the obtained tablet may be 10 to 200 N, preferably 30 to 150 N.

[0165] The amount of the alkalizing agent in the pharmaceutical composition containing the alkalizing agent as an active ingredient provided by the present invention can be appropriately set.

[0166] In one embodiment, the amount of the alkalinizer in the pharmaceutical composition provided by the present invention can be set to: the dosage of the alkalinizer is an amount that improves acidic urine caused by gout or hyperuricemia by administration to a human, or an amount less than or greater than the amount thereof. For example, it can be set to: 100-800 mass%, 200-800 mass%, or 400-800 mass% of the daily dosage approved in Japan for improving acidic urine caused by gout or hyperuricemia (for example, when the alkalinizer is a citric acid preparation: a tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) is orally administered as two tablets three times a day; when the alkalinizer is sodium bicarbonate: 3-5 g is orally administered per day).

[0167] In one embodiment, the pharmaceutical composition comprising an alkalizing agent as an active ingredient provided by the present invention is in the form of a tablet. One 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.

[0168] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient is in the form of a tablet. One tablet may contain 10 mg to 300 mg of potassium citrate monohydrate and sodium citrate dihydrate, each 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.

[0169] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient is in the form of a tablet. One tablet may contain 10 mg to 1 g, preferably 100 mg to 500 mg, of sodium bicarbonate as the alkalizing agent.

[0170] As one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient is in the form of a tablet. The active ingredients may include 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate, and the additives may include anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, polyethylene glycol 6000, titanium oxide, and carnauba wax.

[0171] As one embodiment, a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate can be set as one dosage unit.

[0172] In this specification, "dosage unit" means the unit of a preparation, and "1 dosing unit" means the minimum unit of a preparation. Therefore, for example, in the case of tablets, the dosing unit is each tablet, and 1 dosing unit means 1 tablet. In the case of injections, the dosing unit is the injection placed in a sealed container such as an ampoule or vial, and 1 dosing unit means the injection placed in a sealed container such as 1 ampoule or vial. In the case of powders or gel preparations, the dosing unit is the powder or gel preparation sealed in a bag made of a single-layer or multi-layer film sheet such as polyethylene or a sheet having an aluminum layer on the sheet, and 1 dosing unit means the powder or gel preparation placed in 1 sealed bag. In the case of capsules (hard capsules, soft capsules, seamless capsules, etc.), the dosing unit is each capsule, and 1 dosing unit means 1 capsule.

[0173] When the pharmaceutical composition provided by the present invention is administered to humans or other mammals, one or more of the above-mentioned dosage units may be administered at a time, and one dosage unit may be divided and administered.

[0174] The dosage of the active ingredient can be appropriately determined based on the type of active ingredient, the method of administration, the age, weight, sex, symptoms, sensitivity to the drug of the subject, the dosing schedule of the chemotherapeutic drug, the degree of peripheral neuropathy induced by the chemotherapeutic drug, etc. The dosage can be adjusted based on the dosing schedule of the chemotherapeutic drug, the degree of peripheral neuropathy induced by the chemotherapeutic drug, and the improvement of symptoms.

[0175] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients is orally administered to a human, potassium citrate monohydrate and sodium citrate dihydrate can be administered at a dose of 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. Administration can be divided into 1 to 5 doses per day, preferably 3 times a day.

[0176] In one embodiment, when potassium citrate monohydrate or sodium citrate dihydrate as the active ingredient is orally administered to humans, 3 to 24 g / day, 3 to 18 g / day, or 3 to 12 g / day can be administered, and the administration can be divided into 1 to 5 times a day, preferably 3 times a day.

[0177] In one embodiment, when sodium bicarbonate as an active ingredient is orally administered to humans, 2.25 to 9 g / day can be administered, which can be divided into 1 to 5 times a day, preferably 3 times a day.

[0178] In one embodiment, the pharmaceutical composition provided by the present invention, comprising an alkalinizing agent as an active ingredient, can be administered to a subject who is scheduled to receive a chemotherapeutic drug and is at risk of inducing peripheral neuropathy prior to the administration of the chemotherapeutic drug for the purpose of preventing the expression of the chemotherapeutic drug-induced peripheral neuropathy. Alternatively, the composition can be administered starting before the administration of the chemotherapeutic drug and continuing after the administration of the chemotherapeutic drug. Alternatively, the composition can be administered to a subject who has developed a chemotherapeutic drug-induced peripheral neuropathy for the purpose of treating the chemotherapeutic drug-induced peripheral neuropathy. The administration can be continued based on the chemotherapeutic drug administration schedule, the degree of the chemotherapeutic drug-induced peripheral neuropathy, and the improvement of the symptoms.

[0179] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalizing agent as an active ingredient can also be administered long-term, for example, for 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 ... 0 weeks or more, 80 weeks or more, 100 weeks or more, 120 weeks or more, 6 weeks to 24 weeks, 12 weeks to 24 weeks, 6 weeks to 30 weeks, 12 weeks to 30 weeks, 6 weeks to 40 weeks, 12 weeks to 40 weeks, 6 weeks to 60 weeks, 12 weeks to 60 weeks, 6 weeks to 80 weeks, 12 weeks to 80 weeks, 6 weeks to 100 weeks, 12 weeks to 100 weeks, 6 weeks to 120 weeks, 12 weeks to 120 weeks, or 24 weeks to 120 weeks.

[0180] In one embodiment, the pharmaceutical composition provided by the present invention comprising an alkalinizing agent as an active ingredient can be evaluated for its therapeutic or preventive effect on peripheral nerve disorders induced by chemotherapeutic drugs after continuous daily administration for 2 weeks.

[0181] <Anticancer pharmaceutical composition for suppressing peripheral nerve dysfunction induced by cancer chemotherapy drugs>

[0182] In one embodiment, the present invention provides an anticancer pharmaceutical composition for suppressing peripheral nerve dysfunction induced by a cancer chemotherapeutic drug, wherein the anticancer pharmaceutical composition comprises an alkalizing agent and a cancer chemotherapeutic drug as active ingredients.

[0183] As described above, it is known that some cancer chemotherapy drugs have a tendency to induce peripheral nerve disorders.

[0184] Therefore, by combining an alkalizing agent with an anticancer drug that induces peripheral nerve disorders to form a combination, it is possible to provide an anticancer pharmaceutical composition that can suppress the expression of peripheral nerve disorders induced by cancer chemotherapy drugs.

[0185] In one aspect, an "anti-cancer pharmaceutical composition that suppresses the expression of peripheral nerve disorders induced by cancer chemotherapy drugs" refers to an anti-cancer pharmaceutical composition that can suppress the expression of peripheral nerve disorders induced by anti-cancer drugs, compared to an "anti-cancer pharmaceutical composition without an alkalizing agent" containing an amount of anti-cancer drugs equivalent to the content of the anti-cancer drugs contained in the anti-cancer pharmaceutical composition provided by the present invention.

[0186] On the other hand, the "anti-cancer pharmaceutical composition that suppresses the expression of peripheral nerve disorders induced by cancer chemotherapeutic drugs" refers to an anti-cancer pharmaceutical composition that does not express peripheral nerve disorders induced by cancer chemotherapeutic drugs.

[0187] In another aspect, an "anticancer pharmaceutical composition that suppresses the expression of peripheral nerve disorders induced by cancer chemotherapy drugs" refers to an anticancer pharmaceutical composition that can suppress the expression of peripheral nerve disorders induced by anticancer drugs to 90% or less, compared to an "anticancer pharmaceutical composition without an alkalizing agent" containing an amount of anticancer drug equivalent to the amount of anticancer drug contained in the anticancer pharmaceutical composition provided by the present invention. The expression of the above-mentioned peripheral nerve disorder is preferably 85% or less, and more preferably 82% or less. In one aspect, the expression of the above-mentioned peripheral nerve disorder is 0-90%, in another aspect, 0-85%, in another aspect, 0-82%, in another aspect, 20-85%, in another aspect, 20-82%, in another aspect, 30-82%, in another aspect, 40-82%, and in another aspect, 42-82%. Here, the inhibition rate of the expression of the above-mentioned peripheral nerve disorder, for example, in the case of "pain", can be calculated based on an appropriate evaluation index, such as the "pain score" described below.

[0188] In one embodiment, the cancer chemotherapy drug (also referred to as an anticancer drug) contained as an active ingredient in the anticancer pharmaceutical composition provided by the present invention that can suppress the expression of peripheral nerve disorders induced by cancer chemotherapy drugs, for example, can be selected from cytotoxic anticancer drugs such as paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin and nelarabine; bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebutinib, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin and nelarabine; Molecular targeted anticancer drugs such as anti-cancer drugs, including levofloxacin, tadalafil, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemritinib; immunotherapeutic drugs such as nivolumab, ipilimumab, pembrolizumab, atezolizumab and avelumab; and at least one anticancer drug selected from other anticancer drugs such as cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide and pomalidomide, preferably at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin and bortezomib, among which paclitaxel or oxaliplatin is preferred.

[0189] In one embodiment, the alkalizing agent contained as an active ingredient in the anticancer pharmaceutical composition provided by the present invention that can suppress the expression of peripheral nerve disorders induced by cancer chemotherapy drugs can be the above-mentioned pharmaceutically acceptable salts of citric acid, or hydrates thereof, or mixtures thereof, and sodium bicarbonate.

[0190] In the anticancer pharmaceutical composition provided by the present invention that can inhibit the expression of peripheral nerve disorders induced by cancer chemotherapy drugs, the mixing ratio of the alkalizing agent to the cancer chemotherapy drug varies depending on, for example, the inducibility of the cancer chemotherapy drug to induce peripheral nerve disorders. In one embodiment, when the alkalizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof, the amount of the alkalizing agent can be 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, relative to 1 part by mass of the anticancer drug.

[0191] In one embodiment, the alkalizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof. When the 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, relative to 1 part by mass of the anticancer drug.

[0192] In one embodiment, the alkalizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof. When the 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, relative to 1 part by mass of the anticancer drug.

[0193] In one embodiment, the alkalizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof, and when the anticancer drug is vincristine, the amount of the alkalizing agent can be 1000 to 10000 parts by mass, preferably 3000 to 7000 parts by mass, and more preferably 4500 to 5500 parts by mass, relative to 1 part by mass of the anticancer drug.

[0194] In one embodiment, the alkalizing agent is sodium citrate, potassium citrate or a hydrate thereof, or a mixture thereof. When the anticancer drug is bortezomib, the amount of the alkalizing agent can be 1000 to 10000 parts by mass, preferably 3000 to 7000 parts by mass, and more preferably 5000 to 6000 parts by mass, relative to 1 part by mass of the anticancer drug.

[0195] In one embodiment, the anticancer pharmaceutical composition provided by the present invention that can suppress the expression of peripheral nerve disorders induced by cancer chemotherapeutic drugs is administered to a subject already suffering from cancer, such as a human or other mammal, thereby suppressing the expression of peripheral nerve disorders and treating cancer.

[0196] The cancer to be treated is determined by the type of anticancer drug contained as an active ingredient in the anticancer pharmaceutical composition provided by the present invention. Since the anticancer drugs exemplified above are known anticancer drugs themselves, the cancers for which each anticancer drug is effective are also known.

[0197] For example, when the active ingredient anticancer drug 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 active ingredient anticancer drug is oxaliplatin, it is known to be effective against colorectal cancer, gastric cancer, pancreatic cancer, or small intestinal cancer. When the active ingredient anticancer drug is vincristine, it is known to be effective against leukemia, malignant lymphoma, pediatric tumors, multiple myeloma, glioma, or pheochromocytoma. When the active ingredient anticancer drug is bortezomib, it is known to be effective against multiple myeloma, mantle cell lymphoma, primary macroglobulinemia, or lymphoplasmacytic lymphoma.

[0198] In one embodiment, the anticancer pharmaceutical composition provided by the present invention, which can suppress the expression of peripheral nerve dysfunction induced by a cancer chemotherapeutic drug, can be effective against cancers for which the anticancer drug as an active ingredient is effective.

[0199] In one embodiment, the anticancer pharmaceutical composition provided by the present invention that can inhibit the expression of peripheral nerve disorders induced by cancer chemotherapy drugs is orally or parenterally administered to a subject already suffering from cancer, such as a human or other mammal. Examples of parenterally administered administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, mucosal administration, transdermal administration, nasal administration, rectal administration, intramedullary administration, intraperitoneal administration, and topical administration.

[0200] In one embodiment, when the anticancer drug as the active ingredient of the anticancer pharmaceutical composition provided by the present invention is itself 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 the established administration method and administration schedule for the above-mentioned anticancer drug.

[0201] By administering the anticancer pharmaceutical composition provided by the present invention, which can inhibit the expression of peripheral nerve disorders induced by cancer chemotherapy drugs, the expression of peripheral nerve disorders can be suppressed. Therefore, even for subjects who cannot continue treatment with existing anticancer drugs due to the expression of peripheral nerve disorders, cancer treatment using the above-mentioned anticancer drugs can be continued, and the quality of life of the subjects can be improved, thereby enabling more effective cancer treatment than existing cancer treatments.

[0202] In one embodiment, when the anticancer drug as an 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 according to a known formulation containing the above-mentioned anticancer drug.

[0203] In one embodiment, the anticancer pharmaceutical composition provided by the present invention can be prepared using the formulation technology described above for the pharmaceutical composition containing an alkalizing agent as an active ingredient.

[0204] 2. Combination preparations

[0205] In one embodiment, the present invention provides a combination preparation for suppressing the expression of peripheral nerve disorders, for simultaneous, separate or sequential administration in the treatment of cancer, wherein the combination preparation comprises at least two independent preparations: an alkalinizing agent and a cancer chemotherapeutic drug.

[0206] The alkalizing agent and cancer chemotherapeutic drug in the above-mentioned combination preparation can be already disclosed alkalizing agents and cancer chemotherapeutic drugs, respectively. The preparations involving the alkalizing agent and the preparations involving the cancer chemotherapeutic drug can also be already disclosed preparations, respectively.

[0207] The cancer that the combination preparation is intended to treat is determined by the type of cancer chemotherapy drug (also known as anticancer drug) contained in the combination preparation provided by the present invention. Since the anticancer drugs exemplified above are known anticancer drugs themselves, the cancers for which each anticancer drug is effective are also known.

[0208] In the present specification, the term "simultaneously" used in the above-mentioned combination preparation means that the preparation of the alkalinizing agent and the preparation of the cancer chemotherapeutic drug contained in the above-mentioned combination preparation are administered simultaneously at an appropriate time.

[0209] In this specification, the term "separately" used in the above-mentioned combination preparation means that the preparation of the alkalinizing agent and the preparation of the cancer chemotherapeutic drug contained in the above-mentioned combination preparation are administered at different times during the course of a common treatment regimen.

[0210] In this specification, the term "sequentially" used in the above-mentioned combination preparation means that the preparation of the alkalinizing agent and the preparation of the cancer chemotherapeutic drug contained in the above-mentioned combination preparation are administered after the administration of any one of the preparations. The other preparation may be administered immediately after the administration of one preparation, or the other preparation may be administered after the administration of one preparation for a period of time while the effectiveness of the first preparation is maintained. Alternatively, the other preparation may be administered after repeated administration of one preparation for a period of time while the effectiveness of the first preparation is maintained.

[0211] The use of the above-mentioned combination preparation can provide a cancer treatment that suppresses the expression of peripheral nerve disorders induced by cancer chemotherapeutic drugs.

[0212] By using the combination preparation provided by the present invention, the expression of peripheral nerve disorders induced by cancer chemotherapy drugs can be suppressed. Therefore, even for subjects who cannot continue treatment with existing anticancer drugs due to the expression of peripheral nerve disorders, cancer treatment using the above-mentioned anticancer drugs can be continued, and the QOL of the subjects can also be improved, thereby enabling more effective cancer treatment than existing cancer treatments.

[0213] The content ratio of the alkalinizing agent to the cancer chemotherapeutic drug in the combination preparation provided by the present invention can be determined based on the content ratio of the alkalinizing agent to the cancer chemotherapeutic drug in the above-mentioned anticancer pharmaceutical composition capable of suppressing the expression of peripheral nerve disorders induced by cancer chemotherapeutic drugs.

[0214] 3.Drug kit

[0215] In one embodiment, the present invention provides an anticancer drug kit for suppressing the expression of peripheral nerve disorders, wherein the first compartment contains an alkalinizing agent and the second compartment contains a cancer chemotherapy drug.

[0216] The alkalizing agent and the cancer chemotherapeutic drug in the above-mentioned drug kit can be respectively disclosed alkalizing agents and cancer chemotherapeutic drugs. In addition, the alkalizing agent contained in the first compartment and the cancer chemotherapeutic drug contained in the second compartment are preferably formulated separately, and the formulations related to the alkalizing agent and the formulations related to the cancer chemotherapeutic drug can also be respectively disclosed formulations.

[0217] The cancer that the drug kit is intended to treat is determined by the type of cancer chemotherapy drug (also known as anticancer drug) contained in the drug kit provided by the present invention. Since the anticancer drugs exemplified above are known anticancer drugs themselves, the cancers for which each anticancer drug is effective are also known.

[0218] In one embodiment, the first compartment can be further divided into two or three or more compartments according to the number of administrations and the dosage of the alkalizing agent contained therein, and each compartment contains an amount of the alkalizing agent suitable for a single administration.

[0219] In one embodiment, the second compartment can be further divided into two or three or more compartments according to the number of administrations and dosage of the cancer chemotherapy drug contained therein, and each compartment contains a cancer chemotherapy drug suitable for a single administration.

[0220] By using the above-mentioned pharmaceutical kit, it is possible to provide a cancer treatment that suppresses the expression of peripheral nerve disorders induced by cancer chemotherapy drugs.

[0221] By using the drug kit provided by the present invention, the expression of peripheral nerve disorders induced by cancer chemotherapy drugs can be suppressed. Therefore, for subjects who cannot continue treatment with existing anticancer drugs due to the expression of peripheral nerve disorders, cancer treatment using the above-mentioned anticancer drugs can be continued, and the QOL of the subjects can also be improved, thereby enabling cancer treatment that is more effective than existing cancer treatments.

[0222] The content ratio of the alkalinizing agent to the cancer chemotherapeutic drug in the drug kit provided by the present invention can be determined based on the content ratio of the alkalinizing agent to the cancer chemotherapeutic drug in the above-mentioned anticancer pharmaceutical composition capable of suppressing the expression of peripheral nerve disorders induced by cancer chemotherapeutic drugs.

[0223] As other embodiment examples of the present invention, the following configurations can be cited.

[0224] <1-1> An alkalizing agent or a pharmaceutical composition comprising the alkalizing agent for use in the treatment or prevention of peripheral nerve disorders induced by chemotherapeutic drugs.

[0225] <1-2> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-1>, wherein the peripheral nerve disorder induced by the chemotherapeutic drug is pain, sensory impairment, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0226] <1-3> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-1> or <1-2>, wherein the peripheral neuropathy induced by the chemotherapeutic drug is peripheral neuropathy pain.

[0227] <1-4> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-3>, wherein the peripheral neuropathy pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling.

[0228] <1-5> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-1> or <1-2>, wherein the peripheral nerve disorder induced by the chemotherapeutic drug is a sensory disorder caused by the peripheral nerve disorder.

[0229] <1-6> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-5>, wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0230] <1-7> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-6>, wherein the hyperesthesia is allodynia, and the paresthesia is paresthesia or sensory perversion.

[0231] <1-8> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-1> or <1-2>, wherein the peripheral nerve disorder induced by the chemotherapeutic drug is an autonomic nerve disorder caused by the peripheral nerve disorder.

[0232] <1-9> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-8>, wherein the symptom caused by autonomic nervous system disorder is urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0233] <1-10> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-9>, wherein the peripheral neuropathy induced by the chemotherapeutic drug is a peripheral neuropathy with symptoms appearing in the limbs.

[0234] <1-11> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-10>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0235] <1-12> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-11>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

[0236] <1-13> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-12>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0237] <1-14> The alkalizing agent or the pharmaceutical composition containing the 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.

[0238] <1-15> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-14>, wherein the pharmaceutical composition is a tablet.

[0239] <1-16> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-10>, wherein the alkalizing agent is sodium bicarbonate.

[0240] <1-17> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to any one of <1-1> to <1-16>, wherein the chemotherapeutic drug is a cancer chemotherapeutic drug.

[0241] <1-18> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-17>, wherein the cancer chemotherapy drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug.

[0242] <1-19> The alkalinizing agent or the pharmaceutical composition comprising the alkalinizing agent for the use according to <1-18>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine.

[0243] <1-20> An alkalizing agent or a pharmaceutical composition comprising an alkalizing agent for the use according to <1-18>, wherein the molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebacterinib, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemtansine.

[0244] <1-21> The alkalinizing agent or the pharmaceutical composition containing the alkalinizing agent for use according to <1-18>, wherein the immunotherapeutic drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0245] <1-22> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-18>, wherein the other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0246] <1-23> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-17>, wherein the cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin, and bortezomib.

[0247] <1-24> The alkalizing agent or the pharmaceutical composition comprising the alkalizing agent for use according to <1-23>, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

[0248] <1-25> A combination preparation for use in the treatment of cancer by suppressing the expression of peripheral nerve disorders,

[0249] The above-mentioned combined preparation comprises at least two independent preparations of an alkalinizing agent and a cancer chemotherapeutic drug for simultaneous, separate or sequential administration.

[0250] <1-26> The combined preparation for use according to <1-25>, wherein the peripheral nerve disorder is pain, sensory impairment, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0251] <1-27> The combined preparation for use according to <1-25> or <1-26>, wherein the peripheral neuropathy is peripheral neuropathy pain.

[0252] <1-28> The combined preparation for use according to <1-27>, wherein the peripheral neuropathy pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling.

[0253] <1-29> The combined preparation for use according to <1-25> or <1-26>, wherein the peripheral nerve disorder is a sensory disorder caused by the peripheral nerve disorder.

[0254] <1-30> The combined preparation for use according to <1-29>, wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0255] <1-31> The combined preparation for use according to <1-30>, wherein the hyperesthesia is allodynia, and the paresthesia is paresthesia or sensory perversion.

[0256] <1-32> The combined preparation for use according to <1-25> or <1-26>, wherein the peripheral nerve disorder is an autonomic nervous system disorder caused by the peripheral nerve disorder.

[0257] <1-33> The combined preparation for use according to <1-32>, wherein the symptom caused by autonomic nervous system disorder is urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0258] <1-34> The combined preparation for use according to any one of <1-25> to <1-33>, wherein the peripheral neuropathy is a peripheral neuropathy with symptoms appearing in the limbs.

[0259] <1-35> The combined preparation for use according to any one of <1-25> to <1-34>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0260] <1-36> The combined preparation for use according to any one of <1-25> to <1-35>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

[0261] <1-37> The combined preparation for use according to any one of <1-25> to <1-36>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0262] <1-38> The combined preparation for use according to any one of <1-25> to <1-37>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0263] <1-39> The combined preparation for use according to any one of <1-25> to <1-34>, wherein the alkalizing agent is sodium bicarbonate.

[0264] <1-40> The combined preparation for use according to any one of <1-25> to <1-39>, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug.

[0265] <1-41> The combined preparation for use according to <1-40>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine.

[0266] <1-42> The combination preparation for the use according to <1-40>, wherein the molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebacterinib, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemtansine.

[0267] <1-43> The combined preparation for use according to <1-40>, wherein the immunotherapeutic drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0268] <1-44> The combined preparation for use according to <1-40>, wherein the other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0269] <1-45> The combined preparation for use according to any one of <1-25> to <1-39>, wherein the cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin, and bortezomib.

[0270] <1-46> The combined preparation for use according to <1-45>, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

[0271] <1-47> An anticancer pharmaceutical composition for use in treating cancer to suppress the expression of peripheral nerve dysfunction, comprising an alkalizing agent and a cancer chemotherapeutic drug.

[0272] <1-48> The anticancer pharmaceutical composition for use according to <1-47>, wherein the peripheral nerve disorder is pain, sensory impairment, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0273] <1-49> The anticancer pharmaceutical composition according to <1-47> or <1-48>, wherein the peripheral neuropathy is peripheral neuropathy pain.

[0274] <1-50> The anticancer pharmaceutical composition according to <1-49>, wherein the peripheral neuropathy pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling.

[0275] <1-51> The anticancer pharmaceutical composition for use according to <1-47> or <1-48>, wherein the peripheral nerve disorder is a sensory disorder caused by the peripheral nerve disorder.

[0276] <1-52> The anticancer pharmaceutical composition for use according to <1-51>, wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0277] <1-53> The anticancer pharmaceutical composition for use according to <1-52>, wherein the hyperesthesia is allodynia, and the paresthesia is paresthesia or sensory perversion.

[0278] <1-54> The anticancer pharmaceutical composition for use according to <1-47> or <1-48>, wherein the peripheral nerve disorder is an autonomic nervous system disorder caused by the peripheral nerve disorder.

[0279] <1-55> The anticancer pharmaceutical composition for use according to <1-54>, wherein the symptom caused by autonomic nervous system disorder is urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0280] <1-56> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-55>, wherein the peripheral neuropathy is a peripheral neuropathy with symptoms appearing in the limbs.

[0281] <1-57> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-56>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0282] <1-58> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-57>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

[0283] <1-59> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-58>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0284] <1-60> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-59>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0285] <1-61> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-56>, wherein the alkalizing agent is sodium bicarbonate.

[0286] <1-62> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-61>, wherein the cancer chemotherapeutic drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug.

[0287] <1-63> The anticancer pharmaceutical composition for use according to <1-62>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine.

[0288] <1-64> The anticancer pharmaceutical composition for the use according to <1-62>, wherein the molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, velutegravir, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemigatinib.

[0289] <1-65> The anticancer pharmaceutical composition for use according to <1-62>, wherein the immunotherapeutic drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0290] <1-66> The anticancer pharmaceutical composition for use according to <1-62>, wherein the other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0291] <1-67> The anticancer pharmaceutical composition for use according to any one of <1-47> to <1-61>, wherein the cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin, and bortezomib.

[0292] <1-68> The anticancer pharmaceutical composition according to <1-67>, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

[0293] <1-69> A pharmaceutical kit for use in treating cancer by suppressing expression of peripheral nerve disorders,

[0294] The drug kit contains an alkalizing agent in the first compartment and a cancer chemotherapy drug in the second compartment.

[0295] <1-70> The pharmaceutical kit for use according to <1-69>, wherein the peripheral nerve disorder is pain, sensory disorder, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0296] <1-71> The pharmaceutical kit for use according to <1-69> or <1-70>, wherein the peripheral neuropathy is peripheral neuropathy pain.

[0297] <1-72> The pharmaceutical kit for use according to <1-71>, wherein the peripheral neuropathy pain is shooting pain, burning pain, pain (excluding shooting pain and burning pain), or tingling.

[0298] <1-73> The pharmaceutical kit for use according to <1-69> or <1-70>, wherein the peripheral nerve disorder is a sensory disorder caused by the peripheral nerve disorder.

[0299] <1-74> The pharmaceutical kit for use according to <1-73>, wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0300] <1-75> The pharmaceutical kit for use according to <1-74>, wherein the hyperesthesia is allodynia, and the paresthesia is dysesthesia or paresthesia.

[0301] <1-76> The pharmaceutical kit for use according to <1-69> or <1-70>, wherein the peripheral nerve disorder is an autonomic nervous system disorder caused by the peripheral nerve disorder.

[0302] <1-77> The pharmaceutical kit for use according to <1-76>, wherein the symptom caused by autonomic nervous system disorder is urination disorder, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0303] <1-78> The pharmaceutical kit for use according to any one of <1-69> to <1-77>, wherein the peripheral neuropathy is a peripheral neuropathy with symptoms appearing in the limbs.

[0304] <1-79> The pharmaceutical kit for use according to any one of <1-69> to <1-78>, wherein the alkalizing agent is a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0305] <1-80> The pharmaceutical kit for use according to any one of <1-69> to <1-79>, wherein the alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof, or a mixture thereof.

[0306] <1-81> The pharmaceutical kit for use according to any one of <1-69> to <1-80>, wherein the alkalizing agent comprises a mixture of sodium citrate or a hydrate thereof and potassium citrate or a hydrate thereof.

[0307] <1-82> The pharmaceutical kit for use according to any one of <1-69> to <1-81>, wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0308] <1-83> The pharmaceutical kit for use according to any one of <1-69> to <1-78>, wherein the alkalizing agent is sodium bicarbonate.

[0309] <1-84> The pharmaceutical kit for use according to any one of <1-69> to <1-83>, wherein the cancer chemotherapy drug is a cytotoxic anticancer drug, a molecularly targeted anticancer drug, an immunotherapeutic drug, or other anticancer drug.

[0310] <1-85> The pharmaceutical kit for use according to <1-84>, wherein the cytotoxic anticancer drug is at least one anticancer drug selected from paclitaxel, docetaxel, cabazitaxel, vinorelbine, vincristine, vinblastine, vindesine, eribulin, oxaliplatin, carboplatin, cisplatin, and nelarabine.

[0311] <1-86> A drug kit for use according to <1-84>, wherein the molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebacterinib, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemtansine.

[0312] <1-87> The pharmaceutical kit for use according to <1-84>, wherein the immunotherapy drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

[0313] <1-88> The pharmaceutical kit for use according to <1-84>, wherein the other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide, and pomalidomide.

[0314] <1-89> The pharmaceutical kit for use according to any one of <1-69> to <1-83>, wherein the cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin, and bortezomib.

[0315] <1-90> The pharmaceutical kit for use according to <1-89>, wherein the cancer chemotherapy drug is paclitaxel or oxaliplatin.

[0316] <2-1> A method for treating or preventing a peripheral nervous system disorder induced by a chemotherapeutic drug, comprising administering an effective amount of an alkalinizing agent to a subject in need of treatment or prevention of a peripheral nervous system disorder induced by a chemotherapeutic drug.

[0317] <2-2> A method for treating cancer by suppressing the expression of peripheral nerve dysfunction, comprising administering effective amounts of an alkalinizing agent and a cancer chemotherapeutic drug simultaneously, separately, or sequentially to a subject in need of cancer treatment.

[0318] <3-1> Use of an alkalizing agent for producing a pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs.

[0319] <3-2> Use of an alkalizing agent and a cancer chemotherapy drug for the manufacture of a combined preparation for simultaneous, separate or sequential administration in the treatment of cancer,

[0320] The above-mentioned combination preparation is a combination preparation that suppresses the expression of peripheral nerve disorders.

[0321] <3-3> Use of an alkalizing agent and a cancer chemotherapy drug for producing an anticancer pharmaceutical composition that suppresses the expression of peripheral nerve dysfunction.

[0322] <3-4> Use of an alkalinizing agent and a cancer chemotherapy drug for producing an anticancer drug kit for suppressing the expression of peripheral nerve disorders, the drug kit comprising an alkalinizing agent in a first compartment and a cancer chemotherapy drug in a second compartment.

[0323] 4. Food composition

[0324] In one embodiment, the present invention can provide an alkalizing agent or a food composition containing the alkalizing agent for non-therapeutic use to suppress peripheral nerve disorders induced by chemotherapeutic drugs.

[0325] Alkalizing agents described in "1. Pharmaceutical compositions" above can be used. Examples of alkalizing agents include food-acceptable salts of citric acid, i.e., pharmaceutically acceptable salts of citric acid (e.g., alkali metal citrate or its hydrate, or a mixture thereof), or sodium bicarbonate, preferably a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), or sodium citrate dihydrate.

[0326] The content of citric acid, pharmaceutically acceptable salts of citric acid, or hydrates thereof or mixtures thereof in the food composition provided by the present invention; or sodium bicarbonate can be appropriately determined according to the type of food. Examples of food compositions include specific health foods, functionally labeled foods, foods for hospital patients, and nutritional supplements. The form of these food compositions is not particularly limited as long as it contains an effective amount of an alkalizing agent for achieving the above-mentioned effects and can be orally ingested. It can be in the form of a common food or beverage, or can be provided as a preparation suitable for oral administration in the preparation of the above-mentioned pharmaceutical composition, such as tablets, capsules, suspensions, and the like. For the composition and manufacturing method of these preparations, in addition to directly adopting the composition and manufacturing method of the pharmaceutical preparations described in the above-mentioned "1. Pharmaceutical Compositions" in this specification, it is also possible to adopt the formulation technology that is well known in the field of pharmaceutical formulation technology itself.

[0327] For example, in the case of a food for specified health use, a food with a functional label, a food for hospital patients, or a nutritional supplement, one serving of the food may contain one-third of a total of 1 to 3 g of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients. In the case of a food for specified health use, a food with a functional label, a food for hospital patients, or a nutritional supplement provided in tablet form, for example, each 300 mg to 600 mg tablet may contain 70 to 80% by weight of citric acid, a pharmaceutically acceptable salt of citric acid, a hydrate thereof, or a mixture thereof.

[0328] When the food composition provided by the present invention is provided in the form of a common food and beverage without formulation, it can be appropriately manufactured by those skilled in the art according to the type of the food. For example, it can be manufactured by adding citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof (such as potassium citrate and / or sodium citrate) or sodium bicarbonate to the food material.

[0329] Examples of the food and beverages include liquid, emulsified, or pasty foods such as beverages, soy sauce, milk, yogurt, and miso; semisolid foods such as jelly and soft candy; solid foods such as malt sugar, chewing gum, tofu, and nutritional supplements; and powdered foods.

[0330] Examples of beverages include fruit juice / fruit drinks, coffee drinks, oolong tea drinks, green tea drinks, black tea drinks, barley tea drinks, vegetable drinks, carbonated soft drinks, drinks containing fruit extracts, fruit juice containing vegetable extracts, flavored sodas, sports drinks, and diet drinks.

[0331] Beverages may contain additives such as antioxidants, flavorings, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, flavorings, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers, either alone or in combination.

[0332] The food composition provided by the present invention can be used in the same manner as the method of use of the pharmaceutical composition described in the above-mentioned "1. Pharmaceutical composition", and can also be used in a range not for the purpose of treating or preventing a disease (also referred to as non-therapeutic use). That is, when the alkalizer contained in the food composition involved in the present invention is used as a benchmark, the amount of the alkalizer used in the food composition is equal to the amount of the alkalizer contained in the above-mentioned pharmaceutical composition. In addition, in one embodiment, the "food composition" involved in the present invention can be taken by an object (such as a human or other mammal) who has received or is to receive a chemotherapy drug in the future in order to suppress the expression of a peripheral nerve disorder or suppress an already expressed peripheral nerve disorder in the range of non-therapeutic use. In this case, the above-mentioned alkalizer can be a component of the pharmaceutical composition, or it can be a component of the food composition. The pharmacological effects of the above-mentioned alkalizer itself are basically the same, so the amount and method of use of the above-mentioned food composition can be appropriately adjusted based on the above-mentioned alkalizer according to the expected effect.

[0333] Food compositions that are used by subjects (such as humans or other mammals) who do not have "pathological" or "abnormal" symptoms, conditions or diseases, that is, subjects (such as humans or other mammals) who are in a "healthy" or "normal" state in order to maintain or promote a "healthy" or "normal" state are sometimes specifically referred to as "functionally labeled foods".

[0334] The term "administer" described in "1. Pharmaceutical Composition" above can also be applied to the "food composition" of the present invention, and the term "administer" in the "food composition" of the present invention can be replaced with "ingestion." Therefore, for example, the terms "administer" or "administered" can be replaced with "caused to be ingested," "ingestion," or "ingested" depending on the context.

[0335] The present invention is further described below with reference to examples, but the present invention is not limited thereto.

[0336] Example

[0337] Example 1: Evaluation of Alkalizing Agents in Oxaliplatin-Induced Neuropathic Pain Model in Mice

[0338] (Test substance)

[0339] The drug used as the alkalizing agent is a mixture (Uralyt U powder, manufactured by Nippon Chemiphar Co., Ltd., Japan) containing 463 mg of potassium citrate monohydrate (C6H5K3O7·H2O), 390 mg of sodium citrate dihydrate (C6H5Na3O7·2H2O), and 147 mg of a pharmaceutically acceptable additive per 1 g of dry weight. The required amount of Uralyt U powder (hereinafter referred to as "Uralyt") is weighed and dissolved in water for injection to achieve the target concentration. The preparation is then prepared at the time of use.

[0340] The placebo group (Sham group) and the control group used the solvent of the alkalizing agent, namely water for injection.

[0341] (animal)

[0342] Six-week-old male C57BL / 6J mice (Japan SLC) were used. After an acclimatization period of approximately one week, only healthy animals were used in the experiment.

[0343] (Preparation of experimental animals)

[0344] Experimental animals: Oxaliplatin (hereinafter also referred to as OXP)-induced peripheral nerve disorder model mice were prepared by the following method.

[0345] The pain scores were evaluated the day before the start of the study (the day before the test substance was administered). Specifically, the pain scores were averaged and assigned to each group. The groups consisted of: Group 1: Placebo group (Sham group), Group 2: Control group, and Group 3: Alkalizer group.

[0346] From the day after grouping until 17 days later, the placebo group (Sham group) and the control group were orally administered water for injection twice daily (compulsory oral administration), while the alkalinizer group was orally administered 1 g / kg of Uralyt twice daily (compulsory oral administration). The final dose was administered once daily, with a 16.5-day dose administered over 17 days.

[0347] Experimental animals were prepared by administering a single intraperitoneal dose of OXP (3 mg / kg) on ​​day 3 after administration of water for injection or Uralyt. The required amount of OXP was weighed and dissolved in glucose injection (5%, Otsuka Pharmaceutical Co., Ltd.) to a concentration of 0.3 mg / mL. The solution was then prepared immediately prior to use. The placebo group (Sham group) was administered glucose injection (5%) as its dosing vehicle instead of OXP.

[0348] (Measurement time)

[0349] Pain assessment was performed over time after OXP administration. Mechanical allodynia and cold paresthesia were evaluated. Pain assessment was performed 2 hours after administration of water for injection or Uralyt on days 0, 1, 3, 6, 8, 10, and 14, starting from day 0, the start of OXP administration. Pain assessment was performed one day before the start of Uralyt administration and was designated as the Pre value.

[0350] (Pain Assessment)

[0351] Pain assessment was performed after the rats were moved to an individual cage with a mesh bottom (W110×D180×H150 mm) for pain score measurement and waited for 30 minutes until they adapted to the new environment.

[0352] Thereafter, when mechanical allodynia was evaluated, the sole of the hind paw was stimulated with von Frey hair (0.69 mN), and the responsiveness to the stimulation was scored.

[0353] When evaluating cold paresthesia (OXP model only), acetone was applied to the skin of the plantar surface of the hind paw, and the aversion reaction after acetone stimulation was scored.

[0354] (Rating Method)

[0355] (1) Mechanical allodynia

[0356] Press a von Frey hair vertically against the center of the sole of the hind paw, holding it in a slightly curved position for 1 to 3 seconds. Apply the same intensity of stimulation three times alternately to each hind paw at intervals of several seconds, and the average of the six times is used as the score (maximum score is 2).

[0357] 0: No reaction or hind paw sideways behavior

[0358] 1: Lifting

[0359] 2: Flinching or licking of the irritated area

[0360] (2) Poor cold sensation

[0361] Acetone was applied to the skin of the hind paw sole, and the reaction immediately after application (not evaluated) and the subsequent reaction of the hind paw were observed for 10 seconds. Acetone was applied alternately to each hind paw three times at intervals of 20 seconds or more, and the average of the total of 6 times was used as the score (maximum score was 2).

[0362] 0: No reaction or hind paw sideways behavior

[0363] 1: Lifting

[0364] 2: Flinching or licking of the irritated area

[0365] (result)

[0366] In OXP-induced peripheral nerve disorder model mice, the onset of cold paresthesia peaked on the 3rd day and mechanical allodynia peaked on the 10th day ( Figure 1 ).

[0367] Repeated administration of Uralyt U combined with powder to OXP-induced peripheral nerve disorder model mice suppressed the onset of mechanical allodynia and cold allodynia ( Figure 2 ).

[0368] In conclusion, it is believed that repeated oral administration of Uralyt U combined with powder is very effective for OXP-induced peripheral nerve disorders.

[0369] Example 2: Evaluation of Alkalizing Agents in Paclitaxel-Induced Neuropathic Pain Model in Mice

[0370] (Test substance)

[0371] The same test substances as in Example 1 were used.

[0372] (animal)

[0373] The same animals as in 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 used in the experiment.

[0374] (Preparation of experimental animals)

[0375] Experimental animals: paclitaxel-induced peripheral neuropathy model mice were prepared by intraperitoneal administration of 5 mg / kg PTX in the same manner as in Example 1, except that the peripheral neuropathy-inducing chemotherapeutic agent in Example 1 was changed to paclitaxel (hereinafter also referred to as PTX) and pain evaluation was continued until the 18th day after PTX administration.

[0376] After weighing the required amount of PTX, the following administration medium was added to dissolve it at a concentration of 0.5 mg / mL and prepared at the time of use.

[0377] The administration medium used was prepared before use by adding Kolliphor and ethanol to physiological saline solution to make each 10% (v / v).

[0378] (Measurement time)

[0379] Pain assessment was performed over time after PTX administration. Pain assessment evaluated mechanical allodynia. Starting from the start day of PTX administration as Day 0, pain assessment was performed 2 hours after administration of water for injection or Uralyt on Days 0, 1, 3, 5, 7, 10, 12, 14, and 18. Pain assessment was performed the day before the start of Uralyt administration and this value was designated as the Pre value.

[0380] (Pain Assessment)

[0381] Pain evaluation was performed by the same method as in Example 1.

[0382] (result)

[0383] In PTX-induced peripheral nerve disorder model mice, the onset of mechanical allodynia, which peaked on the 14th day, was confirmed ( Figure 3 ).

[0384] Repeated administration of Uralyt to PTX-induced peripheral nerve disorder model mice suppressed the onset of mechanical allodynia ( Figure 4 ).

[0385] In conclusion, repeated oral administration of Uralyt is considered to be very effective against PTX-induced peripheral nerve disorders.

[0386] Example 3: Evaluation of Alkalizing Agents in Bortezomib-Induced Mouse Neuropathic Pain Model (Test Substances)

[0387] The same test substances as in Example 1 were used.

[0388] (animal)

[0389] The same animals as in 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 used in the experiment.

[0390] (Preparation of experimental animals)

[0391] Experimental animals: bortezomib-induced peripheral neuropathy model mice were prepared by intravenously administering 0.3 mg / kg of BTZ as a single dose in the same manner as in Example 1, except that the peripheral neuropathy-inducing chemotherapeutic agent in Example 1 was changed to bortezomib (hereinafter also referred to as BTZ) and pain evaluation was continued until the 15th day after BTZ administration.

[0392] After weighing the required amount of BTZ, it was dissolved in physiological saline to a concentration of 0.6 mg / mL and prepared before use.

[0393] (Measurement time)

[0394] Pain assessment was performed over time after BTZ administration. Pain assessment evaluated mechanical allodynia. Starting from the start day of BTZ administration as Day 0, pain assessment was performed 2 hours after administration of water for injection or Uralyt on Days 0, 3, 6, 9, 12, and 15. Pain assessment was performed one day before the start of Uralyt administration and this value was designated as the Pre value.

[0395] (Pain Assessment)

[0396] Pain evaluation was performed by the same method as in Example 1.

[0397] (result)

[0398] In BTZ-induced peripheral nerve disorder model mice, the onset of mechanical allodynia, which peaked on the 12th day, was confirmed ( Figure 5 ).

[0399] Repeated administration of Uralyt to BTZ-induced peripheral nerve disorder model mice inhibited the onset of mechanical allodynia ( Figure 6 ).

[0400] In conclusion, repeated oral administration of Uralyt is considered to be very effective against BTZ-induced peripheral nerve disorders.

[0401] Example 4: Evaluation of Alkalizing Agents in Vincristine-Induced Mouse Neuropathic Pain Model (Test Substances)

[0402] The same test substances as in Example 1 were used.

[0403] (animal)

[0404] The same animals as in 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 used in the experiment.

[0405] (Preparation of experimental animals)

[0406] Experimental animals, vincristine-induced peripheral neuropathy model mice, were prepared by intraperitoneally administering 0.1 mg / kg of VCN as a single dose in the same manner as in Example 1, except that the peripheral neuropathy-inducing chemotherapeutic agent in Example 1 was changed to vincristine (hereinafter also referred to as VCN), and pain evaluation was performed until the 18th day after VCN administration.

[0407] After weighing the required amount of VCN, physiological saline solution was added to dissolve it at a concentration of 0.01 mg / mL and the solution was prepared before use.

[0408] (Measurement time)

[0409] Pain assessment was performed over time after VCN administration. Pain assessment evaluated mechanical allodynia. Starting from Day 0, the start day of VCN administration, pain assessment was performed 2 hours after administration of water for injection or Uralyt on Days 0, 3, 7, 10, 14, and 18. Pain assessment was performed one day before the start of Uralyt administration and this value was designated as the Pre value.

[0410] (Pain Assessment)

[0411] Pain evaluation was performed by the same method as in Example 1.

[0412] (result)

[0413] In VCN-induced peripheral nerve disorder model mice, the onset of mechanical allodynia, which peaked on the 14th day, was confirmed ( Figure 7 ).

[0414] Repeated administration of Uralyt to VCN-induced peripheral nerve disorder model mice suppressed the onset of mechanical allodynia ( Figure 8 ).

[0415] In conclusion, repeated oral administration of Uralyt is considered to be very effective in treating VCN-induced peripheral nerve disorders.

[0416] Example 5: Evaluation of Alkalizing Agents in Paclitaxel-Induced Neuropathic Pain Model in Rats

[0417] (Test substance)

[0418] The same test substances as in Example 1 were used.

[0419] (animal)

[0420] Seven-week-old male SD rats (Jackson Laboratory Japan) were used. After an acclimatization period of approximately one week, only healthy animals were used in the experiment.

[0421] (Preparation of experimental animals)

[0422] Experimental animals were prepared by the following method: PTX-induced peripheral nerve disorder model rats.

[0423] The 50% paw withdrawal threshold (50% paw withdrawal threshold) assessed the day before the start of the experiment (the day before test substance administration) was used as a benchmark. Specifically, the subjects were assigned to groups based on the average of their 50% paw withdrawal threshold and body weight. The groups consisted of: Group 1: Placebo Group (Sham Group), Group 2: Control Group, and Group 3: Alkalizer Group.

[0424] From the day after grouping until 24 days later, the placebo group (Sham group) and the control group were orally administered water for injection twice daily (compulsory oral administration), while the alkalinizer group was orally administered 1 g / kg of Uralyt twice daily (compulsory oral administration). The final dose was administered once daily, with a 23.5-day dose administered over 24 days.

[0425] Experimental animals were prepared by intraperitoneally administering 2 mg / kg of PTX four times every other day starting on the third day after administration of water for injection or Uralyt (on days 3, 5, 7, and 9 from the start of water for injection or Uralyt administration). PTX was prepared by adding 30 mg of TAXOL injection (Taxol paclitaxel injection) to physiological saline to a concentration of 2 mg / mL.

[0426] In addition, the placebo group (Sham group) was administered with physiological saline solution instead of PTX.

[0427] (Measurement time)

[0428] Pain assessment was performed over time after PTX administration. Pain assessment evaluated mechanical allodynia. The starting day of PTX administration was set as Day 0 and was performed 3 hours after administration of water for injection or Uralyt on Days 7, 14, and 21. It should be noted that pain assessment was performed the day before Uralyt administration began (Day-3) and this was designated as the Pre value.

[0429] (Pain Assessment)

[0430] Pain assessment was performed by vertically pressing von Frey filaments on the center of the plantar surface of the rat's left hind paw, observing the withdrawal response, and calculating the 50% withdrawal threshold according to the Up-Down method of Chaplan et al. (J. Neurosci. Methods. 1994; 53: 55-63).

[0431] (result)

[0432] In PTX-induced peripheral nerve disorder model rats, the onset of mechanical allodynia, which peaked on the 21st day, was confirmed ( Figure 9 ).

[0433] Repeated administration of Uralyt to PTX-induced peripheral nerve disorder model rats inhibited the onset of mechanical allodynia ( Figure 9 ).

[0434] In conclusion, it is believed that repeated oral administration of Uralyt is very effective for peripheral nerve disorders induced by repeated administration of PTX.

[0435] Example 6: Evaluation of Alkalizing Agents in Paclitaxel-Induced Neuropathic Pain Model in Mice

[0436] This example examined the effects of administration of an alkalinizing agent on the spontaneous discharge and mechanical stimulation-induced discharge of dorsal horn neurons in a paclitaxel-induced neuropathic pain model.

[0437] (Test substance)

[0438] The same test substances as in Example 1 were used.

[0439] (animal)

[0440] The same animals as in 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 used in the experiment.

[0441] (Preparation of experimental animals)

[0442] Experimental animals: paclitaxel-induced peripheral neuropathy model mice were prepared by intraperitoneal administration of 5 mg / kg PTX in the same manner as in Example 1, except that the chemotherapeutic agent inducing peripheral neuropathy was paclitaxel and pain evaluation was performed until day 14 after PTX administration.

[0443] After weighing the required amount of PTX, the following administration medium was added to dissolve it at a concentration of 0.5 mg / mL and prepared at the time of use.

[0444] The administration medium used was prepared before use by adding Kolliphor and ethanol to physiological saline solution to make each 10% (v / v).

[0445] (evaluate)

[0446] (1) Pain evaluation of mechanical allodynia

[0447] (Measurement time)

[0448] 3 days before and 13 days after PTX administration.

[0449] (Pain Assessment)

[0450] Pain evaluation regarding mechanical allodynia was performed by the same method as in Example 1.

[0451] (Rating Method)

[0452] Scoring was performed by the same method as in Example 1.

[0453] (result)

[0454] In PTX-induced peripheral nerve disorder model mice, the onset of mechanical allodynia was confirmed on day 13, but repeated administration of Uralyt suppressed the onset of mechanical allodynia ( Figure 10 ).

[0455] (2) Electrophysiological analysis

[0456] (Preparation of Animals for Electrophysiological Experiments)

[0457] For experimental animals 14 days after the administration of PTX, mice were deeply anesthetized with urethane (1.2-1.5 g / kg, ip), and after laminectomy of the thoracic and lumbar spine, they were placed in a brain positioning and fixation device. Under a stereomicroscope, the dura mater, arachnoid mater, and pia mater were peeled off in sequence to expose the dorsal roots to ensure space for electrode insertion. Subsequently, Krebs solution saturated with 95% oxygen and 5% carbon dioxide and heated to 37°C was perfused into the surface of the spinal cord at a rate of 10-15 mL / min. Next, a tungsten electrode (FHC) was inserted into the surface layer of the posterior horn of the spinal cord at the L4-L5 input site (10-150 μm (Laminae I-II)) and recorded.

[0458] (Measurement time)

[0459] The electrophysiological experiment animals prepared above were measured at two time points: before and after stimulation with von Frey hairs.

[0460] (Electrophysiological evaluation)

[0461] The signal obtained from the measurement result was amplified with EX1 (Dagan corporation), converted into digital data using 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.). The discharge was recorded without applying stimulation to the mouse, and the frequency of occurrence per unit time was evaluated as spontaneous discharge. Subsequently, a single neuron was identified with a paintbrush and hooked tweezers, and the receptive field was identified. A 0.69 mN von Frey fiber (vFF) was pressed against the area for 5 seconds, and the resulting discharge was recorded as a mechanical stimulation-induced discharge to evaluate the frequency of occurrence per unit time.

[0462] (result)

[0463] Repeated administration of Uralyt suppressed both the increase in spontaneous discharge frequency and vFF-induced discharge frequency in the dorsal horn of the spinal cord in PTX-induced peripheral nerve disorder model mice ( Figure 11 and Figure 12 ).

[0464] In conclusion, repeated oral administration of Uralyt is considered to be very effective against PTX-induced peripheral nerve disorders.

[0465] Example 7: Evaluation of Alkalizing Agents in Oxaliplatin-Induced Neuropathic Pain Model in Mice

[0466] (Test substance)

[0467] The test substance used in Example 1 and sodium bicarbonate (also referred to herein as baking soda, manufactured by Tokyo Chemical Industry Co., Ltd., purity: 99.0% or greater) were used as the alkalizing agent. The required amount of sodium bicarbonate was weighed and dissolved in water for injection to achieve the target concentration. The solution was prepared immediately before use.

[0468] The placebo group (Sham group) and the control group used the solvent of the alkalizing agent, namely water for injection.

[0469] (animal)

[0470] The same animals as in 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 used in the experiment.

[0471] (Preparation of experimental animals)

[0472] Experimental animals were prepared by the following method: Oxaliplatin-induced peripheral nerve disorder model mice.

[0473] The pain scores assessed the day before the start of the study (the day before test substance administration) were used as a benchmark. Specifically, the pain scores were averaged and assigned to each group. The groups consisted of four groups: Group 1: Placebo (Sham), Group 2: Control, Group 3: Alkalizer (Uralyt), and Group 4: Alkalizer (Sodium Bicarbonate).

[0474] From the day after grouping to 13 days, the placebo group (Sham group) and the control group were orally administered (compulsory oral administration) water for injection twice a day, the alkalinizer (Uralyt) group was orally administered (compulsory oral administration) 1 g / kg of Uralyt twice a day, and the alkalinizer (sodium bicarbonate) group was orally administered (compulsory oral administration) 0.75 g / kg of sodium bicarbonate twice a day. The final dose was administered once a day, with a 12.5-day dose administered over 13 days.

[0475] Experimental animals were prepared by administering OXP (3 mg / kg) intraperitoneally once on day 3 following administration of water for injection, Uralyt, or sodium bicarbonate. The required amount of OXP was weighed and dissolved in glucose injection (5%, Otsuka Pharmaceutical Co., Ltd.) to a concentration of 0.3 mg / mL. The mixture was prepared immediately prior to use.

[0476] In addition, the placebo group (Sham group) was administered with glucose injection (5%) as its administration vehicle instead of OXP.

[0477] (Measurement time)

[0478] Pain assessment was performed over time after OXP administration. Pain assessment evaluated mechanical allodynia. Starting from Day 0, the start day of OXP administration, pain assessment was 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 one day before the start of alkalizing agent administration, and this value was designated as the Pre value.

[0479] (Pain Assessment)

[0480] The same method as in Example 1 was used to evaluate mechanical allodynia.

[0481] (result)

[0482] In OXP-induced peripheral nerve disorder model mice, the onset of mechanical allodynia, which peaked on the 10th day, was confirmed ( Figure 13 ).

[0483] Repeated administration of Uralyt U combined with powder to OXP-induced peripheral nerve disorder model mice suppressed the onset of mechanical allodynia ( Figure 14 ).

[0484] Although repeated administration of sodium bicarbonate to OXP-induced peripheral nerve disorder model mice also suppressed the onset of mechanical allodynia, the effect was smaller than that of the Uralyt-administered group ( Figure 14 ).

[0485] In conclusion, it is believed that repeated oral administration of alkalinizing agents (particularly Uralyt) is very effective against OXP-induced peripheral nerve disorders.

[0486] Example 8: Evaluation of Alkalizing Agents in Paclitaxel-Induced Neuropathic Pain Model in Mice

[0487] (Test substance)

[0488] The test substance used in Example 1 and sodium bicarbonate (also referred to herein as baking soda, manufactured by Tokyo Chemical Industry Co., Ltd., purity: 99.0% or greater) were used as the alkalizing agent. The required amount of sodium bicarbonate was weighed and dissolved in water for injection to achieve the target concentration. The solution was prepared immediately before use.

[0489] The placebo group (Sham group) and the control group used the solvent of the alkalizing agent, namely water for injection.

[0490] (animal)

[0491] The same animals as in 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 used in the experiment.

[0492] (Preparation of experimental animals)

[0493] Experimental animals were prepared by the following method: Paclitaxel-induced peripheral nerve disorder model mice.

[0494] The pain scores assessed the day before the start of the study (the day before test substance administration) were used as a benchmark. Specifically, the pain scores were averaged and assigned to each group. The groups consisted of four groups: Group 1: Placebo (Sham), Group 2: Control, Group 3: Alkalizer (Uralyt), and Group 4: Alkalizer (Sodium Bicarbonate).

[0495] From the day after grouping until 17 days later, the placebo group (Sham group) and the control group were orally administered (compulsory oral administration) water for injection twice a day. The alkalinizer (Uralyt) group was orally administered (compulsory oral administration) 1 g / kg of Uralyt twice a day, and the alkalinizer (sodium bicarbonate) group was orally administered (compulsory oral administration) 0.75 g / kg of sodium bicarbonate twice a day. The final dose was administered once a day, with a 16.5-day dose administered over 17 days.

[0496] On the third day after the administration of water for injection, Uralyt, or sodium bicarbonate, a single intraperitoneal administration of PTX 5 mg / kg was performed to prepare paclitaxel-induced peripheral nerve disorder model mice.

[0497] After weighing the required amount of PTX, the following administration medium was added to dissolve it at a concentration of 0.5 mg / mL and prepared at the time of use.

[0498] The administration medium was prepared before use by adding Kolliphor and ethanol to physiological saline solution to make 10% (v / v), respectively.

[0499] (Measurement time)

[0500] Pain assessment was performed over time after PTX administration. Pain assessment evaluated mechanical allodynia. Starting from the start day of PTX administration as Day 0, pain assessment was performed 2 hours after administration of water for injection, Uralyt, or sodium bicarbonate on Days 0, 1, 3, 5, 7, 10, 12, and 14. Pain assessment was performed one day before the start of alkalizing agent administration and this value was designated as the Pre value.

[0501] (Pain Assessment)

[0502] The pain evaluation in mechanical allodynia was performed in the same manner as in Example 1.

[0503] (result)

[0504] In PTX-induced peripheral nerve disorder model mice, the onset of mechanical allodynia, which peaked on day 14, was confirmed ( Figure 15 ).

[0505] Repeated administration of Uralyt to PTX-induced peripheral nerve disorder model mice suppressed the onset of mechanical allodynia ( Figure 16 ).

[0506] Repeated administration of sodium bicarbonate to PTX-induced peripheral nerve disorder model mice also inhibited the onset of mechanical allodynia, but the effect was smaller than that of the Uralyt-administered group ( Figure 16 ).

[0507] In conclusion, it is believed that repeated oral administration of alkalizing agents (particularly Uralyt) is very effective against PTX-induced peripheral nerve disorders.

[0508] Industrial applicability

[0509] The pharmaceutical composition, combined preparation and drug kit provided by the present invention can be used to treat or prevent peripheral nerve disorders induced by chemotherapy drugs.

[0510] Furthermore, the pharmaceutical composition, combined preparation, and pharmaceutical kit provided by the present invention can be used to treat cancer by suppressing peripheral nerve disorders induced by chemotherapeutic drugs, particularly cancer chemotherapeutic drugs.

Claims

A pharmaceutical composition for treating or preventing peripheral nerve disorders induced by chemotherapeutic drugs, comprising an alkalizing agent.

2. The pharmaceutical composition according to claim 1, wherein The peripheral nerve disorder induced by chemotherapy drugs is pain, sensory impairment, movement disorder, autonomic nerve disorder or their complications caused by peripheral nerve disorder.

3. The pharmaceutical composition according to claim 1 or 2, wherein Peripheral nerve pain induced by chemotherapy drugs is called peripheral nerve pain.

4. The pharmaceutical composition according to claim 3, wherein Peripheral neuropathic pain is electric pain, burning pain, pain other than electric pain and burning pain, or a tingling sensation.

5. The pharmaceutical composition according to claim 1 or 2, wherein Peripheral nerve disorders induced by chemotherapeutic drugs are sensory disorders caused by peripheral nerve disorders.

6. The pharmaceutical composition according to claim 5, wherein Sensory disturbances caused by peripheral nerve disorders are dysesthesia, hyperesthesia, or paresthesia.

7. The pharmaceutical composition according to claim 6, wherein Hyperesthesia is allergic sensation, and paresthesia is poor sensation or sensory perversion.

8. The pharmaceutical composition according to claim 1 or 2, wherein Peripheral nerve disorder induced by chemotherapy drugs is autonomic nerve disorder caused by peripheral nerve disorder.

9. The pharmaceutical composition according to claim 8, wherein Symptoms caused by autonomic dysfunction include urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein Chemotherapeutic drug-induced peripheral neuropathy refers to a peripheral neuropathy in which symptoms appear in the limbs.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein The alkalizing agent is a pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein The alkalizing agent is sodium citrate, potassium citrate, or a hydrate thereof or a mixture thereof.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein The alkalizing agent comprises a mixture of sodium citrate or its hydrate and potassium citrate or its hydrate.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein The alkalizing agent is sodium citrate or its hydrate.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein The pharmaceutical composition is a tablet.

16. The pharmaceutical composition according to any one of claims 1 to 10, wherein The alkalizing agent is sodium bicarbonate.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein Chemotherapy drugs are chemotherapy drugs for cancer.

18. The pharmaceutical composition according to claim 17, wherein Cancer chemotherapy drugs include cytotoxic anticancer drugs, molecular targeted anticancer drugs, immunotherapy drugs, or other anticancer drugs.

19. The pharmaceutical composition according to claim 18, 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.

20. The pharmaceutical composition according to claim 18, wherein The molecular targeted anticancer drug is at least one anticancer drug selected from bortezomib, ixazomib, romidepsin, gilteritinib, trastuzumab-emtansine conjugate, vebacterinib, obinutuzumab, belintozumab, lorlatinib, entrectinib, connefenib, bimetinib and pemtansine.

21. The pharmaceutical composition according to claim 18, wherein The immunotherapy drug is at least one anticancer drug selected from nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab.

22. The pharmaceutical composition according to claim 18, wherein The other anticancer drug is at least one anticancer drug selected from cytarabine, ifosfamide, nedaplatin, thalidomide, lenalidomide and pomalidomide.

23. The pharmaceutical composition according to claim 17, wherein The cancer chemotherapy drug is at least one anticancer drug selected from paclitaxel, vincristine, oxaliplatin and bortezomib.

24. The pharmaceutical composition according to claim 23, wherein The chemotherapy drugs for cancer are paclitaxel or oxaliplatin.

25. A combined preparation for inhibiting the expression of peripheral nerve disorders, which is administered simultaneously, separately or sequentially in the treatment of cancer. The combined preparation comprises at least two separate preparations of an alkalinizing agent and a chemotherapeutic agent for cancer.

26. An anticancer pharmaceutical composition for suppressing the expression of peripheral nerve disorders, comprising an alkalizing agent and a cancer chemotherapy drug.

27. An anticancer drug kit for suppressing the expression of peripheral nerve disorders, the kit comprising an alkalinizing agent in a first compartment and a cancer chemotherapy drug in a second compartment.

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