Pharmaceutical agent for treating or preventing peripheral nerve disorder

Abstract

The present invention provides a pharmaceutical composition for treating or preventing peripheral nerve disorders, containing an alkalizing agent. The pharmaceutical composition can be used for treating or preventing some lesions, diseases and the like, especially peripheral nerve disorders of diabetes. Also provided are an alkalizing agent or a pharmaceutical composition containing the alkalizing agent for inhibiting the expression of peripheral nerve disorders. Administration of the pharmaceutical composition makes it possible to suppress the occurrence of peripheral nerve disorders.

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 for treating or preventing peripheral nerve disorders comprising an alkalizing agent.

[0002] This application claims priority based on Japanese Patent Application No. 2023-027474, filed in Japan on February 24, 2023, the contents of which are incorporated herein by reference. Background Art

[0003] Peripheral nerve disorders are symptoms caused by dysfunction of peripheral nerve cells, resulting from damage to the cell bodies or axons of peripheral nerve cells, and the surrounding medullary sheath formed by Schwann cells. Peripheral nerve disorders are known to occur due to various causes, including trauma, administration of anticancer drugs, and metabolic diseases such as diabetes. These disorders can lead to sensory abnormalities such as pain, hyperalgesia, hypoesthesia, and paralysis, significantly reducing patients' quality of life (QOL) and causing social harm.

[0004] The pain caused by peripheral nerve disorder is the pain caused by a one-time injury or dysfunction of any part of the peripheral nerve conduction system. The important factor of this nerve damage is mainly trauma or damage to peripheral nerves, nerve plexus or peripheral soft tissue etc. In addition, the pain caused by peripheral nerve disorder is also caused by the damage of central somatosensory pathway (such as the ascending somatosensory pathway of spinal cord, brain stem, thalamus or cortex). The pain caused by peripheral nerve disorder can also be brought out by any one of the treatment of such as neurodegenerative disease, bone degenerative disease, metabolic abnormality disease, cancer, infection, inflammation, after surgical operation, trauma, radiotherapy, anticancer agent etc.

[0005] For example, diabetic peripheral neuropathy is a peripheral neuropathy induced by diabetes, and it is known that peripheral neuropathy such as hyperesthesia and dysesthesia develops as diabetes progresses.

[0006] Diabetic peripheral neuropathy can be categorized into multiple neurological disorders characterized by symptoms such as limb paralysis, pain and temperature sensitivity, and dysesthesia; autonomic disorders, such as abnormal sweating and defecation; and single neurological disorders, characterized by abnormalities in the cranial nerves, such as facial nerve paralysis and extraocular muscle paralysis. Multiple neurological disorders and autonomic disorders are caused by abnormalities in polyol metabolism and are collectively referred to as generalized symmetrical neurological disorders. Single neurological disorders are also caused by vascular occlusion.

[0007] Among them, pain in the limbs in multiple neurological disorders that are considered to be the earliest stage of onset is classified as neuropathic pain, which is believed to be caused by dysfunction or disorder of the peripheral nervous system or the central nervous system itself. The main symptoms are allodynia and hyperalgesia, which are the misinterpretation of contact stimuli as pain.

[0008] In addition, multiple neuropathy is most common in diabetic neuropathy, and symptoms appear in multiple areas of the body. It is caused by sensory nerve and motor nerve disorders. Therefore, in the case of sensory nerve disorders, abnormal sensations (hyperalgesia, insensitivity, numbness (including tingling), coldness, burning sensation, formication (the feeling of crawling insects), etc.) and pain (sciatica, trigeminal neuralgia, intercostal neuralgia or neuralgia of the limbs, etc.) will occur. The pain is manifested as "tingling pain" accompanied by numbness, and often intensifies at night. Symptoms start from the extremities of the hands and feet, just where the socks or gloves cover the part, or dull numbness that feels like thin paper is attached to the soles of the feet (glove / sock type). Then, the symptoms spread from the toes to the knees, from the fingertips to the elbows toward the center of the body. In addition, the above-mentioned pain can also be caused by neuropathic pain. Motor nerve disorders appear later than sensory disorders, and muscle strength decreases and muscles atrophy. Specifically, there may be muscle atrophy and decreased muscle strength in the buttocks and thighs, accompanied by pain.

[0009] Treatment guidelines indicate that tricyclic antidepressants have a more significant analgesic effect than placebo for a wide variety of peripheral and central nervous system pain disorders. However, tricyclic antidepressants have been reported to increase the incidence of falls and sudden cardiac death in elderly patients, and should be used with caution starting at a low dose. Duloxetine is the only drug certified as moderately effective in treatment guidelines (Non-Patent Document 1).

[0010] However, duloxetine has been reported to cause suicidal thoughts and attempts, and to cause side effects such as dizziness, headache, and nausea when its administration is discontinued (especially abruptly), necessitating careful administration (Non-Patent Document 2).

[0011] 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 representative lifestyle diseases. In addition, it is known that by administering an alkalinizing agent, acidic urine tends to be alkaline, which can inhibit the formation of urinary stones. In addition, it is known that by administering an alkalinizing agent to early CKD patients, the progression of renal dysfunction is inhibited and the blood concentration of uremic substances is reduced (Patent Documents 1 and 2). In addition, citric acid preparations are known to inhibit renal fibrosis in diabetic nephropathy (Patent Document 3).

[0012] However, it is not known that alkalizing agents are effective for preventing or treating peripheral nerve disorders.

[0013] Prior art literature

[0014] Patent Literature

[0015] Patent Document 1: International Publication No. 2018 / 193648

[0016] Patent Document 2: International Publication No. 2018 / 193752

[0017] Patent Document 3: International Publication No. 2020 / 080451

[0018] Non-patent literature

[0019] Non-patent Document 1: Guidelines for the Treatment of Neuropathic Pain with Pharmacotherapy (Revised 2nd Edition)

[0020] Non-Patent Document 2: Duloxetine Hydrochloride Capsules Cymbalta Pharmaceutical Information Recording Guide, January 2017 Revision (11th Edition)

[0021] Non-patent document 3: Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL: Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994 Jul; 53(1): 55-63. Summary of the Invention

[0022] An object of the present invention is to provide a pharmaceutical useful for treating or preventing peripheral nerve disorders.

[0023] Another object of the present invention is to provide a pharmaceutical composition comprising an alkalizing agent and suppressing the occurrence of peripheral nerve disorders.

[0024] Another object of the present invention is to provide a method for treating or preventing peripheral nerve disorders induced by certain lesions or diseases.

[0025] Another object of the present invention is to provide a method for treating or preventing peripheral nerve disorders induced by diabetes.

[0026] Another object of the present invention is to provide a method for treating peripheral neuropathy that suppresses the occurrence of peripheral neuropathy.

[0027] 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 the treatment or prevention of peripheral nerve disorders, thereby completing the present invention.

[0028] That is, the present invention has the following aspects.

[0029] (1) A pharmaceutical composition for treating or preventing a peripheral nerve disorder, comprising an alkalizing agent.

[0030] (2) The pharmaceutical composition according to (1), wherein the peripheral nerve disorder is pain, sensory disorder, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0031] (3) The pharmaceutical composition according to (1) or (2), wherein the peripheral neuropathy is peripheral neuropathy pain.

[0032] (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.

[0033] (5) The pharmaceutical composition according to (1) or (2), wherein the peripheral nerve disorder is a sensory disorder caused by peripheral nerve disorder.

[0034] (6) The pharmaceutical composition according to (5), wherein the sensory impairment caused by peripheral nerve disorder is dysesthesia, hyperesthesia, or paresthesia.

[0035] (7) The pharmaceutical composition according to (6), wherein the hyperesthesia is allodynia, and the abnormal sensation is dysesthesia or paresthesia.

[0036] (8) The pharmaceutical composition according to (1) or (2), wherein the peripheral nerve disorder is an autonomic nervous system disorder caused by the peripheral nerve disorder.

[0037] (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.

[0038] (10) The pharmaceutical composition according to any one of (1) to (9), wherein the peripheral neuropathy is a peripheral neuropathy with symptoms appearing in the limbs.

[0039] (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.

[0040] (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.

[0041] (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.

[0042] (14) The pharmaceutical composition according to any one of (1) to (13), wherein the alkalizing agent is sodium citrate or a hydrate thereof.

[0043] (15) The pharmaceutical composition according to any one of (1) to (14), wherein the pharmaceutical composition is a tablet.

[0044] (16) The pharmaceutical composition according to any one of (1) to (10), wherein the alkalizing agent is sodium bicarbonate.

[0045] (17) The pharmaceutical composition according to any one of (1) to (16), wherein the peripheral neuropathy is diabetic peripheral neuropathy.

[0046] The pharmaceutical compositions, combined preparations, and drug kits provided by the present invention can treat or prevent peripheral nerve disorders. Furthermore, the pharmaceutical compositions and drug kits provided by the present invention can achieve the treatment or prevention of peripheral nerve disorders, particularly peripheral nerve disorder pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a graph showing the effect of an alkalizing agent on neuropathic pain in STZ-induced diabetic model rats, and shows the pain score of each test group regarding mechanical allodynia on day 21 from STZ administration. DETAILED DESCRIPTION

[0048] 1. Pharmaceutical compositions

[0049] <Pharmaceutical composition for treating or preventing peripheral nervous system disorders>

[0050] The pharmaceutical composition for treating or preventing peripheral nerve disorders provided by the present invention may contain an alkalizing agent as an active ingredient.

[0051] “Containing an alkalizer as an active ingredient” means that the alkalizer is a main ingredient in the pharmaceutical composition, or that the alkalizer functions as a substantial active ingredient for the treatment or prevention of peripheral nerve disorders and is contained in an effective amount for the treatment or prevention.

[0052] An alkalizing agent refers to an agent that has the ability to increase the HCO3- concentration or pH of a mammalian (particularly human) body fluid, 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.

[0053] Examples of preferred alkalizing agents included in the pharmaceutical composition provided by the present invention 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 set to 0.01 to 100 parts sodium citrate dihydrate per 1 part 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.

[0054] In addition, other examples of the active ingredient contained in the pharmaceutical composition provided by the present invention include sodium citrate or its hydrate, for example, sodium citrate dihydrate (C6H5Na3O7·2H2O).

[0055] 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).

[0056] 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.

[0057] In one embodiment, the alkalizing agent included in the pharmaceutical composition of the present invention can be a mixture of potassium citrate, sodium citrate, 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.

[0058] 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.

[0059] 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.

[0060] 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.

[0061] In one embodiment, the treatment or prevention of a peripheral nerve disorder may be the treatment or prevention of an organic disorder of the peripheral nerves.

[0062] In another embodiment, the treatment or prevention of peripheral nerve disorders may be the treatment or prevention of symptoms caused by peripheral nerve disorders, such as pain, sensory impairment, movement disorder, autonomic nerve disorder, or complications thereof.

[0063] In one embodiment, the "peripheral nerve disorder" may be pain, sensory disorder, movement disorder, autonomic nerve disorder, or complications thereof caused by peripheral nerve disorder.

[0064] In another embodiment, the "peripheral nerve disorder" may be peripheral nerve disorder pain.

[0065] In another embodiment, the "peripheral nerve disorder pain" may be electric pain, burning pain, pain (excluding electric pain and burning pain), or a tingling sensation.

[0066] In one embodiment, the above-mentioned "peripheral nerve disorder" can be a sensory disorder such as insensitivity, hyperesthesia or paresthesia caused by peripheral nerve disorder. 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 dysesthesia 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 can be a pharmaceutical composition for the treatment or prevention of paralysis caused by peripheral nerve disorder.

[0067] In one embodiment, the "peripheral nerve disorder" may be autonomic nerve disorder caused by peripheral nerve disorder. Typical symptoms of autonomic nerve disorder include urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0068] In one embodiment, the aforementioned "peripheral nerve disorder" may manifest symptoms in the limbs of mammals (particularly humans), and particularly in the extremities of the limbs.

[0069] In one embodiment, peripheral nerve disorders can be treated or prevented by administering the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient.

[0070] In one embodiment, the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be administered to treat or prevent pain, sensory impairment, movement impairment, autonomic nervous system impairment, or complications thereof caused by peripheral nerve disorders.

[0071] In this specification, pain caused by peripheral nerve disorder may be referred to as peripheral nerve disorder pain.

[0072] The type and degree of peripheral nerve disorder pain that can be treated or prevented by the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient are not particularly limited. Typically, it can treat or prevent shooting pain, burning pain, pain (excluding shooting pain and burning pain), or pain known as tingling.

[0073] In this specification, sensory disturbances caused by peripheral nerve disorders are concepts including dysesthesia, hyperesthesia, or paresthesia. In addition, the above-mentioned hyperesthesia includes allodynia, and the above-mentioned paresthesia is a concept including dysesthesia and paresthesia. Therefore, by administering a pharmaceutical composition containing an alkalizing agent as an active ingredient provided by the present invention, sensory disturbances such as dysesthesia, hyperesthesia, and paresthesia caused by peripheral nerve disorders can be treated or prevented.

[0074] In one embodiment, the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be administered to treat or prevent symptoms caused by autonomic nervous system disorders, such as dysuria, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0075] In one embodiment, symptoms manifested in the limbs, particularly the extremities, of mammals (particularly humans) can be treated or prevented by administering a pharmaceutical composition comprising an alkalizing agent as an active ingredient.

[0076] In this specification, "treatment" means to eliminate, recover, cure or alleviate "pathological" or "abnormal" symptoms, conditions or diseases, and includes actions or means used to achieve the above purposes, "inhibit" the deterioration of "pathological" or "abnormal" symptoms, conditions or diseases, and includes actions or means used to achieve the above purposes, or includes the concept of "improvement".

[0077] In one embodiment, "treatment" refers to the disappearance, recovery, cure, or alleviation of "pathological" or "abnormal" symptoms, conditions, or diseases, as well as actions or means used to achieve the above-mentioned purposes. In another embodiment, "treatment" refers to the disappearance, recovery, cure, or alleviation of "pathological" or "abnormal" symptoms, conditions, or diseases.

[0078] In this specification, "inhibit" refers to stopping, slowing down, or alleviating the deterioration or progression of a symptom, condition, or disease, and includes the behavior or means used to achieve the above purpose, or improving the above symptom, condition, or disease, or the concept of the behavior or means used to achieve the above purpose. Here, "improve" refers to bringing a "morbid" or "abnormal" symptom, condition, or disease close to a "healthy" or "normal" state, or including the behavior or means used to achieve the above purpose, and reaching a "healthy" or "normal" state, or including the concept of the behavior or means used to achieve the above purpose. Therefore, in one embodiment, "improve" includes the numerical value of an indicator of a "morbid" or "abnormal" symptom or condition becoming smaller or larger as the "improvement" mentioned above approaches a normal value or becomes 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, condition, or disease, or an act or means for achieving the above-mentioned purpose. In another embodiment, "inhibit" refers to stopping, slowing down, or alleviating the worsening or progression of a symptom, condition, or disease.

[0079] In this specification, "healthy" refers to a state without acute or chronic diseases or disorders, and "normal" refers to a state in which a healthy subject behaves normally.

[0080] As used herein, "prevention" refers to the concept of avoiding the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and includes actions or means used to achieve such purposes. Therefore, "suppressing" "pathological" or "abnormal" symptoms, conditions, or diseases without their onset (also referred to as occurrence) also encompasses the concept of "prevention."

[0081] 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.

[0082] Thus, for example, "treatment of peripheral neuropathy pain" refers to the elimination, recovery, cure, or alleviation of peripheral neuropathy pain induced by a certain lesion, disease, or the like, and includes actions or means for achieving such a purpose. Suppression of peripheral neuropathy pain induced by a certain lesion, disease, or the like, and includes actions or means for achieving such a purpose, further encompasses the concept of improving peripheral neuropathy pain induced by a certain lesion, disease, or the like. Alternatively, the concept encompasses the suppression of the aforementioned pain symptoms or conditions by administration of a pharmaceutical composition containing an alkalizing agent as an active ingredient, as compared to placebo administration or a control.

[0083] Furthermore, for example, the term "prevention of peripheral neuropathy pain" refers to the concept of avoiding the onset of peripheral neuropathy pain induced by a certain pathology, disease, etc., and includes actions or means for achieving such a purpose. It also refers to the concept of suppressing the onset of such pain before the onset of such pain, and includes actions or means for achieving such a purpose. Alternatively, if the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient is administered before the onset of peripheral neuropathy pain induced by a certain pathology, disease, etc., and even if such pain develops, the symptoms or state of such pain are suppressed compared to administration of a placebo or a control, such phenomenon may be included in the scope of prevention.

[0084] Regarding the aforementioned "suppressive" effect, in the case of "pain", it can be evaluated based on the "pain score" described later, in comparison with placebo administration or a control.

[0085] By replacing the above-mentioned "pain" with the symptoms or conditions of peripheral nerve disorders already described, the concepts of treatment and prevention can be understood. For effect evaluation, appropriate indicators can be used instead of "pain scores."

[0086] In this specification, the expression [A, B and / or C] means "at least one selected from A, B and C".

[0087] The pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient is administered orally or parenterally to humans or other mammals. 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.

[0088] The pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be prepared by mixing citric acid, a pharmaceutically acceptable salt of citric acid, or a hydrate thereof or a mixture thereof, or sodium bicarbonate directly or 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, 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., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), etc. to prepare the tablets.

[0089] Hereinafter, the tablet of the present invention will be described in more detail.

[0090] In one embodiment, the pharmaceutical composition containing an alkalizing agent as an active ingredient provided by the present invention is a tablet. The tablet provided by the present invention may contain 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, flow agents, flavoring agents, lubricants, pH regulators, surfactants, stabilizers, and spices.

[0091] The content of the active ingredient in the tablet provided by the present invention is 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.

[0092] Examples of excipients that can be used in the tablets provided by the present invention include sugars such as lactose (e.g., lactose hydrate, anhydrous lactose), glucose, sucrose, fructose, maltose, erythritol, sorbitol, maltitol, xylitol, D-mannitol, and other sugar alcohols, starch (e.g., corn starch, potato starch, rice starch, wheat starch), crystalline cellulose, magnesium aluminosilicate, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate, calcium lactate, and ethyl cellulose, with crystalline cellulose being particularly preferred.

[0093] The content of the excipient in the tablet provided by the present invention is 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.

[0094] 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 copolymer, polyethylene glycol, pregelatinized starch (e.g., partially pregelatinized starch), agar and gelatin, with hydroxypropyl cellulose being particularly preferred.

[0095] The content of the binder in the tablet provided by the present invention is 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.

[0096] Examples of disintegrants that can be used in the tablets provided by the present invention include cross-linked sodium carboxymethylcellulose, carboxymethylcellulose calcium, 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.

[0097] The content of the disintegrant in the tablet provided by the present invention is 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.

[0098] Examples of fluidizing agents that can be used in the tablets provided by the present invention include light anhydrous silicic acid, talc, and magnesium aluminometasilicate.

[0099] The content of the fluidizing agent in the tablet provided by the present invention is 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.

[0100] Examples of flavoring agents that can be used in the tablets provided by the present invention include acidulants such as citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, fumaric acid, and ascorbic acid (however, these flavoring agents are not included in the active ingredients of the present invention), and sweeteners such as saccharin sodium, dipotassium glycyrrhizate, aspartame (registered trademark), stevia, thaumatin, and sucralose.

[0101] The content of the flavoring agent in the tablet provided by the present invention is 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.

[0102] 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.

[0103] The content of the lubricant in the tablet provided by the present invention is 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.

[0104] Examples of pH adjusters that can be used in the tablets provided by the present invention include citric acid, phosphates (e.g., sodium dihydrogen phosphate, potassium dihydrogen phosphate), carbonates (e.g., magnesium carbonate, sodium carbonate), tartrates, fumarates, acetates, and amino acid salts (however, the above pH adjusters are not included in the active ingredients of the present invention).

[0105] The content of the pH adjuster in the tablet provided by the present invention is 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.

[0106] 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.

[0107] The content of the surfactant in the tablet provided by the present invention is 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.

[0108] Examples of stabilizers that can be used in the tablets provided by the present invention include citric acid (e.g., anhydrous citric acid), malic acid, acetic acid, tartaric acid, maleic acid, ascorbic acid, sodium edetate, and tocopherol (however, the above stabilizers are not included in the active ingredients of the present invention), with anhydrous citric acid being particularly preferred.

[0109] The content of the stabilizer in the tablet provided by the present invention is 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.

[0110] 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).

[0111] 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.

[0112] The tablets provided herein can be prepared as bare tablets containing the aforementioned ingredients without a coating layer, or as film-coated tablets with a coating layer. The coating layer content can be appropriately determined by those skilled in the art, for example, 0.1 to 10% by weight relative to the bare tablet. In addition to the coating base, the coating layer may also contain, as appropriate, a plasticizer, a colorant, a glossing agent, and the like.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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, in the case of 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.

[0118] 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.

[0119] 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.

[0120] As one embodiment, the mixture obtained in the mixing step and the granulated product obtained in the granulation step can be appropriately pulverized and / or sieved to obtain a mixture or granulated product 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 (1000 μm opening) to a 32-mesh sieve (500 μm opening) or the like.

[0121] 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 external lubrication tableting. For example, the mixture and 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.

[0122] 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 bare chip.

[0123] 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 bare 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) or a glossing agent (such as carnauba wax) is formed on the outside of the bare tablets.

[0124] In one embodiment, the hardness of the obtained tablet may be 10 to 200 N, preferably 30 to 150 N.

[0125] 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.

[0126] In one embodiment, the amount of the alkalinizer in the pharmaceutical composition provided by the present invention can be set so that the dosage of the alkalinizer is an amount that improves the acidic urine of 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 dose certified in Japan for improving acidic urine of gout or hyperuricemia (for example, when the alkalinizer is a citric acid preparation: one tablet containing 231.5 mg of potassium citrate (C6H5K3O7·H2O) and 195.0 mg of sodium citrate hydrate (C6H5Na3O7·2H2O) is orally administered, two tablets at a time, three times a day; when the alkalinizer is sodium bicarbonate: oral administration, 3-5 g per day).

[0127] In one embodiment, the pharmaceutical composition provided by the present invention containing 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, and more preferably 400 mg to 500 mg, of potassium citrate monohydrate or sodium citrate dihydrate as an active ingredient.

[0128] In one embodiment, the pharmaceutical composition provided by the present invention containing 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.

[0129] In one embodiment, the pharmaceutical composition provided by the present invention containing 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.

[0130] As one embodiment, the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient is in the form of a tablet, which contains 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate as active ingredients, and may contain anhydrous citric acid, crystalline cellulose, partially pregelatinized starch, hydroxypropyl cellulose, magnesium stearate, hypromellose, polyethylene glycol 6000, titanium oxide, and carnauba wax as additives.

[0131] As one embodiment, a tablet containing 231.5 mg of potassium citrate monohydrate and 195.0 mg of sodium citrate dihydrate can be used as one dosage unit.

[0132] In this specification, "dosage unit" refers to the unit of the preparation, and "1 dosing unit" means the minimum unit of the preparation. Therefore, for example, if it is a tablet, the dosing unit is each tablet, and 1 dosing unit means 1 tablet. If it is an injection, the dosing unit is the injection placed in a sealed container such as an ampoule or a vial, and 1 dosing unit means the injection placed in a sealed container such as an ampoule or a vial. If it is a powder or a gel-like preparation, the dosing unit is a powder or gel-like preparation sealed in a bag made of a sheet made of a single-layer or multi-layer film such as polyethylene or a sheet provided with an aluminum layer on the sheet, and 1 dosing unit means the powder or gel-like preparation placed in 1 sealed bag. If it is a capsule (hard capsule, soft capsule, seamless capsule, etc.), the dosing unit is each capsule, and 1 dosing unit means 1 capsule.

[0133] 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.

[0134] 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, the degree of the lesion or disease that can cause peripheral nerve disorder, the degree of peripheral nerve disorder, etc. The dosage can be adjusted based on the degree of the lesion or disease that can cause peripheral nerve disorder, the degree of peripheral nerve disorder and the improvement of symptoms.

[0135] In one embodiment, when a mixture of potassium citrate monohydrate and sodium citrate dihydrate as active ingredients is orally administered to humans, potassium citrate monohydrate and sodium citrate dihydrate can be administered at 1.5 to 6 g / day each and a total of 3 to 12 g / day, 1.5 to 9 g / day each and a total of 3 to 18 g / day, 1.5 to 12 g / day each and a total of 3 to 24 g / day, preferably 3 to 12 g / day each and a total of 6 to 24 g / day, 3 to 9 g / day each and a total of 6 to 18 g / day, or 6 to 9 g / day each and a total of 12 to 18 g / day. The administration can be divided into 1 to 5 doses per day, preferably 3 times a day.

[0136] 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.

[0137] 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.

[0138] In one embodiment, the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be administered to a subject who has a lesion or disease that can cause peripheral neuropathy or has developed a disease, or who is at risk of inducing peripheral neuropathy, for the purpose of preventing the occurrence of the peripheral neuropathy before the onset of the aforementioned peripheral neuropathy. Alternatively, the composition can be administered before the onset of the aforementioned peripheral neuropathy and continued after the onset of the aforementioned peripheral neuropathy. Alternatively, the composition can be administered to a subject who has developed a peripheral neuropathy caused by a certain lesion or disease for the purpose of treating the aforementioned peripheral neuropathy. The administration can be continued depending on the extent of the lesion or disease that can cause peripheral neuropathy, the extent of the peripheral neuropathy, and the improvement of the symptoms.

[0139] In one embodiment, the pharmaceutical composition provided by the present invention containing 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.

[0140] In one embodiment, the pharmaceutical composition provided by the present invention containing an alkalizing agent as an active ingredient can be evaluated for its therapeutic or preventive effect on peripheral neuropathy induced by a certain lesion, disease, etc. by continuously administering the composition daily from the onset or onset of the lesion or disease that may cause peripheral neuropathy.

[0141] <Medical composition for treating diabetes that suppresses the occurrence of peripheral nerve disorders induced by diabetes>

[0142] In one embodiment, the present invention provides a pharmaceutical composition for treating diabetes that suppresses the occurrence of peripheral nerve disorders induced by diabetes, wherein the pharmaceutical composition contains a diabetes treatment and an alkalizing agent as active ingredients.

[0143] In one aspect, a "pharmaceutical composition for treating diabetes that suppresses the onset of peripheral neuropathy induced by diabetes" refers to a pharmaceutical composition for treating diabetes that suppresses the onset of peripheral neuropathy compared to a placebo.

[0144] On the other hand, a "pharmaceutical composition for treating diabetes that suppresses the occurrence of peripheral neuropathy induced by diabetes" refers to a pharmaceutical composition for treating diabetes that suppresses the occurrence of peripheral neuropathy induced by diabetes compared to a "pharmaceutical composition for treating diabetes that does not contain an alkalizing agent" containing an amount of diabetes drug equivalent to the content of the diabetes drug contained in the "pharmaceutical composition for treating diabetes that suppresses the occurrence of peripheral neuropathy induced by diabetes" provided by the present invention.

[0145] In another aspect, the "pharmaceutical composition for treating diabetes that suppresses the occurrence of peripheral neuropathy induced by diabetes" refers to a pharmaceutical composition for treating diabetes that does not cause peripheral neuropathy induced by diabetes.

[0146] Here, the inhibition rate of the occurrence of the peripheral nerve disorder can be calculated based on an appropriate evaluation index such as the "pain score" described later, for example, in the case of "pain".

[0147] In one embodiment, the diabetes therapeutic drug contained as an active ingredient in the "pharmaceutical composition for treating diabetes for inhibiting the occurrence of peripheral nerve disorders induced by diabetes" provided by the present invention includes, for example, sulfonylurea drugs selected from the group consisting of glibenclamide, gliclazide and glimepiride; fast-acting insulin secretagogues such as nateglinide, mitiglinide calcium hydrate and repaglinide; sitagliptin phosphate hydrate, vildagliptin, alogliptin benzoate, linagliptin, tenegliptin hydrobromide hydrate, alagliptin, saxagliptin hydrate, trelagliptin succinate and ogliptin. At least one diabetes treatment drug selected from the group consisting of: DPP-4 inhibitors such as statins; GLP-1 receptor agonists such as semaglutide; glimepirides such as imeglitinide hydrochloride; biguanides such as buformin hydrochloride and metformin hydrochloride; thiazolidinediones such as pioglitazone hydrochloride; glimepirides such as imeglitinide hydrochloride; α-glucosidase inhibitors such as acarbose, voglibose and miglitol; and SGLT2 inhibitors such as ipragliflozin L-proline, dapagliflozin propylene glycol hydrate, rupagliflozin hydrate, togliflozin hydrate, canagliflozin hydrate and empagliflozin.

[0148] In one embodiment, as the alkalizing agent contained as an active ingredient in the pharmaceutical composition provided by the present invention, the pharmaceutically acceptable salt of citric acid, or a hydrate thereof, or a mixture thereof, and sodium bicarbonate can be used.

[0149] In one embodiment, the pharmaceutical composition provided by the present invention can be administered to a subject, such as a human or other mammal, suffering from a lesion or disease that may cause a peripheral neuropathy, to suppress the occurrence of the peripheral neuropathy.

[0150] In one embodiment, the pharmaceutical composition provided by the present invention is administered orally or parenterally to a subject, such as a human or other mammal, suffering from a certain pathology or disease that may cause peripheral nerve disorders. 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.

[0151] In one embodiment, the pharmaceutical composition provided by the present invention can be applied with the formulation technology described above for the pharmaceutical composition containing an alkalizing agent as an active ingredient.

[0152] As other examples of embodiments of the present invention, the following embodiments can be mentioned.

[0153] <1-1> An alkalizing agent or a pharmaceutical composition containing an alkalizing agent for treating or preventing peripheral nerve disorders.

[0154] <1-2> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-1>, wherein the peripheral nerve disorder is pain, sensory impairment, movement disorder, autonomic nerve disorder, or a combination thereof caused by the peripheral nerve disorder.

[0155] <1-3> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-1> or <1-2>, wherein the peripheral neuropathy is peripheral neuropathy pain.

[0156] <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.

[0157] <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 is a sensory disorder caused by the peripheral nerve disorder.

[0158] <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.

[0159] <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.

[0160] <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 is an autonomic nerve disorder caused by the peripheral nerve disorder.

[0161] <1-9> The alkalizing agent or the pharmaceutical composition containing the alkalizing agent for use according to <1-8>, wherein the symptom caused by the autonomic nervous system disorder is urinary dysfunction, abnormal sweating, orthostatic hypotension, constipation, or paralytic ileus.

[0162] <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 is a peripheral neuropathy with symptoms appearing in the limbs.

[0163] <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, or a hydrate thereof, or a mixture thereof.

[0164] <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.

[0165] <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.

[0166] <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.

[0167] <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.

[0168] <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.

[0169] <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 peripheral neuropathy is diabetic peripheral neuropathy.

[0170] <2-1> A method for treating or preventing a peripheral nervous system disorder, comprising the step of administering an effective amount of an alkalinizing agent to a subject in need of treatment or prevention of a peripheral nervous system disorder.

[0171] <2-2> A method for treating a peripheral neuropathy for suppressing the occurrence of the peripheral neuropathy, comprising the step of administering an effective amount of an alkalizing agent to a subject in need of treatment for the peripheral neuropathy.

[0172] <2-3> The method according to any one of <2-1> or <2-2>, wherein the peripheral neuropathy is diabetic peripheral neuropathy.

[0173] <3-1> Use of an alkalizing agent for producing a pharmaceutical composition for treating or preventing peripheral nerve disorders.

[0174] <3-2> Use of an alkalizing agent in the production of a pharmaceutical composition for suppressing the occurrence of peripheral nerve disorders.

[0175] <3-3> The use according to any one of <3-1> or <3-2>, wherein the peripheral neuropathy is diabetic peripheral neuropathy.

[0176] 2. Food composition

[0177] 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.

[0178] Alkalizing agents described in "1. Pharmaceutical Compositions" above can be used. Examples of alkalizing agents include food-approved salts of citric acid, i.e., pharmaceutically acceptable salts of citric acid (e.g., alkali metal citrate, hydrates thereof, or mixtures thereof), or sodium bicarbonate, preferably a mixture of potassium citrate monohydrate (C6H5K3O7·H2O) and sodium citrate dihydrate (C6H5Na3O7·2H2O), or sodium citrate dihydrate.

[0179] 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 they contain an effective amount of an alkalizing agent for achieving the above-mentioned effects and can be orally ingested. They can be in the form of ordinary food and beverages, or can be provided as preparations suitable for oral administration in the preparations of the above-mentioned pharmaceutical compositions, such as tablets, capsules, suspensions, and the like. For the composition and manufacturing method of these preparations, in addition to directly applying the composition and manufacturing method of the pharmaceutical preparations described in the above-mentioned "1. Pharmaceutical Compositions" in this specification, the formulation technology known per se in the field of pharmaceutical formulation technology can also be applied.

[0180] 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.

[0181] When the food composition provided by the present invention is not formulated and is provided in the form of a common diet product, it can be suitably 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 (for example, potassium citrate and / or sodium citrate) or sodium bicarbonate to the food material.

[0182] Examples of the food and beverage 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.

[0183] 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.

[0184] 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.

[0185] 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 of the present invention is used as a benchmark, the amount of the alkalizer used in the food composition is applied to the application object of the above-mentioned pharmaceutical composition in a manner that is equal to the amount of the alkalizer contained in the above-mentioned pharmaceutical composition. In addition, in one embodiment, the "food composition" of the present invention is a subject (for example, a human or other mammal) who has received a therapeutic or preventive drug for a disease such as diabetes that can cause peripheral neuropathy, or who has subsequently received a therapeutic or preventive drug for a disease such as diabetes that can cause peripheral neuropathy, in order to inhibit the occurrence of peripheral neuropathy or to inhibit an already occurred peripheral neuropathy, and in the range of non-therapeutic use, it is taken. 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, and the pharmacological effects of the above-mentioned alkalizer itself are basically the same, so the applicable amount and application method of the above-mentioned food composition can be appropriately adjusted based on the above-mentioned alkalizer according to the expected effect.

[0186] Food compositions that are used to maintain or promote a "healthy" or "normal" state in a subject (e.g., a human or other mammal) that does not have "pathological" or "abnormal" symptoms, conditions or diseases, i.e., a subject (e.g., a human or other mammal) that is in a "healthy" or "normal" state are sometimes specifically referred to as "functionally labeled foods."

[0187] The term "administration" described in "1. Pharmaceutical Compositions" above can also be applied to the "food compositions" of the present invention. Furthermore, the term "administration" can be replaced with "ingestion" for the "food compositions" of the present invention. Thus, for example, the terms "administer" or "give" can be replaced with "ingestion," "ingestion," or "ingested," depending on the context.

[0188] Hereinafter, the present invention will be further described based on examples, but the present invention is not limited thereto.

[0189] Example

[0190] Example 1: Evaluation of Alkalizing Agents in STZ-Induced Diabetes Model

[0191] (Test substance)

[0192] The drug used was a mixture of 463 mg of potassium citrate monohydrate (C₆H₅K₃O₇·H₂O) per 1 g dry weight, 390 mg of sodium citrate dihydrate (C₆H₅Na₃O₇·2H₂O) per 1 g dry weight, and 147 mg of a pharmaceutically acceptable additive per 1 g (Uralyt U powder, manufactured by Chemiphar Co., Ltd., Japan) as the alkalizing agent. The required amount of Uralyt U powder (hereinafter referred to as "Uralyt") was weighed and dissolved in water for injection to achieve the target concentration. The preparation was performed as needed.

[0193] The sham group and the control group used the solvent of the alkalizing agent, namely water for injection.

[0194] (animal)

[0195] Eight-week-old male Crl:CD (SD) rats (JACKSON LABORATORY JAPAN) were used. The animals were given an acclimatization period of six days or more, during which pain evaluation was performed once. Only healthy animals showing a 50% paw withdrawal threshold of 8 g or more in the pain evaluation were used for the test.

[0196] (Preparation of experimental animals)

[0197] Experimental animals were prepared by the following method: Streptozotocin (hereinafter also referred to as STZ)-induced diabetic neuropathy model rats.

[0198] The day of STZ administration was designated as Day 1 of the experiment, and rats were divided into groups on Day 14 of the experiment after STZ administration. Specifically, animals with a 50% paw withdrawal threshold of 8 g or higher and a blood glucose level of 300 mg / dL or lower on the day of grouping were excluded from the grouping. Using a computer program (IBUKI, Nihon Bioresearch Inc.), the animals were divided into a control group and an alkalinizing group, each consisting of 8 rats, so that the average values ​​of the 50% paw withdrawal threshold, blood glucose level, and body weight were approximately equal. The groups consisted of 1 (Sham group), 2 (Control group), and 3 (Alkalinizing group).

[0199] Rats in Group 2 (control group) and Group 3 (alkalinizing agent group candidate) were injected with STZ via the tail vein. Similarly, a 0.75 mmol / L CAB solution was injected into the tail vein of Group 1 (sham group). From Day 15 to Day 21 of the experiment, Water for Injection was administered orally twice daily to Group 1 (sham group) and Group 2 (control group), and Uralyt 1 g / kg was administered orally twice daily to Group 3 (alkalinizing agent group).

[0200] (Measurement time)

[0201] The pain evaluation was performed 3 hours after the administration of the test substance and vehicle on day 21 of the experiment.

[0202] (Pain Assessment)

[0203] Pain assessment was performed using the von Frey test according to the method of Non-Patent Document 3. The 50% paw withdrawal threshold was calculated using an up-down stimulation method using von Frey filaments (target force: 0.4, 0.6, 1, 2, 4, 6, 8, 15 g, DanMic Global, LLC).

[0204] Calculation Method for the 50% Foot Retraction Threshold

[0205] 50% withdrawal threshold = (10(Xf+k×δ)) / 10000

[0206] Xf: The evaluator size of the final von Frey fiber used

[0207] k: withdrawal response pattern

[0208] δ: Average value of the difference between the fibers used

[0209] It should be noted that the test animals were moved to an independent cage with a mesh bottom (W110×D180×H150 mm) for pain score measurement and allowed to adapt to the new environment for at least 30 minutes.

[0210] (result)

[0211] Repeated administration of Uralyt U combined with powder to STZ-induced diabetic neuropathy model rats suppressed the onset of mechanical allodynia ( Figure 1 ).

[0212] In conclusion, it is believed that repeated oral administration of Uralyt U combined powder is very effective for STZ-induced peripheral nerve disorders.

[0213] Industrial applicability

[0214] The pharmaceutical composition provided by the present invention can treat or prevent peripheral nerve disorders.

[0215] Furthermore, the pharmaceutical composition provided by the present invention can suppress peripheral nerve disorders induced by certain lesions or diseases, particularly diabetes.

Claims

1. A pharmaceutical composition for treating or preventing a peripheral nervous system disorder, comprising an alkalizing agent.

2. The pharmaceutical composition according to claim 1, wherein Peripheral nerve disorders refer to pain, sensory disorders, movement disorders, autonomic nerve disorders, or complications thereof caused by peripheral nerve disorders.

3. The pharmaceutical composition according to claim 1 or 2, wherein Peripheral nerve disorder is peripheral nerve disorder 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 disorder is a sensory disorder caused by peripheral nerve disorder.

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 impaired sensation or sensory perversion.

8. The pharmaceutical composition according to claim 1 or 2, wherein Peripheral nerve disorder is an autonomic nervous system disorder caused by peripheral nerve disorder.

9. The pharmaceutical composition according to claim 8, wherein Symptoms caused by autonomic nervous system disorders 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 Peripheral nerve disorders are peripheral nerve disorders with symptoms 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 Peripheral nerve disorder is a peripheral nerve disorder induced by diabetes.

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