Pharmaceutical compositions for the treatment or inhibition of progression of multiple system atrophy

Abstract

To provide a pharmaceutical composition for the treatment or suppression of the progression of multiple system atrophy, or for extending the survival period of patients with multiple system atrophy. [Solution] A pharmaceutical composition is disclosed for the treatment or suppression of the progression of multiple system atrophy, or for extending the survival time of a patient having multiple system atrophy, the pharmaceutical composition comprising a DPP4 inhibitor.

Description

Technical Field

[0001] The present disclosure relates to a pharmaceutical composition for treating or suppressing the progression of multiple system atrophy, etc.

Background Art

[0002] Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the formation of glial cytoplasmic inclusions (GCIs) composed of insoluble α-synuclein in glial cells (mainly oligodendroglial cells). MSA is a clinicopathological concept that includes olivopontocerebellar atrophy (OPCA) with cerebellar ataxia as the main feature, striatonigral degeneration with parkinsonism as the main feature, and Shy-Drager syndrome with autonomic neuropathy as the main feature. It is classified into MSA-C with dominant cerebellar ataxia and MSA-P with dominant Parkinson's symptoms (Non-Patent Document 1). An effective treatment method for MSA has not been established, and usually, symptomatic treatment according to each symptom is performed.

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] The object of the present disclosure includes providing a pharmaceutical composition for treating or suppressing the progression of multiple system atrophy, and a pharmaceutical composition for extending the survival period of patients with multiple system atrophy.

Means for Solving the Problems

[0005] As a result of diligent research, the inventors have found that a pharmaceutical composition containing a DPP inhibitor is useful for treating or inhibiting the progression of multiple system atrophy, and for extending the survival period of patients with multiple system atrophy. Based on these findings, the inventors have completed this disclosure through further research.

[0006] This disclosure includes the following embodiments.

[0007] [Section 1] A pharmaceutical composition for the treatment or inhibition of progression of multiple system atrophy, comprising a DPP4 inhibitor. [Section 2] A pharmaceutical composition for extending the survival time of patients with multiple system atrophy, comprising a DPP4 inhibitor. [Section 3] A pharmaceutical composition for the treatment or suppression of the progression of multiple system atrophy in diabetic patients, comprising a DPP4 inhibitor. [Section 4] A pharmaceutical composition for extending the survival time of diabetic patients with multiple system atrophy, comprising a DPP4 inhibitor. [Section 5] The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP4 inhibitor is at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof. [Section 6] The pharmaceutical composition according to any one of claims 1 to 5, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof. [Section 7] The pharmaceutical composition according to any one of claims 1 to 6, wherein the DPP4 inhibitor is administered once daily in a dose of 5 mg to 100 mg. [Section 8] The pharmaceutical composition according to any one of claims 1 to 7, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 20 mg. [Section 9] A pharmaceutical composition according to any one of items 1 to 8, which is administered in combination with other diabetes medications. [Section 10] The pharmaceutical composition according to item 9, wherein the other diabetes drug is an SGLT2 inhibitor. [Section 11] The pharmaceutical composition according to claim 10, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof. [Section 12] The pharmaceutical composition according to claim 10 or 11, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof. [Section 13] The pharmaceutical composition according to any one of claims 10 to 12, wherein the SGLT2 inhibitor is administered once daily in a dose of 5 mg to 100 mg. [Section 14] The pharmaceutical composition according to any one of claims 10 to 13, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 100 mg.

[0008] [Section A1] A method for treating or slowing the progression of multiple system atrophy in a subject requiring treatment or slowing the progression of the disease, the method comprising the step of administering a DPP4 inhibitor to the subject. [Section A2] A method for extending the survival period of a patient with multiple system atrophy, comprising the step of administering a DPP4 inhibitor to the patient. [Section A3] A method for treating or slowing the progression of multiple system atrophy in a diabetic patient who requires treatment or slowing the progression of multiple system atrophy, the method comprising the step of administering a DPP4 inhibitor to the diabetic patient. [Section A4] A method for extending the survival period of a diabetic patient with multiple system atrophy, comprising the step of administering a DPP4 inhibitor to the diabetic patient. [Section A5] The method according to any one of items A1 to A4, wherein the DPP4 inhibitor is at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof. [Item A6] The method according to any one of items A1 to A5, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof. [Item A7] The method according to any one of items A1 to A6, wherein the step is a step of administering the DPP4 inhibitor once a day at a dose of 5 mg or more and 100 mg or less. [Item A8] The method according to any one of items A1 to A7, wherein the step is a step of administering teneligliptin or a pharmaceutically acceptable salt thereof once a day at a dose of 20 mg. [Item A9] The method according to any one of items A1 to A8, wherein the step is a step of administering another antidiabetic drug in combination with the DPP4 inhibitor. [Item A10] The method according to item A9, wherein the other antidiabetic drug is an SGLT2 inhibitor. [Item A11] The method according to item A10, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof. [Item A12] The method according to item A10 or A11, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof. [Item A13] The method according to any one of items A9 to A12, wherein the step is a step of administering an SGLT2 inhibitor once a day at a dose of 5 mg or more and 100 mg or less in combination with the DPP4 inhibitor. [Item A14] The method according to any one of items A9 to A13, wherein the step is a step of administering canagliflozin or a pharmaceutically acceptable salt thereof once a day at a dose of 100 mg in combination with the DPP4 inhibitor.

[0009] [Item B1] A DPP4 inhibitor for use in the treatment or suppression of progression of multiple system atrophy. [Item B2] A DPP4 inhibitor for use in prolonging the survival period of patients with multiple system atrophy. [Item B3] A DPP4 inhibitor for use in the treatment or suppression of progression of multiple system atrophy in diabetic patients. [Item B4] A DPP4 inhibitor for use in prolonging the survival period of diabetic patients with multiple system atrophy. [Item B5] The DPP4 inhibitor according to any one of Items B1 to B4, which is at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof. [Item B6] The DPP4 inhibitor according to any one of Items B1 to B5, which is teneligliptin or a pharmaceutically acceptable salt thereof. [Item B7] The DPP4 inhibitor according to any one of Items B1 to B6, which is administered once a day at a dose of 5 mg or more and 100 mg or less. [Item B8] The DPP4 inhibitor according to any one of Items B1 to B7, which is administered once a day at a dose of 20 mg. [Item B9] The DPP4 inhibitor according to any one of Items B1 to B8, which is administered in combination with other antidiabetic drugs. [Item B10] The DPP4 inhibitor according to Item B9, wherein the other antidiabetic drug is an SGLT2 inhibitor. [Item B11] The DPP4 inhibitor according to Item B10, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof. [Item B12] A DPP4 inhibitor according to item B10 or B11, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof. [Section B13] A DPP4 inhibitor as described in any of sections B10 to B12, wherein the SGLT2 inhibitor is administered once daily at a dose of 5 mg to 100 mg. [Section B14] The SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 100 mg, as described in any of items B10 to B13, for a DPP4 inhibitor.

[0010] [Section C1] Use of DPP4 inhibitors for the manufacture of drugs for the treatment or slowing of the progression of multiple system atrophy. [Section C2] The use of DPP4 inhibitors to manufacture drugs that extend the survival time of patients with multiple system atrophy. [Section C3] Use of DPP4 inhibitors for the manufacture of drugs for the treatment or slowing of the progression of multiple system atrophy in diabetic patients. [Section C4] The use of DPP4 inhibitors to manufacture drugs for extending the survival time of diabetic patients with multiple system atrophy. [Section C5] The use described in any of items C1 to C4, wherein the DPP4 inhibitor is at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof. [Section C6] The use described in any of items C1 to C5, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof. [Section C7] The use described in any of items C1 to C6, wherein the drug is administered once daily at a dose of 5 mg or more and 100 mg or less (in terms of the DPP4 inhibitor). [Section C8] The use described in any of items C1 to C7, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof, and the drug is administered once daily at a dose of 20 mg (in terms of the DPP4 inhibitor). [Section C9] The use described in any of sections C1 to C8, wherein the aforementioned drug is administered in combination with other diabetes medications. [Section C10] The use described in item C9, wherein the other diabetes drug is an SGLT2 inhibitor. [Section C11] The use described in item C10, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof. [Section C12] The use described in item C10 or C11, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof. [Section C13] The use described in any of sections C10 to C12, wherein the SGLT2 inhibitor is administered once daily at a dose of 5 mg to 100 mg. [Section C14] The use described in any of sections C10 to C13, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 100 mg. [Effects of the Invention]

[0011] According to one embodiment of this disclosure, it is extremely useful for treating or slowing the progression of multiple system atrophy, and for extending the survival time of patients with multiple system atrophy. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 compares the survival curve (Kaplan-Meier curve) of the group treated with DPP4 inhibitors with the survival curve of the group not treated with DPP4 inhibitors (e.g., the group treated with other diabetes medications). [Figure 2]Figure 2 shows the correlation between the frequency of DPP4 inhibitor administration after diagnosis of multiple system atrophy (MSA) (months of DPP4 prescription / MSA survival period (months)) and overall survival. [Figure 3] Figure 3 compares the survival curves of the group that received both insulin and DPP4 inhibitors with the survival curve of the group that received insulin but not DPP4 inhibitors. [Modes for carrying out the invention]

[0013] All disclosures of each publication cited herein are incorporated herein by reference.

[0014] (1) Definition In this specification, "approximately" means within an acceptable margin of error for the indicated value, for example, within ±10% (preferably ±5%) of the indicated value.

[0015] In this specification, multiple system atrophy (MSA) is used in the broadest sense as used in this field. MSA is a neurodegenerative disease characterized by the formation of glial cytoplasmic inclusion bodies (GCIs) consisting of insoluble α-synuclein in glial cells (mainly oligodendroglycal cells).

[0016] Multiple system atrophy (MSA) encompasses olivopontocerebellar atrophy (OPCA), characterized primarily by cerebellar ataxia; striatonigral degeneration, characterized primarily by parkinsonism; and Shy-Drager syndrome, characterized primarily by autonomic dysfunction. Multiple system atrophy can be classified into MSA-C, where cerebellar ataxia is dominant, and MSA-P, where parkinsonian symptoms are dominant. While multiple system atrophy is mostly sporadic, it can also be familial.

[0017] Symptoms of multiple system atrophy include, for example, ataxia, extrapyramidal symptoms, pyramidal tract symptoms, and autonomic nervous system symptoms. Ataxia is a condition in which muscles do not move in coordination despite normal muscle strength, making smooth movement difficult. Examples include gait disturbance (unsteadiness), limb ataxia, and dysarthria. Extrapyramidal symptoms are caused by impaired motor control in the basal ganglia and other areas of the brain, resulting in involuntary movements or difficulty in smooth movement. Examples include parkinsonism, such as muscle rigidity (stiffness), bradykinesia or reduced movement, and impaired postural reflexes. Pyramidal tract symptoms are caused by impaired pathways that transmit motor commands from the brain, resulting in abnormalities related to voluntary movement, such as motor paralysis. Examples include spasticity (stiffness). Autonomic nervous system symptoms are caused by disruptions in the function of the autonomic nervous system, which regulates things like sweat volume and blood pressure. Examples include orthostatic hypotension (dizziness, lightheadedness), urinary dysfunction, and sweating disorders.

[0018] The severity of multiple system atrophy can be measured, for example, using the Unified Multiple System Atrophy Rating Scale (UMSARS). The UMSARS consists of Part I (Assessment of Activities of Daily Living based on medical history), Part II (Assessment of Motor Symptoms based on Physical Examination), Part III (Assessment of Autonomic Nervous System Function), and Part IV (Assessment of Overall Impairment). Details of the evaluation criteria for each part are shown below.

[0019] Part I: Assessment of Activities of Daily Living Based on Medical History Unless otherwise specified, the average function over the two weeks prior to the assessment will be evaluated through questions to the patient and their caregiver. Select the score that best reflects the patient's condition. The patient's function will be assessed independently of clinical signs. TIFF2026108904000001.tif222170

[0020] Part II: Evaluation of motor symptoms through physical examination Regarding findings in the limbs, the limb with the most severe symptoms in each category will be evaluated. TIFF2026108904000002.tif242170

[0021] Part III: Autonomic Nervous System Function Assessment TIFF2026108904000003.tif17170

[0022] Part IV: Overall Disability Assessment TIFF2026108904000004.tif28170

[0023] In this specification, treatment is used to mean not only improvement, remission, and complete cure of symptoms, but also relief (or reduction) of symptoms and prevention of progression (or worsening) of symptoms. Treatment includes, for example, preventing or reducing the score (total) of Part I, Part II, and / or Part IV of the Unified Multiple System Atrophy Rating Scale, and alleviating or improving the symptoms of Part III by standing.

[0024] In this specification, suppression of symptom progression means stopping or reducing the rate of symptom progression, at least temporarily.

[0025] In this specification, extended survival usually means surviving longer than the survival period estimated based on factors such as the severity of multiple system atrophy.

[0026] In this specification, the subject is not particularly limited as long as it is an animal having multiple system atrophy. The subject may be a human or a non-human animal. Examples of non-human animals include rodents such as rats, mice, and guinea pigs; and mammals other than humans such as monkeys, pigs, dogs, and cats.

[0027] In this specification, low molecular weight compounds generally refer to compounds with a molecular weight of less than 10,000, and high molecular weight compounds generally refer to compounds with a molecular weight of 10,000 or more, and include nucleic acids, polypeptides (e.g., antibodies), and conjugates containing these.

[0028] In this specification, pharmaceutically acceptable salts may be inorganic or organic salts. Examples of inorganic salts include hydrochlorides, hydrochlorides, hydrobromids, nitrates, sulfates, bisulfates, borates, and phosphates; alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as magnesium and calcium salts; and ammonium salts. Examples of organic salts include acetates, lactates, malates, benzoates, oxalates, succinates, tartrates, fumarates, maleates, citrates, methanesulfons, ethanesulfons, benzenesulfons, toluenesulfons, and tosylates. The pharmaceutically acceptable salts used herein also include their hydrates and solvates.

[0029] In this specification, the DPP4 inhibitor is not particularly limited as long as it is a substance that inhibits dipeptidyl peptidase (DPP) 4. The DPP4 inhibitor may be a low molecular weight compound or a high molecular weight compound. The DPP4 inhibitor may be used alone or in combination of two or more.

[0030] When DPP4 inhibitors are small molecule compounds, specific examples include the compounds shown in Table 1.

[0031] [Table 1] TIFF2026108904000006.tif225170

[0032] The compounds shown in Table 1 may be pharmaceutically acceptable hydrates or solvates, or prodrugs.

[0033] As DPP-4 inhibitors, compounds described in the following literature can also be used. Tanabe Pharmaceutical Co., Ltd.: WO02 / 30891 or its corresponding U.S. patent (No. 6,849,622), and WO02 / 30890 or its corresponding U.S. patent (No. 7,138,397), FERRING BV: WO95 / 15309, WO01 / 40180, WO01 / 81304, WO01 / 81337, WO03 / 000250, and WO03 / 035057, ·PROBIODRUG: WO97 / 40832, EP1082314, WO99 / 61431, WO03 / 015775, NOVARRTIS AG: WO98 / 19998, WO00 / 34241, WO01 / 96295, U.S. Patent No. 6,107,317, U.S. Patent No. 6,110,949, and U.S. Patent No. 6,172,081. ·SMITHKLINE: WO03 / 002531, WO03 / 002530, and WO03 / 002553, • BRISTOL-MYERS SQUIBB GmbH: WO01 / 68603, WO02 / 83128, and WO2005 / 012249, • MERCK & CO.: WO02 / 76450 and WO03 / 004498, TAKEDA SAN DIEGO Co., Ltd.: WO2005 / 026148, WO2005 / 030751, and WO2005 / 095381 SYRRX Corporation: WO2004 / 087053 and WO2004 / 103993, Mitsubishi Welpharma Co., Ltd.: WO02 / 14271, U.S. Patent No. 7,060,722, U.S. Patent No. 7,074,794, WO2003 / 24942, JP 2002-265439, JP 2005-170792, and WO2006 / 088129, Taisho Pharmaceutical Co., Ltd.: WO2004 / 020407 Yamanouchi Pharmaceutical Co., Ltd.: WO2004 / 009544, Kyowa Hakko Kogyo Co., Ltd.: WO02 / 051836 Kyorin Pharmaceutical Co., Ltd.: WO2005 / 075421, WO2005 / 077900, and WO2005 / 082847, ·ALANTOS PHARMACEUTICALS: WO2006 / 116157, GLENMARK PHARMACEUTICALS: WO2006 / 090244 and WO2005 / 075426, • Sanwa Chemical Research Institute Co., Ltd.: WO2004 / 067509, and LG LIFE SCIENCES: WO2005 / 037828 and WO2006 / 104356.

[0034] In this specification, other diabetes medications are not particularly limited as long as they are diabetes medications other than DPP4 inhibitors. Examples of other diabetes medications include SGLT2 inhibitors, α-glucosidase inhibitors, GLP-1 receptor agonists, and insulin. Other diabetes medications may be used individually or in combination of two or more.

[0035] In this specification, SGLT2 inhibitors are not particularly limited as long as they are substances that inhibit sodium-glucose transport protein 2 (SGLT2). SGLT2 inhibitors may be small molecule compounds or large molecule compounds. SGLT2 inhibitors can be used alone or in combination of two or more.

[0036] When SGLT2 inhibitors are small molecule compounds, specific examples include the compounds shown in Table 2.

[0037] [Table 2]

[0038] The compounds shown in Table 2 may be pharmaceutically acceptable hydrates or solvates, or prodrugs.

[0039] Examples of SGLT2 inhibitors include WO01 / 16147, WO01 / 27128, WO01 / 68660, WO01 / 74834, WO02 / 028872, WO02 / 053573, WO2004 / 013118, WO2004 / 080990, WO2006 / 035796, WO2005 / 085265, WO2005 / 085267, and WO2005 / 0928. Compounds described in 77, WO2006 / 034489, WO2006 / 117359, WO2006 / 117360, U.S. Patent Publication No. 2005 / 0233988, U.S. Patent No. 6,048,842, U.S. Patent No. 5,380,873, U.S. Patent No. 5,424,406, U.S. Patent No. 5,731,292, U.S. Patent No. 5,767,094, etc. may also be used.

[0040] In this specification, “combined administration” means administering individual drugs simultaneously (for example, as a single pharmaceutical composition such as Canaria Combination Tablets) or consecutively, and administering individual drugs separately in any order with predetermined intervals (for example, 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, or 24 hours) between them.

[0041] (2) Pharmaceutical composition A pharmaceutical composition according to one aspect of this disclosure (hereinafter sometimes referred to as "Pharmaceutical Composition A") is a pharmaceutical composition comprising a DPP4 inhibitor for the treatment or inhibition of the progression of multiple system atrophy. Pharmaceutical Composition A can be suitably used for the treatment or inhibition of the progression of multiple system atrophy in subjects, preferably patients (humans), and more preferably patients with diabetes (e.g., patients with type 2 diabetes).

[0042] Another aspect of the present disclosure (which may be referred to as "Pharmaceutical Composition B") is a pharmaceutical composition comprising a DPP4 inhibitor for extending the survival time of patients with multiple system atrophy. The patients are preferably diabetic patients (e.g., type 2 diabetes patients).

[0043] In pharmaceutical compositions A and B, the DPP4 inhibitor is preferably a low molecular weight compound, and is preferably at least one selected from the group consisting of the compounds shown in Table 1, namely at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, vildagliptin, and pharmaceutically acceptable salts thereof; more preferably at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof; and even more preferably teneligliptin or a pharmaceutically acceptable salt thereof.

[0044] Pharmaceutical compositions A and B preferably further contain pharmaceutically acceptable additives. Examples of additives include excipients, disintegrants or disintegration aids, binders, lubricants, fluidizers, coating agents, dyes, diluents, bases, solubilizers or solubilizers, isotonic agents, pH adjusters, stabilizers, propellants, adhesives, dispersants, thickeners, sweeteners, and defoamers. These additives can be used individually or in combination of two or more.

[0045] Pharmaceutical compositions A and B can be provided as formulations in forms known to those skilled in the art. Specific examples of formulations suitable for oral or intragastric administration include tablets, capsules, powders, granules, liquids, syrups, and suspensions. Specific examples of formulations suitable for parenteral administration include injections, intravenous infusions, eye drops, patches, and suppositories.

[0046] The preparations suitable for oral or intragastric administration may contain, as additives, excipients such as glucose, lactose, D-mannitol, D-sorbitol, corn starch, dextrin, and crystalline cellulose; disintegrants or disintegration aids such as carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, and crospovidone; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and gelatin; lubricants such as magnesium stearate, calcium stearate, and talc; fluidizing agents such as anhydrous silicic acid; and hydroxypropylmethylcellulose. Coating agents such as sucrose, sucrose, polyethylene glycol, and titanium dioxide; bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat; dispersants such as polyvinyl alcohol and sucrose fatty acid esters; thickeners such as xanthan gum and tragacanth powder; sweeteners such as sorbitol; stabilizers such as sodium bisulfite and L-cysteine ​​hydrochloride; pH adjusters such as phosphoric acid, acetic acid, and sodium hydroxide; defoaming agents such as dimethicone emulsion; solvents such as aqueous solvents such as water, buffer solutions, and physiological saline, and oily solvents such as olive oil; and fragrances can be used.

[0047] The preparation suitable for injection or intravenous infusion may use, as additives, a solvent or solubilizer that can constitute an aqueous or dissolvable injectable preparation such as distilled water for injection, physiological saline, or propylene glycol; an isotonic agent such as glucose, sodium chloride, D-mannitol, or glycerin; a pH adjuster such as an inorganic acid, an organic acid, an inorganic base, or an organic base; or a combination of two or more of these.

[0048] In one embodiment, pharmaceutical compositions A and B are preferably Tenelia tablets or Tenelia OD tablets.

[0049] The dose (amount) of a DPP4 inhibitor may be an effective amount appropriately selected according to the patient's age, weight, sex, severity, and route of administration. The daily dose may be, for example, approximately 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. It may also be within a range (for example, approximately 5 mg to approximately 100 mg) with two values ​​selected from these as the upper and lower limits. If the DPP4 inhibitor is a salt, the above dose may be the amount in free form equivalent.

[0050] DPP4 inhibitors can be administered in one dose or in several divided doses (e.g., two or three doses).

[0051] In one embodiment, it is preferable that a DPP4 inhibitor is administered once daily at a dose of 5 mg to 100 mg, and it is even more preferable that teneligliptin or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 20 mg.

[0052] Pharmaceutical compositions A and B may be pharmaceutical compositions administered in combination with other antidiabetic drugs. The other antidiabetic drugs are preferably other than insulin, and more preferably SGLT2 inhibitors. The SGLT2 inhibitor is preferably a low molecular weight compound, and is preferably at least one selected from the group consisting of the compounds shown in Table 2, namely, at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof, and more preferably canagliflozin or a pharmaceutically acceptable salt thereof.

[0053] Other diabetes medications are preferably administered in the form of a pharmaceutical composition. The pharmaceutically acceptable excipients contained in the pharmaceutical composition may be one or more components as exemplified in pharmaceutical compositions A and B. In one embodiment, the pharmaceutical composition containing an SGLT2 inhibitor as the other diabetes medication is preferably Canaglu tablets.

[0054] The dosage of other diabetes medications (e.g., SGLT2 inhibitors) may be an effective amount appropriately selected according to the patient's age, weight, sex, severity, and route of administration. The daily dose may be, for example, approximately 0.1 mg, 0.5 mg, 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg. It may also be within a range (e.g., approximately 5 mg to approximately 100 mg) with two values ​​selected from these as the upper and lower limits. If the DPP4 inhibitor is a salt, the above dosage may be the free form equivalent.

[0055] SGLT2 inhibitors can be administered in a single dose or in several divided doses (e.g., two or three times).

[0056] In one embodiment, it is preferable that another antidiabetic drug (e.g., an SGLT2 inhibitor) is administered once daily at a dose of 5 mg to 100 mg, and it is even more preferable that canagliflozin or a pharmaceutically acceptable salt thereof is administered once daily at a dose of 100 mg.

[0057] (3) Method A method according to one aspect of this disclosure is a method for treating or slowing the progression of multiple system atrophy in a subject who requires treatment or slowing the progression of the disease, the method comprising the step of administering a DPP4 inhibitor to the subject. Preferably, the subject is a diabetic patient (e.g., a patient with type 2 diabetes).

[0058] Another aspect of the present disclosure relates to a method for extending the survival time of a patient having multiple system atrophy, the method comprising the step of administering a DPP4 inhibitor to the patient. The patient is preferably a diabetic patient (e.g., a patient with type 2 diabetes).

[0059] Each component in these methods (symptoms, dosage, method of administration, etc.) can be the same as the components in "(2) Pharmaceutical composition" described above.

[0060] (4) DPP4 inhibitors A DPP4 inhibitor according to one aspect of this disclosure is a DPP4 inhibitor for use in the treatment or suppression of the progression of multiple system atrophy. This DPP4 inhibitor can be suitably used in the treatment or suppression of the progression of multiple system atrophy in subjects, preferably patients (humans), and more preferably patients with diabetes (e.g., patients with type 2 diabetes).

[0061] Another embodiment of the present disclosure is a DPP4 inhibitor for use in extending the survival time of patients with multiple system atrophy. The patients are preferably diabetic patients (e.g., type 2 diabetes patients).

[0062] The components of these DPP4 inhibitors (symptoms, dosage, method of administration, etc.) can be the same as those in "(2) Pharmaceutical Composition" above.

[0063] (5) Use One aspect of use relating to this disclosure is the use of a DPP4 inhibitor to manufacture a drug for the treatment or slowing of the progression of multiple system atrophy. Such use is preferably for the manufacture of a drug for the treatment or slowing of the progression of multiple system atrophy in subjects, preferably patients (humans), and more preferably patients with diabetes (e.g., patients with type 2 diabetes).

[0064] Another use relating to this disclosure is the use of DPP4 inhibitors to manufacture agents for extending the survival time of patients with multiple system atrophy. The patients are preferably diabetic patients (e.g., type 2 diabetes patients).

[0065] Each component in these uses (symptoms, dosage, method of administration, etc.) may be the same as the components in "(2) Pharmaceutical Composition" described above.

[0066] (6) Kit A kit according to one aspect of this disclosure is a kit for the treatment or slowing the progression of multiple system atrophy, comprising a DPP4 inhibitor. The kit can be suitably used for the treatment or slowing the progression of multiple system atrophy in subjects, preferably patients (humans), and more preferably patients with diabetes (e.g., patients with type 2 diabetes).

[0067] Another embodiment of the present disclosure is a kit comprising a DPP4 inhibitor for extending the survival time of a patient with multiple system atrophy. The patient is preferably a diabetic patient (e.g., a patient with type 2 diabetes).

[0068] The kit may also contain other diabetes medications, preferably SGLT2 inhibitors. The kit may include containers for filling with or containing drugs, and / or equipment necessary for administering the drugs. The kit may also include instructions describing the details of the drug (such as the method of administration). Furthermore, the kit may be in packaged form. Other components of the kit (such as symptoms, dosage, and method of administration) may be the same as those described in "(2) Pharmaceutical Composition" above. [Examples]

[0069] The embodiments of this disclosure will be described in more detail below, but this disclosure is not limited to such embodiments.

[0070] 1. Extraction of patients with multiple system atrophy from medical claims data. This analysis used a claims database provided by Medical Data Vision Co., Ltd., and the analysis period was from April 2008 to September 2020. Patients with multiple system atrophy (MSA) were extracted from the diagnostic disease name information (DiseaseData) of the database, specifically those patients diagnosed with "multiple system atrophy."

[0071] 2. Obtaining death information and calculating survival time Of the patients extracted in step 1, those whose discharge summary information (FF1data) had an outcome of 6 (death) or 7 (other death) were selected. Furthermore, the survival period was calculated as the time from the date MSA treatment began (fromdate) to the date the death information was entered (dischargingdate).

[0072] 3. Obtaining information on diabetes prevalence and antidiabetic drug use. Of the patients extracted in step 1, those diagnosed with diseases with ICD-10 codes E10-E14 (diabetes-related diseases) in their diagnostic disease information (DiseaseData) were classified as patients with diabetes. Furthermore, patients with the ATC code A10 for antidiabetic drugs assigned to their medical practice information (ActData) were classified as patients prescribed antidiabetic drugs, and among these, patients prescribed DPP4 inhibitors or combination drugs containing DPP4 inhibitors with ATC codes (A10N1-9, A10P5) were classified as patients prescribed DPP4.

[0073] 4. Obtaining information on diabetes prevalence and antidiabetic drug use. Of the patients extracted in step 1, those diagnosed with diseases with ICD-10 codes E10-E14 (diabetes-related diseases) in their diagnostic disease information (DiseaseData) were classified as patients with diabetes. Furthermore, patients with the ATC code A10 for antidiabetic drugs assigned to their medical practice information (ActData) were classified as patients prescribed antidiabetic drugs, and among these, those prescribed DPP-4 inhibitors or combination drugs containing DPP-4 inhibitors with the ATC code (A10N) were classified as patients prescribed DPP-4 drugs.

[0074] 5. Patients included in the analysis Based on the patient information extracted in steps 1-4, the patients to be analyzed were selected. Patients who had started treatment for multiple system atrophy more than two years prior to registration in the database, and patients who died within two years of starting treatment for multiple system atrophy, were excluded, leaving 180 patients for analysis. Of these, patients without diabetes and without prescriptions for antidiabetic drugs were classified as Group 1 (106 patients), patients with diabetes as Group 2 (28 patients), patients prescribed DPP4 inhibitors as Group 3 (25 patients), and patients prescribed antidiabetic drugs other than DPP4 inhibitors as Group 4 (21 patients).

[0075] 6. Analysis of survival period For each patient group selected in step 5, survival time was analyzed using the Kaplan-Meier method and log-rank test. As a result, Kaplan-Meier curves (survival curves) were drawn as shown in Figure 1, and the log-rank test results shown in Table 3 revealed that the survival time of Group 3 was significantly longer than that of Group 1 and Group 2. This suggests that DPP4 inhibitors extend the survival time of patients with multiple system atrophy.

[0076] [Table 3]

[0077] 7. Analysis of the duration of DPP4 inhibitor administration From the medication prescription information (ActData) of patients in Group 3, the number of months for which DPP4 was prescribed after the diagnosis of MSA was calculated. When the correlation between the frequency of medication after MSA diagnosis (number of months of DPP4 prescription / MSA survival period (months)) and the survival period was calculated, a significant correlation was confirmed (ρ=0.41, p<0.05) (Figure 2).

[0078] 8. Breakdown of DPP4 inhibitors When we reviewed the prescription history of DPP4 inhibitors for patients in Group 3, the breakdown was as shown in Table 4. The median survival time for patients with a history of prescription for any of these drugs was found to be longer than that for patients in Group 1.

[0079] [Table 4]

[0080] 9. Comparison with insulin To evaluate whether a similar life-prolonging effect can be obtained with insulin, a representative diabetes medication, the same analysis as in Study 6 was performed on patients with a history of insulin prescriptions (ATC code: A10C). Of the 40 patients prescribed insulin, 21 (Group 5) were prescribed DPP4 inhibitors and 19 (Group 6) were not. To exclude the influence of DPP4 inhibitors, a comparison was made between Group 5 and Group 6. As a result, a significant life-prolonging effect was observed in Group 5, which was prescribed DPP4 inhibitors, compared to Groups 1 and 2, but no significant difference was observed in Group 6, indicating that insulin does not have a life-prolonging effect (Figure 3, Table 5).

[0081] [Table 5]

Claims

1. A pharmaceutical composition for the treatment or inhibition of progression of multiple system atrophy, comprising a DPP4 inhibitor.

2. A pharmaceutical composition for extending the survival time of patients with multiple system atrophy, comprising a DPP4 inhibitor.

3. A pharmaceutical composition for the treatment or suppression of the progression of multiple system atrophy in diabetic patients, comprising a DPP4 inhibitor.

4. A pharmaceutical composition for extending the survival time of diabetic patients with multiple system atrophy, comprising a DPP4 inhibitor.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP4 inhibitor is at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharmaceutically acceptable salts thereof.

6. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP4 inhibitor is administered once daily in a dose of 5 mg to 100 mg.

8. The pharmaceutical composition according to any one of claims 1 to 4, wherein the DPP4 inhibitor is teneligliptin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 20 mg.

9. A pharmaceutical composition according to any one of claims 1 to 4, which is administered in combination with other diabetes medications.

10. The pharmaceutical composition according to claim 9, wherein the other diabetes drug is an SGLT2 inhibitor.

11. The pharmaceutical composition according to claim 10, wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutically acceptable salts thereof.

12. The pharmaceutical composition according to claim 10, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof.

13. The pharmaceutical composition according to claim 10, wherein the SGLT2 inhibitor is administered once daily in a dose of 5 mg to 100 mg.

14. The pharmaceutical composition according to claim 10, wherein the SGLT2 inhibitor is canagliflozin or a pharmaceutically acceptable salt thereof, and is administered once daily at a dose of 100 mg.

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