WO2011052500A1 - Wax stable formulation - Google Patents

Wax stable formulation Download PDF

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Publication number
WO2011052500A1
WO2011052500A1 PCT/JP2010/068685 JP2010068685W WO2011052500A1 WO 2011052500 A1 WO2011052500 A1 WO 2011052500A1 JP 2010068685 W JP2010068685 W JP 2010068685W WO 2011052500 A1 WO2011052500 A1 WO 2011052500A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
substance
compound
wax
acceptable salt
Prior art date
Application number
PCT/JP2010/068685
Other languages
French (fr)
Japanese (ja)
Inventor
秀章 田邊
知行 渡部
Original Assignee
第一三共株式会社
宇部興産株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 第一三共株式会社, 宇部興産株式会社 filed Critical 第一三共株式会社
Publication of WO2011052500A1 publication Critical patent/WO2011052500A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • a pharmacologically acceptable salt thereof and (B) a wax-like substance, and a pharmaceutical composition containing the pharmaceutical composition and a pharmacologically acceptable additive.
  • a compound having the above formula (I) or a pharmacologically acceptable salt thereof is known as a compound having a platelet aggregation inhibitory action (Patent Document 1 or 2).
  • Patent Documents 2 to 12 exemplify many additives that can be used in the preparation of the compound having the above formula (I) or a pharmacologically acceptable salt thereof, and one of them is beeswax, gay wax, stearic acid. And sucrose fatty acid esters are listed, but are only exemplified as one of many possible additives and are not specifically used in formulation examples. Further, the patent document describes that storage stability is improved by including a waxy substance in a pharmaceutical composition containing the compound having the above formula (I) or a pharmacologically acceptable salt thereof. There is no suggestion.
  • An object of the present invention is to provide a pharmaceutical composition excellent in storage stability, containing a compound having the above formula (I) or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition comprising (A) a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance, (2) (A) a pharmaceutical composition obtained by melt-mixing a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance, (3) (A) a pharmaceutical composition obtained by melt granulating a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance, (4) A compound having the formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)
  • the pharmaceutical composition according to any one of (1) to (3) which is a compound having (5)
  • the waxy substance is one or more selected from hardened oil, vegetable or animal oil, higher alcohol, higher fatty acid, glycerin fatty acid ester and sucrose fatty acid ester (1) to (5)
  • a pharmaceutical composition according to any one of (7) The pharmaceutical composition according to any one of (1) to (5), wherein the waxy substance is a higher alcohol or a glycerin fatty acid ester, (8)
  • the pharmaceutical composition according to any one of (1) to (5), wherein the waxy substance is stearyl alcohol or glyceryl monostearate, (9)
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance for the treatment and / or prevention of heart or cerebrovascular diseases.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance for the treatment and / or prevention of heart or cerebrovascular diseases.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance for the treatment and / or prevention of heart or cerebrovascular diseases.
  • a waxy substance for the treatment and / or prevention of heart or cerebrovascular diseases.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance, which is used in combination with another heart or brain protective agent for treating heart or cerebrovascular disease. Concerning the use of things.
  • the present invention relates to a method for improving the stability of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof, comprising the compound having the general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention relates to a method of including a waxy substance in a solid preparation containing a salt to be prepared.
  • the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof, comprising a waxy substance in the preparation, and having a base equivalent of about 1 mg to about 70 mg
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention provides a method for treating and / or preventing a heart or cerebrovascular disease, comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance.
  • the present invention relates to a method for administration to a patient with the disease.
  • the present invention is a method for treating and / or preventing a heart or cerebrovascular disease by administering a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance.
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance.
  • a pharmaceutical composition containing a waxy substance is initially administered and then about 1 mg to 15 mg (preferably 3.75 mg to 10 mg, more preferably 3.75 mg, 5 mg or 10 mg, particularly preferred Relates to a method for maintaining and administering a pharmaceutical composition containing 10 mg) or equivalent of a pharmaceutically acceptable salt and a wax-like substance.
  • the present invention relates to the initial administration of a pharmaceutical composition
  • a pharmaceutical composition comprising a compound (preferably hydrochloride) having a general formula (I) of 20 to 60 mg (preferably 60 mg) of base equivalent and a waxy substance, and at suitable intervals.
  • a pharmaceutical composition containing a compound (generally a hydrochloride salt) of general formula (I) with a base equivalent weight of 3.75 mg to 15 mg (preferably 10 mg) and a waxy substance,
  • a method for treating and / or preventing heart or cerebrovascular disease is provided.
  • the present invention is a method for producing a pharmaceutical composition for single administration, or for combined administration with other heart or brain protective agents for treatment, prevention and / or recovery of heart or cerebrovascular diseases.
  • the present invention relates to a method for producing a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance.
  • a pharmaceutical composition excellent in storage stability which contains a compound having the above formula (I) or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition of the present invention is effective for, for example, treatment and / or prevention (preferably a thrombosis therapeutic and / or prophylactic agent) such as thrombosis or embolism (preferably thrombosis). It is.
  • the pharmaceutical composition containing the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof and a waxy substance is effective for the treatment and / or prevention of heart or cerebrovascular disease.
  • a compound having the above formula (I) which is an active ingredient of the pharmaceutical composition of the present invention that is, 2-acetoxy-5- ( ⁇ -cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydro Thieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof is described in JP-A-6-41139 or JP-A-2002-145883 and can be produced.
  • hydrohalide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide
  • nitrate perchlorine Inorganic acid salts such as acid salts, sulfates or phosphates
  • lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate
  • Aryl sulfonates such as salts; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or Glycine salt, lysine salt, arginine salt, ornithine salt, amino acid salt such as glutamate or aspartate, etc.
  • a hydrohalide salt or an organic acid salt more preferably a hydrochloride
  • the ⁇ -position of the benzyl group is an asymmetric carbon, and there are optically active substances based on the asymmetric carbon, and the isomers and mixtures thereof are also included in the compound of the present invention.
  • an isomer of a pharmacologically acceptable salt (eg, hydrochloride) of a compound represented by formula (I) and a mixture thereof are also converted into a pharmacologically acceptable salt (eg, hydrochloride) of the compound of the present invention. Is included.
  • the wax-like substance of the present invention preferably has a melting point of 40 to 150 ° C.
  • the “wax-like substance” of the present invention include hardened oils such as hardened castor oil, hardened soybean oil, hardened rapeseed oil, and hardened cottonseed oil; vegetable or animal fats and oils such as carnauba wax, white beeswax and beef tallow; Higher alcohols such as alcohol and cetanol; higher fatty acids such as stearic acid and palmitic acid; monofatty acid glycerin such as glyceryl monostearate, glycerin fatty acid ester such as trifatty acid glycerin; or sucrose fatty acid ester Preferred are higher alcohols or glycerin fatty acid esters, and more preferred are stearyl alcohol or glyceryl monostearate.
  • one kind of wax-like substance can be used, or two or more kinds can be used in combination. From the viewpoint of the effect of stabilizing the drug
  • the amount of the wax-like substance used is preferably a weight ratio of the compound having the formula (I) or a pharmacologically acceptable salt thereof to the wax-like substance, preferably 1: 0.2 to 1: 5, more preferably. Is in the range of 1: 0.4 to 1: 3.
  • the blending amount of the waxy substance to be used is preferably 0.2 to 52% by weight, more preferably 0.5 to 16% by weight with respect to the total weight of the pharmaceutical composition.
  • the melt mixing in the present invention is a method in which a wax-like substance is heated and melted, and a target compound is dispersed or dissolved therein, followed by primary granulation using the dispersion or solution, and primary granulation means. Examples thereof include spray granulation, melt granulation, and a method of pulverizing the dispersion or solution after cooling and solidification.
  • the pharmaceutical composition of the present invention may further contain excipients, lubricants, binders, emulsifiers, stabilizers, flavoring agents and / or flavoring agents other than appropriate pharmacologically acceptable wax-like substances.
  • additives such as a disintegrating agent, can be included.
  • Excipients used include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; Dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium metasilicate aluminate; phosphorus Inorganic fillers such as phosphates such as calcium oxyhydrogenate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate can be mentioned, and preferably from cellulose derivatives and sugar derivatives.
  • One or more excipients selected, more preferably Lactose is another crystalline and one or more excipients selected from microcrystalline cellulose mannitol, and most preferably lactose and / or microcrystalline cellulose.
  • Lubricants used include, for example, metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid Sodium stearyl; sucrose fatty acid ester; sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; A starch derivative etc. can be mentioned, Preferably it is a stearic acid metal salt. Also, beeswax, gay wax or stearic acid can be used as a lubricant.
  • binder examples include hydroxypropyl cellulose, hypromellose, polyvinyl pyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients, preferably hydroxypropyl cellulose or hypromellose. is there.
  • Emsifiers used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
  • colloidal clays such as bentonite or bee gum
  • metal hydroxides such as magnesium hydroxide or aluminum hydroxide
  • anionic surfactants such as sodium lauryl sulfate or calcium stearate
  • a cationic surfactant such as benzalkonium chloride
  • a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
  • “Stabilizers” used include, for example, paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Phenols; thimerosal; dehydroacetic acid; or sorbic acid.
  • sweeteners such as sodium saccharin or aspartame
  • acidifiers such as citric acid, malic acid or tartaric acid
  • flavorings such as menthol, lemon or orange. Can do.
  • Disintegrants used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Examples include chemically modified water-soluble polymers such as sodium.
  • the compounding amount of the compound having the above formula (I) or a pharmacologically acceptable salt thereof in the pharmaceutical composition is not particularly limited, but is, for example, 1.0 to 30.0% by weight with respect to the total weight of the pharmaceutical composition. % (Preferably 1.3 to 20.0% by weight).
  • the amount of the additive in the total amount of the pharmaceutical composition is not particularly limited.
  • the excipient is 10.0 to 93.5% by weight (preferably, based on the total weight of the pharmaceutical composition) 44.0-90.0% by weight), lubricant 0.5-5.0% by weight (preferably 0.5-3.0% by weight), binder 0.0-15.0% % By weight (preferably 2.5 to 10.0% by weight) and disintegrant 2.5 to 40.0% by weight (preferably 5.0 to 30.0% by weight) are preferably blended. .
  • the pharmaceutical composition of the present invention includes, for example, tablets (including sublingual tablets and orally disintegrating agents), capsules (including soft capsules and microcapsules), granules, fine granules, powders, pills, chewable drugs, or the like.
  • tablets including sublingual tablets and orally disintegrating agents
  • capsules including soft capsules and microcapsules
  • granules fine granules, powders, pills, chewable drugs, or the like.
  • examples include solid preparations such as troches; injections; suspensions; liquids and the like, preferably solid preparations, more preferably powders, fine granules, granules, capsules or tablets, Most preferred is a tablet.
  • the pharmaceutical composition of the present invention may be coated with one or more layers, and the coating is performed using, for example, a film coating apparatus.
  • film coating base examples include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.
  • sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like can be used in combination. .
  • water-soluble film coating bases examples include cellulose derivatives such as hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylhydroxyethylcellulose, or sodium carboxymethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, or polyvinylpyrrolidone. A molecule; or a polysaccharide such as pullulan.
  • enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose or cellulose acetate phthalate; (meth) acrylic acid copolymer L, (meth) acrylic acid Examples thereof include acrylic acid derivatives such as copolymer LD or (meth) acrylic acid copolymer S; or natural products such as shellac.
  • sustained-release film coating base examples include cellulose derivatives such as ethyl cellulose; or acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS or ethyl acrylate / methyl methacrylate / copolymer emulsion. be able to.
  • the above coating bases may be used as a mixture of two or more thereof in an appropriate ratio. Furthermore, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents and / or preservatives can be further included as necessary.
  • plasticizer that can be used in the present invention is not particularly limited, and can be appropriately selected by those skilled in the art.
  • plasticizers include propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and sorbitol, glycerin triacetate, diethyl phthalate and triethyl citrate, lauric acid, sucrose, dextrose, sorbitol, triacetin, and acetyl triethyl titrate. , Triethyl titrate, tributyl titrate, acetyl tributyl titrate and the like.
  • Examples of the concealing agent that can be used in the present invention include titanium oxide.
  • Examples of the colorant that can be used in the present invention include titanium oxide, iron oxide, iron sesquioxide, yellow iron sesquioxide, or yellow No. 5 aluminum lake talc.
  • preservatives examples include parabens.
  • heart or cerebrovascular disease refers to treatment by administering a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance,
  • diseases that are treatable, preventable, or recoverable by performing percutaneous coronary angioplasty (PTCA) and / or coronary aortic bypass graft (CABG) including (percutaneous) catheter intervention (PCI) Point to.
  • PTCA percutaneous coronary angioplasty
  • CABG coronary aortic bypass graft
  • PCI percutaneous catheter intervention
  • heart or cerebrovascular diseases encompassed by the present invention include coronary artery occlusion, restenosis (after PTCA and / or CABG), stroke, acute coronary syndrome (ACS), ACS without PCI (PCI treatment Untreated and treated with drugs), high-risk vascular disease (HRVD), cerebral vascular aneurysm (CVA), congestive heart failure, alternans, ventricular aneurysm, neurological aneurysm, myocardial infarction, heart Arrest, including atrial fibrillation, cardiac edema, cardiac dyspnea, cardiac palsy, tachycardia, cardiac hemoptysis, heart failure, heart murmur, cardiogenic syncope, cardiac tamponade, and / or peripheral arterial disorder Can be mentioned.
  • thrombosis and embolism are used in their general sense. That is, “thrombosis-induced or embolism-induced disease” refers to a disease that develops or worsens due to the onset of thrombosis or embolism, morbidity or signs thereof. . Examples of these diseases include myocardial infarction, angina pectoris, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombosis or restenosis following PTCA or CABG, peripheral vascular thrombus Vascular disease derived from diabetes, diabetes or syndrome X, or heart failure.
  • administration refers to a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance by oral, sublingual and other forms of administration.
  • a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance by oral, sublingual and other forms of administration.
  • the pharmaceutical composition of the present invention alone or as part of a combination therapy (treatment) such as PCI treatment, or as part of a combination therapy with other heart or brain protective agents It is possible to carry out functions intended for the treatment and / or prevention of the onset or recurrence of vascular diseases.
  • Such administration in combination therapy may include PCI treatment (eg, stent implantation or balloon angioplasty).
  • treatment refers to a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance, either alone or with other cardiac or brain protective agents.
  • the method is not particularly limited, such as use in combination with or as an adjuvant for PTCA and / or CABG including PCI, but restenosis, ACS including ACS without PCI, myocardial infarction, brain It refers to recovering, inhibiting or preventing the onset or recurrence of heart or cerebrovascular diseases such as vascular aneurysms and HRVD, or reducing the severity thereof.
  • terapéuticaally effective amount refers to a compound having the general formula (I) or a pharmacologically acceptable salt thereof prescribed by a qualified treating physician or approved by an appropriate regulatory authority.
  • a general formula that is necessary or sufficient to treat a specific heart or cerebrovascular disease with a single dose or multiple dose units in a treatment regimen comprising administering a pharmaceutical composition containing a salt and a waxy substance.
  • the therapeutically effective amount depends on factors known to those skilled in the art (qualified prescribers) such as the use of aspirin and other heart or brain protective agents, the type of surgical procedure (eg PCI), the use of drug-coated stents. It may vary depending on factors including presence or absence, mode of administration and treatment regimen, subject's age, height or weight, genetic or behavioral predisposition to heart or cerebrovascular disease or severity and recurrence of heart or cerebrovascular disease. Those skilled in the art can consider these factors and related factors to make an appropriate decision regarding a therapeutically effective amount for a particular disease.
  • other heart or brain protective agents refers to beneficial effects (treatment of onset or recurrence and / or treatment) for patients suffering from or expected to suffer from heart or cerebrovascular disease.
  • beneficial effects treatment of onset or recurrence and / or treatment
  • heart or brain protective agents include, but are not limited to, for example, effective antiplatelet agents (eg, aspirin), effective GPIIb / IIIa antagonists, effective statins (eg, HMG-CoA reductase inhibition) Agents), superstatins, acyl coenzyme A-cholesterol O-acyltransferase (ACAT) inhibitors, effective anticoagulants, effective thienopyridines (eg ticlopidine or clopidogrel) and other effective lipid modifiers Aspirin is preferred.
  • effective antiplatelet agents eg, aspirin
  • effective GPIIb / IIIa antagonists e.g, aspirin
  • statins eg, HMG-CoA reductase inhibition
  • superstatins eg, acyl coenzyme A-cholesterol O-acyltransferase (ACAT) inhibitors
  • effective anticoagulants eg ticlopidine or clopidogrel
  • the pharmaceutical composition comprising a compound having the general formula (I) or a pharmaceutically acceptable salt thereof and a wax-like substance of the present invention is another effective anti-oxidant selected from aspirin, clopidogrel and its active metabolite.
  • each treatment may be started simultaneously or sequentially in a short period (usually within 0 to 30 days) after the start of the first treatment.
  • “Combination therapy” may refer to the use of a combination of dosing methods, with other selected antiplatelet agents being dosed by a single tablet, capsule, inhalation device, intravenous solution or suppository. Also good.
  • the duration of the combined treatment is as described above, for example, from about 30 days to about 700 days, preferably from about 30 days to about 365 days.
  • the exact duration of treatment consisting of administering the pharmaceutical composition of the present invention is determined by the treating physician or attending physician and is tailored to the particular patient's symptoms, such as consideration for signs of comorbidity, for example. .
  • the pharmaceutical composition of the present invention provides a therapeutically effective amount of the pharmaceutical composition of the present invention for patients undergoing PCI treatment or other surgical treatment, before and / or after PCI or other surgical treatment. It can optionally be administered with other cardiac or cerebral protective agents for a reasonable period of time. Prior to PCI or other surgical treatment, administration of the present pharmaceutical composition, optionally with the use of other cardiac or cerebral protective agents, may be performed up to about 60 days in advance for a reasonable period of time. It does not have to be included.
  • the purpose of pre-administration is to rapidly add the effect of the pharmaceutical composition of the present invention prior to surgical treatment, and maximizing the therapeutic effect on the patient by performing pre-treatment (initial administration). can do.
  • a new effect is further added in addition to those effects, and the therapeutic effect on the patient can be maximized.
  • Administration of the pharmaceutical composition of the present invention prior to surgical treatment such as stenting or balloon angioplasty may not be feasible or necessary in an emergency situation.
  • a reasonable period of combined treatment with the pharmaceutical composition of the present invention performed after PCI or other surgical treatment is, for example, from about 5 days to about 700 days, and preferably from about 30 days to about 365 days.
  • the exact duration of treatment according to the present invention is ultimately determined by the treating physician or attending physician and is tailored to the individual patient.
  • “equivalent” refers to the molar weight equivalent or chemical equivalent of a compound having the general formula (I) when administered as an acid addition salt (preferably hydrochloride).
  • base equivalent is used in its usual meaning, that is, it refers to the amount of the compound (acid addition salt) having the general formula (I) corresponding to the base form. ) Is possible.
  • an initial dose of a compound having the general formula (I) or a pharmaceutically acceptable salt thereof of about 60 mg equivalent is calculated based on 60 mg of the compound having the general formula (I) unless otherwise specified.
  • the dosage of the hydrochloride salt of the compound having general formula (I) of about 10.98 mg is 10 mg equivalent of the compound having general formula (I) and the hydrochloric acid of the compound having general formula (I) of about 16.46 mg.
  • the dosage of the salt is 15 mg equivalent of the compound having general formula (I).
  • the dose of 43.91 mg of the hydrochloride salt of the compound having general formula (I) is 40 mg equivalent of the compound having general formula (I).
  • “Equivalent” is not synonymous with “bioequivalence”.
  • the dose of the compound having the above formula (I), which is an active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof varies depending on various conditions such as drug activity, patient symptoms, age or body weight. Can do. In the case of oral administration, the dose is usually 0.01 mg (preferably 1 mg) as the lower limit for adults, and 200 mg (preferably 100 mg) as the upper limit. can do.
  • the pharmaceutical composition of the present invention includes, for example, a pharmaceutical composition for initial administration containing about 10 mg to 100 mg of a base equivalent of a compound having the general formula (I) and a waxy substance, and the general formula (I)
  • examples include pharmaceutical compositions for daily maintenance administration containing about 1 mg to 15 mg of a base equivalent of hydrochloride and a waxy substance, preferably about 20 mg to 60 mg of a compound having the general formula (I)
  • Pharmaceutical composition for initial administration containing an equivalent amount of hydrochloride and a waxy substance, and a hydrochloride and a wax of about 3.75 mg to 10 mg base equivalent (more preferably 10 mg base equivalent) of a compound having general formula (I)
  • a pharmaceutical composition for daily maintenance administration containing a substance-like substance can be mentioned, and particularly preferred is a compound having the general formula (I) for the first administration containing about 60 mg of a base equivalent of hydrochloride and a wax-like substance Doctor Composition, and it can include a pharmaceutical composition of the daily maintenance for
  • first dose refers to the gradual expansion of a particular vascular disease or acute vascular disease (eg, embolism, restenosis) in an acute or life-threatening patient. Or other) refers to the amount of a compound having the general formula (I) that is necessary, sufficient and / or effective for the control, suppression, treatment or prevention of symptoms presenting.
  • initial dose is a compound having the formula (I) that is administered to a patient from the onset of symptoms to the start of other methods (including PCI, CABG or other angioplasty), It refers to the amount of a pharmaceutically acceptable salt, solvate or other platelet aggregation inhibitor.
  • the initial dose is a drug dose that controls, suppresses or prevents further deterioration of the patient's symptoms, after the onset, but before or after the start of surgical treatment.
  • the amount of drug administered before the start of administration may be administered to a diagnosed patient, for example, for a period of about 7 days immediately after onset, more preferably for a period of about 1 to 3 days after onset. Preferably, it may be administered for a period of about one day from about 15 minutes after onset, and may include multiple doses diagnosed as necessary by the attending physician within that period. If it is a doctor in charge, it may be recommended to divide the initial dose into several doses for a specific patient or patient group.
  • a physician may divide an initial dose of about 20 mg to 30 mg equivalents of a compound having general formula (I) for a particular patient or patient population, and / or a special population in a particular patient Alternatively, it may be recommended to divide the maintenance dose for patients with specific symptoms and / or history. Similarly, in the initial dose of 40 mg to 60 mg, the attending physician may recommend that the 20 mg to 30 mg dose be divided into two doses at appropriate intervals appropriate to the patient's specific symptoms. That is, a desired initial dose can be administered to a specific patient or patient population by employing an initial dose divided into one or more. Regardless of the method chosen, the initial administration is made before the start of surgical treatment or immediately after the surgical treatment and before the start of maintenance administration. In the absence of surgical treatment, an initial dose can be given to suppress, sedate or control symptoms, followed by a maintenance dose as needed.
  • the term “maintenance dose” in the present invention means a dose administered to a patient after an initial administration period.
  • the dosage refers to an effective amount that provides the desired effect in the long, medium or short term when used as directed when there are no other factors.
  • a considerable maintenance period (the period following the initial administration period, in order to beneficially maintain the platelet aggregation inhibitory effect in the patient, at a dosage level lower than the initial dosage,
  • the period during which the pharmaceutical composition is administered may be, for example, from about 3 days to about 700 days, preferably from about 7 days to about 365 days.
  • the maintenance dose is preferably administered daily.
  • the dose of the compound is preferably about 10 mg to 15 mg equivalent / day of the compound having formula (I).
  • the attending physician may recommend that maintenance doses be administered in divided doses for a particular patient or patient population. For example, a physician may recommend a maintenance dose divided into about 5 mg to 7.5 mg equivalents of a compound having formula (I) for a particular patient or patient population. Similarly, to provide a 10 mg / day maintenance dose, the attending physician may recommend two doses of 5 mg at appropriate intervals, depending on the patient's specific symptoms. That is, the present invention encompasses performing single or multiple divided doses and administering a desired maintenance dose for a particular patient or patient population.
  • the exact amount, initial frequency and duration in the present invention will be determined by the treating physician or attending physician and will depend on the specific factors or history of the individual patient such as age, height, weight, medical history, predisposition and comorbidities. It is adjusted together.
  • the dosage may include about 1 mg to 15 mg equivalent / day of compound (I), preferably about 2 mg to 10 mg equivalent / day, particularly preferably about 2.5 mg equivalent / day, 3.75 mg equivalent / day or 5 mg equivalent / day.
  • Example 1 Compound A (138 g) was added to stearyl alcohol (322 g) melted at about 80 ° C. and stirred for 1 hour. The molten mixture obtained by cooling this to room temperature was pulverized to obtain a melt-pulverized product.
  • a melt-pulverized product 22.87 g
  • low-substituted hydroxypropyl cellulose 75 g
  • hydroxypropyl cellulose 37.5 g
  • lactose hydrate 309.6 g
  • crystalline cellulose 50 g
  • the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg.
  • the obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A.
  • the stability test was done about the obtained tablet. The test results are shown in Table 1.
  • Example 2 Compound A (45 g) and talc (15 g) were added to glyceryl monostearate (90 g) melted at about 70 ° C. and stirred for 1 hour. The molten mixture obtained by cooling this to room temperature was pulverized to obtain a melt-pulverized product.
  • a melt-pulverized product 22.87 g), low-substituted hydroxypropyl cellulose (75 g), hydroxypropyl cellulose (37.5 g), lactose hydrate (309.6 g) and crystalline cellulose (50 g) were mixed with a V-type mixer. Mixed for minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
  • the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg.
  • the obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A.
  • the stability test was done about the obtained tablet. The test results are shown in Table 1.
  • Example 3 A mixture of compound A (75 g), glyceryl monostearate (30 g) and talc (45 g) was melt-granulated using a fluid bed granulator at about 65-70 ° C., and then sieved with a sieve having an opening of 300 ⁇ m. A melt-granulated product was obtained. Melt granulated product (13.72 g), low-substituted hydroxypropyl cellulose (75 g), hydroxypropyl cellulose (37.5 g), lactose hydrate (322.9 g) and crystalline cellulose (50 g) in a V-type mixer Mix for 30 minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
  • the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg.
  • the obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A.
  • the stability test was done about the obtained tablet. The test results are shown in Table 1.
  • the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg.
  • the obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A.
  • the stability test was done about the obtained tablet. The test results are shown in Table 1.
  • Test Example 1 Stability test The tablets obtained in Examples 1 to 3 and Comparative Example 1 were placed in a brown glass bottle and allowed to stand still in a sealed state at 40 ° C / 75% relative humidity. The related substance of Compound A was measured by high performance liquid chromatography, and the total content (%) of related substances was obtained from the area (%) of the peak obtained.
  • the measurement conditions for high performance liquid chromatography are as follows.
  • a pharmaceutical composition having an improved storage stability comprising a compound having the above formula (I) or a pharmacologically acceptable salt thereof, and a waxy substance.

Abstract

Provided is a pharmaceutical composition having improved storage stability, said composition containing (A) a compound represented by general formula (I) or a pharmacologically permitted salt thereof, and (B) a waxy substance.

Description

ワックス安定製剤Wax stable formulation
　本発明は、
（Ａ）下記式（Ｉ） The present invention
(A) The following formula (I)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
を有する化合物又はその薬理上許容される塩及び
（Ｂ）ワックス状物質を含有する医薬組成物、並びに、当該医薬組成物及び薬理上許容される添加物を含有する医薬組成物に関する。 Or a pharmacologically acceptable salt thereof and (B) a wax-like substance, and a pharmaceutical composition containing the pharmaceutical composition and a pharmacologically acceptable additive.
　上記式（Ｉ）を有する化合物又はその薬理上許容される塩は、血小板凝集抑制作用を有する化合物として知られている（特許文献１又は２）。 A compound having the above formula (I) or a pharmacologically acceptable salt thereof is known as a compound having a platelet aggregation inhibitory action (Patent Document 1 or 2).
　特許文献２乃至１２に、上記式（Ｉ）を有する化合物又はその薬理上許容される塩の製剤に使用しうる添加剤が多数例示されており、その一つとしてビーズワックス、ゲイ蝋、ステアリン酸及びショ糖脂肪酸エステルが一行記載されているが、多数の使用しうる添加剤の中の一つとして例示されているにすぎず、具体的に製剤例において使用されていない。さらに当該特許文献には、上記式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する医薬組成物にワックス状物質を含有することにより貯蔵安定性が改善されることは、記載も示唆もされていない。 Patent Documents 2 to 12 exemplify many additives that can be used in the preparation of the compound having the above formula (I) or a pharmacologically acceptable salt thereof, and one of them is beeswax, gay wax, stearic acid. And sucrose fatty acid esters are listed, but are only exemplified as one of many possible additives and are not specifically used in formulation examples. Further, the patent document describes that storage stability is improved by including a waxy substance in a pharmaceutical composition containing the compound having the above formula (I) or a pharmacologically acceptable salt thereof. There is no suggestion.
特開平６－４１１３９号公報JP-A-6-41139 特開２００２－１４５８８３号公報JP 2002-145883 A 特開平１０－３１０５８６号公報JP-A-10-310586 特開２００２－２５５８１４号公報JP 2002-255814 A 特開２００４－５１６３９号公報JP 2004-51639 A 国際公開番号ＷＯ２００７／１１４５２６号パンフレットInternational Publication Number WO2007 / 114526 国際公開番号ＷＯ２００８／０６９２６２号パンフレットInternational Publication Number WO2008 / 069262 Pamphlet 国際公開番号ＷＯ２００８／０７２５３２号パンフレットInternational Publication Number WO2008 / 072532 Pamphlet 国際公開番号ＷＯ２００８／０７２５３３号パンフレットInternational Publication Number WO2008 / 072533 Pamphlet 国際公開番号ＷＯ２００８／０７２５３４号パンフレットInternational Publication Number WO2008 / 072534 Pamphlet 国際公開番号ＷＯ２００８／０７２５３５号パンフレットInternational Publication Number WO2008 / 072535 Pamphlet 国際公開番号ＷＯ２００８／１０８２９１号パンフレットInternational Publication Number WO2008 / 108291 Pamphlet
　本発明の課題は、上記式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する、貯蔵安定性に優れた医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition excellent in storage stability, containing a compound having the above formula (I) or a pharmacologically acceptable salt thereof.
　本発明者らは、上記の課題を解決すべく鋭意研究を行った結果、ワックス状物質を含有することにより、上記式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する医薬組成物が優れた貯蔵安定性を有することを見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a pharmaceutical composition containing a compound having the above formula (I) or a pharmacologically acceptable salt thereof by containing a wax-like substance. It was found that the product has excellent storage stability, and the present invention has been completed.
　すなわち、本発明は、
（１）　（Ａ）上記式（Ｉ）を有する化合物又はその薬理上許容される塩及び（Ｂ）ワックス状物質を含有する医薬組成物であり、好適には、
（２）　（Ａ）上記式（Ｉ）を有する化合物又はその薬理上許容される塩及び（Ｂ）ワックス状物質を溶融混合した医薬組成物、
（３）　（Ａ）上記式（Ｉ）を有する化合物又はその薬理上許容される塩及び（Ｂ）ワックス状物質を溶融造粒した医薬組成物、
（４）　式（Ｉ）を有する化合物又はその薬理上許容される塩が、下記式（Ｉａ） That is, the present invention
(1) A pharmaceutical composition comprising (A) a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance,
(2) (A) a pharmaceutical composition obtained by melt-mixing a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance,
(3) (A) a pharmaceutical composition obtained by melt granulating a compound having the above formula (I) or a pharmacologically acceptable salt thereof and (B) a wax-like substance,
(4) A compound having the formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
を有する化合物である（１）～（３）のいずれか１つに記載の医薬組成物、
（５）　ワックス状物質が、融点４０～１５０℃のワックス状物質である、（１）～（４）のいずれか１つに記載の医薬組成物、
（６）　ワックス状物質が、硬化油、植物性若しくは動物性油脂、高級アルコール、高級脂肪酸、グリセリン脂肪酸エステル及びショ糖脂肪酸エステルから選ばれる１種又は２種以上である（１）～（５）のいずれか１項に記載の医薬組成物、
（７）　ワックス状物質が、高級アルコール又はグリセリン脂肪酸エステルである（１）～（５）のいずれか１つに記載の医薬組成物、
（８）　ワックス状物質が、ステアリルアルコール又はモノステアリン酸グリセリンである（１）～（５）のいずれか１つに記載の医薬組成物、
（９）　（１）～（８）のいずれか１つに記載の医薬組成物及び薬理上許容される添加物を含有する医薬組成物、
（１０）　医薬組成物が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である（１）～（９）のいずれか１つに記載の医薬組成物、
（１１）　医薬組成物が、錠剤である（１）～（９）のいずれか１つに記載の医薬組成物、
（１２）　ワックス状物質の配合量が、医薬組成物全量に対して０．２～５２重量％である、（１）～（１１）のいずれか１つに記載の医薬組成物。
（１３）　ワックス状物質の配合量が、医薬組成物全量に対して０．５～１６重量％である、（１）～（１１）のいずれか１つに記載の医薬組成物、
（１４）　上記式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融混合することを特徴とする、（２）又は（４）～（１３）のいずれか１つに記載の医薬組成物の製造方法、
（１５）　上記式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融造粒することを特徴とする、（３）～（１３）のいずれか１つに記載の医薬組成物の製造方法、
（１６）　上記式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有することを特徴とする、（１）～（１３）のいずれか１つに記載の医薬組成物の安定化方法、
（１７）　上記式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融混合することを特徴とする、（２）又は（４）～（１３）のいずれか１つに記載の医薬組成物の安定化方法、及び、
（１８）　上記式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融造粒することを特徴とする、（３）～（１３）のいずれか１つに記載の医薬組成物の安定化方法である。 The pharmaceutical composition according to any one of (1) to (3), which is a compound having
(5) The pharmaceutical composition according to any one of (1) to (4), wherein the waxy substance is a waxy substance having a melting point of 40 to 150 ° C.
(6) The waxy substance is one or more selected from hardened oil, vegetable or animal oil, higher alcohol, higher fatty acid, glycerin fatty acid ester and sucrose fatty acid ester (1) to (5) A pharmaceutical composition according to any one of
(7) The pharmaceutical composition according to any one of (1) to (5), wherein the waxy substance is a higher alcohol or a glycerin fatty acid ester,
(8) The pharmaceutical composition according to any one of (1) to (5), wherein the waxy substance is stearyl alcohol or glyceryl monostearate,
(9) A pharmaceutical composition comprising the pharmaceutical composition according to any one of (1) to (8) and a pharmacologically acceptable additive,
(10) The pharmaceutical composition according to any one of (1) to (9), wherein the pharmaceutical composition is a powder, fine granules, granules, capsules or tablets,
(11) The pharmaceutical composition according to any one of (1) to (9), wherein the pharmaceutical composition is a tablet,
(12) The pharmaceutical composition according to any one of (1) to (11), wherein the compounding amount of the wax-like substance is 0.2 to 52% by weight with respect to the total amount of the pharmaceutical composition.
(13) The pharmaceutical composition according to any one of (1) to (11), wherein the compounding amount of the wax-like substance is 0.5 to 16% by weight based on the total amount of the pharmaceutical composition,
(14) In any one of (2) or (4) to (13), the compound having the above formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance are melt-mixed. A method for producing the pharmaceutical composition described above,
(15) The medicament according to any one of (3) to (13), wherein the compound having the formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance are melt-granulated. Production method of the composition,
(16) The pharmaceutical composition according to any one of (1) to (13), comprising a compound having the above formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance. Stabilization method,
(17) In any one of (2) or (4) to (13), the compound having the above formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance are melt-mixed. A method for stabilizing the described pharmaceutical composition, and
(18) The pharmaceutical according to any one of (3) to (13), wherein the compound having the formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance are melt-granulated. A method for stabilizing a composition.
　本発明は、心臓若しくは脳血管疾患の治療及び／又は予防の為の、治療上有効量の一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物の使用に関する。 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance for the treatment and / or prevention of heart or cerebrovascular diseases. About the use of.
　本発明は、心臓若しくは脳血管疾患の治療用の他の心臓又は脳保護剤と併用される、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物の使用に関する。 The present invention relates to a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance, which is used in combination with another heart or brain protective agent for treating heart or cerebrovascular disease. Concerning the use of things.
　本発明は、一般式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する医薬組成物の安定性を改善する方法であって、一般式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する固形製剤に、ワックス状物質を含ませる方法に関する。 The present invention relates to a method for improving the stability of a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof, comprising the compound having the general formula (I) or a pharmacologically acceptable salt thereof. The present invention relates to a method of including a waxy substance in a solid preparation containing a salt to be prepared.
　本発明は、一般式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する医薬組成物であって、当該製剤中にワックス状物質を含み、塩基当量が約1mg乃至約70mgである治療上有効量の一般式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する医薬組成物を提供する。 The present invention is a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof, comprising a waxy substance in the preparation, and having a base equivalent of about 1 mg to about 70 mg Provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof.
　本発明は、心臓若しくは脳血管疾患の治療及び／又は予防方法であって、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を、その必要のある患者に投与する方法に関する。 The present invention provides a method for treating and / or preventing a heart or cerebrovascular disease, comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance. The present invention relates to a method for administration to a patient with the disease.
　本発明は、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を投与することによる、心臓若しくは脳血管疾患の治療及び／又は予防方法であって、一般式（Ｉ）を有する化合物約10mg乃至100mg（好適には20mg乃至60mg、更に好適には20mg、40mg又は60mg、特に好適には60mg）又はその当量の薬学的に許容される塩及びワックス状物質を含有する医薬組成物を初回投与し、次いで、一般式（Ｉ）を有する化合物約1mg乃至15mg（好適には3.75mg乃至10mg、更に好適には3.75mg、5mg又は10mg、特に好適には10mg）又はその当量の薬学的に許容される塩及びワックス状物質を含有する医薬組成物を維持投与する方法に関する。 The present invention is a method for treating and / or preventing a heart or cerebrovascular disease by administering a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance. About 10 mg to 100 mg (preferably 20 mg to 60 mg, more preferably 20 mg, 40 mg or 60 mg, particularly preferably 60 mg) of a compound having the general formula (I) or an pharmaceutically acceptable salt thereof and A pharmaceutical composition containing a waxy substance is initially administered and then about 1 mg to 15 mg (preferably 3.75 mg to 10 mg, more preferably 3.75 mg, 5 mg or 10 mg, particularly preferred Relates to a method for maintaining and administering a pharmaceutical composition containing 10 mg) or equivalent of a pharmaceutically acceptable salt and a wax-like substance.
　本発明は、20mg乃至60mg（好適には60mg）の塩基当量の一般式（Ｉ）を有する化合物（好適には塩酸塩）とワックス状物質を含有する医薬組成物の初回投与、及び適当な間隔を置いてそれに続く3.75mg乃至15mg（好適には10mg）の塩基当量の一般式（Ｉ）を有する化合物（好適には塩酸塩）とワックス状物質を含有する医薬組成物の維持投与からなる、心臓若しくは脳血管疾患の治療及び／又は予防方法を提供する。 The present invention relates to the initial administration of a pharmaceutical composition comprising a compound (preferably hydrochloride) having a general formula (I) of 20 to 60 mg (preferably 60 mg) of base equivalent and a waxy substance, and at suitable intervals. Followed by maintenance administration of a pharmaceutical composition containing a compound (generally a hydrochloride salt) of general formula (I) with a base equivalent weight of 3.75 mg to 15 mg (preferably 10 mg) and a waxy substance, A method for treating and / or preventing heart or cerebrovascular disease is provided.
　本発明は、医薬組成物の製造方法であって、単独投与用に、或いは、心臓若しくは脳血管疾患の治療、予防及び／又は回復用の他の心臓又は脳保護剤との併用投与用に、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物の製造方法に関する。 The present invention is a method for producing a pharmaceutical composition for single administration, or for combined administration with other heart or brain protective agents for treatment, prevention and / or recovery of heart or cerebrovascular diseases. The present invention relates to a method for producing a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance.
　本発明によれば、上記式（Ｉ）を有する化合物又はその薬理上許容される塩を含有する、貯蔵安定性に優れた医薬組成物を提供することが可能となる。 According to the present invention, it is possible to provide a pharmaceutical composition excellent in storage stability, which contains a compound having the above formula (I) or a pharmacologically acceptable salt thereof.
　本発明の医薬組成物は、例えば、血栓症又は塞栓症（好適には、血栓症）等の治療及び／又は予防（好適には、血栓症の治療薬及び／又は予防薬である）に有効である。 The pharmaceutical composition of the present invention is effective for, for example, treatment and / or prevention (preferably a thrombosis therapeutic and / or prophylactic agent) such as thrombosis or embolism (preferably thrombosis). It is.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物は、心臓若しくは脳血管疾患の治療及び／又は予防に有効である。 The pharmaceutical composition containing the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof and a waxy substance is effective for the treatment and / or prevention of heart or cerebrovascular disease.
　本発明の医薬組成物の有効成分である、上記式（Ｉ）を有する化合物、すなわち２－アセトキシ－５－（α－シクロプロピルカルボニル－２－フルオロベンジル）－４，５，６，７－テトラヒドロチエノ［３，２－ｃ］ピリジン、又はその薬理上許容される塩は、特開平６－４１１３９号公報又は特開２００２－１４５８８３号公報に記載されており、製造することができる。 A compound having the above formula (I) which is an active ingredient of the pharmaceutical composition of the present invention, that is, 2-acetoxy-5- (α-cyclopropylcarbonyl-2-fluorobenzyl) -4,5,6,7-tetrahydro Thieno [3,2-c] pyridine or a pharmacologically acceptable salt thereof is described in JP-A-6-41139 or JP-A-2002-145883 and can be produced.
　本発明の「その薬理上許容される塩」としては、例えば、フッ化水素酸塩、塩酸塩、臭化水素酸塩若しくはヨウ化水素酸塩のようなハロゲン化水素酸塩；硝酸塩、過塩素酸塩、硫酸塩若しくはリン酸塩のような無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩若しくはエタンスルホン酸塩のような低級アルキルスルホン酸塩；ベンゼンスルホン酸塩若しくはｐ－トルエンスルホン酸塩のようなアリールスルホン酸塩；酢酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、シュウ酸塩若しくはマレイン酸塩のような有機酸塩；又は、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩若しくはアスパラギン酸塩のようなアミノ酸塩等を挙げることができ、好適には、ハロゲン化水素酸塩又は有機酸塩であり、更に好適には、塩酸塩又はマレイン酸塩であり、最も好適には、塩酸塩である。 As the “pharmacologically acceptable salt” of the present invention, for example, hydrohalide such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide; nitrate, perchlorine Inorganic acid salts such as acid salts, sulfates or phosphates; lower alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate; benzenesulfonate or p-toluenesulfonic acid Aryl sulfonates such as salts; organic acid salts such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate or maleate; or Glycine salt, lysine salt, arginine salt, ornithine salt, amino acid salt such as glutamate or aspartate, etc. A hydrohalide salt or an organic acid salt, more preferably a hydrochloride or maleate, and most preferably is the hydrochloride salt.
　式（Ｉ）で表される化合物において、ベンジル基のα位は不斉炭素であり、それに基づく光学活性体が存在するが、その異性体及びそれらの混合物も本発明の化合物に包含される。同様に、式（Ｉ）で表される化合物の薬理上許容される塩（例えば塩酸塩）の異性体及びそれらの混合物も、本発明の化合物の薬理上許容される塩（例えば塩酸塩）に包含される。 In the compound represented by the formula (I), the α-position of the benzyl group is an asymmetric carbon, and there are optically active substances based on the asymmetric carbon, and the isomers and mixtures thereof are also included in the compound of the present invention. Similarly, an isomer of a pharmacologically acceptable salt (eg, hydrochloride) of a compound represented by formula (I) and a mixture thereof are also converted into a pharmacologically acceptable salt (eg, hydrochloride) of the compound of the present invention. Is included.
　本発明のワックス状物質は、融点４０～１５０℃のものが好ましい。本発明の「ワックス状物質」としては、例えば、硬化ヒマシ油、硬化大豆油、硬化ナタネ油、硬化綿実油のような硬化油；カルナウバロウ、サラシミツロウ、牛脂のような植物性若しくは動物性油脂；ステアリルアルコール、セタノールのような高級アルコール；ステアリン酸、パルミチン酸のような高級脂肪酸；モノステアリン酸グリセリン等のモノ脂肪酸グリセリン、トリ脂肪酸グリセリンのようなグリセリン脂肪酸エステル；又は、ショ糖脂肪酸エステル等を挙げることができ、好適には高級アルコール又はグリセリン脂肪酸エステルであり、より好適にはステアリルアルコール又はモノステアリン酸グリセリンである。本発明においては、１種のワックス状物質を用いることもできるし、又は２種以上を組み合わせて用いることもできる。また、薬物の安定化効果の点から、ワックス状物質の融点は、薬物の融点よりも低いものが好ましい。 The wax-like substance of the present invention preferably has a melting point of 40 to 150 ° C. Examples of the “wax-like substance” of the present invention include hardened oils such as hardened castor oil, hardened soybean oil, hardened rapeseed oil, and hardened cottonseed oil; vegetable or animal fats and oils such as carnauba wax, white beeswax and beef tallow; Higher alcohols such as alcohol and cetanol; higher fatty acids such as stearic acid and palmitic acid; monofatty acid glycerin such as glyceryl monostearate, glycerin fatty acid ester such as trifatty acid glycerin; or sucrose fatty acid ester Preferred are higher alcohols or glycerin fatty acid esters, and more preferred are stearyl alcohol or glyceryl monostearate. In the present invention, one kind of wax-like substance can be used, or two or more kinds can be used in combination. From the viewpoint of the effect of stabilizing the drug, the melting point of the wax-like substance is preferably lower than the melting point of the drug.
　使用するワックス状物質の配合量は、式（Ｉ）を有する化合物又はその薬理上許容される塩とワックス状物質の重量比は、好適には１：０．２～１：５、より好適には１：０．４～１：３の範囲である。 The amount of the wax-like substance used is preferably a weight ratio of the compound having the formula (I) or a pharmacologically acceptable salt thereof to the wax-like substance, preferably 1: 0.2 to 1: 5, more preferably. Is in the range of 1: 0.4 to 1: 3.
　また、使用するワックス状物質の配合量は、医薬組成物全重量に対して、好適には０．２～５２重量％であり、より好適には０．５～１６重量％である。 In addition, the blending amount of the waxy substance to be used is preferably 0.2 to 52% by weight, more preferably 0.5 to 16% by weight with respect to the total weight of the pharmaceutical composition.
　本発明における溶融混合とは、ワックス状物質を加温融解し、そこに目的の化合物を分散又は溶解させた後、当該分散液又は溶液を用いて一次造粒する方法であり、一次造粒手段としては、噴霧造粒、溶融造粒及び分散液若しくは溶液を冷却固化後粉砕する方法が挙げられる。 The melt mixing in the present invention is a method in which a wax-like substance is heated and melted, and a target compound is dispersed or dissolved therein, followed by primary granulation using the dispersion or solution, and primary granulation means. Examples thereof include spray granulation, melt granulation, and a method of pulverizing the dispersion or solution after cooling and solidification.
　本発明の医薬組成物は、更に必要に応じて、適宜の薬理学的に許容されるワックス状物質以外の、賦形剤、滑沢剤、結合剤、乳化剤、安定剤、矯味矯臭剤及び／又は崩壊剤等の添加剤を含むことができる。 If necessary, the pharmaceutical composition of the present invention may further contain excipients, lubricants, binders, emulsifiers, stabilizers, flavoring agents and / or flavoring agents other than appropriate pharmacologically acceptable wax-like substances. Or additives, such as a disintegrating agent, can be included.
　使用される「賦形剤」としては、例えば、乳糖、白糖、ブドウ糖、マンニトール、若しくはソルビトールのような糖誘導体；トウモロコシデンプン、バレイショデンプン、α－デンプン若しくはデキストリンのようなデンプン誘導体；結晶セルロースのようなセルロース誘導体；アラビアゴム；デキストラン；又は、プルラン等の有機系賦形剤；或いは、軽質無水ケイ酸、合成ケイ酸アルミニウム、ケイ酸カルシウム若しくはメタケイ酸アルミン酸マグネシウムのようなケイ酸塩誘導体；リン酸水素カルシウムのようなリン酸塩；炭酸カルシウムのような炭酸塩；又は、硫酸カルシウムのような硫酸塩等の無機系賦形剤を挙げることができ、好適には、セルロース誘導体及び糖誘導体から選択される一つ以上の賦形剤であり、更に好適には、乳糖、マンニトールの他の結晶及び結晶セルロースから選択される一つ以上の賦形剤であり、最も好適には、乳糖及び／又は結晶セルロースである。 “Excipients” used include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; Dextran; or organic excipients such as pullulan; or silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, or magnesium metasilicate aluminate; phosphorus Inorganic fillers such as phosphates such as calcium oxyhydrogenate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate can be mentioned, and preferably from cellulose derivatives and sugar derivatives. One or more excipients selected, more preferably Lactose is another crystalline and one or more excipients selected from microcrystalline cellulose mannitol, and most preferably lactose and / or microcrystalline cellulose.
　使用される「滑沢剤」としては、例えば、ステアリン酸カルシウム若しくはステアリン酸マグネシウムのようなステアリン酸金属塩；タルク；コロイドシリカ；ホウ酸；アジピン酸；硫酸ナトリウムのような硫酸塩；グリコール；フマル酸ステアリルナトリウム；ショ糖脂肪酸エステル；安息香酸ナトリウム；Ｄ，Ｌ－ロイシン；ラウリル硫酸ナトリウム若しくはラウリル硫酸マグネシウムのようなラウリル硫酸塩；無水ケイ酸若しくはケイ酸水和物のようなケイ酸類；又は、上記デンプン誘導体等を挙げることができ、好適には、ステアリン酸金属塩である。また、ビーズワックス、ゲイ蝋又はステアリン酸を滑沢剤として使用することもできる。 “Lubricants” used include, for example, metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; boric acid; adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid Sodium stearyl; sucrose fatty acid ester; sodium benzoate; D, L-leucine; lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; A starch derivative etc. can be mentioned, Preferably it is a stearic acid metal salt. Also, beeswax, gay wax or stearic acid can be used as a lubricant.
　使用される「結合剤」としては、例えば、ヒドロキシプロピルセルロース、ヒプロメロース、ポリビニルピロリドン、ポリエチレングリコール、又は、前記賦形剤と同様の化合物等を挙げることができ、好適にはヒドロキシプロピルセルロース又はヒプロメロースである。 Examples of the “binder” used include hydroxypropyl cellulose, hypromellose, polyvinyl pyrrolidone, polyethylene glycol, and the same compounds as the above-mentioned excipients, preferably hydroxypropyl cellulose or hypromellose. is there.
　使用される「乳化剤」としては、例えば、ベントナイト若しくはビーガムのようなコロイド性粘土；水酸化マグネシウム若しくは水酸化アルミニウムのような金属水酸化物；ラウリル硫酸ナトリウム若しくはステアリン酸カルシウムのような陰イオン界面活性剤；塩化ベンザルコニウムのような陽イオン界面活性剤；又は、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル若しくはショ糖脂肪酸エステルのような非イオン界面活性剤を挙げることができる。 “Emulsifiers” used include, for example, colloidal clays such as bentonite or bee gum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate A cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.
　使用される「安定剤」としては、例えば、メチルパラベン若しくはプロピルパラベンのようなパラオキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコールのようなアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾールのようなフェノール類；チメロサール；デヒドロ酢酸；又は、ソルビン酸等を挙げることができる。 “Stabilizers” used include, for example, paraoxybenzoates such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenol or cresol Phenols; thimerosal; dehydroacetic acid; or sorbic acid.
　使用される「矯味矯臭剤」としては、例えば、サッカリンナトリウム若しくはアスパルテームのような甘味料；クエン酸、リンゴ酸若しくは酒石酸のような酸味料；又は、メントール、レモン若しくはオレンジのような香料等を挙げることができる。 Examples of the “flavoring agent” used include sweeteners such as sodium saccharin or aspartame; acidifiers such as citric acid, malic acid or tartaric acid; or flavorings such as menthol, lemon or orange. Can do.
　使用される「崩壊剤」としては、例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースナトリウムのようなセルロース誘導体；架橋ポリビニルピロリドン；又は、カルボキシメチルスターチ若しくはカルボキシメチルスターチナトリウムのような化学修飾された水溶性高分子類等を挙げることができる。 “Disintegrants” used include, for example, cellulose derivatives such as low substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium or sodium carboxymethylcellulose; crosslinked polyvinylpyrrolidone; or carboxymethyl starch or carboxymethyl starch Examples include chemically modified water-soluble polymers such as sodium.
　医薬組成物中の上記式（Ｉ）を有する化合物又はその薬理上許容される塩の配合量には特に制限はないが、例えば、医薬組成物全重量に対して１．０～３０．０重量％（好適には、１．３～２０．０重量％）配合することが好ましい。 The compounding amount of the compound having the above formula (I) or a pharmacologically acceptable salt thereof in the pharmaceutical composition is not particularly limited, but is, for example, 1.0 to 30.0% by weight with respect to the total weight of the pharmaceutical composition. % (Preferably 1.3 to 20.0% by weight).
　また、医薬組成物全量中の添加剤の配合量には特に制限はないが、例えば、医薬組成物全重量に対して、賦形剤を１０．０～９３．５重量％（好適には、４４．０～９０．０重量％）、滑沢剤を０．５～５．０重量％（好適には、０．５～３．０重量％）、結合剤を０．０～１５．０重量％（好適には、２．５～１０．０重量％）、崩壊剤を２．５～４０．０重量％（好適には、５．０～３０．０重量％）配合することが好ましい。 The amount of the additive in the total amount of the pharmaceutical composition is not particularly limited. For example, the excipient is 10.0 to 93.5% by weight (preferably, based on the total weight of the pharmaceutical composition) 44.0-90.0% by weight), lubricant 0.5-5.0% by weight (preferably 0.5-3.0% by weight), binder 0.0-15.0% % By weight (preferably 2.5 to 10.0% by weight) and disintegrant 2.5 to 40.0% by weight (preferably 5.0 to 30.0% by weight) are preferably blended. .
　本発明の医薬組成物は、例えば、錠剤（舌下錠、口腔内崩壊剤を含む）、カプセル剤（ソフトカプセル、マイクロカプセルを含む）、顆粒剤、細粒剤、散剤、丸剤、チュワブル剤又はトローチ剤等の固形製剤；注射剤；懸濁剤；液剤などが挙げられ、好適には、固形製剤であり、より好適には、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤であり、最も好適には、錠剤である。 The pharmaceutical composition of the present invention includes, for example, tablets (including sublingual tablets and orally disintegrating agents), capsules (including soft capsules and microcapsules), granules, fine granules, powders, pills, chewable drugs, or the like. Examples include solid preparations such as troches; injections; suspensions; liquids and the like, preferably solid preparations, more preferably powders, fine granules, granules, capsules or tablets, Most preferred is a tablet.
　本発明における製剤の製造方法としては、Ｐｏｗｄｅｒ　Ｔｅｃｈｎｏｌｏｇｙ　ａｎｄ　Ｐｈａｒｍａｃｅｕｔｉｃａｌ　Ｐｒｏｃｅｓｓ　（Ｄ．　Ｃｈｕｌｉａ他，Ｅｌｓｅｒｖｉｅｒ　Ｓｃｉｅｎｃｅ　Ｐｕｂ　Ｃｏ（Ｄｅｃｅｍｂｅｒ　１，　１９９３））のような刊行物に記載されている一般的な方法を用いて製造すればよい。 As a method for producing a preparation in the present invention, a general method described in a publication such as Powder Technology and Pharmaceutical Process (D. Chulia et al., Elsier Science Pub Co (December 1, 1993)) is used. do it.
　本発明の医薬組成物は、１層以上のフィルムコーティングを施しても良く、コーティングは、例えば、フィルムコーティング装置を用いて行われる。 The pharmaceutical composition of the present invention may be coated with one or more layers, and the coating is performed using, for example, a film coating apparatus.
　使用されるフィルムコーティング基剤としては、例えば、糖衣基剤、水溶性フィルムコーティング基剤、腸溶性フィルムコーティング基剤又は徐放性フィルムコーティング基剤等を挙げることができる。 Examples of the film coating base used include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base, and the like.
　糖衣基剤としては、白糖が用いられ、更に、タルク、沈降炭酸カルシウム、リン酸カルシウム、硫酸カルシウム、ゼラチン、アラビアゴム、ポリビニルピロリドン及びプルラン等より選ばれる１種または２種以上を組み合わせて用いることもできる。 As the sugar coating base, sucrose is used, and one or more kinds selected from talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, pullulan and the like can be used in combination. .
　水溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルセルロース、ヒプロメロース、ヒドロキシエチルセルロース、メチルヒドロキシエチルセルロース若しくはカルボキシメチルセルロースナトリウムのようなセルロース誘導体；ポリビニルアセタールジエチルアミノアセテート、アミノアルキルメタクリレートコポリマー若しくはポリビニルピロリドンのような合成高分子；又は、プルランのような多糖類等を挙げることができる。 Examples of water-soluble film coating bases include cellulose derivatives such as hydroxypropylcellulose, hypromellose, hydroxyethylcellulose, methylhydroxyethylcellulose, or sodium carboxymethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, or polyvinylpyrrolidone. A molecule; or a polysaccharide such as pullulan.
　腸溶性フィルムコーティング基剤としては、例えば、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、カルボキシメチルエチルセルロース若しくは酢酸フタル酸セルロースのようなセルロース誘導体；（メタ）アクリル酸コポリマーＬ、（メタ）アクリル酸コポリマーＬＤ若しくは（メタ）アクリル酸コポリマーＳのようなアクリル酸誘導体；又は、セラックのような天然物等を挙げることができる。 Examples of enteric film coating bases include cellulose derivatives such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose or cellulose acetate phthalate; (meth) acrylic acid copolymer L, (meth) acrylic acid Examples thereof include acrylic acid derivatives such as copolymer LD or (meth) acrylic acid copolymer S; or natural products such as shellac.
　徐放性フィルムコーティング基剤としては、例えば、エチルセルロースのようなセルロース誘導体；又は、アミノアルキルメタクリレートコポリマーＲＳ若しくはアクリル酸エチル・メタクリル酸メチル・共重合体乳濁液のようなアクリル酸誘導体等を挙げることができる。 Examples of the sustained-release film coating base include cellulose derivatives such as ethyl cellulose; or acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS or ethyl acrylate / methyl methacrylate / copolymer emulsion. be able to.
　上記コーティング基剤は、その２種以上を適宜の割合で混合して用いてもよい。また、さらに必要に応じて、適宜の薬理学的に許容される可塑剤、賦形剤、滑沢剤、隠蔽剤、着色剤及び／又は防腐剤等の添加剤を含むことができる。 The above coating bases may be used as a mixture of two or more thereof in an appropriate ratio. Furthermore, additives such as appropriate pharmacologically acceptable plasticizers, excipients, lubricants, masking agents, coloring agents and / or preservatives can be further included as necessary.
　本発明に使用できる可塑剤の種類は特に限定されず、当業者が適宜選択可能である。そのような可塑剤としては、例えば、プロピレングリコール、ポリエチレングリコール、ポリプロピレングリコール、グリセリン及びソルビトール、グリセリントリアセテート、フタル酸ジエチル及びクエン酸トリエチル、ラウリル酸、ショ糖、デキストロース、ソルビトール、トリアセチン、アセチルトリエチルチトレート、トリエチルチトレート、トリブチルチトレート又はアセチルトリブチルチトレート等を挙げることができる。 The type of plasticizer that can be used in the present invention is not particularly limited, and can be appropriately selected by those skilled in the art. Examples of such plasticizers include propylene glycol, polyethylene glycol, polypropylene glycol, glycerin and sorbitol, glycerin triacetate, diethyl phthalate and triethyl citrate, lauric acid, sucrose, dextrose, sorbitol, triacetin, and acetyl triethyl titrate. , Triethyl titrate, tributyl titrate, acetyl tributyl titrate and the like.
　本発明に使用できる隠蔽剤としては、例えば、酸化チタン等を挙げることができる。 Examples of the concealing agent that can be used in the present invention include titanium oxide.
　本発明に使用できる着色剤としては、例えば、酸化チタン、酸化鉄、三二酸化鉄、黄色三二酸化鉄又は黄色５号アルミニウムレーキタルク等を挙げることができる。 Examples of the colorant that can be used in the present invention include titanium oxide, iron oxide, iron sesquioxide, yellow iron sesquioxide, or yellow No. 5 aluminum lake talc.
　本発明に使用できる防腐剤としては、例えば、パラベン等を挙げることができる。 Examples of preservatives that can be used in the present invention include parabens.
　本明細書で用いられる「心臓若しくは脳血管疾患」とは、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を投与することによる治療によって、或いは、（経皮的）カテーテルインターベンション（PCI）を含む経皮的冠動脈形成術（PTCA）及び／又は冠動脈大動脈バイパス移植術（CABG）等の実施によって、治療可能、予防可能又は回復可能な疾患を指す。本発明に包含される心臓若しくは脳血管疾患の例としては、冠状動脈閉塞症、(PTCA及び／又はCABG後の)再狭窄、脳卒中、急性冠症候群（ACS）、PCIを行わないACS（PCI治療を受けず、薬物で治療されるACS）、ハイリスク血管疾患（HRVD）、脳脈管の動脈瘤（CVA）、うっ血性心不全、交互脈、心室瘤、神経性の動脈瘤、心筋梗塞、心停止、心房性細動を含む不整脈、心臓性浮腫、心臓性呼吸困難、心臓麻痺、頻脈、心臓性喀血、心不全、心雑音、心原性失神、心臓タンポナーデ、及び／又は末梢動脈障害等を挙げることができる。 As used herein, “heart or cerebrovascular disease” refers to treatment by administering a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance, Alternatively, diseases that are treatable, preventable, or recoverable by performing percutaneous coronary angioplasty (PTCA) and / or coronary aortic bypass graft (CABG) including (percutaneous) catheter intervention (PCI) Point to. Examples of heart or cerebrovascular diseases encompassed by the present invention include coronary artery occlusion, restenosis (after PTCA and / or CABG), stroke, acute coronary syndrome (ACS), ACS without PCI (PCI treatment Untreated and treated with drugs), high-risk vascular disease (HRVD), cerebral vascular aneurysm (CVA), congestive heart failure, alternans, ventricular aneurysm, neurological aneurysm, myocardial infarction, heart Arrest, including atrial fibrillation, cardiac edema, cardiac dyspnea, cardiac palsy, tachycardia, cardiac hemoptysis, heart failure, heart murmur, cardiogenic syncope, cardiac tamponade, and / or peripheral arterial disorder Can be mentioned.
　本明細書で用いられる「血栓症」及び「塞栓症」とは、それらの一般的な意味で用いられる。即ち、「血栓症によって誘発される、又は塞栓症によって誘発される疾患」とは、血栓症又は塞栓症の発症、それらへの罹患又はそれらの徴候によって発症する、又は悪化する疾患のことを指す。これらの疾患の例としては、心筋梗塞、狭心症、脳卒中、肺動脈塞栓症、一過性脳虚血発作、深部静脈血栓症、PTCA若しくはCABGに続く血栓症又は再狭窄、末梢性脈管血栓症、糖尿病若しくはシンドロームＸに由来する血管疾患、或いは心不全を挙げることができる。 As used herein, “thrombosis” and “embolism” are used in their general sense. That is, “thrombosis-induced or embolism-induced disease” refers to a disease that develops or worsens due to the onset of thrombosis or embolism, morbidity or signs thereof. . Examples of these diseases include myocardial infarction, angina pectoris, stroke, pulmonary embolism, transient ischemic attack, deep vein thrombosis, thrombosis or restenosis following PTCA or CABG, peripheral vascular thrombus Vascular disease derived from diabetes, diabetes or syndrome X, or heart failure.
　本明細書で用いられる「投与」とは、口腔、舌下及び他の形態の投与による一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物の経口投与を指し、本願発明の医薬組成物を単独で、或いはPCI処置等による併用療法（治療）の一部として、或いは、他の心臓若しくは脳保護剤による併用療法の一部として、心臓若しくは脳血管疾患の発症又は再発の治療及び／又は予防を意図した機能を実施することを可能にするものである。併用療法に於ける斯かる投与がなされる場合としては、PCI処置の実施（例えばステントの体内移植又はバルーン血管形成術の実施）が挙げられる。 As used herein, “administration” refers to a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a wax-like substance by oral, sublingual and other forms of administration. Refers to oral administration, the pharmaceutical composition of the present invention alone or as part of a combination therapy (treatment) such as PCI treatment, or as part of a combination therapy with other heart or brain protective agents It is possible to carry out functions intended for the treatment and / or prevention of the onset or recurrence of vascular diseases. Such administration in combination therapy may include PCI treatment (eg, stent implantation or balloon angioplasty).
　本明細書で用いられる「治療」とは、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を、単独で又は他の心臓若しくは脳保護剤と併用投与して、或いは、PCIを含むPTCA及び／又はCABG等に対する補助剤として使用すること等、方法は特に限定はされないが、再狭窄、PCIを行わないACSを含むACS、心筋梗塞、脳脈管の動脈瘤及びHRVD等の、心臓若しくは脳血管疾患の発症又は再発を回復、阻害又は予防すること、或いは、その重症度を低減することを指す。 As used herein, "treatment" refers to a pharmaceutical composition comprising a compound having general formula (I) or a pharmacologically acceptable salt thereof and a waxy substance, either alone or with other cardiac or brain protective agents. The method is not particularly limited, such as use in combination with or as an adjuvant for PTCA and / or CABG including PCI, but restenosis, ACS including ACS without PCI, myocardial infarction, brain It refers to recovering, inhibiting or preventing the onset or recurrence of heart or cerebrovascular diseases such as vascular aneurysms and HRVD, or reducing the severity thereof.
　本明細書で用いられる「治療上有効量」とは、有資格の治療担当医師によって処方、或いは、適切な規制当局によって承認される、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を投与することからなる治療計画において、単回投与又は多回投与単位により、特定の心臓若しくは脳血管疾患を治療するために必要または十分な、一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物の量を指す。 As used herein, “therapeutically effective amount” refers to a compound having the general formula (I) or a pharmacologically acceptable salt thereof prescribed by a qualified treating physician or approved by an appropriate regulatory authority. A general formula that is necessary or sufficient to treat a specific heart or cerebrovascular disease with a single dose or multiple dose units in a treatment regimen comprising administering a pharmaceutical composition containing a salt and a waxy substance. The amount of the pharmaceutical composition containing the compound having (I) or a pharmacologically acceptable salt thereof and a waxy substance.
　上記治療上有効量は、当業者(有資格の処方者)にとって公知の要因、例えばアスピリンや他の心臓若しくは脳保護剤、外科的処置の種類（例えばPCI）、薬剤をコーティングしたステントの使用の有無、投与の様式及び治療計画、被験者の年齢、身長又は体重、心臓若しくは脳血管疾患に対する遺伝的若しくは行動的な疾病素因又は心臓若しくは脳血管疾患の重症度及び再発を含む要因によって変化し得る。当業者は、特定の疾患に対する治療上有効量に関して適切な決定をするために、これらの要因や関連要因を考慮することが可能である。 The therapeutically effective amount depends on factors known to those skilled in the art (qualified prescribers) such as the use of aspirin and other heart or brain protective agents, the type of surgical procedure (eg PCI), the use of drug-coated stents. It may vary depending on factors including presence or absence, mode of administration and treatment regimen, subject's age, height or weight, genetic or behavioral predisposition to heart or cerebrovascular disease or severity and recurrence of heart or cerebrovascular disease. Those skilled in the art can consider these factors and related factors to make an appropriate decision regarding a therapeutically effective amount for a particular disease.
　本明細書で用いられる「他の心臓若しくは脳保護剤」とは、心臓若しくは脳血管疾患に罹患しているか、或いは、罹患が予想される患者に、有益効果（発症又は再発の治療及び／又は予防）を提供することが証明されているか、又は、適切な規制当局に承認されている治療薬を指す。心臓若しくは脳保護剤の例としては、限定されるものではないが、例えば、有効な抗血小板剤（例えば、アスピリン）、有効なGPIIb/IIIa拮抗剤、有効なスタチン（例えば、HMG-CoAレダクターゼ阻害剤）、スーパースタチン、アシル補酵素A-コレステロールO-アシルトランスフェラーゼ(ACAT)阻害剤、有効な抗凝血剤、有効なチエノピリジン(例えば、チクロピジン又はクロピドグレル)及び他の有効な脂質改質剤が挙げられ、好適にはアスピリンである。 As used herein, “other heart or brain protective agents” refers to beneficial effects (treatment of onset or recurrence and / or treatment) for patients suffering from or expected to suffer from heart or cerebrovascular disease. Refers to therapeutic agents that have been proven to provide prevention) or have been approved by appropriate regulatory authorities. Examples of heart or brain protective agents include, but are not limited to, for example, effective antiplatelet agents (eg, aspirin), effective GPIIb / IIIa antagonists, effective statins (eg, HMG-CoA reductase inhibition) Agents), superstatins, acyl coenzyme A-cholesterol O-acyltransferase (ACAT) inhibitors, effective anticoagulants, effective thienopyridines (eg ticlopidine or clopidogrel) and other effective lipid modifiers Aspirin is preferred.
　本発明である一般式（Ｉ）を有する化合物又はその薬学的に許容される塩及びワックス状物質を含有する医薬組成物は、アスピリン、クロピドグレル及びその活性代謝物から選択される他の有効な抗血小板剤との複合治療に於いて使用する場合、それぞれの治療は、同時に、或いは、第一の治療の開始後、短い期間（通常は0乃至30日以内）に順次開始しても良い。「複合治療」とは、投薬方法の組み合わせの使用を表すこともあり、選ばれた他の抗血小板剤は、単一の錠剤、カプセル、吸入装置、静脈注射用溶液又は座剤により投薬されてもよい。複合治療の期間は上記の通り、例えば約30日乃至約700日であり、好ましくは約30日乃至約365日である。 The pharmaceutical composition comprising a compound having the general formula (I) or a pharmaceutically acceptable salt thereof and a wax-like substance of the present invention is another effective anti-oxidant selected from aspirin, clopidogrel and its active metabolite. When used in combination treatment with platelet agents, each treatment may be started simultaneously or sequentially in a short period (usually within 0 to 30 days) after the start of the first treatment. “Combination therapy” may refer to the use of a combination of dosing methods, with other selected antiplatelet agents being dosed by a single tablet, capsule, inhalation device, intravenous solution or suppository. Also good. The duration of the combined treatment is as described above, for example, from about 30 days to about 700 days, preferably from about 30 days to about 365 days.
　本発明の医薬組成物を投与することからなる治療法の正確な期間は、治療担当医又は主治医によって決定され、例えば共存症の徴候に対する考慮などの、特定の患者の症状に合わせて調整される。 The exact duration of treatment consisting of administering the pharmaceutical composition of the present invention is determined by the treating physician or attending physician and is tailored to the particular patient's symptoms, such as consideration for signs of comorbidity, for example. .
　本発明の医薬組成物は、PCI処置又は他の外科的治療を受ける患者に対して、治療上有効量の本願発明の医薬組成物を、PCI又は他の外科的治療の前及び／又は後の妥当な期間に於いて、任意に他の心臓若しくは脳保護剤と共に投与することができる。PCI又は他の外科的治療の前に、他の心臓若しくは脳保護剤の使用を任意に伴う本願医薬組成物の投与を、妥当な期間として最高約60日前に行っても良いが、事前投与を含めなくともよい。事前投与の目的は、外科的治療前に於いて、本発明の医薬組成物の効果を急速に付加することであり、事前処置(初回投与)を実施することにより、患者に対する治療効果を最大化することができる。また、他の心臓若しくは脳保護剤を併用している場合、それらの効果に加えて、新たな効果を更に付加することになり、患者に対する治療効果を最大化することができる。ステント術又はバルーン血管形成術などの外科的治療の前に、本発明の医薬組成物を投与することは、緊急事態に於いては実施不可能か、或いは、不要と考えられる。PCI又は他の外科的治療後に行われる、本発明の医薬組成物による併用治療の妥当な期間は、例えば約5日乃至約700日であり、好ましくは、約30日乃至約365日である。本発明による正確な治療期間は、最終的には治療医又は主治医によって決定され、個々の患者に合わせて調整される。 The pharmaceutical composition of the present invention provides a therapeutically effective amount of the pharmaceutical composition of the present invention for patients undergoing PCI treatment or other surgical treatment, before and / or after PCI or other surgical treatment. It can optionally be administered with other cardiac or cerebral protective agents for a reasonable period of time. Prior to PCI or other surgical treatment, administration of the present pharmaceutical composition, optionally with the use of other cardiac or cerebral protective agents, may be performed up to about 60 days in advance for a reasonable period of time. It does not have to be included. The purpose of pre-administration is to rapidly add the effect of the pharmaceutical composition of the present invention prior to surgical treatment, and maximizing the therapeutic effect on the patient by performing pre-treatment (initial administration). can do. In addition, when other heart or brain protective agents are used in combination, a new effect is further added in addition to those effects, and the therapeutic effect on the patient can be maximized. Administration of the pharmaceutical composition of the present invention prior to surgical treatment such as stenting or balloon angioplasty may not be feasible or necessary in an emergency situation. A reasonable period of combined treatment with the pharmaceutical composition of the present invention performed after PCI or other surgical treatment is, for example, from about 5 days to about 700 days, and preferably from about 30 days to about 365 days. The exact duration of treatment according to the present invention is ultimately determined by the treating physician or attending physician and is tailored to the individual patient.
　本明細書で用いられる「当量」とは、酸付加塩（好ましくは塩酸塩）として投与する場合の、一般式(Ｉ）を有する化合物のモル重量当量又は化学当量を指す。また、「塩基当量」とは、その通常の意味で用いられ、即ち、塩基形に相当する一般式（Ｉ）を有する化合物（酸付加塩）の量を指し、当業者は容易に計算（変換）することが可能である。例えば、「約60mg当量の一般式（Ｉ）を有する化合物又はその薬学的に許容される塩の初回投与量」とは、特に明記しない限り、一般式（Ｉ）を有する化合物60mgに基づいて算出されることを意味する。すなわち、一般式（Ｉ）を有する化合物の塩酸塩約65.86mgは、一般式（Ｉ）を有する化合物60mg当量である。同様に、約10.98mgの一般式（Ｉ）を有する化合物の塩酸塩の投与量は、一般式（Ｉ）を有する化合物10mg当量であり、約16.46mgの一般式（Ｉ）を有する化合物の塩酸塩の投与量は、一般式（Ｉ）を有する化合物15mg当量である。また、モル比（例えば分子量差の為に調整される）の場合は、一般式（Ｉ）を有する化合物の塩酸塩43.91mgの投与量は、一般式（Ｉ）を有する化合物40mg当量である。「当量」は「生物学的同等性」と同義ではない。　本発明の医薬組成物の有効成分である上記式（Ｉ）を有する化合物又はその薬理上許容される塩の投与量は、薬剤の活性、患者の症状、年齢又は体重等の種々の条件により変化し得る。その投与量は、経口投与の場合には、各々、通常は成人に対して１日、下限として０．０１ｍｇ（好適には、１ｍｇ）であり、上限として２００ｍｇ（好適には、１００ｍｇ）を投与することができる。 As used herein, “equivalent” refers to the molar weight equivalent or chemical equivalent of a compound having the general formula (I) when administered as an acid addition salt (preferably hydrochloride). The term “base equivalent” is used in its usual meaning, that is, it refers to the amount of the compound (acid addition salt) having the general formula (I) corresponding to the base form. ) Is possible. For example, “an initial dose of a compound having the general formula (I) or a pharmaceutically acceptable salt thereof of about 60 mg equivalent” is calculated based on 60 mg of the compound having the general formula (I) unless otherwise specified. Means that That is, about 65.86 mg of the hydrochloride salt of the compound having the general formula (I) is 60 mg equivalent of the compound having the general formula (I). Similarly, the dosage of the hydrochloride salt of the compound having general formula (I) of about 10.98 mg is 10 mg equivalent of the compound having general formula (I) and the hydrochloric acid of the compound having general formula (I) of about 16.46 mg. The dosage of the salt is 15 mg equivalent of the compound having general formula (I). Also, in the case of a molar ratio (eg adjusted for molecular weight difference), the dose of 43.91 mg of the hydrochloride salt of the compound having general formula (I) is 40 mg equivalent of the compound having general formula (I). “Equivalent” is not synonymous with “bioequivalence”. The dose of the compound having the above formula (I), which is an active ingredient of the pharmaceutical composition of the present invention, or a pharmacologically acceptable salt thereof varies depending on various conditions such as drug activity, patient symptoms, age or body weight. Can do. In the case of oral administration, the dose is usually 0.01 mg (preferably 1 mg) as the lower limit for adults, and 200 mg (preferably 100 mg) as the upper limit. can do.
　本発明の医薬組成物は、例えば、一般式（Ｉ）を有する化合物約10mg乃至100mg塩基当量の塩酸塩及びワックス状物質を含有する初回投与用の医薬組成物、及び、一般式（Ｉ）を有する化合物約1mg乃至15mg塩基当量の塩酸塩及びワックス状物質を含有する連日維持投与用の医薬組成物を挙げることができ、好適なものとして、一般式（Ｉ）を有する化合物約20mg乃至60mg塩基当量の塩酸塩及びワックス状物質を含有する初回投与用の医薬組成物、及び、一般式（Ｉ）を有する化合物約3.75mg乃至10mg塩基当量（更に好適には10mg塩基当量）の塩酸塩及びワックス状物質を含有する連日維持投与用の医薬組成物を挙げることができ、特に好適なものとして、一般式（Ｉ）を有する化合物約60mg塩基当量の塩酸塩及びワックス状物質を含有する初回投与用の医薬組成物、及び、一般式（Ｉ）を有する化合物約10mg塩基当量の塩酸塩及びワックス状物質を含有する連日維持投与用の医薬組成物を挙げることができる。また、それらは単独で、或いは、心臓若しくは脳血管疾患の治療又は予防の為の他の有効な抗血小板剤（例えば、一日量約50mg乃至500mg、好ましくは約75乃至325mgのアスピリン）と組み合わせて投与することができる。 The pharmaceutical composition of the present invention includes, for example, a pharmaceutical composition for initial administration containing about 10 mg to 100 mg of a base equivalent of a compound having the general formula (I) and a waxy substance, and the general formula (I) Examples include pharmaceutical compositions for daily maintenance administration containing about 1 mg to 15 mg of a base equivalent of hydrochloride and a waxy substance, preferably about 20 mg to 60 mg of a compound having the general formula (I) Pharmaceutical composition for initial administration containing an equivalent amount of hydrochloride and a waxy substance, and a hydrochloride and a wax of about 3.75 mg to 10 mg base equivalent (more preferably 10 mg base equivalent) of a compound having general formula (I) A pharmaceutical composition for daily maintenance administration containing a substance-like substance can be mentioned, and particularly preferred is a compound having the general formula (I) for the first administration containing about 60 mg of a base equivalent of hydrochloride and a wax-like substance Doctor Composition, and it can include a pharmaceutical composition of the daily maintenance for administration containing a compound of about 10mg base equivalent of the hydrochloride salt and wax-like substance having the general formula (I). They may also be used alone or in combination with other effective antiplatelet agents for the treatment or prevention of heart or cerebrovascular diseases (eg, a daily dose of about 50 mg to 500 mg, preferably about 75 to 325 mg aspirin). Can be administered.
　本明細書で用いられる「初回投与量」とは、急性期の若しくは生命の危険に瀕した患者における、特定の血管疾患の段階的拡大、又は、急性の血管疾患（例えば、塞栓症、再狭窄又はその他）の形を呈する症状の制御、抑止、治療又は予防に必要、充分及び／又は効果的な、一般式（Ｉ）を有する化合物の量を指す。初回投与量の一つの定義は、症状の発症時から他の方法（PCI、CABG又はその他の血管形成術を含む）を開始する時までに患者に投与される式（Ｉ）を有する化合物、その薬学的に許容できる塩、溶媒和物、その他血小板凝集阻害薬の量を指す。さらに一般的には、初回投与量とは、患者の症状の更なる悪化を制御、抑えるか又は防止するための薬剤投与量であって、発症以降であるが、外科的治療の開始前又は維持投与の開始前に投与される薬剤の量である。本発明の目的に於いて、合理的な初回投与量を、診断された患者に対して、例えば発症直後から約7日間の期間、より好ましくは、発症後約1時間から3日の期間、最も好ましくは、発症後約15分後から約1日の期間に於いて投与しても良く、またその期間内に、担当医師により必要であると診断された多回投与を含めても良い。担当医師であれば、特定の患者又は患者集団の為に、初回量を何度かに分けて服用することを推奨しても良い。例えば、医師であれば、特定の患者又は患者集団の為に、一般式（Ｉ）を有する化合物約20mg乃至30mg当量の初回投与量を分割すること、及び／又は特定の患者中の特別な集団又は特異的な症状及び／又は既往歴を有する患者の為に、維持投与量を分割することを推奨してもよい。同様に、40mg乃至60mgの量の初回投与に於いて、担当医師は、患者の特定の症状に適する適当な間隔で、20mg乃至30mgの投与量を2回に分けることを推奨しても良い。即ち、一つ以上に分割した初回投与を採用して、特定の患者又は患者集団に所望の初回投与量を投与することができる。選択される方法に関係なく、外科的治療の開始前に、又は外科的治療直後であって維持投与の開始前に初回投与がなされる。外科的な治療を行わない場合、症状を抑止、鎮静又は制御するために初回投与を行い、それに続いて必要に応じて維持投与を行うことができる。 As used herein, “first dose” refers to the gradual expansion of a particular vascular disease or acute vascular disease (eg, embolism, restenosis) in an acute or life-threatening patient. Or other) refers to the amount of a compound having the general formula (I) that is necessary, sufficient and / or effective for the control, suppression, treatment or prevention of symptoms presenting. One definition of initial dose is a compound having the formula (I) that is administered to a patient from the onset of symptoms to the start of other methods (including PCI, CABG or other angioplasty), It refers to the amount of a pharmaceutically acceptable salt, solvate or other platelet aggregation inhibitor. More generally, the initial dose is a drug dose that controls, suppresses or prevents further deterioration of the patient's symptoms, after the onset, but before or after the start of surgical treatment. The amount of drug administered before the start of administration. For the purposes of the present invention, a reasonable initial dose may be administered to a diagnosed patient, for example, for a period of about 7 days immediately after onset, more preferably for a period of about 1 to 3 days after onset. Preferably, it may be administered for a period of about one day from about 15 minutes after onset, and may include multiple doses diagnosed as necessary by the attending physician within that period. If it is a doctor in charge, it may be recommended to divide the initial dose into several doses for a specific patient or patient group. For example, a physician may divide an initial dose of about 20 mg to 30 mg equivalents of a compound having general formula (I) for a particular patient or patient population, and / or a special population in a particular patient Alternatively, it may be recommended to divide the maintenance dose for patients with specific symptoms and / or history. Similarly, in the initial dose of 40 mg to 60 mg, the attending physician may recommend that the 20 mg to 30 mg dose be divided into two doses at appropriate intervals appropriate to the patient's specific symptoms. That is, a desired initial dose can be administered to a specific patient or patient population by employing an initial dose divided into one or more. Regardless of the method chosen, the initial administration is made before the start of surgical treatment or immediately after the surgical treatment and before the start of maintenance administration. In the absence of surgical treatment, an initial dose can be given to suppress, sedate or control symptoms, followed by a maintenance dose as needed.
　本発明の用語「維持投与量」とは、初期投与期間の後で患者に投与される投与量を意味する。当該投与量は、他の要因がないときに指示通りに使用した場合の、長期、中期又は短期に於ける所望の効果を提供する有効量を指す。本発明に於いては、相当の維持期間（初期投与期間に続く期間であって、患者に於ける血小板凝集抑制効果を有益に維持する為に、初回投与量より低い投与量レベルで本発明の医薬組成物を投与する期間）は、例えば約3日乃至約700日、好ましくは約7日乃至約365日の期間でも良い。維持投与量は、好ましくは連日投与される。患者が投与量をスキップする場合、又は患者が調整又はスキップすることを申し出る場合、化合物の投与量は、式（Ｉ）を有する化合物約10mg乃至15mg当量／日とするのが好ましい。担当医師が、特定の患者又は患者集団の為に維持投与量を分割量で投与するよう勧めても良い。例えば、医師は、特定の患者又は患者集団の為に、式（Ｉ）を有する化合物約5mg乃至7.5mg当量に分割した維持投与量を推奨してもよい。同様に、10mg／日の維持投与量を提供する為に、担当医師は、患者の特定の症状に応じて、適当な間隔で5mgの投与量の2回投与を推奨しても良い。すなわち、本発明では、単回又は多数回の分割投与を行い、特定の患者又は患者集団の為に所望の維持投与量を投与することが包含される。 The term “maintenance dose” in the present invention means a dose administered to a patient after an initial administration period. The dosage refers to an effective amount that provides the desired effect in the long, medium or short term when used as directed when there are no other factors. In the present invention, a considerable maintenance period (the period following the initial administration period, in order to beneficially maintain the platelet aggregation inhibitory effect in the patient, at a dosage level lower than the initial dosage, The period during which the pharmaceutical composition is administered may be, for example, from about 3 days to about 700 days, preferably from about 7 days to about 365 days. The maintenance dose is preferably administered daily. If the patient skips the dose, or if the patient offers to adjust or skip, the dose of the compound is preferably about 10 mg to 15 mg equivalent / day of the compound having formula (I). The attending physician may recommend that maintenance doses be administered in divided doses for a particular patient or patient population. For example, a physician may recommend a maintenance dose divided into about 5 mg to 7.5 mg equivalents of a compound having formula (I) for a particular patient or patient population. Similarly, to provide a 10 mg / day maintenance dose, the attending physician may recommend two doses of 5 mg at appropriate intervals, depending on the patient's specific symptoms. That is, the present invention encompasses performing single or multiple divided doses and administering a desired maintenance dose for a particular patient or patient population.
　本発明に於ける正確な量、初回投与頻度及び期間は、治療担当医又は主治医によって決定され、個々の患者の年齢、身長、体重、既往歴、素因及び共存症などの特定の要因又は履歴に合わせて調整される。 The exact amount, initial frequency and duration in the present invention will be determined by the treating physician or attending physician and will depend on the specific factors or history of the individual patient such as age, height, weight, medical history, predisposition and comorbidities. It is adjusted together.
　本発明の一般式（Ｉ）を有する化合物又はその薬理上許容される塩及びワックス状物質を含有する医薬組成物を、脳血管疾患の発症、再発の治療及び／又は予防の為に用いる場合の投与量として、化合物（Ｉ）約1mg乃至15mg当量／日を挙げることができ、好適には、約2mg乃至10mg当量／日、特に好適には約2.5mg当量／日、3.75mg当量／日又は5mg当量／日である。 When the pharmaceutical composition containing the compound having the general formula (I) of the present invention or a pharmacologically acceptable salt thereof and a waxy substance is used for the treatment and / or prevention of cerebrovascular disease onset and recurrence The dosage may include about 1 mg to 15 mg equivalent / day of compound (I), preferably about 2 mg to 10 mg equivalent / day, particularly preferably about 2.5 mg equivalent / day, 3.75 mg equivalent / day or 5 mg equivalent / day.
　以下、実施例、比較例及び試験例により本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto.
　なお、実施例及び比較例において使用されている「化合物Ａ」は、下記構造式（Ｉａ） In addition, “Compound A” used in Examples and Comparative Examples has the following structural formula (Ia)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
を有し、特開２００２－１４５８８３号公報に記載の方法に準じて製造することができる。 And can be produced according to the method described in JP-A-2002-145883.
　（実施例１）
　約８０℃で融解したステアリルアルコール（３２２ｇ）に化合物Ａ（１３８ｇ）を加え、１時間撹拌した。これを室温に冷却することで得られた溶融混合物を粉砕し、溶融粉砕品を得た。溶融粉砕品（２２．８７ｇ）、低置換度ヒドロキシプロピルセルロース（７５ｇ）、ヒドロキシプロピルセルロース（３７．５ｇ）、乳糖水和物（３０９．６ｇ）及び結晶セルロース（５０ｇ）をＶ型混合機で３０分間混合した。得られた混合末を篩過した後、ステアリン酸マグネシウム（５ｇ）を添加し、再度Ｖ型混合機で混合することにより、打錠用混合末を得た。 Example 1
Compound A (138 g) was added to stearyl alcohol (322 g) melted at about 80 ° C. and stirred for 1 hour. The molten mixture obtained by cooling this to room temperature was pulverized to obtain a melt-pulverized product. A melt-pulverized product (22.87 g), low-substituted hydroxypropyl cellulose (75 g), hydroxypropyl cellulose (37.5 g), lactose hydrate (309.6 g) and crystalline cellulose (50 g) were mixed with a V-type mixer. Mixed for minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
　次に得られた混合末をロータリー式打錠機にて、錠剤質量が約１００ｍｇになるよう打錠した。得られた素錠に、ヒプロメロース、酸化チタン、タルク及び水からなるコーティング液を、パンコーティング機中で噴霧することにより、化合物Ａを含有する錠剤を得た。得られた錠剤について安定性試験を行った。試験結果を表１に示す。 Next, the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A. The stability test was done about the obtained tablet. The test results are shown in Table 1.
　（実施例２）
　約７０℃で融解したモノステアリン酸グリセリン（９０ｇ）に化合物Ａ（４５ｇ）及びタルク（１５ｇ）を加え、１時間撹拌した。これを室温に冷却することで得られた溶融混合物を粉砕し、溶融粉砕品を得た。溶融粉砕品（２２．８７ｇ）、低置換度ヒドロキシプロピルセルロース（７５ｇ）、ヒドロキシプロピルセルロース（３７．５ｇ）、乳糖水和物（３０９．６ｇ）及び結晶セルロース（５０ｇ）をＶ型混合機で３０分間混合した。得られた混合末を篩過した後、ステアリン酸マグネシウム（５ｇ）を添加し、再度Ｖ型混合機で混合することにより、打錠用混合末を得た。 (Example 2)
Compound A (45 g) and talc (15 g) were added to glyceryl monostearate (90 g) melted at about 70 ° C. and stirred for 1 hour. The molten mixture obtained by cooling this to room temperature was pulverized to obtain a melt-pulverized product. A melt-pulverized product (22.87 g), low-substituted hydroxypropyl cellulose (75 g), hydroxypropyl cellulose (37.5 g), lactose hydrate (309.6 g) and crystalline cellulose (50 g) were mixed with a V-type mixer. Mixed for minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
　次に得られた混合末をロータリー式打錠機にて、錠剤質量が約１００ｍｇになるよう打錠した。得られた素錠に、ヒプロメロース、酸化チタン、タルク及び水からなるコーティング液を、パンコーティング機中で噴霧することにより、化合物Ａを含有する錠剤を得た。得られた錠剤について安定性試験を行った。試験結果を表１に示す。 Next, the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A. The stability test was done about the obtained tablet. The test results are shown in Table 1.
　（実施例３）
　化合物Ａ（７５ｇ）、モノステアリン酸グリセリン（３０ｇ）及びタルク（４５ｇ）の混合物を約６５－７０℃で流動層造粒機を用いて溶融造粒した後、目開き３００μmの篩で篩過し、溶融造粒品を得た。溶融造粒品（１３．７２ｇ）、低置換度ヒドロキシプロピルセルロース（７５ｇ）、ヒドロキシプロピルセルロース（３７．５ｇ）、乳糖水和物（３２２．９ｇ）及び結晶セルロース（５０ｇ）をＶ型混合機で３０分間混合した。得られた混合末を篩過した後、ステアリン酸マグネシウム（５ｇ）を添加し、再度Ｖ型混合機で混合することにより、打錠用混合末を得た。 (Example 3)
A mixture of compound A (75 g), glyceryl monostearate (30 g) and talc (45 g) was melt-granulated using a fluid bed granulator at about 65-70 ° C., and then sieved with a sieve having an opening of 300 μm. A melt-granulated product was obtained. Melt granulated product (13.72 g), low-substituted hydroxypropyl cellulose (75 g), hydroxypropyl cellulose (37.5 g), lactose hydrate (322.9 g) and crystalline cellulose (50 g) in a V-type mixer Mix for 30 minutes. After sieving the obtained mixed powder, magnesium stearate (5 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
　次に得られた混合末をロータリー式打錠機にて、錠剤質量が約１００ｍｇになるよう打錠した。得られた素錠に、ヒプロメロース、酸化チタン、タルク及び水からなるコーティング液を、パンコーティング機中で噴霧することにより、化合物Ａを含有する錠剤を得た。得られた錠剤について安定性試験を行った。試験結果を表１に示す。 Next, the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A. The stability test was done about the obtained tablet. The test results are shown in Table 1.
 
　（比較例１）
　化合物Ａ（１３．７２ｇ）、低置換度ヒドロキシプロピルセルロース（１５０ｇ）、ヒドロキシプロピルセルロース（７５ｇ）、乳糖水和物（６５１．３ｇ）及び結晶セルロース（１００ｇ）をＶ型混合機で３０分間混合した。得られた混合末を篩過した後、ステアリン酸マグネシウム（１０ｇ）を添加し、再度Ｖ型混合機で混合することにより、打錠用混合末を得た。
(Comparative Example 1)
Compound A (13.72 g), low-substituted hydroxypropylcellulose (150 g), hydroxypropylcellulose (75 g), lactose hydrate (651.3 g) and crystalline cellulose (100 g) were mixed in a V-type mixer for 30 minutes. . After sieving the obtained mixed powder, magnesium stearate (10 g) was added and mixed again with a V-type mixer to obtain a mixed powder for tableting.
　次に得られた混合末をロータリー式打錠機にて、錠剤質量が約１００ｍｇになるよう打錠した。得られた素錠に、ヒプロメロース、酸化チタン、タルク及び水からなるコーティング液を、パンコーティング機中で噴霧することにより、化合物Ａを含有する錠剤を得た。得られた錠剤について安定性試験を行った。試験結果を表１に示す。 Next, the obtained mixed powder was tableted with a rotary tableting machine so that the tablet mass was about 100 mg. The obtained uncoated tablet was sprayed with a coating solution composed of hypromellose, titanium oxide, talc and water in a pan coating machine to obtain a tablet containing Compound A. The stability test was done about the obtained tablet. The test results are shown in Table 1.
　（試験例１）安定性試験
　実施例１～３及び比較例１で得られた錠剤を褐色ガラス瓶に入れ、密閉状態４０℃／７５％相対湿度下で静置し、６ヶ月経過後に、試験錠剤中の化合物Ａの類縁物質を高速液体クロマトグラフィーにより測定し、得られたピークの面積（％）から、類縁物質の総含量（％）を得た。高速液体クロマトグラフィーの測定条件は、次の通りである。
カラム：Ｓｙｎｅｒｇｉ　４ｕ　ＭＡＸ－ＲＰ　８０Ａ（４．６　ｍｍＩＤ×１５０　ｍｍ，Ｐｈｅｎｏｍｅｎｅｘ社製）
移動相Ａ：２５　ｍｍｏｌ／Ｌ　リン酸緩衝液（ｐＨ　４．０）／アセトニトリル混液（９：１）（Ｖ／Ｖ）
移動相Ｂ：アセトニトリル／水混液（９：１）（Ｖ／Ｖ）
グラジエント：
時間（分）　　０　　　２　　３０　　３７　　３８　　４５
移動相Ａ：１００　１００　　　０　　　０　１００　１００
移動相Ｂ：　　０　　　０　１００　１００　　　０　　　０
カラム温度：４５℃付近の一定温度
検出波長：２１０　ｎｍ
流量：１．５０　ｍＬ／分
　（表１）４０℃、７５％相対湿度下、６ヶ月経過後の類縁物質の総含量
―――――――――――――――――――――――――――――
試験錠剤　　測定時の化合物Ａに対する類縁物質の総含量（％）
―――――――――――――――――――――――――――――
実施例１　　　　　　　　　　２．１６
実施例２　　　　　　　　　　２．５０
実施例３　　　　　　　　　　２．３６
―　―　―　―　―　―　―　―　―　―　―　―　―　―　―
比較例１　　　　　　　　　　４．９６
――――――――――――――――――――――――――――― (Test Example 1) Stability test The tablets obtained in Examples 1 to 3 and Comparative Example 1 were placed in a brown glass bottle and allowed to stand still in a sealed state at 40 ° C / 75% relative humidity. The related substance of Compound A was measured by high performance liquid chromatography, and the total content (%) of related substances was obtained from the area (%) of the peak obtained. The measurement conditions for high performance liquid chromatography are as follows.
Column: Synergi 4u MAX-RP 80A (4.6 mm ID × 150 mm, manufactured by Phenomenex)
Mobile phase A: 25 mmol / L phosphate buffer (pH 4.0) / acetonitrile mixture (9: 1) (V / V)
Mobile phase B: acetonitrile / water mixture (9: 1) (V / V)
Gradient:
Time (minutes) 0 2 30 37 38 45
Mobile phase A: 100 100 0 0 100 100
Mobile phase B: 0 0 100 100 0 0
Column temperature: Constant temperature around 45 ° C Detection wavelength: 210 nm
Flow rate: 1.50 mL / min (Table 1) Total content of related substances after 6 months at 40 ° C and 75% relative humidity ――――――――――――――――――― ――――――――――
Test tablet Total content of related substances relative to Compound A at the time of measurement (%)
―――――――――――――――――――――――――――――
Example 1 2.16
Example 2 2.50
Example 3 2.36
---------------
Comparative Example 1 4.96
―――――――――――――――――――――――――――――
　本発明によれば、上記式（Ｉ）を有する化合物又はその薬理上許容される塩、及びワックス状物質を含有する貯蔵安定性の改善された医薬組成物が得られる。
  According to the present invention, there can be obtained a pharmaceutical composition having an improved storage stability comprising a compound having the above formula (I) or a pharmacologically acceptable salt thereof, and a waxy substance.

Claims (18)

  1. 　（Ａ）下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
    を有する化合物又はその薬理上許容される塩及び
    （Ｂ）ワックス状物質を含有する医薬組成物。     (A) The following formula (I)
    Figure JPOXMLDOC01-appb-C000001
    Or a pharmacologically acceptable salt thereof and (B) a wax-like substance.
  2. 　（Ａ）下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000002
    を有する化合物又はその薬理上許容される塩及び
    （Ｂ）ワックス状物質を溶融混合した医薬組成物。     (A) The following formula (I)
    Figure JPOXMLDOC01-appb-C000002
    Or a pharmacologically acceptable salt thereof and (B) a waxy substance melt-mixed.
  3. 　（Ａ）下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000003
    を有する化合物又はその薬理上許容される塩及び
    （Ｂ）ワックス状物質を溶融造粒した医薬組成物。     (A) The following formula (I)
    Figure JPOXMLDOC01-appb-C000003
    Or a pharmacologically acceptable salt thereof and (B) a wax-like substance melt-granulated.
  4. 　式（Ｉ）を有する化合物又はその薬理上許容される塩が、下記式（Ｉａ）
    Figure JPOXMLDOC01-appb-C000004
    を有する化合物である請求項１乃至３のいずれか１項に記載の医薬組成物。     The compound having the formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)
    Figure JPOXMLDOC01-appb-C000004
    4. The pharmaceutical composition according to any one of claims 1 to 3, which is a compound having
  5. 　ワックス状物質が、融点４０～１５０℃のワックス状物質である請求項１乃至４のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the wax-like substance is a wax-like substance having a melting point of 40 to 150 ° C.
  6. 　ワックス状物質が、硬化油、植物性若しくは動物性油脂、高級アルコール、高級脂肪酸、グリセリン脂肪酸エステル及びショ糖脂肪酸エステルから選ばれる１種又は２種以上である請求項１乃至５のいずれか１項に記載の医薬組成物。 The wax-like substance is at least one selected from hydrogenated oil, vegetable or animal oil, higher alcohol, higher fatty acid, glycerin fatty acid ester, and sucrose fatty acid ester. A pharmaceutical composition according to 1.
  7. 　ワックス状物質が、高級アルコール又はグリセリン脂肪酸エステルである請求項１乃至５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the wax-like substance is a higher alcohol or a glycerin fatty acid ester.
  8. 　ワックス状物質が、ステアリルアルコール又はモノステアリン酸グリセリンである請求項１乃至５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the wax-like substance is stearyl alcohol or glyceryl monostearate.
  9. 　請求項１乃至８のいずれか１項に記載の医薬組成物及び薬理上許容される添加物を含有する医薬組成物。 A pharmaceutical composition comprising the pharmaceutical composition according to any one of claims 1 to 8 and a pharmacologically acceptable additive.
  10. 　医薬組成物が、散剤、細粒剤、顆粒剤、カプセル剤又は錠剤である請求項１乃至９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is a powder, fine granules, granules, capsules or tablets.
  11. 　医薬組成物が、錠剤である請求項１乃至９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, wherein the pharmaceutical composition is a tablet.
  12. ワックス状物質の配合量が、医薬組成物全量に対して０．２～５２重量％である、請求項１乃至１１のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 11, wherein the compounding amount of the wax-like substance is 0.2 to 52% by weight based on the total amount of the pharmaceutical composition.
  13. ワックス状物質の配合量が、医薬組成物全量に対して０．５～１６重量％である、請求項１乃至１１のいずれか１項に記載の医薬組成物、 The pharmaceutical composition according to any one of claims 1 to 11, wherein the compounding amount of the wax-like substance is 0.5 to 16% by weight based on the total amount of the pharmaceutical composition,
  14. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000005
    を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融混合することを特徴とする、請求項２又は請求項４乃至１３のいずれか１項に記載の医薬組成物の製造方法。     Formula (I)
    Figure JPOXMLDOC01-appb-C000005
    14. The method for producing a pharmaceutical composition according to any one of claims 2 and 4 to 13, wherein the compound having a salt or a pharmacologically acceptable salt thereof and a wax-like substance are melt-mixed.
  15. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000006
    を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融造粒することを特徴とする、請求項３乃至１３のいずれか１項に記載の医薬組成物の製造方法。     Formula (I)
    Figure JPOXMLDOC01-appb-C000006
    14. The method for producing a pharmaceutical composition according to any one of claims 3 to 13, wherein the compound having a salt or a pharmacologically acceptable salt thereof and a waxy substance are melt-granulated.
  16. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000007
    を有する化合物又はその薬理上許容される塩及びワックス状物質を含有することを特徴とする、請求項１乃至１３のいずれか１項に記載の医薬組成物の安定化方法。     Formula (I)
    Figure JPOXMLDOC01-appb-C000007
    14. The method for stabilizing a pharmaceutical composition according to any one of claims 1 to 13, comprising a compound having a pharmaceutically acceptable salt or a pharmacologically acceptable salt thereof and a wax-like substance.
  17. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000008
    を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融混合することを特徴とする、請求項２又は請求項９乃至１３のいずれか１項に記載の医薬組成物の安定化方法。     Formula (I)
    Figure JPOXMLDOC01-appb-C000008
    14. The method for stabilizing a pharmaceutical composition according to any one of claims 2 and 9 to 13, wherein the compound having a salt or a pharmacologically acceptable salt thereof and a wax-like substance are melt-mixed.
  18. 　下記式（Ｉ）
    Figure JPOXMLDOC01-appb-C000009
    を有する化合物又はその薬理上許容される塩及びワックス状物質を溶融造粒することを特徴とする、請求項３乃至１３のいずれか１項に記載の医薬組成物の安定化方法。
          Formula (I)
    Figure JPOXMLDOC01-appb-C000009
    14. The method for stabilizing a pharmaceutical composition according to any one of claims 3 to 13, wherein the compound having a salt or a pharmacologically acceptable salt thereof and a waxy substance are melt granulated.
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