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US20170042887A1 - Combination of Brexpiprazole and Nalmefene and Use Thereof for Treating Substance-Related Disorders - Google Patents

Combination of Brexpiprazole and Nalmefene and Use Thereof for Treating Substance-Related Disorders Download PDF

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Publication number
US20170042887A1
US20170042887A1 US15/305,782 US201515305782A US2017042887A1 US 20170042887 A1 US20170042887 A1 US 20170042887A1 US 201515305782 A US201515305782 A US 201515305782A US 2017042887 A1 US2017042887 A1 US 2017042887A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
nalmefene
alcohol
brexpiprazole
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US15/305,782
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Inventor
Kenji Maeda
Mai Nakamura
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H Lundbeck AS
Otsuka Pharmaceutical Co Ltd
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H Lundbeck AS
Otsuka Pharmaceutical Co Ltd
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Application filed by H Lundbeck AS, Otsuka Pharmaceutical Co Ltd filed Critical H Lundbeck AS
Assigned to OTSUKA PHARMACEUTICAL CO., LTD., H. LUNDBECK A/S reassignment OTSUKA PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MAEDA, KENJI, NAKAMURA, MAI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a medicament using brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof in combination.
  • brexpiprazole (7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-1H-quinolin-2-one) or a pharmaceutically acceptable salt thereof has a dopamine D 2 receptor partial agonist activity (D 2 receptor partial agonist activity), a serotonin 5-HT 2A receptor antagonist activity (5-HT 2A receptor antagonist activity) and an adrenergic ⁇ 1 receptor antagonist activity ( ⁇ 1 receptor antagonist activity) and, in addition thereto, concurrently has a serotonin uptake inhibitory action (or serotonin reuptake inhibitory action) (patent document 1 and patent document 2).
  • brexpiprazole has a serotonin 5-HT 1A receptor antagonist activity (5-HT 1A receptor antagonist activity) (non-patent document 1).
  • Nalmefene (17-(cyclopropylmethyl)-4,5 ⁇ -epoxy-6-methylenemorphinan-3,14-diol) has the following formula
  • Nalmefene is an opioid system modulator with a distinct ⁇ , ⁇ and ⁇ receptor profile.
  • nalmefene is a selective opioid receptor ligand with antagonist activity at the ⁇ and ⁇ receptors and partial agonist activity at the ⁇ receptor.
  • Acute alcohol intake was shown to result in mesolimbic dopamine release (facilitated by the release of ⁇ -endorphins), which can provide positive reinforcement.
  • Nalmefene is thought to counteract the reinforcement effects and to reduce alcohol consumption, possibly by modulating these cortico-mesolimbic functions.
  • WO2005/089486 discloses that when coadministered with an opioid antagonist naltrexone, a dopamine D 2 receptor partial agonist aripiprazole does not affect (i.e., neither impairs nor enhances) naltrexone's ability to decrease ethanol intake.
  • the object of the present invention is to provide a medicament for use in the prophylaxis or treatment of substance-related disorders such as alcohol-related disorder and the like.
  • naltrexone which is an opioid antagonist and aripiprazole which is a dopamine D 2 receptor partial agonist does not affect the ability of both drugs. That is, it is disclosed that such combined administration does not show a synergistic effect or even an additive effect.
  • the present inventors have conducted intensive studies in an attempt to solve the aforementioned problems and found that the use of nalmefene which is an opioid antagonist and brexpiprazole which is a dopamine D 2 receptor partial agonist in combination surprisingly affords not only an additive effect but also a synergistic effect.
  • the present invention has been completed based on such finding.
  • the present invention preferably provides medicaments, use, methods for preventing or treating diseases, a pharmaceutical composition, a production method of a pharmaceutical composition and kits shown in item 1 to item 63 below.
  • a medicament comprising (I) brexpiprazole or a pharmaceutically acceptable salt thereof, and (II) nalmefene or a pharmaceutically acceptable salt thereof in combination, wherein brexpiprazole or a pharmaceutically acceptable salt thereof, and nalmefene or a pharmaceutically acceptable salt thereof are contained in a single preparation, or a pharmaceutical composition containing brexpiprazole or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing nalmefene or a pharmaceutically acceptable salt thereof are formulated for use in combination.
  • a pharmaceutical composition containing brexpiprazole or a pharmaceutically acceptable salt thereof and a pharmaceutical composition containing nalmefene or a pharmaceutically acceptable salt thereof are formulated for use in combination.
  • the medicament according to any one of items 1 to 3, for use in the prophylaxis or treatment of a substance-related disorder.
  • the medicament according to item 5 wherein the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • the medicament according to item 5 for use in the prophylaxis or treatment of an impulsive symptom in an alcohol-related disorder.
  • the medicament according to item 7, wherein the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • a medicament comprising brexpiprazole or a pharmaceutically acceptable salt thereof, for a combined use with nalmefene or a pharmaceutically acceptable salt thereof.
  • a medicament comprising nalmefene or a pharmaceutically acceptable salt thereof, for a combined use with brexpiprazole or a pharmaceutically acceptable salt thereof.
  • the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • a method for preventing or treating a substance-related disorder comprising administering (I) brexpiprazole or a pharmaceutically acceptable salt thereof, and (II) nalmefene or m a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein brexpiprazole or a pharmaceutically acceptable salt thereof, and nalmefene or a pharmaceutically acceptable salt thereof are administered as a single preparation or separate preparations simultaneously or separately in a staggered manner.
  • the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • the method according to item 19 which is a method for preventing or treating an impulsive symptom in an alcohol-related disorder.
  • the alcohol-related disorder is selected from the group consisting of an alcohol use disorder, an alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication and an alcohol withdrawal symptom.
  • a pharmaceutical composition comprising (I) brexpiprazole or a pharmaceutically acceptable salt thereof, (II) nalmefene or a pharmaceutically acceptable salt thereof, and (III) a pharmacologically acceptable carrier.
  • a method for producing a pharmaceutical composition comprising mixing (I) brexpiprazole or a pharmaceutically acceptable salt thereof and (II) nalmefene or a pharmaceutically acceptable salt thereof with a pharmacologically acceptable carrier.
  • a kit comprising (I) a medicament containing brexpiprazole or a pharmaceutically acceptable salt thereof, and (II) a medicament containing nalmefene or a pharmaceutically acceptable salt thereof.
  • kit according to item 26 for use in the prophylaxis or treatment of a substance-related disorder.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is a solvate of brexpiprazole or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is monohydrate or dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is a solvate of brexpiprazole or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is monohydrate or dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is a solvate of brexpiprazole or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is monohydrate or dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • composition according to item 24 wherein brexpiprazole or a pharmaceutically acceptable salt thereof is a solvate of brexpiprazole or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is monohydrate or dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • kit according to any one of items 26 to 28, wherein brexpiprazole or a pharmaceutically acceptable salt thereof is a solvate of brexpiprazole or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is monohydrate or dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is dihydrate of nalmefene or of a pharmaceutically acceptable salt thereof.
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • the medicament according to item 54 wherein the existing therapeutic drug for alcohol-related disorder is selected from the group consisting of cyanamide, disulfiram, acamprosate, nalmefene and naltrexone.
  • a medicament for use in the treatment of an alcohol-related disorder comprising brexpiprazole or a pharmaceutically acceptable salt thereof as an active ingredient, which is used for a patient receiving a treatment with a preparation of nalmefene or a pharmaceutically acceptable salt thereof.
  • a medicament for use in the treatment of an alcohol-related disorder comprising nalmefene or a pharmaceutically acceptable salt thereof as an active ingredient, which is used for a patient receiving a treatment with a preparation of brexpiprazole or a pharmaceutically acceptable salt thereof.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • composition according to item 24 wherein brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole, and nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole
  • nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • kit according to item 28 wherein brexpiprazole or a pharmaceutically acceptable salt thereof is brexpiprazole, and nalmefene or a pharmaceutically acceptable salt thereof is nalmefene hydrochloride dihydrate.
  • a combined administration of brexpiprazole and nalmefene can afford a synergistic effect as compared to single administration of each medicament.
  • a combined use of extremely low doses of brexpiprazole and nalmefene can suppress an impulsive ethanol-intake behavior.
  • the combined use of the both medicaments is shown to enable brexpiprazole to enhance the treatment effect of nalmefene.
  • the combined use of the both medicaments is shown to enable nalmefene to enhance the treatment effect of brexpiprazole.
  • Lower side effects are expected as a result of the lower doses that may be applied.
  • FIG. 1 is a graph showing the test results of Example 1.
  • the pharmaceutically acceptable salt of brexpiprazole usable in the present invention include salt with inorganic acid such as sulfate, nitrate, hydrochloride, phosphate, hydrobromide and the like; salt with organic acid such as acetate, sulfonate (e.g., p-toluenesulfonate, methanesulfonate, ethanesulfonate etc.), oxalate, maleate, fumarate, malate, tartrate, citrate, succinate, pamoate, benzoate and the like.
  • Brexpiprazole or a pharmaceutically acceptable salt thereof may be a solvate.
  • the preferred example of the solvate is dihydrate of brexpiprazole or of a pharmaceutically acceptable salt thereof (WO2013/162046).
  • Brexpiprazole or a pharmaceutically acceptable salt thereof usable in the present invention is also encompasses the same isotopically-labeled compounds, wherein one or plural atoms is(are) replaced by one or plural atoms having a particular atomic mass or mass number.
  • isotope that can be incorporated into brexpiprazole or a pharmaceutically acceptable salt thereof include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine isotopes such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 36 Cl and the like.
  • Certain isotopically-labeled brexpiprazole or a pharmaceutically acceptable salt thereof which contains the above-mentioned isotope and/or other isotope of other atom, for example, brexpiprazole or a pharmaceutically acceptable salt thereof incorporating a radioactive isotope such as 3 H, 14 C and the like, is useful for drug tissue distribution assay and/or substrate tissue distribution assay.
  • Tritiated (i.e., 3 H) or carbon-14 (i.e., 4 C) isotope are particularly preferred because of easiness of preparation and detectability.
  • An isotopically-labeled compound of brexpiprazole or a pharmaceutically acceptable salt thereof can be generally prepared according to the method disclosed in WO2006/112464 and WO2013/162046, by substituting a non-isotopically-labeled reagent with an easily available isotopically-labeled reagent.
  • Brexpiprazole or a pharmaceutically acceptable salt thereof, a production method thereof, a dose to be used thereof and the like are disclosed in WO2006/112464 and WO2013/162046, and the disclosure thereof is incorporated herein by reference.
  • Nalmefene or a pharmaceutically acceptable salt thereof, a production method thereof, a dose to be used thereof and the like are disclosed in U.S. Pat. No. 3,814,768, U.S. Pat. No. 4,751,307, U.S. Pat. No. 4,535,157 and WO2010/063292, and the disclosure thereof is incorporated herein by reference.
  • Examples of the pharmaceutically acceptable salt of nalmefene include hydrochloride, hydrochloride monohydrate, hydrochloride dihydrate and the like. A more preferable example is nalmefene hydrochloride dihydrate.
  • a medicament using brexpiprazole or a pharmaceutically acceptable salt thereof in combination with nalmefene or a pharmaceutically acceptable salt thereof has an excellent effect. Therefore, such medicament is expected to cause a fewer side effects and has an excellent safety profile as a results of lower doses that may be applied.
  • Brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof may be administered orally or parenterally.
  • brexpiprazole or a pharmaceutically acceptable salt thereof in combination with nalmefene or a pharmaceutically acceptable salt thereof when used, the administration period of brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof is not limited, and brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof may be simultaneously formulated into a single preparation, or brexpiprazole or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof and nalmefene or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof may be administered to a subject of administration simultaneously or in a staggered manner.
  • brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof are administered, they may be administered simultaneously.
  • nalmefene or a pharmaceutically acceptable salt thereof may be administered in advance, and then brexpiprazole or a pharmaceutically acceptable salt thereof may be administered, or brexpiprazole or a pharmaceutically acceptable salt thereof may be administered in advance, and then nalmefene or a pharmaceutically acceptable salt thereof may be administered.
  • the time difference varies depending on the dosage form and administration method.
  • a method including administering nalmefene or a pharmaceutically acceptable salt thereof within 1 min-3 days, preferably 10 min-1 day, more preferably 15 min-1 hr, after the administration of brexpiprazole or a pharmaceutically acceptable salt thereof can be mentioned.
  • the dose of nalmefene or a pharmaceutically acceptable salt thereof may be similar to the dose clinically used, and can be appropriately determined according to the subject of administration, administration route, disease and the like.
  • the administration form of the medicament of the present invention is not particularly limited, and brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof only need to be combined on administration.
  • administration form include (1) administration of a single preparation obtained by simultaneously formulating brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof, (2) simultaneous administration of two kinds of preparations obtained by separately formulating brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof by the same administration route, (3) administration of two kinds of preparations obtained by separately formulating brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof by the same administration route in a staggered manner (e.g., administration in the order of brexpiprazole or a pharmaceutically acceptable salt thereof; nalmefene or a pharmaceutical
  • the medicaments of the present invention comprising brexpiprazole or a pharmaceutically acceptable salt thereof, nalmefene or a pharmaceutically acceptable salt thereof and/or brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof in combination, which are constituent components of the present invention, show low toxicity and, for example, brexpiprazole or a pharmaceutically acceptable salt thereof and/or nalmefene or a pharmaceutically acceptable salt thereof can be mixed with a pharmacologically acceptable carrier according to a known method to give a pharmaceutical composition, such as tablets (including sugar-coated tablet, film-coated tablet), powders, granules, capsules (including soft capsule), liquids, injections, suppositories, sustained-release preparations and the like, which can be safely administered orally or parenterally (e.g., local, rectum, vein, and the like).
  • a pharmaceutical composition such as tablets (including sugar-
  • An injection can be administered by intravenous, intramuscular, subcutaneous or intraorgan administration or directly to the lesion.
  • a pharmacologically acceptable carrier which may be used for producing the pharmaceutical composition of the present invention, excipient, disintegrant, binder, glidant, lubricant, coating agent, colorant, suspending agent, sweetening agent or surfactant is appropriately used, and a general pharmaceutical preparation is formed according to a known method. Examples of the form of the pharmaceutical preparation include powder, tablet, pill, capsule and the like.
  • excipient examples include lactose, anhydrous lactose, purified sucrose, sucrose, D-mannitol, D-sorbitol, xylitol, erythritol, dextrin, crystalline cellulose, microcrystalline cellulose, cornstarch, potato starch, anhydrous calcium hydrogen phosphate and the like.
  • disintegrant examples include sodium carboxymethyl starch, carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch and the like.
  • binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, pregelatinized starch, syrup, starch syrup and the like.
  • Examples of the glidant include light anhydrous silicic acid, synthetic aluminum silicate, hydrated silicon dioxide, calcium stearate, magnesium aluminometasilicate, talc and the like.
  • lubricant examples include magnesium stearate, calcium stearate, magnesium silicate, magnesium oxide, talc, hydrogenated oil, sucrose fatty acid ester, sodium stearyl fumarate and the like.
  • the coating agent examples include hydroxypropylmethylcellulose, polyvinyl alcohol, polysorbate, macrogol, talc and the like.
  • colorant examples include yellow iron sesquioxide, brown iron oxide, iron sesquioxide, black iron oxide, titanium oxide, Food Blue No. 1, Food Red No. 2, Food Red No. 3, Food Yellow No. 4 and the like.
  • suspending agent examples include polysorbate, polyethylene glycol, gum arabic, glycerol, gelatin and the like.
  • sweetening agent examples include aspartame, saccharin, saccharin sodium, starch syrup, fructose and the like.
  • surfactant examples include sodium lauryl sulfate, polysorbate, polyoxyethylene hydrogenated castor oil and the like.
  • a capsule is prepared by filling a hard capsule such as gelatin capsule, hydroxypropylmethylcellulose capsule, polyvinyl alcohol capsule and the like or a soft capsule based on gelatin, according to a known method.
  • a hard capsule such as gelatin capsule, hydroxypropylmethylcellulose capsule, polyvinyl alcohol capsule and the like or a soft capsule based on gelatin
  • Conventional various organic or inorganic carrier substances can be used as preparation starting materials and examples thereof include excipient, lubricant, binder and disintegrant for solid preparations, and solvent, solubilizing agent, suspending agent, isotonic agent, buffering agent and soothing agent for liquid preparations and the like.
  • additives such as general preservative, antioxidant, colorant, sweetening agent, adsorbent, wetting agent and the like can be appropriately used in an appropriate amount.
  • brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof to be used in the present invention is determined in consideration of the properties of the drug after combination, and the condition of the patients. As shown above, brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof may be separately administered without being combined in one composition. As the general outline of the dose, for example, the following guideline can be applied.
  • Brexpiprazole or a pharmaceutically acceptable salt thereof generally about 0.01-about 100 mg/l time/1 day (or about 0.005-about 50 mg/2 times/1 day), preferably about 0.1-about 4 mg/l time/1 day (or about 0.05-about 2 mg/2 times/1 day).
  • the dose may be 0.05-2 mg/l time/1 day on an as-needed basis.
  • Nalmefene or a pharmaceutically acceptable salt thereof generally about 0.1-about 100 mg/l time/1 day (or about 0.05-about 50 mg/2 times/1 day), preferably about 1-about 20 mg/l time/1 day (or about 0.5-about 10 mg/2 times/1 day).
  • the dose may be 0.5-10 mg/l time/1 day on an as-needed basis.
  • the proportion of brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof to be used may be generally about 0.01-about 500 parts by weight, preferably about 0.1-about 100 parts by weight, of the latter relative to 1 part by weight of the former.
  • the mixing ratio of brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof in the medicament of the present invention can be appropriately determined according to the subject of administration, administration route, disease and the like.
  • the total proportion of brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof in the medicament of the present invention varies depending on the preparation form, it is generally about 0.01-about 99.99 wt %, preferably about 0.1-about 99.9 wt %, more preferably about 1-about 30 wt %, relative to the whole preparation.
  • the above-mentioned pharmacologically acceptable carrier is used for the remaining part.
  • brexpiprazole or a pharmaceutically acceptable salt thereof and nalmefene or a pharmaceutically acceptable salt thereof are to be separately formulated, a similar content may be used.
  • the present invention may also be in the form of a kit comprising a medicament containing brexpiprazole or a pharmaceutically acceptable salt thereof and a medicament containing nalmefene or a pharmaceutically acceptable salt thereof, which are separately formulated.
  • the kind of the preparation is not particularly limited, and tablets (including sugar-coated tablet, film-coated tablet), powder, granule, capsule (including soft capsule), liquid, injection, suppository, sustained-release preparation and the like can be mentioned.
  • kits comprising an oral preparation containing brexpiprazole or a pharmaceutically acceptable salt thereof (tablet, powder, granule, capsule or liquid), and an oral preparation containing nalmefene or a pharmaceutically acceptable salt thereof (tablet, powder, granule, capsule or liquid).
  • the medicament and pharmaceutical composition of the present invention are useful for the prophylaxis or treatment of substance-related disorders (e.g., alcohol-related disorder (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal symptoms, etc.), amphetamine-related disorder (amphetamine use disorder etc.), cannabis -related disorder ( cannabis use disorder etc.), cocaine-related disorder (cocaine use disorder etc.), hallucinogen-related disorder (hallucinogen use disorder etc.) and the like).
  • substance-related disorders e.g., alcohol-related disorder (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal symptoms, etc.), amphetamine-related disorder (amphetamine use disorder etc.), cannabis -related disorder ( cannabis use disorder etc.), cocaine-related disorder (cocaine use disorder etc.), hallucinogen-related disorder (hallucinogen use disorder etc.) and the like).
  • the medicament and pharmaceutical composition of the present invention are useful for the prophylaxis or treatment of an impulsive symptom in substance-related disorders (e.g., alcohol-related disorder (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal symptoms, etc.), amphetamine-related disorder (amphetamine use disorder etc.), cannabis -related disorder ( cannabis use disorder etc.), cocaine-related disorder (cocaine use disorder etc.), hallucinogen-related disorder (hallucinogen use disorder etc.) and the like).
  • substance-related disorders e.g., alcohol-related disorder (alcohol use disorder, alcohol-induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal symptoms, etc.), amphetamine-related disorder (amphetamine use disorder etc.), cannabis -related disorder ( cannabis use disorder etc.), cocaine-related disorder (cocaine use disorder etc.), hallucinogen-related disorder (hallucinogen use disorder etc.) and the like).
  • substance-related disorders e.g
  • the medicament and pharmaceutical composition of the present invention are particularly useful for the prophylaxis or treatment of alcohol-related disorders, and the prophylaxis or treatment of an impulsive symptom in alcohol-related disorders.
  • the impulsive symptom is a symptom associated with an impulsive action.
  • Specific examples of the impulsive behavior include physical attack, wandering, restlessness, agitation, senseless behavior and deviant behavior (e.g., sexual deviant behavior), roaming, shrill voice, screaming, violent language, loss of motivation, constant questioning, shadowing, suicide attempt and suicide, self-injurious behavior, threat, stealing, overeating, act of threatening, short-circuit reaction, panic reaction, property damage, inappropriate dressing/undressing, underselling and the like.
  • impulsive symptom in alcohol-related disorders include not only impulsive drinking behavior wherein a patient cannot suppress an intake action of alcohol, but also a symptom to take quick action to satisfy the immediate desire even though it can lead to an m undesirable effect in the future. In the latter case, patients often commit a crime such as violent behavior and the like.
  • the medicament and pharmaceutical composition of the present invention can be used for treating a patient for whom an existing therapeutic drug for alcohol-related disorder provides only an insufficient effect.
  • the “patient for whom an existing therapeutic drug for alcohol-related disorder provides only an insufficient effect” means “those who could not achieve a Medium risk (male: 41 to 60 g/day, female: 21 to 40 g/day) or below in a sobriety treatment according to the standard of WHO drinking classification (WHO/MSD/MSB/00.4, INTERNATIONAL GUIDE FOR MONITORING ALCOHOL CONSUMPTION AND RELATED HARM, chapter 2.2 and The quantification of drug-caused mortality and morbidity in Australia, 1998, chapter 2.5.1), or those who could not achieve abstinence from alcohol by an alcohol abstinence therapy”.
  • Examples of the existing therapeutic drugs for alcohol-related disorder includes
  • antialcoholic drugs cyanamide, disulfiram, etc.
  • therapeutic drugs for alcohol dependence acamprosate etc.
  • drugs for reducing alcohol consumption nalmefene, naltrexone etc.
  • antipsychotics typically antipsychotics such as aripiprazole, quetiapine, olanzapine, risperidone, etc.
  • antiepileptic agents topiramate, zonisamide, gabapentin, vigabatrin, lamotrigine, valproic acid, carbamazepine, etc.
  • antidepressants [selective serotonin reuptake inhibitors (fluoxetine, citalopram, fluvoxamine, paroxetine, sertraline, escitalopram, etc.), serotonin and norepinephrine reuptake inhibitors (venlafaxine, duloxetine, milnacipran, desvenlafaxine, etc.), noradrenergic and specific serotonergic antidepressants (mirtazapine etc.), tricyclic and tetracyclic antidepressants (desipramine etc.), monoamine oxidase inhibitors, etc.], (7) antianxiety drugs or sleeping drugs (ethyl loflazepate, etizolam, nitrazepam, fluorophen, etc.
  • Alcohol dependence mice are generated by breeding C57BL/6J mice (male) under individual housing for 5 days with free ingestion of skimmed milk containing 3% ethanol. On day 6, locomotor activity is measured after changing to an ethanol-free diet. An animal with average ethanol intake on days 2 to 4 of not less than 20 g/kg/day, and the body weight of not less than 14.5 g on day 5 is subjected to the test.
  • Brexpiprazole is suspended in distilled water containing 5% gum arabic. The drug is orally administered to each mouse immediately before measurement of the locomotor activity on day 6. The dose of brexpiprazole is set to 0.02 to 0.03 mg/kg.
  • Nalmefene hydrochloride monohydrate is dissolved in saline. The drug is subcutaneously administered to each mouse immediately before measurement of the locomotor activity on day 6. The dose of nalmefene hydrochloride monohydrate is set to 0.08 to 0.12 mg/kg.
  • the ethanol withdrawal-induced locomotor activity increasing action is measured by calculating difference between the locomotor activity on day 5 and the locomotor activity on day 6 after ethanol withdrawal in each animal.
  • Measurement method An impulsive behavior of cravings for drinking alcohol was evaluated as follows by reference to the method of Sinclair et al. (Alcohol 1992; 9:441-44 and Alcohol & Alcoholism 2001; 36:2-10). First, Wistar rats (male) were allowed to freely drink 10% aqueous ethanol solution and tap water for several weeks under isolated rearing. After the ethanol intake of each animal became stable, limited access paradigm allowing ethanol intake only for 1 hr per day was started, and the ethanol intake in 1 hr was measured every day. The ethanol intake was calculated from the results of weight measurement of a water supply bottle filled with 10% aqueous ethanol solution immediately before the start of the limited access paradigm and immediately after the completion of the limited access paradigm. Animals that showed an average ethanol intake of not less than 0.4 g/kg/hr based on 100% ethanol in the limited access paradigm for 4 days immediately before drug evaluation were used. The limited access paradigm test was performed during 9:00 AM-4:00 PM.
  • Brexpiprazole was suspended in distilled water containing 5% gum arabic. The drug was orally administered to each rat once per day for 4 days at 1 hr before the start of the limited access paradigm. The dose of brexpiprazole was selected to be 0.01 mg/kg that does not, by itself, influence the ethanol intake and the spontaneous locomotor activity under novel environments (data not shown).
  • Nalmefene hydrochloride monohydrate (Tocris Bioscience) was dissolved in saline. The drug was subcutaneously administered to each rat once per day for 4 days at 1 hr before the start of the limited access paradigm. The dose of nalmefene hydrochloride monohydrate was selected to be 0.04 mg/kg that does not, by itself, influence the ethanol intake and the spontaneous locomotor activity under novel environments (data not shown).
  • the significance level of the test was set to 5%.
  • SAS R9.3, SAS Institute Japan
  • the difference between an average ethanol intake in the limited access paradigm for 4 days immediately before drug evaluation and an average ethanol intake in the limited access paradigm for 4 days during the drug administration period was calculated for every animal, and analyzed by two-way factorial analysis of variance by using the presence or absence of brexpiprazole and the presence or absence of nalmefene as factors.
  • the test results are shown in FIG. 1 .
  • test results show that the combined use of the both medicaments not only suppresses impulsive drinking behavior of patients with alcohol dependence but also enables brexpiprazole to enhance treatment effects of nalmefene. Conversely, the test results show that the combined use of the both medicaments enables nalmefene to enhance treatment effects of brexpiprazole. Lower side effects are expected as a result of the lower doses that may be applied.

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