WO2011052499A1 - Composition pharmaceutique présentant une stabilité au stockage améliorée - Google Patents

Composition pharmaceutique présentant une stabilité au stockage améliorée Download PDF

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Publication number
WO2011052499A1
WO2011052499A1 PCT/JP2010/068684 JP2010068684W WO2011052499A1 WO 2011052499 A1 WO2011052499 A1 WO 2011052499A1 JP 2010068684 W JP2010068684 W JP 2010068684W WO 2011052499 A1 WO2011052499 A1 WO 2011052499A1
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Prior art keywords
pharmaceutical composition
compound
chelating agent
acceptable salt
composition according
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PCT/JP2010/068684
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English (en)
Japanese (ja)
Inventor
栄二 上山
Original Assignee
第一三共株式会社
宇部興産株式会社
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Publication of WO2011052499A1 publication Critical patent/WO2011052499A1/fr

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • 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 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 fumaric acid. Is only exemplified as one of many possible additives and is not specifically used in formulation examples. Furthermore, the patent document also states that storage stability is improved by including a chelating agent in a pharmaceutical composition containing the compound having the above formula (I) or a pharmacologically acceptable salt thereof. It has not been done.
  • 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 chelating agent, (2) A compound having the formula (I) or a pharmacologically acceptable salt thereof is represented by the following formula (Ia)
  • the pharmaceutical composition according to (1) which is a compound having (3) The pharmaceutical composition according to (1) or (2), wherein the preparation is a solid preparation, (4) The pharmaceutical composition according to (1) or (2), wherein the preparation is a powder, fine granules, granules, capsules or tablets, (5) The pharmaceutical composition according to (1) or (2), wherein the preparation is a tablet, (6) The pharmaceutical composition according to any one of (1) to (5), wherein the chelating agent is a chelating agent capable of forming a water-soluble chelating compound, (7) The pharmaceutical composition according to any one of (1) to (5), wherein the chelating agent is edetic acid or edetate salt, (8) The pharmaceutical composition according to any one of (1) to (5), wherein the chelating agent is sodium edetate, (9) The pharmaceutical composition according to any one of (1) to (8), wherein the compounding amount of the chelating agent is 0.01 to 20% by weight relative to the total amount of the pharmaceutical composition, (10) The pharmaceutical composition according to any one of (1) to
  • 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 chelating agent for the treatment and / or prevention of heart or cerebrovascular diseases.
  • a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent 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 chelating agent, which is used in combination with other heart or brain protective agents for the treatment of heart or cerebrovascular diseases.
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent, which is used in combination with other heart or brain protective agents for the treatment of heart or cerebrovascular diseases.
  • a chelating agent which is used in combination with other heart or brain protective agents for the treatment of heart or cerebrovascular diseases.
  • 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 chelating agent in a solid preparation containing a salt.
  • 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, comprising a chelating agent in the preparation and having a base equivalent of about 1 mg to about 70 mg
  • a pharmaceutical composition comprising a top effective amount of a compound having the general formula (I) or a pharmacologically acceptable salt thereof.
  • the present invention relates to a method for the treatment and / or prevention of heart or cerebrovascular disease, comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent. It relates to a method of administration to a patient.
  • 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 chelating agent.
  • a pharmaceutical composition comprising a compound having the general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent.
  • the pharmaceutical composition containing the agent is first administered, 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 preferably the compound having general formula (I)
  • the present invention relates to a method for maintaining and administering a pharmaceutical composition containing 10 mg) or equivalent of a pharmaceutically acceptable salt and a chelating agent.
  • the present invention provides for the initial administration of a pharmaceutical composition comprising a compound (preferably hydrochloride) having a base equivalent of 20 mg to 60 mg (preferably 60 mg) of the general formula (I) and a chelating agent, and suitable intervals.
  • a pharmaceutical composition comprising a chelating agent comprising a compound (preferably a hydrochloride salt) of general formula (I) with a base equivalent of 3.75 mg to 15 mg (preferably 10 mg)
  • a method for treating and / or preventing 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 chelating agent.
  • 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 chelating agent is effective for the treatment and / or prevention of heart or cerebrovascular diseases.
  • 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 chelating agent in the present invention is a compound having a plurality of donor atoms that bind to a metal ion to form a chelate compound, such as polyaminocarboxylic acids such as EDTA, oxycarboxylic acids such as citric acid, and condensed phosphates.
  • a chelate compound such as polyaminocarboxylic acids such as EDTA, oxycarboxylic acids such as citric acid, and condensed phosphates.
  • Edetic acid salts such as trisodium acid; citric acid; citrates such as calcium citrate, sodium citrate, sodium dihydrogen citrate or disodium citrate; glycine; diethylenetriaminepentaacetic acid; fumaric acid; sodium fumarate Fumarate such as; gluconate such as sodium gluconate; tartrate such as sodium tartrate; salicylate such as sodium salicylate; lactate such as sodium lactate; maleic acid; Preferably edetic acid or An edetate salt, most preferably sodium edetate.
  • a single chelating agent can be used, or two or more can be used in combination.
  • the amount of the chelating agent used is usually 0.01 to 20% by weight, preferably 0.1 to 10% by weight, more preferably 0.4 to 10% by weight based on the total weight of the pharmaceutical composition. 5% by weight.
  • the pharmaceutical composition of the present invention may further contain excipients, lubricants, binders, emulsifiers, stabilizers, flavoring agents and / or other than appropriate pharmacologically acceptable chelating agents as necessary. Additives such as disintegrants 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, stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or whale wax; boric acid; adipine Acids; sulfates such as sodium sulfate; glycols; sodium stearyl fumarate; sucrose fatty acid esters; sodium benzoate; D, L-leucine; lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; Examples thereof include silicic acids such as silicate hydrates; or the above-mentioned starch derivatives, and preferred are metal stearates. Moreover, fumaric acid can also 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 containing a compound having general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent, or , Treatable, preventable or recoverable disease 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 oral administration of a pharmaceutical composition containing a compound having general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent by oral, sublingual and other forms of administration.
  • a pharmaceutical composition containing a compound having general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent by oral, sublingual and other forms of administration.
  • administration of the pharmaceutical composition of the present invention alone or as part of a combination therapy (treatment) by PCI treatment or the like, 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 a disease.
  • Such administration in combination therapy may include PCI treatment (eg, stent implantation or balloon angioplasty).
  • treatment refers to a pharmaceutical composition containing a compound having general formula (I) or a pharmacologically acceptable salt thereof and a chelating agent, alone or with other cardiac or brain protective agents.
  • the method is not particularly limited, such as administration in combination or use as an adjuvant for PTCA and / or CABG including PCI, but restenosis, ACS including ACS without PCI, myocardial infarction, cerebral pulse It refers to recovering, inhibiting or preventing the onset or recurrence of heart or cerebrovascular diseases, such as vascular aneurysms and HRVD, or reducing its severity.
  • 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 therapeutic regimen consisting of administering a pharmaceutical composition containing a salt and a chelating agent, a general formula (necessary or sufficient to treat a particular heart or cerebrovascular disease with a single dose or multiple dose units.
  • the amount of the pharmaceutical composition containing the compound having I) or a pharmacologically acceptable salt thereof and a chelating agent is administered 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.
  • 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
  • composition containing a compound having the general formula (I) or a pharmaceutically acceptable salt thereof and a chelating agent according to the present invention is selected from aspirin, clopidogrel and other active metabolites thereof.
  • each therapy may be started simultaneously or sequentially within a short period (usually within 0 to 30 days) after the start of the first therapy.
  • “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 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 has, 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 chelating agent, and the general formula (I) Mention may be made of a pharmaceutical composition for daily maintenance administration containing about 1 mg to 15 mg of a base equivalent of a hydrochloride and a chelating agent, preferably about 20 mg to 60 mg of a base equivalent of a compound having the general formula (I)
  • a pharmaceutical composition for first-time administration comprising about 60 mg base equivalent of a compound having the general formula (I) and a chelating agent
  • general (I) can be given daily maintenance pharmaceutical composition for administration containing about 10mg base equivalent of the hydrochloride
  • 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 amount 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 (3.43 g), sodium edetate (1.25 g), lactose hydrate (161.6 g), low-substituted hydroxypropylcellulose (37.50 g), hydroxypropylcellulose (18.75 g) and crystalline cellulose (25.00 g) was mixed with a high-speed stirring mixer for 3 minutes. After adding purified water (60 g) to the obtained mixed powder, the mixture was kneaded for 3 minutes with a high-speed agitation granulator and then subjected to condyles with a 1400 ⁇ m sieve.
  • the obtained kneaded material was dried with a fluidized bed dryer and then granulated with an 850 ⁇ m sieve to obtain granulated granules.
  • Magnesium stearate was added to the obtained granulated granules so that the weight percentage thereof was 1% with respect to the mixed granules for tableting, and mixed with a V-type mixer to obtain mixed granules for tableting.
  • the obtained mixed granule for tableting was tableted with a rotary tableting machine at a tableting pressure of about 7 kN so that the tablet mass was about 100 mg, and the resulting uncoated tablet was mixed with hypromellose, titanium oxide, talc. And the coating liquid which consists of water was sprayed in the pan coating machine, and the film coating tablet was obtained. The film-coated tablet was dried to obtain a tablet containing the test compound. The stability test was done about the obtained tablet. The test results are shown in Table 1.
  • Example 2 Compound A (3.43 g), sodium edetate (11.25 g), lactose hydrate (151.6 g), low-substituted hydroxypropylcellulose (37.50 g), hydroxypropylcellulose (18.75 g) and crystalline cellulose (25.00 g) was mixed with a high-speed stirring mixer for 3 minutes. After adding purified water (60 g) to the obtained mixed powder, the mixture was kneaded for 3 minutes with a high-speed agitation granulator and then subjected to condyles with a 1400 ⁇ m sieve.
  • the obtained kneaded material was dried with a fluidized bed dryer and then granulated with an 850 ⁇ m sieve to obtain granulated granules.
  • Magnesium stearate was added to the obtained granulated granules so that the weight percentage thereof was 1% with respect to the mixed granules for tableting, and mixed with a V-type mixer to obtain mixed granules for tableting.
  • the obtained mixed granule for tableting was tableted with a rotary tableting machine at a tableting pressure of about 7 kN so that the tablet mass was about 100 mg, and the resulting uncoated tablet was mixed with hypromellose, titanium oxide, talc. And the coating liquid which consists of water was sprayed in the pan coating machine, and the film coating tablet was obtained. The film-coated tablet was dried to obtain a tablet containing the test compound. The stability test was done about the obtained tablet. The test results are shown in Table 1.
  • Magnesium stearate was added to the obtained granulated granules so that the weight percentage thereof was 1% with respect to the mixed granules for tableting, and mixed with a V-type mixer to obtain mixed granules for tableting.
  • the obtained mixed granule for tableting was tableted with a rotary tableting machine at a tableting pressure of about 7 kN so that the tablet mass was about 100 mg, and the resulting uncoated tablet was mixed with hypromellose, titanium oxide, talc. And the coating liquid which consists of water was sprayed in the pan coating machine, and the film coating tablet was obtained. The film-coated tablet was dried to obtain a tablet containing the test compound. 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 Example 1, Example 2 and Comparative Example 1 were placed in a brown glass bottle and allowed to stand in a sealed state at 40 ° C / 75% relative humidity. After a week, the related substance of the active ingredient (compound A) in the test tablet was measured by high performance liquid chromatography, and the total content (%) of the related substance 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 containing a compound having the above formula (I) or a pharmacologically acceptable salt thereof and a chelating agent.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique présentant une stabilité au stockage améliorée, ladite composition contenant: (A) un composé représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci; et (B) un chélateur.
PCT/JP2010/068684 2009-10-28 2010-10-22 Composition pharmaceutique présentant une stabilité au stockage améliorée WO2011052499A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107600688A (zh) * 2017-10-18 2018-01-19 上海合全医药有限公司 一种多重保护的药品储存装置

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5753414A (en) * 1980-07-29 1982-03-30 Sanofi Sa Stabilized medicinal composition
JP2005531515A (ja) * 2002-03-14 2005-10-20 ユーロ−セルティーク エス．エイ． 塩酸ナルトレキソン組成物
JP2005533075A (ja) * 2002-06-19 2005-11-04 エスビー ファームコ プエルト リコ インコーポレーテッド 安定化された医薬製剤の一酸化窒素シンターゼ阻害剤（２ｓ）−２−アミノ−４−［２−（エタンイミドイルアミノ）エチル］チオブタン酸
WO2007046411A1 (fr) * 2005-10-19 2007-04-26 Dainippon Sumitomo Pharma Co., Ltd. Procede de stabilisation d'un compose d'isoxazole
WO2008069262A1 (fr) * 2006-12-07 2008-06-12 Daiichi Sankyo Company, Limited Préparation revêtue d'un film ayant une stabilité améliorée
WO2008072532A1 (fr) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Composition pharmaceutique présentant une stabilité au stockage améliorée
JP2008543755A (ja) * 2005-06-10 2008-12-04 イーライ リリー アンド カンパニー チエノピリジン系血小板凝集阻害剤を含有する製剤
US20090281136A1 (en) * 2008-05-08 2009-11-12 Sandeep Mhetre Prasugrel pharmaceutical formulations
WO2010094471A1 (fr) * 2009-02-17 2010-08-26 Krka, D. D., Novo Mesto Compositions pharmaceutiques comprenant du prasugrel ou ses sels d'addition d'acide pharmaceutiquement acceptables, et leurs procédés de préparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5753414A (en) * 1980-07-29 1982-03-30 Sanofi Sa Stabilized medicinal composition
JP2005531515A (ja) * 2002-03-14 2005-10-20 ユーロ−セルティーク エス．エイ． 塩酸ナルトレキソン組成物
JP2005533075A (ja) * 2002-06-19 2005-11-04 エスビー ファームコ プエルト リコ インコーポレーテッド 安定化された医薬製剤の一酸化窒素シンターゼ阻害剤（２ｓ）−２−アミノ−４−［２−（エタンイミドイルアミノ）エチル］チオブタン酸
JP2008543755A (ja) * 2005-06-10 2008-12-04 イーライ リリー アンド カンパニー チエノピリジン系血小板凝集阻害剤を含有する製剤
WO2007046411A1 (fr) * 2005-10-19 2007-04-26 Dainippon Sumitomo Pharma Co., Ltd. Procede de stabilisation d'un compose d'isoxazole
WO2008069262A1 (fr) * 2006-12-07 2008-06-12 Daiichi Sankyo Company, Limited Préparation revêtue d'un film ayant une stabilité améliorée
WO2008072532A1 (fr) * 2006-12-07 2008-06-19 Daiichi Sankyo Company, Limited Composition pharmaceutique présentant une stabilité au stockage améliorée
US20090281136A1 (en) * 2008-05-08 2009-11-12 Sandeep Mhetre Prasugrel pharmaceutical formulations
WO2010094471A1 (fr) * 2009-02-17 2010-08-26 Krka, D. D., Novo Mesto Compositions pharmaceutiques comprenant du prasugrel ou ses sels d'addition d'acide pharmaceutiquement acceptables, et leurs procédés de préparation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107600688A (zh) * 2017-10-18 2018-01-19 上海合全医药有限公司 一种多重保护的药品储存装置

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