WO2016148260A1 - Composition médicinale - Google Patents

Composition médicinale Download PDF

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Publication number
WO2016148260A1
WO2016148260A1 PCT/JP2016/058591 JP2016058591W WO2016148260A1 WO 2016148260 A1 WO2016148260 A1 WO 2016148260A1 JP 2016058591 W JP2016058591 W JP 2016058591W WO 2016148260 A1 WO2016148260 A1 WO 2016148260A1
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WO
WIPO (PCT)
Prior art keywords
dopa
istradefylline
dopamine agonist
disease
parkinson
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PCT/JP2016/058591
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English (en)
Japanese (ja)
Inventor
神田　知之
真一 内田
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協和発酵キリン株式会社
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Publication of WO2016148260A1 publication Critical patent/WO2016148260A1/fr

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/48—Ergoline derivatives, e.g. lysergic acid, ergotamine
    • 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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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

Definitions

  • the present invention relates to a therapeutic and / or prophylactic agent for early Parkinson's disease containing, for example, istradefylline, L-DOPA and a dopamine agonist.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • a dopamine agonist is performed as a first option (Movement Disord. 23, S497-508 (2008)).
  • Dopamine agonists are often used as a first-line monotherapy, especially in the treatment of early-onset early Parkinson's disease.
  • high doses of dopamine agonists often cause impulse control disorders (ICDs), vascular lesions, hallucinations, mental disorders, etc. (CNS (Drugs 24, 941-968 (2010); Curr. Drug Saf. 7, 63-75 (2012 )).
  • L-DOPA low-dose dopamine agonist therapy for patients with early Parkinson's disease
  • the L-DOPA dose should be kept at the lowest dose so as not to cause the above motor complications. It is suggested that However, as the disease progresses, it is necessary to increase the dose of L-DOPA in order to maintain its efficacy. This leads to an increased risk of causing motor complications such as wear-off and dyskinesia.
  • Istradefylline (KW-6002) has an adenosine A 2A receptor antagonistic action and is known as a therapeutic agent for Parkinson's disease (see, for example, Patent Documents 1 and 2).
  • istradefylline can suppress motor complications such as wear-off phenomenon and dyskinesia caused by L-DOPA therapy (for example, Patent Document 3, Non-Patent Document 3) References 1-4).
  • istradefylline can be used in combination with L-DOPA and / or a dopamine agonist (see, for example, Patent Document 3).
  • An object of the present invention is to provide a therapeutic and / or prophylactic agent for early Parkinson's disease containing Istradefylline, L-DOPA and a dopamine agonist.
  • the present invention relates to the following (1) to (13).
  • a therapeutic and / or prophylactic agent for early Parkinson's disease comprising (A) Istradefylline, (B) L-DOPA and (C) a dopamine agonist as active ingredients.
  • (2) (A) Istradefylline, (B) L-DOPA and (C) each of dopamine agonists are administered simultaneously or separately at different times, and / or the treatment according to (1) Preventive agent.
  • a pharmaceutical composition comprising Istradefylline, L-DOPA and ropinirole.
  • a pharmaceutical composition comprising istradefylline, L-DOPA and pergolide.
  • (10) treatment of early Parkinson's disease comprising the step of administering (A) Istradefylline, (B) L-DOPA and (C) dopamine agonist simultaneously or separately with time, and / or Or prevention methods.
  • a pharmaceutical composition comprising (A) istradefylline, (B) L-DOPA, and (C) a dopamine agonist for use in the treatment and / or prevention of early Parkinson's disease.
  • the present invention provides a therapeutic and / or preventive agent for early-stage Parkinson's disease containing istradefylline, L-DOPA and dopamine agonist as active ingredients.
  • FIG. 6 shows a 6-hour movement failure score when MPTP-treated common marmoset is administered with or without Istradefylline, L-DOPA and ropinirole.
  • the vertical axis represents the movement failure score, and the horizontal axis represents the administered drug.
  • the vertical axis represents the amount of spontaneous exercise (count), and the horizontal axis represents the administered drug.
  • 6 shows a 6-hour motor dysfunction score when MPTP-treated common marmoset was administered Istradefylline, L-DOPA and Pergolide alone or in combination.
  • the vertical axis represents the movement failure score, and the horizontal axis represents the administered drug.
  • Istradefylline in the present invention can be used in any form such as free form, salt, hydrate, solvate and the like. These can be obtained as commercial products, or can be obtained by a known method. Examples of commercially available products include Nouriast (registered trademark). L-DOPA in the present invention can be used in any form such as free form, salt, hydrate, solvate and the like. These can be obtained as commercial products, or can be obtained by a known method. Examples of commercially available products include Menesit (registered trademark), Eseed Pearl (registered trademark), Dopar (registered trademark), and Madopa (registered trademark).
  • Examples of the dopamine agonist in the present invention include pramipexole, rotigotine, taripexole, ropinirole, cabergoline, pergolide and the like, and ropinirole or pergolide is particularly preferable. These can be used in any form such as free form, salt, hydrate, solvate, prodrug, etc., and can be obtained as a commercial product or can be obtained by a known method. Examples of commercially available products include Domin (registered trademark), Permax (registered trademark), and Kabasar (registered trademark).
  • “Istradefylline”, “L-DOPA” and “dopamine agonist” in the present invention include all usable forms including free forms, salts, hydrates, solvates and the like thereof.
  • Benserazide in the present invention can be used in any form such as free form, salt, hydrate, solvate and the like. These can be obtained as commercial products, or can be obtained by a known method.
  • the salt is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; acetate , Oxalate, maleate, fumarate, citrate, benzoate, methanesulfonate, and other organic acid salts; sodium salts, potassium salts and other alkali metal salts; magnesium salts, calcium salts, and other alkali salts Earth metal salts; aluminum salts; zinc salts; ammonium salts, tetramethylammonium salts; addition salts of morpholine, piperidine, lysine, glycine, phenylalanine, aspartic acid, glutamic acid and the like.
  • the hydrate and solvate are not particularly limited as long as water and various solvents are added to the respective active ingredients, but for example, organic solvents such as water and ethanol are the active ingredients or salts thereof.
  • organic solvents such as water and ethanol are the active ingredients or salts thereof.
  • examples include those coordinated 0.5 to 3 molecules to the molecule.
  • the prodrug include prodrugs used in a general meaning in pharmacology, and are not particularly limited as long as they generate a corresponding active ingredient by causing decomposition or chemical reaction in vivo. Examples thereof include those in which the carboxyl group in the molecule of each active ingredient is converted to an ester such as a methyl ester.
  • “Early Parkinson's disease” in the present invention is a patient with Parkinson's disease who has not yet received medical examination or has received medical examinations such as L-DOPA therapy. It refers to Parkinson's disease symptoms in patients who have not developed motor complications such as wear-off phenomenon or dyskinesia (see, for example, Parkinson's Disease Treatment Guidelines 2001 (Neurology 56 (Suppl 5), S1-S88 (2001))). In contrast, “advanced Parkinson's disease” refers to symptoms of Parkinson's disease in patients who have already received L-DOPA therapy and have developed motor complications such as wear-off and dyskinesia. .
  • the early-stage Parkinson's disease treatment and / or prevention agent and pharmaceutical composition of the present invention contain, for example, the active ingredients of (A) istradefylline, (B) L-dopa and (C) dopamine agonists, respectively.
  • a pharmaceutically acceptable carrier it can be used or administered as a single agent (mixture) or as a combination of a plurality of formulations. Of these, a combination of two or more preparations is preferred. When used or administered as a combination of a plurality of preparations, they can be used or administered separately at the same time or at intervals.
  • These preparations are preferably used in the form of tablets, injections, external preparations and the like.
  • compositions can contain any other active ingredient in addition to the above active ingredients (A) to (C).
  • active ingredients include drugs that suppress L-DOPA metabolism such as carbidopa and benserazide.
  • formulations are also well known in the pharmaceutical arts by mixing the active ingredient with one or more pharmaceutically acceptable carriers (eg, diluents, solvents, excipients, etc.). Manufactured by any method.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • the dosage form suitable for the external preparation is not particularly limited, and examples thereof include an ointment, cream, liniment, lotion, poultice, plaster, and tape.
  • ointments, creams and the like can be produced by dissolving or mixing and dispersing active ingredients in a base such as white petrolatum.
  • each of the three components can be formulated separately and prepared as a kit. Using this kit, each component can be administered to the same subject by the same route or different routes at the same time or at different times. .
  • kits There are no particular limitations on the material and shape of the kit, as long as it is a container that does not show, for example, denaturation of components that are the contents due to external temperature or light during storage, or elution of chemical components from the container. Consists of the above containers (eg, vials, bags, etc.) and contents, and the contents of the first component, second component, and third component can be administered via separate routes (eg, tubes) or the same route Those having various forms are used. Specific examples include tablets and injection kits.
  • the dose ratio (weight / weight) of (A) istradefylline, (B) L-dopa and (C) dopamine agonist in the therapeutic and / or prophylactic agent and pharmaceutical composition of early Parkinson's disease of the present invention is used ( C) Depending on the type of dopamine agonist, it may be appropriately adjusted in consideration of the efficacy of each.
  • (C) 0.02 to 5 mg of dopamine agonist is used.
  • Test Example 1 Anti-Parkinson Disease Activity by Administering Istradefylline, L-DOPA and Ropinirole in Combination in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated Common Marmoset Parkinson's Disease Is a disease based on degeneration / dropout of nigro-striatal dopamine nerve. In primates, treatment with MPTP, a dopamine neurotoxin, results in selective degeneration and loss of nigrostriatal dopamine nerves, causing symptoms such as ataxia and muscle rigidity.
  • MPTP 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • This MPTP-treated primate is known as a Parkinson's disease model (Proceedings of the National Academy of Science USA, 80, p. 4546 (1983)). Moreover, it is known that common marmoset belongs to the monkeys and exhibits Parkinson's disease symptoms by MPTP like other monkeys (Neuroscience Letter, 57, p.37 (1985)).
  • MPTP (Sigma Aldrich) is administered to common marmoset (CLEA Japan) at a dose of 2 mg / kg once a day for 5 days subcutaneously in the back, and after 1-2 weeks, once again 1-2 mg / kg once or twice Common Marmoset (MPTP) that developed chronic Parkinson's disease symptoms (decreased locomotor activity, slow motion, abnormal gait, posture disorder, abnormal coordinated movement, decreased vocalization, etc.) by additional administration twice subcutaneously on the back Treatment marmoset) was made and used for testing.
  • MPTP Common Marmoset
  • Parkinson's symptoms were determined using the indices described in the previous report (Annals Neurology, 43, p.507 (1998)). The observation items and scores are shown in Table 1. All drugs were used as suspensions in 0.5% methylcellulose solution (MC400) and 10% aqueous sucrose. The test animals were placed in an observation cage (with a spontaneous momentum measuring device) the day before the evaluation and were accustomed to the environment.
  • MC400 methylcellulose solution
  • sucrose aqueous sucrose
  • Parkinson's disease symptoms were 10
  • the dyskinetic movement was scored by observing through a unidirectional fluoroscopic window for 6 hours every minute.
  • Spontaneous momentum was automatically measured by a computer using a measuring device with a photocell.
  • a tablet having the following composition is prepared by a conventional method. 80 gram of Istradefylline, 286.8 gram of lactose and 60 gram of potato starch are mixed, and 120 gram of 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2 g of magnesium stearate to this and mix, and tablet with a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (20 mg of Istradefylline per tablet) Containing).
  • RT-15 tableting machine
  • a tablet having the following composition is prepared by a conventional method. Istradefylline (20 g), L-DOPA (100 g), ropinirole (6 g), lactose (200.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution of hydroxypropylcellulose (120 g) is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2 g of magnesium stearate to this and mix, and tablet with a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch. Tablets (10 mg of Istradefylline per tablet) , Containing 50 mg of L-DOPA and 3 mg of ropinirole).
  • a tablet having the following composition is prepared by a conventional method. 20 g of Istradefylline, 100 g of L-DOPA, 1 g of pergolide, 205.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2 g of magnesium stearate to this and mix, and tablet with a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch. Tablets (10 mg of Istradefylline per tablet) L-DOPA (50 mg) and pergolide (0.5 mg).
  • a tablet having the following composition is prepared by a conventional method.
  • L-DOPA (80 g), lactose (286.8 g) and potato starch (60 g) are mixed, and 10% aqueous solution of hydroxypropylcellulose (120 g) is added thereto.
  • This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting.
  • a tablet having the following composition is prepared by a conventional method. 80 g of ropinirole, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2 g of magnesium stearate to this, mix, and tablet using a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm, containing 20 mg of ropinirole per tablet. To get).
  • RT-15 manufactured by Kikusui Co., Ltd.
  • a tablet having the following composition is prepared by a conventional method. 80 g of pergolide, 286.8 g of lactose and 60 g of potato starch are mixed, and 120 g of a 10% aqueous solution of hydroxypropylcellulose is added thereto. This mixture is kneaded by a conventional method, granulated and dried, and then sized to obtain granules for tableting. Add 1.2 g of magnesium stearate to this, mix, and tablet using a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a 8 mm diameter punch, containing 20 mg of pergolide per tablet To get).
  • RT-15 manufactured by Kikusui Co., Ltd.
  • the present invention can be used for the treatment and / or prevention of early Parkinson's disease, for example.
  • Step-Dwass test. # P ⁇ 0.05 Comparison with ropinirole group or pergolide group (Steel-Dwass test.) + P ⁇ 0.05 L-DOPA group comparison (Steel-Dwass test.) $ P ⁇ 0.05 Istradefylline group comparison (Steel-Dwass test.)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un agent de traitement et/ou de prévention de la maladie de Parkinson précoce qui comprend en tant que principes actifs (A) une istradefylline, (B) L-DOPA et (C) un antagoniste dopaminergique. Plus précisément, l'invention fournit cet agent de traitement et/ou de prévention qui est caractéristique en ce que (A) une istradefylline, (B) L-DOPA et (C) un antagoniste dopaminergique sont tous administrés en même temps ou séparément à intervalles de temps.
PCT/JP2016/058591 2015-03-17 2016-03-17 Composition médicinale WO2016148260A1 (fr)

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JP2015052885 2015-03-17
JP2015-052885 2015-03-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211856A (ja) * 1992-09-28 1994-08-02 Kyowa Hakko Kogyo Co Ltd パーキンソン氏病治療剤
JP2005523898A (ja) * 2002-01-28 2005-08-11 協和醗酵工業株式会社 運動障害を患っている患者を治療する方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06211856A (ja) * 1992-09-28 1994-08-02 Kyowa Hakko Kogyo Co Ltd パーキンソン氏病治療剤
JP2005523898A (ja) * 2002-01-28 2005-08-11 協和醗酵工業株式会社 運動障害を患っている患者を治療する方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
UCHIDA,S. ET AL.: "The adenosine A2A receptor antagonist, istradefylline enhances anti- parkinsonian activity induced by combined treatment with low doses of L-DOPA and dopamine agonists in MPTP-treated common marmosets", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 766, 5 November 2015 (2015-11-05), pages 25 - 30, XP055312240, ISSN: 0014-2999 *
UCHIDA,S. ET AL.: "The adenosine A2A receptor antagonist, istradefylline enhances the anti- parkinsonian activity of low doses of dopamine agonists in MPTP-treated common marmosets", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 747, 15 January 2015 (2015-01-15), pages 160 - 165, XP029189900, ISSN: 0014-2999 *

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