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WO2024204772A1 - Composition pharmaceutique pour le traitement de l'atrophie multisystémique ou l'inhibition de la progression de l'atrophie multisystémique - Google Patents

Composition pharmaceutique pour le traitement de l'atrophie multisystémique ou l'inhibition de la progression de l'atrophie multisystémique Download PDF

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WO2024204772A1
WO2024204772A1 PCT/JP2024/013202 JP2024013202W WO2024204772A1 WO 2024204772 A1 WO2024204772 A1 WO 2024204772A1 JP 2024013202 W JP2024013202 W JP 2024013202W WO 2024204772 A1 WO2024204772 A1 WO 2024204772A1
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pharmaceutical composition
inhibitor
dpp4
item
patients
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Japanese (ja)
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裕一 西村
史照 小島
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present disclosure relates to pharmaceutical compositions for treating or inhibiting the progression of multiple system atrophy.
  • MSA Multiple system atrophy
  • GCIs glial cytoplasmic inclusions
  • MSA is a clinical pathological concept that includes olivopontocerebellar atrophy (OPCA), whose main symptom is cerebellar ataxia, striatonigral degeneration, whose main symptom is parkinsonism, and Shy-Drager syndrome, whose main symptom is autonomic neuropathy. It is classified into MSA-C, in which cerebellar ataxia predominates, and MSA-P, in which parkinsonism predominates (Non-Patent Document 1). No effective treatment for MSA has been established, and symptomatic treatment is usually performed according to each symptom.
  • the objectives of the present disclosure include providing a pharmaceutical composition for treating or inhibiting the progression of multiple system atrophy, and a pharmaceutical composition for extending the survival time of patients with multiple system atrophy.
  • a pharmaceutical composition containing a DPP inhibitor is useful for treating or inhibiting the progression of multiple system atrophy, and for extending the survival time of patients with multiple system atrophy. Based on this finding, the inventors have conducted further research and have completed the present disclosure.
  • [Item 4] A pharmaceutical composition for extending the survival time of a diabetic patient with multiple system atrophy, the pharmaceutical composition comprising a DPP4 inhibitor.
  • the DPP4 inhibitor is at least one selected from the group consisting of the compounds shown in Table 1 below, preferably teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, vildagliptin, and pharma- ceutical acceptable salts thereof.
  • the DPP4 inhibitor is anagliptin, linagliptin, teneligliptin, or a pharma- ceutical acceptable salt thereof.
  • Item 8 Item 8. The pharmaceutical composition according to any one of Items 1 to 7, wherein the DPP4 inhibitor is teneligliptin or a pharma- ceutical acceptable salt thereof, and is administered once a day at a dose of 20 mg.
  • Item 10 Item 10.
  • the pharmaceutical composition according to Item 9, wherein the other diabetes drug is an SGLT2 inhibitor.
  • Item 11 Item 11.
  • the pharmaceutical composition according to item 10 wherein the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharma- ceutical acceptable salts thereof.
  • the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharma- ceutical acceptable salts thereof.
  • the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharma- ceutical
  • Item 14 The pharmaceutical composition according to any one of items 10 to 13, wherein the SGLT2 inhibitor is canagliflozin or a pharma- ceutical acceptable salt thereof and is administered once a day at a dose of 100 mg.
  • [Item A1] A method for treating or inhibiting progression of multiple system atrophy in a subject in need thereof, the method comprising administering to the subject a DPP4 inhibitor.
  • [Item A2] A method of extending survival of a patient having multiple system atrophy, comprising administering to said patient a DPP4 inhibitor.
  • [Item A3] 1. A method for treating or inhibiting the progression of multiple system atrophy in a diabetic patient in need of such treatment or inhibition of progression, the method comprising the step of administering a DPP4 inhibitor to the diabetic patient.
  • [Item A4] 1. A method for extending the survival time of a diabetic patient having multiple system atrophy, comprising administering to said diabetic patient a DPP4 inhibitor.
  • the DPP4 inhibitor is at least one selected from the group consisting of the compounds shown in Table 1 below, preferably teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, vildagliptin, and pharma- ceutically acceptable salts thereof.
  • the DPP4 inhibitor is anagliptin, linagliptin, teneligliptin, or a pharma- ceutically acceptable salt thereof.
  • [Item A7] The method according to any one of items A1 to A6, wherein the step comprises administering the DPP4 inhibitor at a dose of 5 mg or more and 100 mg or less once a day.
  • the step comprises administering teneligliptin or a pharma- ceutically acceptable salt thereof once a day at a dose of 20 mg.
  • the step is a step of administering another diabetes drug in combination with the DPP4 inhibitor.
  • the other diabetes drug is an SGLT2 inhibitor.
  • the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharma- ceutically acceptable salts thereof.
  • the SGLT2 inhibitor is canagliflozin or a pharma- ceutically acceptable salt thereof.
  • the SGLT2 inhibitor is canagliflozin or a pharma- ceutically acceptable salt thereof.
  • [Item C1] Use of a DPP4 inhibitor for the manufacture of a medicament for treating or inhibiting the progression of multiple system atrophy.
  • [Item C2] 23. Use of a DPP4 inhibitor for the manufacture of a medicament for extending the survival of patients with multiple system atrophy.
  • [Item C3] Use of a DPP4 inhibitor for the manufacture of a medicament for treating or inhibiting the progression of multiple system atrophy in a diabetic patient.
  • [Item C4] Use of a DPP4 inhibitor for the manufacture of a medicament for extending the survival time of a diabetic patient with multiple system atrophy.
  • the SGLT2 inhibitor is at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharma- ceutically acceptable salts thereof.
  • the SGLT2 inhibitor is canagliflozin or a pharma- ceutically acceptable salt thereof.
  • One embodiment of the present disclosure is extremely useful for treating or inhibiting the progression of multiple system atrophy, and for extending the survival time of patients with multiple system atrophy.
  • Figure 1 compares the survival curves (Kaplan-Meier curves) of the group treated with DPP4 inhibitors with the survival curves of the group not treated with DPP4 inhibitors (e.g., the group treated with diabetes drugs other than DPP4 inhibitors).
  • Figure 2 shows the correlation between the frequency of DPP4 inhibitor administration after the diagnosis of multiple system atrophy (MSA) (number of months of DPP4 prescription/MSA survival time (months)) and survival time.
  • Figure 3 compares the survival curves of the group administered both insulin and a DPP4 inhibitor with the survival curves of the group administered insulin but not a DPP4 inhibitor.
  • Figure 4 compares the survival curves (Kaplan-Meier curves) of the group treated with DPP4 inhibitors with the survival curves of the group not treated with DPP4 inhibitors (e.g., the group treated with diabetes drugs other than DPP4 inhibitors) in patients who did not undergo tracheostomy.
  • MSA multiple system atrophy
  • GCIs glial cytoplasmic inclusions
  • Multiple system atrophy includes olivopontocerebellar atrophy (OPCA), whose main symptom is cerebellar ataxia, striatonigral degeneration, whose main symptom is parkinsonism, and Shy-Drager syndrome, whose main symptom is autonomic neuropathy.
  • OPCA olivopontocerebellar atrophy
  • MSA-C in which cerebellar ataxia predominates
  • MSA-P in which parkinsonism predominates.
  • Multiple system atrophy is almost always sporadic, but can also be familial.
  • Ataxia is a condition in which muscles do not move in a coordinated manner despite normal muscle strength, making it difficult to move smoothly. Examples of this include gait disturbance (unsteadiness), limb ataxia, and speech disorders.
  • Extrapyramidal symptoms are when motor control in the basal ganglia and other organs is impaired, resulting in involuntary movements or the inability to move smoothly. Examples of these symptoms include parkinsonism, which includes muscular rigidity, slow or reduced movement, and impaired postural reflexes.
  • Pyramidal symptoms are when the pathways that transmit motor commands from the cerebrum are impaired, causing abnormalities in voluntary movement such as motor paralysis, and examples of these symptoms include spasticity.
  • Autonomic nervous system symptoms are various abnormalities that occur due to a disruption in the functioning of the autonomic nervous system, which regulates factors such as the amount of sweating and blood pressure, and include orthostatic hypotension (dizziness, lightheadedness when standing up), urinary problems, and sweating disorders.
  • the severity of multiple system atrophy can be measured, for example, based on the Unified Multiple System Atrophy Rating Scale (UMSARS).
  • UMSARS Unified Multiple System Atrophy Rating Scale
  • 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 function), and Part IV (assessment of overall disability). Details of the assessment criteria for each part are provided below.
  • treatment is used to mean not only improvement, remission, and complete cure of symptoms, but also the alleviation (or reduction) of symptoms and prevention of progression (or worsening) of symptoms.
  • Treatment includes, for example, preventing or reducing the score (total) in Part I, the score in Part II, and/or the score in Part IV of the Unified Multiple System Atrophy Rating Scale, as well as alleviating or improving symptoms due to standing in Part III.
  • inhibiting the progression of a symptom means at least temporarily stopping or slowing the progression of the symptom.
  • extended survival generally means surviving longer than the expected survival time based on factors such as the severity of multiple system atrophy.
  • the subject is not particularly limited as long as it is an animal with multiple system atrophy.
  • the subject may be a human or a non-human animal.
  • Non-human animals include, for example, rodents such as rats, mice, and guinea pigs; and mammals other than humans such as monkeys, pigs, dogs, and cats.
  • a low molecular weight compound generally refers to a compound with a molecular weight of less than 10,000
  • a high molecular weight compound generally refers to a compound with a molecular weight of 10,000 or more, including nucleic acids, polypeptides (e.g., antibodies), and conjugates containing these.
  • a pharma- ceutically acceptable salt may be an inorganic salt or an organic salt.
  • inorganic salts include hydrochlorides, hydrochlorides, hydrobromides, nitrates, sulfates, bisulfates, borates, and phosphates; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts.
  • organic salts examples include acetates, lactates, malates, benzoates, oxalates, succinates, tartrates, fumarates, maleates, citrates, methanesulfonates, ethanesulfonates, benzenesulfonates, toluenesulfonates, and tosylates.
  • pharma- ceutically acceptable salts also include their hydrates and solvates.
  • 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 types.
  • DPP4 inhibitor is a low molecular weight compound
  • specific examples include the compounds shown in Table 1.
  • the compounds shown in Table 1 may be pharma- ceutically acceptable hydrates or solvates, or prodrugs.
  • DPP-4 inhibitor for example, the compounds described in the following documents can be used. Tanabe Seiyaku Co., Ltd.: WO02/30891 or its corresponding U.S. patent (No. 6,849,622) (particularly compound (1c-10)), and WO02/30890 or its corresponding U.S. patent (No.
  • the other diabetes drugs are not particularly limited as long as they are diabetes drugs other than DPP4 inhibitors.
  • examples of other diabetes drugs include SGLT2 inhibitors, ⁇ -glucosidase inhibitors, GLP-1 receptor agonists, insulin, etc.
  • the other diabetes drugs may be used alone or in combination of two or more.
  • the SGLT2 inhibitor is not particularly limited as long as it is a substance that inhibits sodium glucose transport protein 2 (SGLT2).
  • the SGLT2 inhibitor may be a low molecular weight compound or a high molecular weight compound.
  • the SGLT2 inhibitor may be used alone or in combination of two or more types.
  • the SGLT2 inhibitor is a low molecular weight compound
  • specific examples include the compounds shown in Table 2.
  • the compounds shown in Table 2 may be pharma- ceutically acceptable hydrates or solvates, or prodrugs.
  • SGLT2 inhibitors include, for example, WO01/16147, WO01/27128, WO01/68660, WO01/74834, WO02/028872, WO02/053573, WO2004/013118, WO2004/080990, WO2006/035796, WO2005/085265, WO2005/085267, WO2005/0928 Compounds described in, for example, 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, and U.S. Patent No. 5,767,094 can also be used.
  • administration in combination refers to administration of individual drugs simultaneously (e.g., as a single pharmaceutical composition such as Canalia combination tablets) or consecutively, and also refers to administration of individual drugs separately in any order with a specified interval between each drug (e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, or 24 hours).
  • composition A is a pharmaceutical composition for treating or inhibiting the progression of multiple system atrophy, comprising a DPP4 inhibitor.
  • Pharmaceutical composition A can be suitably used for treating or inhibiting the progression of multiple system atrophy in a subject, preferably a patient (human), more preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • a pharmaceutical composition according to another embodiment of the present disclosure is a pharmaceutical composition for extending the survival time of a patient with multiple system atrophy, comprising a DPP4 inhibitor.
  • the patient is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the DPP4 inhibitor is preferably a low molecular weight compound, more preferably at least one selected from the group consisting of the compounds shown in Table 1, even more preferably at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, vildagliptin, and pharma- ceutically acceptable salts thereof, even more preferably at least one selected from the group consisting of teneligliptin, anagliptin, linagliptin, alogliptin, sitagliptin, and pharma-ceutically acceptable salts thereof, and particularly preferably anagliptin, linagliptin, teneligliptin, or a pharma-ceutically acceptable salt thereof.
  • compositions A and B further contain pharma- ceutical acceptable additives.
  • additives include excipients, disintegrants or disintegration aids, binders, lubricants, flow agents, coating agents, dyes, diluents, bases, solubilizers or solubilization aids, isotonicity agents, pH regulators, stabilizers, propellants, adhesives, dispersants, thickeners, sweeteners, and antifoaming agents.
  • additives can be used alone or in combination of two or more.
  • compositions A and B can be provided as formulations in forms known to those skilled in the art.
  • Specific examples of the formulations suitable for oral or intragastric administration include tablets, capsules, powders, fine granules, granules, liquids, syrups, and suspensions, while specific examples of the formulations suitable for parenteral administration include injections, drops, eye drops, patches, and suppositories.
  • the formulations 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, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, and crospovidone; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, and gelatin; lubricants such as magnesium stearate, calcium stearate, and talc; flow agents such as silicic anhydride; and hydroxypropylmethylcellulose.
  • excipients such as glucose, lactose, D-mannitol, D-sorbitol, corn starch, dextrin, and crystalline cellulose
  • disintegrants or disintegration aids such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose
  • Examples of the materials that can be used include coating agents such as sucrose, white sugar, polyethylene glycol, and titanium oxide; 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 powdered tragacanth; sweeteners such as sorbitol; stabilizers such as sodium hydrogen sulfite and L-cysteine hydrochloride; pH regulators such as phosphoric acid, acetic acid, and sodium hydroxide; antifoaming agents such as dimethicone emulsion; solvents such as aqueous solvents such as water, buffer solutions, and saline, and oily solvents such as olive oil; and fragrances.
  • bases such as petrolatum, liquid paraffin, polyethylene glycol, gelatin, kaolin, glycerin, purified water, and hard fat
  • the above preparations suitable for injection or infusion may contain, as additives, for example, dissolving agents or solubilizing aids capable of forming aqueous or ready-to-use injectables such as distilled water for injection, physiological saline, and propylene glycol; isotonicity agents such as glucose, sodium chloride, D-mannitol, and glycerin; pH regulators such as inorganic acids, organic acids, inorganic bases, and organic bases; and combinations of two or more of these.
  • dissolving agents or solubilizing aids capable of forming aqueous or ready-to-use injectables
  • isotonicity agents such as glucose, sodium chloride, D-mannitol, and glycerin
  • pH regulators such as inorganic acids, organic acids, inorganic bases, and organic bases; and combinations of two or more of these.
  • compositions A and B are preferably Tenelia tablets or Tenelia OD tablets.
  • the dose (administration amount) of the DPP4 inhibitor may be an effective amount selected appropriately depending on the age, weight, sex, severity, and administration route of the subject.
  • the daily dose may be, for example, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. It may also be a range (for example, about 5 mg or more and about 100 mg or less) with two values selected from among these as the upper and lower limits.
  • the DPP4 inhibitor is a salt
  • the dosage may be the amount converted to the free form.
  • the DPP4 inhibitor can be administered in the above doses once or in several divided doses (e.g., two or three times).
  • the DPP4 inhibitor is preferably administered at a dose of 5 mg to 100 mg once daily, and more preferably, teneligliptin or a pharma- ceutically acceptable salt thereof is administered at a dose of 20 mg once daily.
  • compositions A and B may be pharmaceutical compositions administered in combination with other diabetes drugs.
  • the other diabetes drugs are preferably other than insulin, and more preferably biguanides and/or SGLT2 inhibitors.
  • the biguanides are preferably at least one selected from the group consisting of metformin, buformin, and pharmaceutical acceptable salts thereof (e.g., hydrochlorides).
  • 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, i.e., at least one selected from the group consisting of canagliflozin, empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, tofogliflozin, and pharmaceutical acceptable salts thereof, and more preferably canagliflozin or a pharmaceutical acceptable salt thereof.
  • the other diabetes drug is preferably administered in the form of a pharmaceutical composition.
  • the pharma- ceutically acceptable additives contained in the pharmaceutical composition may be one or more of the components exemplified in pharmaceutical compositions A and B.
  • the pharmaceutical composition containing an SGLT2 inhibitor as the other diabetes drug is preferably a Canaglu tablet.
  • the dosage of other diabetes drugs may be an effective amount selected appropriately depending on the age, weight, sex, severity, and administration route of the subject.
  • the daily dose may be, for example, about 0.1 mg, about 0.5 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, or about 100 mg. It may also be a range (e.g., about 5 mg or more and about 100 mg or less) with two values selected from these as the upper and lower limits.
  • the DPP4 inhibitor is a salt
  • the dosage may be the amount converted to the free form.
  • diabetes medications e.g., SGLT2 inhibitors
  • SGLT2 inhibitors can be administered in the above doses once or in several divided doses (e.g., two or three times).
  • the other diabetes drug e.g., an SGLT2 inhibitor
  • the other diabetes drug is preferably administered once daily at a dose of 5 mg to 100 mg, and more preferably, canagliflozin or a pharma- ceutically acceptable salt thereof is administered once daily at a dose of 100 mg.
  • Method A method according to one embodiment of the present disclosure is a method for treating or inhibiting the progression of multiple system atrophy in a subject in need of such treatment or inhibition of progression, comprising administering a DPP4 inhibitor to the subject.
  • the subject is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • a method according to another aspect of the present disclosure is a method for extending the survival time of a patient with multiple system atrophy, the method comprising a step of administering a DPP4 inhibitor to the patient.
  • the patient is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the patient may or may not have undergone a tracheotomy. Even if the patient has not undergone a tracheotomy, the survival time can be significantly extended by administering a DPP4 inhibitor. If the patient has undergone a tracheotomy, the survival time can be further extended by administering a DPP4 inhibitor.
  • the DPP4 inhibitor according to one embodiment of the present disclosure is a DPP4 inhibitor for use in the treatment or inhibition of progression of multiple system atrophy.
  • the DPP4 inhibitor can be suitably used in the treatment or inhibition of progression of multiple system atrophy in a subject, preferably a patient (human), more preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the subject may or may not have undergone tracheotomy.
  • a DPP4 inhibitor according to another embodiment of the present disclosure is a DPP4 inhibitor for use in extending the survival time of a patient with multiple system atrophy.
  • the patient is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the patient may or may not have undergone a tracheotomy.
  • DPP4 inhibitors symptoms, dosage, administration method, etc.
  • symptoms, dosage, administration method, etc. can be the same as those of "(2) Pharmaceutical composition" above.
  • the use according to one embodiment of the present disclosure is the use of a DPP4 inhibitor for the manufacture of a medicament for the treatment or inhibition of progression of multiple system atrophy.
  • the use is preferably for the manufacture of a medicament for the treatment or inhibition of progression of multiple system atrophy in a subject, preferably a patient (human), more preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the subject may or may not have undergone tracheotomy.
  • Another aspect of the present disclosure is the use of a DPP4 inhibitor for the manufacture of a medicament for extending the survival of a patient with multiple system atrophy.
  • the patient is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • kits for treating or inhibiting the progression of multiple system atrophy, comprising a DPP4 inhibitor.
  • the kit can be suitably used for treating or inhibiting the progression of multiple system atrophy in a subject, preferably a patient (human), more preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the subject may or may not have undergone tracheotomy.
  • a kit according to another embodiment of the present disclosure is a kit for extending the survival time of a patient with multiple system atrophy, comprising a DPP4 inhibitor.
  • the patient is preferably a diabetic patient (e.g., a type 2 diabetic patient).
  • the patient may or may not have undergone a tracheotomy.
  • the kit may also include other diabetes drugs, preferably an SGLT2 inhibitor.
  • the kit may also include a container for filling the drug or a container filled with the drug, and/or an instrument required for administering the drug.
  • the kit may also include instructions that describe the details of the drug (such as the administration method).
  • the kit may be in a packaged form.
  • Other components of the kit symptoms, dosage, administration method, etc. may be the same as those of "(2) Pharmaceutical composition" above.
  • Patients to be analyzed were selected from the patient information extracted in steps 1 to 4.
  • the analysis subjects were 180 patients, excluding patients who had been treated for multiple system atrophy for more than two years before being registered in the database, and patients who died within two years of starting treatment for multiple system atrophy.
  • patients who did not suffer from diabetes and were not prescribed antidiabetic drugs were classified into Group 1 (106 patients), patients who suffered from diabetes were classified into Group 2 (28 patients), patients who were prescribed DPP4 inhibitors were classified into Group 3 (25 patients), and patients who were prescribed antidiabetic drugs other than DPP4 inhibitors were classified into Group 4 (21 patients).

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Abstract

L'invention concerne une composition pharmaceutique pour le traitement de l'atrophie multisystémique ou l'inhibition de la progression de l'atrophie multisystémique ou pour l'extension de la période de survie d'un patient atteint d'atrophie multisystémique. Est divulguée une composition pharmaceutique pour le traitement de l'atrophie multisystémique ou l'inhibition de la progression de l'atrophie multisystémique ou pour l'extension de la période de survie d'un patient atteint d'une atrophie multisystémique, la composition pharmaceutique contenant un inhibiteur de DPP4.
PCT/JP2024/013202 2023-03-31 2024-03-29 Composition pharmaceutique pour le traitement de l'atrophie multisystémique ou l'inhibition de la progression de l'atrophie multisystémique Pending WO2024204772A1 (fr)

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JP2023058578 2023-03-31

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014271A1 (fr) * 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Dérivés de proline et leur utilisation comme médicaments
WO2006088129A1 (fr) * 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Sel d'un dérivé de proline, solvate dudit sel, et méthode de production dudit sel
WO2013061161A2 (fr) * 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl Nouvelles polythérapies destinées au traitement de troubles neurologiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002014271A1 (fr) * 2000-08-10 2002-02-21 Mitsubishi Pharma Corporation Dérivés de proline et leur utilisation comme médicaments
WO2006088129A1 (fr) * 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation Sel d'un dérivé de proline, solvate dudit sel, et méthode de production dudit sel
WO2013061161A2 (fr) * 2011-10-28 2013-05-02 Green Bcn Consulting Services Sl Nouvelles polythérapies destinées au traitement de troubles neurologiques

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