WO2016148260A1 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
- 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
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dopa
- istradefylline
- dopamine agonist
- disease
- parkinson
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 87
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 83
- IQVRBWUUXZMOPW-PKNBQFBNSA-N istradefylline Chemical compound CN1C=2C(=O)N(CC)C(=O)N(CC)C=2N=C1\C=C\C1=CC=C(OC)C(OC)=C1 IQVRBWUUXZMOPW-PKNBQFBNSA-N 0.000 claims abstract description 68
- 229950009028 istradefylline Drugs 0.000 claims abstract description 66
- 239000003136 dopamine receptor stimulating agent Substances 0.000 claims abstract description 58
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 44
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 22
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 20
- 239000004480 active ingredient Substances 0.000 claims abstract description 17
- 230000000069 prophylactic effect Effects 0.000 claims abstract description 14
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 claims description 19
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical group CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 claims description 18
- 229960004851 pergolide Drugs 0.000 claims description 17
- 229960001879 ropinirole Drugs 0.000 claims description 17
- 239000000203 mixture Substances 0.000 description 21
- 208000024891 symptom Diseases 0.000 description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- PLRACCBDVIHHLZ-UHFFFAOYSA-N 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Chemical compound C1N(C)CCC(C=2C=CC=CC=2)=C1 PLRACCBDVIHHLZ-UHFFFAOYSA-N 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 12
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- 238000012360 testing method Methods 0.000 description 12
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- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 7
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- 230000002269 spontaneous effect Effects 0.000 description 7
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- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 6
- 229960000911 benserazide Drugs 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
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- 239000000651 prodrug Substances 0.000 description 3
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- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical class NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
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- VIYKYVYAKVNDPS-HKGPVOKGSA-N (2s)-2-azanyl-3-[3,4-bis(oxidanyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 VIYKYVYAKVNDPS-HKGPVOKGSA-N 0.000 description 1
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- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 1
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- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 241000725101 Clea Species 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Chemical class OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical class OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical class OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical class OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Chemical class NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
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- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
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- 208000027089 Parkinsonian disease Diseases 0.000 description 1
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- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical class OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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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Abstract
Provided is a therapeutic and/or prophylactic agent or the like for early-stage Parkinson's disease which includes, as active ingredients, istradefylline (A), L-DOPA (B), and a dopamine agonist (C), and which is characterized in that the istradefylline (A), the L-DOPA (B), and the dopamine agonist (C) are each administered simultaneously or separately at intervals.
Description
本発明は、例えばイストラデフィリン、L-DOPAおよびドパミンアゴニストを含有する早期パーキンソン病の治療および／または予防剤などに関する。
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.
パーキンソン病の薬物治療には、第一選択肢としてL-DOPA（L-3,4-dihydroxyphenylalanine）またはドパミンアゴニストによる治療が行われている（Movement Disord. 23, S497-508 (2008)）。ドパミンアゴニストは単剤療法の第一選択肢として、特に若年性の早期パーキンソン病の治療によく用いられている。しかし、高用量のドパミンアゴニストはしばしば衝動制御障害（ICDs）、血管病変、幻覚、精神障害などを引き起こす（CNS Drugs 24, 941-968 (2010); Curr. Drug Saf. 7, 63-75 (2012)）。低用量のドパミンアゴニスト療法において、多くの場合L-DOPAを併用することにより、運動機能が効果的に改善する（Expert Opin. Investig. Drugs 23, 387-410 (2014)）。しかしながら、L-DOPAとの併用は、その用量が増加するにつれウェアリング・オフ現象やジスキネジアなどの運動合併症を引き起こすリスクを伴う（Movement Disord. 16, 448-458 (2001); Parkinsonism Relat. Disord. 8, 101-108 (2001)）。近年、早期パーキンソン病患者に対するL-DOPAの1日投与量が400 mg以下である場合には、上記の運動合併症を発症するリスクが大きく低減されることが報告された（Movement Disord. 28, 1064-1071 (2013)）。このことは、早期パーキンソン病患者に対して低用量のドパミンアゴニスト療法にL-DOPAを併用する場合、上記の運動合併症を発症させないためにL-DOPAの投与量を最低用量とすることが求められることを示唆している。しかしながら、疾患の進行に伴って、薬効を維持するためにL-DOPAの用量を増加することが余儀なくされる。これは即ちウェアリング・オフ現象やジスキネジアなどの運動合併症を引き起こすリスクを増加させることに繋がる。
For the drug treatment of Parkinson's disease, treatment with L-DOPA (L-3,4-dihydroxyphenylalanine) or 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. However, 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 )). In low-dose dopamine agonist therapy, the combined use of L-DOPA often effectively improves motor function (ExpertExpOpin. Investig. Drugs 23, 387-410 (2014)). However, concomitant use with L-DOPA carries the risk of causing motor complications such as wear-off and dyskinesia as the dose increases (Movement Disord. 16, 448-458 (2001); Parkinsonism Relat. Disord . 8, 101-108 (2001)). In recent years, it has been reported that the risk of developing the above-mentioned motor complications is greatly reduced when the daily dose of L-DOPA for patients with early Parkinson's disease is 400 mg or less (Movement Disord. 28, 1064-1071 (2013)). This means that when L-DOPA is used in combination with 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.
イストラデフィリン（Istradefylline；KW-6002）は、アデノシンA2A受容体拮抗作用を有し、パーキンソン病などの治療薬として知られている（例えば特許文献1および2参照）。特に、進行期のパーキンソン病患者では、イストラデフィリンの投与によりL-DOPA療法で生ずるウェアリング・オフ現象やジスキネジアなどの運動合併症を抑制できることが知られている（例えば特許文献3、非特許文献1～4参照）。また、イストラデフィリンはL-DOPAおよび／またはドパミンアゴニストと併用できることが知られている（例えば特許文献3参照）。
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). In particular, in patients with advanced Parkinson's disease, it is known that administration of 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). It is also known that istradefylline can be used in combination with L-DOPA and / or a dopamine agonist (see, for example, Patent Document 3).
本発明の目的は、イストラデフィリン、L-DOPAおよびドパミンアゴニストを含有する早期パーキンソン病の治療および／または予防剤などを提供することにある。
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.
本発明は、以下の（1）～（13）に関する。
(1)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを有効成分として含有する早期パーキンソン病の治療および／または予防剤。
(2)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストのそれぞれが同時にまたは時間をおいて別々に投与されることを特徴とする (1)記載の治療および／または予防剤。
(3)更にベンセラジドを含有する(1)または(2)記載の治療および／または予防剤。
(4)L-DOPAが１日当たり400 mg以下の用量で投与される(1)～(3)のいずれかに記載の治療および／または予防剤。
(5)イストラデフィリンが１日当たり10～40 mgの用量で投与される(1)～(4)のいずれかに記載の治療および／または予防剤。
(6)ドパミンアゴニストがロピニロールまたはペルゴリドである(1)～(5)のいずれかに記載の治療および／または予防剤。
(7)イストラデフィリン、L-DOPAおよびロピニロールを含有する医薬組成物。
(8)イストラデフィリン、L-DOPAおよびペルゴリドを含有する医薬組成物。
(9)更にベンセラジドを含有する(7)または(8)記載の医薬組成物。
(10)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを同時に、または時間をおいて別々に投与する工程を含むことを特徴とする、早期パーキンソン病の治療および／または予防方法。
(11)早期パーキンソン病の治療および／または予防に使用するための、(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストの組み合わせ。
(12)早期パーキンソン病の治療および／または予防に使用するための、(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを含有する医薬組成物。
(13)早期パーキンソン病の治療および／または予防のために、L-DOPAおよびドパミンアゴニストと同時または逐次的に投与するための、イストラデフィリンを含有する医薬組成物。 The present invention relates to the following (1) to (13).
(1) 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.
(3) The therapeutic and / or prophylactic agent according to (1) or (2), further comprising benserazide.
(4) The therapeutic and / or prophylactic agent according to any one of (1) to (3), wherein L-DOPA is administered at a dose of 400 mg or less per day.
(5) The therapeutic and / or prophylactic agent according to any one of (1) to (4), wherein istradefylline is administered at a dose of 10 to 40 mg per day.
(6) The therapeutic and / or prophylactic agent according to any one of (1) to (5), wherein the dopamine agonist is ropinirole or pergolide.
(7) A pharmaceutical composition comprising Istradefylline, L-DOPA and ropinirole.
(8) A pharmaceutical composition comprising istradefylline, L-DOPA and pergolide.
(9) The pharmaceutical composition according to (7) or (8), further comprising benserazide.
(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.
(11) A combination of (A) Istradefylline, (B) L-DOPA and (C) a dopamine agonist for use in the treatment and / or prevention of early Parkinson's disease.
(12) 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.
(13) A pharmaceutical composition containing istradefylline for simultaneous or sequential administration with L-DOPA and a dopamine agonist for the treatment and / or prevention of early Parkinson's disease.
(1)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを有効成分として含有する早期パーキンソン病の治療および／または予防剤。
(2)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストのそれぞれが同時にまたは時間をおいて別々に投与されることを特徴とする (1)記載の治療および／または予防剤。
(3)更にベンセラジドを含有する(1)または(2)記載の治療および／または予防剤。
(4)L-DOPAが１日当たり400 mg以下の用量で投与される(1)～(3)のいずれかに記載の治療および／または予防剤。
(5)イストラデフィリンが１日当たり10～40 mgの用量で投与される(1)～(4)のいずれかに記載の治療および／または予防剤。
(6)ドパミンアゴニストがロピニロールまたはペルゴリドである(1)～(5)のいずれかに記載の治療および／または予防剤。
(7)イストラデフィリン、L-DOPAおよびロピニロールを含有する医薬組成物。
(8)イストラデフィリン、L-DOPAおよびペルゴリドを含有する医薬組成物。
(9)更にベンセラジドを含有する(7)または(8)記載の医薬組成物。
(10)(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを同時に、または時間をおいて別々に投与する工程を含むことを特徴とする、早期パーキンソン病の治療および／または予防方法。
(11)早期パーキンソン病の治療および／または予防に使用するための、(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストの組み合わせ。
(12)早期パーキンソン病の治療および／または予防に使用するための、(A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを含有する医薬組成物。
(13)早期パーキンソン病の治療および／または予防のために、L-DOPAおよびドパミンアゴニストと同時または逐次的に投与するための、イストラデフィリンを含有する医薬組成物。 The present invention relates to the following (1) to (13).
(1) 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.
(3) The therapeutic and / or prophylactic agent according to (1) or (2), further comprising benserazide.
(4) The therapeutic and / or prophylactic agent according to any one of (1) to (3), wherein L-DOPA is administered at a dose of 400 mg or less per day.
(5) The therapeutic and / or prophylactic agent according to any one of (1) to (4), wherein istradefylline is administered at a dose of 10 to 40 mg per day.
(6) The therapeutic and / or prophylactic agent according to any one of (1) to (5), wherein the dopamine agonist is ropinirole or pergolide.
(7) A pharmaceutical composition comprising Istradefylline, L-DOPA and ropinirole.
(8) A pharmaceutical composition comprising istradefylline, L-DOPA and pergolide.
(9) The pharmaceutical composition according to (7) or (8), further comprising benserazide.
(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.
(11) A combination of (A) Istradefylline, (B) L-DOPA and (C) a dopamine agonist for use in the treatment and / or prevention of early Parkinson's disease.
(12) 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.
(13) A pharmaceutical composition containing istradefylline for simultaneous or sequential administration with L-DOPA and a dopamine agonist for the treatment and / or prevention of early Parkinson's disease.
本発明により、イストラデフィリン、L-DOPAおよびドパミンアゴニストを有効成分として含有する早期パーキンソン病の治療および／または予防剤などが提供される。
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.
本発明におけるイストラデフィリンは、フリー体、塩、水和物、溶媒和物などいずれの形態であっても使用できる。これらは市販品として得られるか、または公知の方法で製造して得ることができる。市販品としては、例えばノウリアスト（登録商標）があげられる。
本発明におけるL-DOPAは、フリー体、塩、水和物、溶媒和物などいずれの形態であっても使用できる。これらは市販品として得られるか、または公知の方法で製造して得ることができる。市販品としては、例えばメネシット（登録商標）、イーシードパール（登録商標）、ドパール（登録商標）、マドパー（登録商標）などがあげられる。 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).
本発明におけるL-DOPAは、フリー体、塩、水和物、溶媒和物などいずれの形態であっても使用できる。これらは市販品として得られるか、または公知の方法で製造して得ることができる。市販品としては、例えばメネシット（登録商標）、イーシードパール（登録商標）、ドパール（登録商標）、マドパー（登録商標）などがあげられる。 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).
本発明におけるドパミンアゴニストとしては、例えば、プラミペキソール、ロチゴチン、タリペキソール、ロピニロール、カベルゴリン、ペルゴリドなどがあげられ、なかでもロピニロールまたはペルゴリドが好ましい。これらはフリー体、塩、水和物、溶媒和物、プロドラッグなどいずれの形態であっても使用でき、市販品として得られるか、または公知の方法で製造して得ることができる。市販品としては、例えばドミン（登録商標）、ペルマックス（登録商標）、カバサール（登録商標）などがあげられる。
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).
従って、本発明における「イストラデフィリン」、「L-DOPA」および「ドパミンアゴニスト」は、それらのフリー体、塩、水和物、溶媒和物などを含めた全ての使用可能な形態を包含する。
本発明におけるベンセラジドは、フリー体、塩、水和物、溶媒和物などいずれの形態であっても使用できる。これらは市販品として得られるか、または公知の方法で製造して得ることができる。 Therefore, “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.
本発明におけるベンセラジドは、フリー体、塩、水和物、溶媒和物などいずれの形態であっても使用できる。これらは市販品として得られるか、または公知の方法で製造して得ることができる。 Therefore, “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.
上記の塩としては、薬学的に許容される塩であれば特に限定されることはなく、例えば塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩などの無機酸塩；酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、安息香酸塩、メタンスルホン酸塩などの有機酸塩；ナトリウム塩、カリウム塩などのアルカリ金属塩；マグネシウム塩、カルシウム塩などのアルカリ土類金属塩；アルミニウム塩；亜鉛塩；アンモニウム塩、テトラメチルアンモニウム塩；モルホリン、ピペリジン、リジン、グリシン、フェニルアラニン、アスパラギン酸、グルタミン酸などの付加塩などがあげられる。
The salt is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, 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.
上記の水和物および溶媒和物としては、水や各種溶媒がそれぞれの有効成分に付加したものであれば特に限定されないが、例えば水、エタノールなどの有機溶媒が各有効成分またはその塩の1分子に対し0.5～3分子配位したものがあげられる。
上記のプロドラッグとしては、薬理学上一般的な意味で用いられているプロドラッグがあげられ、生体内で分解または化学反応を起こして対応する有効成分を発生させるものであれば特に限定されないが、例えば各有効成分の分子中のカルボキシル基がメチルエステルなどのエステルに変換されたものなどがあげられる。 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. Examples include those coordinated 0.5 to 3 molecules to the molecule.
Examples of 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.
上記のプロドラッグとしては、薬理学上一般的な意味で用いられているプロドラッグがあげられ、生体内で分解または化学反応を起こして対応する有効成分を発生させるものであれば特に限定されないが、例えば各有効成分の分子中のカルボキシル基がメチルエステルなどのエステルに変換されたものなどがあげられる。 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. Examples include those coordinated 0.5 to 3 molecules to the molecule.
Examples of 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.
本発明における“早期パーキンソン病”とは、パーキンソン病患者のうち、未だ医師の診察を受けていないか、または医師の診察を受け、L-DOPA療法などの各種薬物療法などを受けているものの未だウェアリング・オフ現象やジスキネジアなどの運動合併症を発症していない患者におけるパーキンソン病症状をいう（例えば、パーキンソン病治療ガイドライン2001（Neurology 56 (Suppl 5), S1-S88 (2001)）参照）。これに対し、“進行期パーキンソン病”とは、既にL-DOPA療法を受けており、かつウェアリング・オフ現象やジスキネジアなどの運動合併症を発症している患者におけるパーキンソン病症状のことをいう。
“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. .
本発明の早期パーキンソン病の治療および／または予防剤および医薬組成物は、(A)イストラデフィリン、(B)L-ドーパおよび(C)ドパミンアゴニストのそれぞれの有効成分を含有するように、例えば薬学的に許容される担体とともに製剤化したものであれば、単剤（合剤）としてでも複数の製剤の組み合わせとしてでも使用または投与することができる。中でも２つ以上の製剤の組み合わせが好ましい。複数の製剤の組み合わせとして使用または投与する際には、同時にまたは時間を置いて別々に使用または投与することができる。なお、これら製剤は、例えば錠剤、注射剤、外用剤などの形態として用いることが好ましい。
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. As long as it is formulated with 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.
これら製剤は、上記(A)～(C)の各有効成分の他に、任意の他の有効成分を含有させることができる。他の有効成分としては、例えばカルビドパ、ベンセラジドなどL-DOPAの代謝を抑制する薬物などがあげられる。また、それら製剤は、活性成分を薬学的に許容される一種またはそれ以上の担体（例えば、希釈剤、溶剤、賦形剤など）と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。
These preparations can contain any other active ingredient in addition to the above active ingredients (A) to (C). Examples of other active ingredients include drugs that suppress L-DOPA metabolism such as carbidopa and benserazide. These 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.
経口投与に適当な、例えば錠剤などは、乳糖などの賦形剤、澱粉などの崩壊剤、ステアリン酸マグネシウムなどの滑沢剤、ヒドロキシプロピルセルロースなどの結合剤などを用いて製造できる。
非経口投与に適当な、例えば注射剤などは、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合液などの希釈剤または溶剤などを用いて製造できる。外用剤に適当な剤型としては、特に限定されるものではなく、例えば軟膏剤、クリーム剤、リニメント剤、ローション剤、パップ剤、プラスター剤、テープ剤などがあげられる。例えば、軟膏剤、クリーム剤などは、例えば白色ワセリンなどの基剤に有効成分を溶解または混合分散して製造できる。 For example, 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.
For example, 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. For example, ointments, creams and the like can be produced by dissolving or mixing and dispersing active ingredients in a base such as white petrolatum.
非経口投与に適当な、例えば注射剤などは、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合液などの希釈剤または溶剤などを用いて製造できる。外用剤に適当な剤型としては、特に限定されるものではなく、例えば軟膏剤、クリーム剤、リニメント剤、ローション剤、パップ剤、プラスター剤、テープ剤などがあげられる。例えば、軟膏剤、クリーム剤などは、例えば白色ワセリンなどの基剤に有効成分を溶解または混合分散して製造できる。 For example, 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.
For example, 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. For example, ointments, creams and the like can be produced by dissolving or mixing and dispersing active ingredients in a base such as white petrolatum.
複数の製剤の組み合わせとして投与する際には、例えば(A)イストラデフィリンを含有する第1成分と、(B)L-ドーパを含有する第2成分と、(C)ドパミンアゴニストを含有する第3成分とを、それぞれ別途製剤化し、キットとして作成しておき、このキットを用いてそれぞれの成分を同時にまたは時間を置いて、同一対象に対して同一経路または異なった経路で投与することもできる。
When administered as a combination of a plurality of preparations, for example, (A) a first component containing istradefylline, (B) a second component containing L-dopa, and (C) a first component containing a dopamine agonist. 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. .
該キットとしては、例えば保存する際に外部の温度や光による内容物である成分の変性、容器からの化学成分の溶出などがみられない容器であれば材質、形状などは特に限定されない２つ以上の容器（例えばバイアル、バッグなど）と内容物からなり、内容物である上記第1成分、第2成分および第3成分が別々の経路（例えばチューブなど）または同一の経路を介して投与可能な形態を有するものが用いられる。具体的には、錠剤、注射剤などのキットがあげられる。
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.
本発明の早期パーキンソン病の治療および／または予防剤ならびに医薬組成物における(A)イストラデフィリン、(B)L-ドーパおよび(C)ドパミンアゴニストの用量比（重量／重量）は、使用する(C)ドパミンアゴニストの種類に応じ、それぞれの効力などを考慮して適宜調整すればよい。具体的には、例えば、(A)イストラデフィリンを5～80 mg、(B)L-ドーパを1～1000 mg、(C)ドパミンアゴニストを0.01～20 mg、好ましくは(A)イストラデフィリンを5～60 mg、(B)L-ドーパを1～500 mg、(C)ドパミンアゴニストを0.02～10 mg、より好ましくは(A)イストラデフィリンを10～40 mg、(B)L-ドーパを1～400 mg、(C)ドパミンアゴニストを0.02～5 mg、さらにより好ましくは (A)イストラデフィリンを10～40 mg、(B)L-ドーパを1～300 mg、(C)ドパミンアゴニストを0.05～3 mgの各用量比の範囲で適宜調整すればよい。
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. Specifically, for example, (A) Istradefylline 5 to 80 mg, (B) L-Dopa 1 to 1000 mg, (C) Dopamine agonist 0.01 to 20 mg, preferably (A) Istradefylline 5-60 mg, (B) L-dopa 1-500 mg, (C) dopamine agonist 0.02-10 mg, more preferably (A) istradefylline 10-40 mg, (B) L-dopa 1 to 400 mg, (C) dopamine agonist 0.02 to 5 mg, even more preferably (A) istradefylline 10 to 40 mg, (B) L-dopa 1 to 300 mg, (C) dopamine agonist May be adjusted appropriately within the range of each dose ratio of 0.05 to 3 mg.
より具体的には、例えば(A)イストラデフィリン5 mgに対し(B)L-ドーパ1～1000 mg、(C)ドパミンアゴニスト0.01～20 mg；(A)イストラデフィリン10 mgに対し(B)L-ドーパ1～1000 mg、(C)ドパミンアゴニスト0.01～20 mg；(A)イストラデフィリン20 mgに対し(B)L-ドーパ1～1000 mg、(C)ドパミンアゴニスト0.01～20 mg；(A)イストラデフィリン40 mgに対し(B)L-ドーパ1～1000 mg、(C)ドパミンアゴニスト0.01～20 mg；(A)イストラデフィリン60 mgに対し(B)L-ドーパ1～1000 mg、(C)ドパミンアゴニスト0.01～20 mgがそれぞれ用いられる。
More specifically, for example, (A) 5 mg of istradefylline (B) 1-1000 mg of L-dopa, (C) 0.01-20 mg of dopamine agonist; (A) 10 mg of istradefylline (B ) L-Dopa 1 to 1000 mg, (C) Dopamine agonist 0.01 to 20 mg; (A) Istradefylline 20 mg to (B) L-Dopa 1 to 1000 mg, (C) Dopamine agonist 0.01 to 20 mg; (B) L-dopa 1 to 1000 mg, (C) dopamine agonist 0.01 to 20 mg; (A) Istradefylline 60 to mg, (B) L-dopa 1 to 1000 mg, and (C) 0.01-20 mg of a dopamine agonist are used.
好ましくは、例えば(A)イストラデフィリン5 mgに対し(B)L-ドーパ1～500 mg、(C)ドパミンアゴニスト0.02～10 mg；(A)イストラデフィリン10 mgに対し(B)L-ドーパ1～500 mg、(C)ドパミンアゴニスト0.02～10 mg；(A)イストラデフィリン20 mgに対し(B)L-ドーパ1～500 mg、(C)ドパミンアゴニスト0.02～10 mg；(A)イストラデフィリン40 mgに対し(B)L-ドーパ1～500 mg、(C)ドパミンアゴニスト0.02～10 mg；(A)イストラデフィリン60 mgに対し(B)L-ドーパ1～500 mg、(C)ドパミンアゴニスト0.05～10 mgがそれぞれ用いられる。
Preferably, for example, (B) L-dopa 1 to 500 mg, (C) dopamine agonist 0.02 to 10 mg, and (A) Istradefylline 10 mg to (B) L- Dopa 1-500 mg, (C) Dopamine agonist 0.02-10 mg; (A) Istradefylline 20 mg, (B) L-Dopa 1-500 mg, (C) Dopamine agonist 0.02-10 mg; (A) (B) L-dopa 1-500 mg, (C) dopamine agonist 0.02-10 mg; (A) Istradefylline 60-mg, (B) L-dopa 1-500 mg, C) 0.05 to 10 mg of dopamine agonist is used.
より好ましくは、例えば(A)イストラデフィリン5 mgに対し(B)L-ドーパ1～400 mg、(C)ドパミンアゴニスト0.02～5 mg；(A)イストラデフィリン10 mgに対し(B)L-ドーパ1～400 mg、(C)ドパミンアゴニスト0.02～5 mg；(A)イストラデフィリン20 mgに対し(B)L-ドーパ1～400 mg、(C)ドパミンアゴニスト0.02～5 mg；(A)イストラデフィリン40 mgに対し(B)L-ドーパ1～400 mg、(C)ドパミンアゴニスト0.02～5 mg；(A)イストラデフィリン60 mgに対し(B)L-ドーパ1～400 mg、(C)ドパミンアゴニスト0.02～5 mgがそれぞれ用いられる。
More preferably, for example, (B) L-dopa 1 to 400 mg, (C) dopamine agonist 0.02 to 5 mg; (A) Istradefylline 10 mg to (B) L -Dopa 1-400 mg, (C) Dopamine agonist 0.02-5 mg; (A) 20-mg Istradefylline (B) L-Dopa 1-400 mg, (C) Dopamine agonist 0.02-5 mg; ) Istradefylline 40 mg to (B) L-Dopa 1 to 400 mg, (C) Dopamine agonist 0.02 to 5 mg; (A) Istradefylline 60 mg to (B) L-Dopa 1 to 400 mg, (C) 0.02 to 5 mg of dopamine agonist is used.
さらにより好ましくは、例えば(A)イストラデフィリン5 mgに対し(B)L-ドーパ1～300 mg、(C)ドパミンアゴニスト0.05～3 mg；(A)イストラデフィリン10 mgに対し(B)L-ドーパ1～300 mg、(C)ドパミンアゴニスト0.05～3 mg；(A)イストラデフィリン20 mgに対し(B)L-ドーパ1～300 mg、(C)ドパミンアゴニスト0.05～3 mg；(A)イストラデフィリン40 mgに対し(B)L-ドーパ1～300 mg、(C)ドパミンアゴニスト0.05～3 mg；(A)イストラデフィリン60 mgに対し(B)L-ドーパ1～300 mg、(C)ドパミンアゴニスト0.05～3 mgがそれぞれ用いられる。なお、これらは使用するドパミンアゴニストの種類や患者の症状によって変動する。
Even more preferably, for example (A) 5 mg of istradefylline (B) L-dopa 1 to 300 mg, (C) dopamine agonist 0.05 to 3 mg, (A) 10 mg of istradefylline (B) L-Dopa 1-300 mg, (C) Dopamine agonist 0.05-3 mg; (A) Istradefylline 20 mg, (B) L-Dopa 1-300 mg, (C) Dopamine agonist 0.05-3 mg; A) Istradefylline 40 mg to (B) L-Dopa 1 to 300 mg, (C) Dopamine agonist 0.05 to 3 mg; (A) Istradefylline 60 mg to (B) L-Dopa 1 to 300 mg , (C) 0.05-3 mg of a dopamine agonist is used. These vary depending on the type of dopamine agonist used and the symptoms of the patient.
また、上記の目的で、(A)イストラデフィリン、(B)L-ドーパおよび(C)ドパミンアゴニストを複数の製剤の組み合わせとして使用または投与する場合には、それぞれの用量および投与回数はそれぞれの有効成分の効力、投与形態、患者の年齢、体重、症状などにより異なるが、通常１回あたり、(A)イストラデフィリン、(B)L-ドーパおよび(C)ドパミンアゴニストを、それぞれ上記早期パーキンソン病の治療および／または予防剤ならびに医薬組成物おける各有効成分の用量比（重量／重量）で同時にまたは時間をおいて別々に投与するのが好ましく、1日1回～数回投与される。
For the above purpose, when (A) Istradefylline, (B) L-dopa and (C) dopamine agonist are used or administered as a combination of a plurality of preparations, the respective doses and the number of times of administration are the same. Although depending on the efficacy of the active ingredient, dosage form, patient age, weight, symptoms, etc., (A) istradefylline, (B) L-dopa and (C) dopamine agonist are usually added to the above-mentioned early Parkinson. It is preferable to administer the active ingredient in a therapeutic and / or prophylactic agent for a disease and a pharmaceutical composition at a dose ratio (weight / weight) at the same time or separately at different times, and is administered once to several times a day.
しかしながら、これら投与量および投与回数に関しては、前述の種々の条件により変動する。
次に、本発明の効果について試験例により具体的に説明する。
試験例1 1-メチル-4-フェニル-1,2,3,6-テトラヒドロピリジン(MPTP)処置コモンマーモセットにおけるイストラデフィリン、L-DOPAおよびロピニロールを組み合わせて投与することによる抗パーキンソン病活性
パーキンソン病は黒質－線条体系ドパミン神経の変性・脱落に基づく疾患である。霊長類においては、ドパミン神経毒であるMPTPを処置すると選択的な黒質－線条体系ドパミン神経の変性・脱落が起こり、無動・筋固縮などの症状が引き起こされる。このMPTPで処置した霊長類はパーキンソン病モデルとして知られている（Proceedings of the National Academy of Science USA, 80, p.4546 (1983)）。また、コモンマーモセットは真猿類に属し、他の真猿類と同様にMPTPによりパーキンソン病症状を示すことが知られている（Neuroscience Letter, 57, p.37 (1985)）。コモンマーモセット（日本クレア）にMPTP（シグマ・アルドリッチ社）を2 mg/kgの用量で1日1回、5日間背部皮下に投与し、約3週間後に再度1-2 mg/kgを1回ないし2回背部皮下に追加投与することによって慢性的なパーキンソン病症状（自発運動量の低下、動作緩慢、歩行異常、姿勢障害、コーディネートされた動作の異常、発声の低下など）を発症したコモンマーモセット（MPTP処置マーモセット）を作製し、試験に用いた。 However, the dose and the number of doses vary depending on the various conditions described above.
Next, the effect of the present invention will be specifically described with reference to test examples.
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. 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.
次に、本発明の効果について試験例により具体的に説明する。
試験例1 1-メチル-4-フェニル-1,2,3,6-テトラヒドロピリジン(MPTP)処置コモンマーモセットにおけるイストラデフィリン、L-DOPAおよびロピニロールを組み合わせて投与することによる抗パーキンソン病活性
パーキンソン病は黒質－線条体系ドパミン神経の変性・脱落に基づく疾患である。霊長類においては、ドパミン神経毒であるMPTPを処置すると選択的な黒質－線条体系ドパミン神経の変性・脱落が起こり、無動・筋固縮などの症状が引き起こされる。このMPTPで処置した霊長類はパーキンソン病モデルとして知られている（Proceedings of the National Academy of Science USA, 80, p.4546 (1983)）。また、コモンマーモセットは真猿類に属し、他の真猿類と同様にMPTPによりパーキンソン病症状を示すことが知られている（Neuroscience Letter, 57, p.37 (1985)）。コモンマーモセット（日本クレア）にMPTP（シグマ・アルドリッチ社）を2 mg/kgの用量で1日1回、5日間背部皮下に投与し、約3週間後に再度1-2 mg/kgを1回ないし2回背部皮下に追加投与することによって慢性的なパーキンソン病症状（自発運動量の低下、動作緩慢、歩行異常、姿勢障害、コーディネートされた動作の異常、発声の低下など）を発症したコモンマーモセット（MPTP処置マーモセット）を作製し、試験に用いた。 However, the dose and the number of doses vary depending on the various conditions described above.
Next, the effect of the present invention will be specifically described with reference to test examples.
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. 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.
パーキンソン症状は既報（Annals of Neurology, 43, p.507 (1998)）に記載された指標を用いて判定した。観察項目とスコアを表1に示した。全ての薬物は0.5%メチルセルロース溶液（MC400）および10%ショ糖水溶液の懸濁液として用いた。被験動物は評価の前日に観察用ケージ（自発運動量測定装置付き）に入れ、環境に慣らしておいた。イストラデフィリン（10 mg/kg）、L-DOPA（2.5 mg/kg）、ベンセラジド（0.625 mg/kg）およびロピニロール（0.025-0.075 mg/kg）を被験動物に経口投与後、パーキンソン病症状は10分毎に6時間、一方向性透視窓から観察し運動不全を得点付けた。自発運動量はフォトセルを配した測定装置により、コンピューターを用いて自動的に計測した。
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. After oral administration of istradefylline (10 mg / kg), L-DOPA (2.5 mg / kg), benserazide (0.625 mg / kg) and ropinirole (0.025-0.075 mg / kg) to the test animals, 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.
結果を図1および2に示した。本試験により、イストラデフィリン、L-DOPAおよびロピニロールの3剤を併用した場合、それぞれを単剤で用いた場合から予想される効果を超えた優れた自発運動量の増強効果や運動障害の改善効果が確認された。即ち、パーキンソン病患者に対し、これら3剤を併用して投与することにより、パーキンソン病症状の優れた治療効果が得られることが見出された。特に、L-DOPAやロピニロールの投与量が低用量であっても、パーキンソン病症状の改善が認められたことから、早期パーキンソン病患者に対するL-DOPA投与で懸念されているウェアリング・オフ現象やジスキネジアなどの運動合併症、ロピニロール投与で懸念されているICDs、血管病変、幻覚、精神障害などの副作用を発現するリスクを低減できることが示唆された。
試験例2 MPTP-処置コモンマーモセットにおけるイストラデフィリン、L-DOPAおよびペルゴリドを組み合わせて投与することによる抗パーキンソン病活性
実施例１と同様の方法で、MPTP処置マーモセットを作製した。全ての化合物は0.5%MC400および10%ショ糖水溶液の懸濁液として用いた。被験動物は評価の前日に観察用ケージ（自発運動量測定装置付き）に入れ、環境に慣らしておいた。イストラデフィリン（10 mg/kg）、L-DOPA（2.5 mg/kg）、ベンセラジド（0.625 mg/kg）およびペルゴリド（0.1 mg/kg）を被験動物に経口投与後、パーキンソン病症状は10分毎に6時間、一方向性透視窓から観察し運動不全を得点付けた。自発運動量はフォトセルを配した測定装置により、コンピューターを用いて自動的に計測した。 The results are shown in FIGS. In this study, when Istradefylline, L-DOPA, and ropinirole were used in combination, they were superior to the effects expected from the use of each single agent, and the effect of enhancing motor activity and improving motor impairment Was confirmed. That is, it was found that an excellent therapeutic effect on Parkinson's disease symptoms can be obtained by administering these three agents in combination to Parkinson's disease patients. In particular, even when the dose of L-DOPA and ropinirole was low, the improvement of Parkinson's disease symptoms was observed, so the wear-off phenomenon that is concerned about L-DOPA administration for patients with early Parkinson's disease These results suggest that the risk of developing side effects such as motor complications such as dyskinesia, ICDs, vascular lesions, hallucinations, and mental disorders, which are concerned by ropinirole administration, can be reduced.
Test Example 2 Anti-Parkinson Disease Activity by Administering Istradefylline, L-DOPA and Pergolide in Combination in MPTP-treated Common Marmoset MPTP-treated marmoset was prepared in the same manner as in Example 1. All compounds were used as suspensions in 0.5% 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. After oral administration of istradefylline (10 mg / kg), L-DOPA (2.5 mg / kg), benserazide (0.625 mg / kg) and pergolide (0.1 mg / kg) to the test animals, Parkinson's disease symptoms are observed every 10 minutes In 6 hours, we observed the dysfunction by observing from the unidirectional fluoroscopic window. Spontaneous momentum was automatically measured by a computer using a measuring device with a photocell.
試験例2 MPTP-処置コモンマーモセットにおけるイストラデフィリン、L-DOPAおよびペルゴリドを組み合わせて投与することによる抗パーキンソン病活性
実施例１と同様の方法で、MPTP処置マーモセットを作製した。全ての化合物は0.5%MC400および10%ショ糖水溶液の懸濁液として用いた。被験動物は評価の前日に観察用ケージ（自発運動量測定装置付き）に入れ、環境に慣らしておいた。イストラデフィリン（10 mg/kg）、L-DOPA（2.5 mg/kg）、ベンセラジド（0.625 mg/kg）およびペルゴリド（0.1 mg/kg）を被験動物に経口投与後、パーキンソン病症状は10分毎に6時間、一方向性透視窓から観察し運動不全を得点付けた。自発運動量はフォトセルを配した測定装置により、コンピューターを用いて自動的に計測した。 The results are shown in FIGS. In this study, when Istradefylline, L-DOPA, and ropinirole were used in combination, they were superior to the effects expected from the use of each single agent, and the effect of enhancing motor activity and improving motor impairment Was confirmed. That is, it was found that an excellent therapeutic effect on Parkinson's disease symptoms can be obtained by administering these three agents in combination to Parkinson's disease patients. In particular, even when the dose of L-DOPA and ropinirole was low, the improvement of Parkinson's disease symptoms was observed, so the wear-off phenomenon that is concerned about L-DOPA administration for patients with early Parkinson's disease These results suggest that the risk of developing side effects such as motor complications such as dyskinesia, ICDs, vascular lesions, hallucinations, and mental disorders, which are concerned by ropinirole administration, can be reduced.
Test Example 2 Anti-Parkinson Disease Activity by Administering Istradefylline, L-DOPA and Pergolide in Combination in MPTP-treated Common Marmoset MPTP-treated marmoset was prepared in the same manner as in Example 1. All compounds were used as suspensions in 0.5% 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. After oral administration of istradefylline (10 mg / kg), L-DOPA (2.5 mg / kg), benserazide (0.625 mg / kg) and pergolide (0.1 mg / kg) to the test animals, Parkinson's disease symptoms are observed every 10 minutes In 6 hours, we observed the dysfunction by observing from the unidirectional fluoroscopic window. Spontaneous momentum was automatically measured by a computer using a measuring device with a photocell.
結果を図3および4に示した。本試験により、イストラデフィリン、L-DOPAおよびペルゴリドの3剤を併用した場合、それぞれを単剤で用いた場合から予想される効果を超えた優れた自発運動量の増強効果や運動障害の改善効果が確認された。即ち、パーキンソン病患者に対し、これら3剤を併用して投与することにより、パーキンソン病症状の優れた治療効果が得られることが見出された。特に、L-DOPAやペルゴリドの投与量が低用量であっても、パーキンソン病症状の改善が認められたことから、早期パーキンソン病患者に対するL-DOPA投与で懸念されているウェアリング・オフ現象やジスキネジアなどの運動合併症、およびペルゴリド投与で懸念されているICDs、血管病変、幻覚、精神障害などの副作用を発現するリスクを低減できることが示唆された。
The results are shown in FIGS. In this study, when Istradefylline, L-DOPA, and Pergolide were used in combination, superior spontaneous exercise amount enhancement effects and motor disorder improvement effects exceeded those expected when using each of them alone. Was confirmed. That is, it was found that an excellent therapeutic effect on Parkinson's disease symptoms can be obtained by administering these three agents in combination to Parkinson's disease patients. In particular, even when the dose of L-DOPA and pergolide was low, the improvement of Parkinson's disease symptoms was observed, so the wear-off phenomenon that is concerned about L-DOPA administration for patients with early Parkinson's disease It was suggested that the risk of developing side effects such as motor complications such as dyskinesia and ICDs, vascular lesions, hallucinations, and psychiatric disorders, which are concerned by pergolide administration, was suggested.
以上より、L-DOPAとドパミンアゴニストにイストラデフィリンを併用することにより、各有効成分の単剤での効果から予想される効果を超えた優れたパーキンソン病症状の治療効果が得られることが示された。特に、低用量のL-DOPAおよびドパミンアゴニストと、イストラデフィリンを併用することで優れた治療効果が認められることから、これら3剤を組み合わせて早期パーキンソン病患者に投与することで、パーキンソン病症状の治療効果が得られるだけでなく、L-DOPAおよび／またはドパミンアゴニストの副作用の発現を抑制または遅延することが期待できる（本治療法により、L-DOPAによるウェアリング・オフ現象やジスキネジアなどの運動合併症の発症やドパミンアゴニストによるICDs、精神障害などの副作用の発生を抑制できる）。
Based on the above, it is shown that the combined use of Istradefylline with L-DOPA and dopamine agonist provides superior therapeutic effects on Parkinson's disease symptoms that exceed the expected effects of each active ingredient alone. It was done. In particular, the combination of low doses of L-DOPA and dopamine agonists with istradefylline has an excellent therapeutic effect.By combining these three agents with early Parkinson's disease patients, Parkinson's disease symptoms In addition to the therapeutic effects of L-DOPA and / or dopamine agonists, it can be expected to suppress or delay the occurrence of side effects (with this treatment, such as wear-off phenomenon caused by L-DOPA and dyskinesia) It can suppress the development of motor complications and side effects such as ICDs and mental disorders caused by dopamine agonists).
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。
Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to these examples.
常法により、次の組成からなる錠剤を調製する。イストラデフィリン80 g、乳糖286.8 gおよび馬鈴薯澱粉60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりイストラデフィリン20 mgを含有する）を得る。
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).
常法により、次の組成からなる錠剤を調製する。イストラデフィリン20 g、L-DOPA 100 g、ロピニロール 6 g、乳糖 200.8 gおよび馬鈴薯澱粉 60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりイストラデフィリン10 mg、L-DOPA 50 mgおよびロピニロール 3 mgを含有する）を得る。
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).
常法により、次の組成からなる錠剤を調製する。イストラデフィリン20 g、L-DOPA 100 g、ペルゴリド 1 g、乳糖 205.8 gおよび馬鈴薯澱粉 60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりイストラデフィリン10 mg、L-DOPA 50 mgおよびペルゴリド 0.5 mgを含有する）を得る。
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).
常法により、次の組成からなる錠剤を調製する。L-DOPA 80 g、乳糖286.8 gおよび馬鈴薯澱粉60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりL-DOPA 20 mgを含有する）を得る。
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. Add 1.2 g of magnesium stearate to this, mix, and tablet with a tableting machine (RT-15, manufactured by Kikusui Co., Ltd.) with a diameter of 8 mm. Tablets (20 mg L-DOPA per tablet) Containing).
常法により、次の組成からなる錠剤を調製する。ロピニロール80 g、乳糖286.8 gおよび馬鈴薯澱粉60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりロピニロール20 mgを含有する）を得る。
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).
常法により、次の組成からなる錠剤を調製する。ペルゴリド80 g、乳糖286.8 gおよび馬鈴薯澱粉60 gを混合し、これにヒドロキシプロピルセルロースの10％水溶液120 gを加える。この混合物を常法により練合し、造粒して乾燥させた後、整粒し打錠用顆粒とする。これにステアリン酸マグネシウム1.2 gを加えて混合し、径8 mmの杵をもった打錠機（菊水社製RT－15型）で打錠を行って、錠剤（１錠あたりペルゴリド20 mgを含有する）を得る。
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).
本発明は、例えば早期パーキンソン病の治療および／または予防に利用することができる。
The present invention can be used for the treatment and / or prevention of early Parkinson's disease, for example.
* P<0.05 コントロール群対比（Steel-Dwass test.）
# P<0.05 ロピニロール群またはペルゴリド群対比（Steel-Dwass test.）
+ P<0.05 L-DOPA群対比（Steel-Dwass test.）
$ P<0.05 イストラデフィリン群対比（Steel-Dwass test.） * P <0.05 Control group comparison (Steel-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.)
# P<0.05 ロピニロール群またはペルゴリド群対比（Steel-Dwass test.）
+ P<0.05 L-DOPA群対比（Steel-Dwass test.）
$ P<0.05 イストラデフィリン群対比（Steel-Dwass test.） * P <0.05 Control group comparison (Steel-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.)
Claims (6)
- (A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストを有効成分として含有する早期パーキンソン病の治療および／または予防剤。 A therapeutic and / or prophylactic agent for early-stage Parkinson's disease comprising (A) Istradefylline, (B) L-DOPA and (C) a dopamine agonist as active ingredients.
- (A)イストラデフィリン、(B)L-DOPAおよび(C)ドパミンアゴニストのそれぞれが同時にまたは時間をおいて別々に投与されることを特徴とする請求項1記載の治療および／または予防剤。 2. The therapeutic and / or prophylactic agent according to claim 1, wherein each of (A) istradefylline, (B) L-DOPA and (C) dopamine agonist is administered simultaneously or separately with time.
- L-DOPAが１日当たり400 mg以下の用量で投与される請求項1または2記載の治療および／または予防剤。 The therapeutic and / or prophylactic agent according to claim 1 or 2, wherein L-DOPA is administered at a dose of 400 mg or less per day.
- ドパミンアゴニストがロピニロールまたはペルゴリドである請求項1～3のいずれかに記載の治療および／または予防剤。 The therapeutic and / or prophylactic agent according to any one of claims 1 to 3, wherein the dopamine agonist is ropinirole or pergolide.
- イストラデフィリン、L-DOPAおよびロピニロールを含有する医薬組成物。 A pharmaceutical composition comprising Istradefylline, L-DOPA and ropinirole.
- イストラデフィリン、L-DOPAおよびペルゴリドを含有する医薬組成物。 A pharmaceutical composition comprising istradefylline, L-DOPA and pergolide.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06211856A (en) * | 1992-09-28 | 1994-08-02 | Kyowa Hakko Kogyo Co Ltd | Anitiparkinosonism agent |
| JP2005523898A (en) * | 2002-01-28 | 2005-08-11 | 協和醗酵工業株式会社 | How to treat patients with movement disorders |
-
2016
- 2016-03-17 WO PCT/JP2016/058591 patent/WO2016148260A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06211856A (en) * | 1992-09-28 | 1994-08-02 | Kyowa Hakko Kogyo Co Ltd | Anitiparkinosonism agent |
| JP2005523898A (en) * | 2002-01-28 | 2005-08-11 | 協和醗酵工業株式会社 | How to treat patients with movement disorders |
Non-Patent Citations (2)
| 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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