WO2013147135A1 - Composition pharmaceutique à libération contrôlée - Google Patents

Composition pharmaceutique à libération contrôlée Download PDF

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WO2013147135A1
WO2013147135A1 PCT/JP2013/059487 JP2013059487W WO2013147135A1 WO 2013147135 A1 WO2013147135 A1 WO 2013147135A1 JP 2013059487 W JP2013059487 W JP 2013059487W WO 2013147135 A1 WO2013147135 A1 WO 2013147135A1
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pharmaceutical composition
controlled
release pharmaceutical
acid
weight
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PCT/JP2013/059487
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English (en)
Japanese (ja)
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宏行 小島
誓詞 ▲高▼江
毅彦 保地
敦司 櫻井
里美 池内
迫　和博
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アステラス製薬株式会社
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Priority to JP2014508081A priority Critical patent/JP6123795B2/ja
Publication of WO2013147135A1 publication Critical patent/WO2013147135A1/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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/437—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 containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or pharmaceutics thereof
  • the present invention relates to a controlled-release pharmaceutical composition comprising a pharmaceutically acceptable salt, an acidic substance, a supersaturation maintaining agent, and a controlled-release base.
  • the present invention relates to 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5-carboxamide.
  • the present invention relates to a controlled-release pharmaceutical composition that suppresses the difference.
  • Compound A has an excellent JAK3 inhibitory activity and is known to be useful as an active ingredient of a therapeutic and / or prophylactic agent for various immune diseases including autoimmune diseases, inflammatory diseases and allergic diseases.
  • Patent Document 1 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5-carboxamide
  • Patent Document 2 A hydrogel sustained-release preparation that enables good drug release in the colon of the lower gastrointestinal tract has been disclosed (Patent Document 2). It is disclosed that when a drug is a poorly soluble drug, a solid dispersion can be formed with a polymer such as hypromellose (HPMC) to improve the solubility.
  • HPMC hypromellose
  • sustained-release preparations containing basic drugs have the problem that the elution rate increases in gastric juice and the elution rate decreases in intestinal fluid, or acidic drugs Since the dissolution rate of gastric juice decreases in the gastric juice, the sustained-release preparation containing a drug, a buffer, and a hydrophobic substance Matrix tablets containing molecules or gel-forming polymers are disclosed.
  • the buffer is retained in the matrix pores for a long time despite being easily soluble, so that the pH in the pores is kept constant. It is known that the elution rate of the drug can be arbitrarily changed by changing the composition of the added buffering agent (Patent Document 3).
  • the subject of the present invention is a digestion after excretion from the stomach (such as the small intestine) when orally administered in a pharmaceutical composition containing Compound A having extremely different solubility in acidic pH range and neutral pH range.
  • An object of the present invention is to maintain the solubility of Compound A even in the neutral pH range of the tube, to exhibit good oral absorption, or to provide a pharmaceutical composition with high bioavailability.
  • the solubility of Compound A is determined in the acidic pH range (approximately 8,600 ⁇ g / mL in the Japanese Pharmacopoeia Dissolution Test Solution No. 1 (JP1 (pH 1.2))) and the neutral pH range (Japanese Pharmacopoeia Dissolution Test Solution No. 2 In the liquid (JP2 (pH 6.8)), there was a 1000-fold difference, and it was found that the solubility was particularly low in a neutral pH environment such as JP2 (about 12, 1 in water). 500 ⁇ g / mL).
  • the present invention [1] 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a pharmaceutical thereof
  • a controlled release pharmaceutical composition comprising an acceptable salt, an acidic substance, a supersaturation maintaining agent, and a controlled release base
  • the controlled-release pharmaceutical composition according to [1] wherein the acidic substance is citric acid, malic acid, tartaric acid, fumaric acid, ascorbic acid, succinic acid, or maleic acid
  • the addition amount of the acidic substance is 4- ⁇ [(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino ⁇ -1H-pyrrolo [2,3-b] pyridine-5 -
  • the controlled-release pharmaceutical composition according to [1] or [2] which is 10% by weight or more and 200% by weight based on the weight of carboxamide or
  • compound A can be recrystallized / precipitated by maintaining the solubility (particularly supersaturation) of compound A even in the neutral pH region in the digestive tract (after gastric emptying). It can be avoided.
  • the drug is continuously released (elution while maintaining the dissolved state) regardless of the pH environment in the digestive tract, and the entire digestive tract becomes an absorption site.
  • inter-individual variation or intra-individual variation for example, pharmacokinetics (PK) parameter variation due to pH variation in the gastrointestinal tract
  • PK pharmacokinetics
  • “solubility” or “solubility” means the degree of dissolution of compound A by the method in the 16th revision Japanese Pharmacopoeia and the like. For example, as a certain aspect, within the range of 30 minutes when compound A is powdered and then placed in a solvent and shaken every 5 minutes at 20 ⁇ 5 ° C. for 30 seconds as “solubility” or “solubility” of compound A It is defined as the degree to which it dissolves.
  • “Practically insoluble, or insoluble” means that the amount of solvent required to dissolve 1 g or 1 mL of compound A is 10,000 mL or more, and “Very slightly soluble” means 1 g of compound A or The amount of solvent required to dissolve 1 mL refers to properties of 1,000 mL or more and less than 10,000 mL.
  • the solubility test tube shaking method after putting the powder of Compound A with a solvent in a test tube and shaking for 10 minutes at 23 ⁇ 5 ° C. (330 strokes / minute, 4 cm / stroke) is also included. .
  • the solubility of Compound A in JP1 is about 8,600 ⁇ g / mL, about 8.6 ⁇ g / mL for JP2, and about 12,500 ⁇ g / mL for water. .
  • the solubility (test tube shaking method) after the powder of Compound A is placed in a test tube together with a solvent and shaken at 37 ° C. for 14 hours is also included.
  • the solubility of Compound A in the United States Pharmacopeia (USP) pH 6.8 phosphate buffer is 10.9 ⁇ g / mL.
  • “supersaturated” means that a solute (compound A) having a solubility or higher is contained.
  • “supersaturated solution” means a solution containing a solute (compound A) having a solubility or higher.
  • “maintaining supersaturation” means, as one embodiment, solubility of Compound A at pH 6.8 (8.6 ⁇ g / mL (23 ° C. in the case of a test tube shaking method), 10.9 ⁇ g / mL (37 ° C)) and maintaining the above solubility.
  • “improvement of bioavailability (rate)” or “improvement of bioavailability” means that “relative bioavailability” for a composition not including the composition of the present invention is higher. means. For example, it is defined that “Bioavailability” is high for a pharmaceutical composition not containing an “acidic substance” used in the present invention.
  • “reducing PK parameter fluctuation” means the ratio of the same parameter when the gastric pH is administered at neutral to the Cmax and AUC when the gastric pH is administered at acidic, for example, It is defined as 0.5 times or more as one aspect, 0.6 times or more as another aspect, and 0.7 times or more as another aspect.
  • release control means, for example, USP pH 6.8 phosphate buffer 900 mL or USP pH 6.8 phosphate buffer as a test solution according to the Japanese Pharmacopoeia Dissolution Test Method 2 (Paddle Method).
  • the dissolution test was conducted under the condition of paddle rotation speed of 100 rpm using 900 mL of a test solution in which 1% of sodium lauryl sulfate was added to the solution, the dissolution rate of Compound A for 30 minutes after the start of the test was less than 80%. In another aspect, it means controlling to less than 50%, and in another aspect, controlling to less than 30%.
  • the known compound A represented by the formula (I) may form an addition salt with an acid or a base.
  • a salt may be a pharmaceutically acceptable salt.
  • an inorganic acid for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid
  • an organic acid for example, And acid addition salts with succinic acid, fumaric acid, L-malic acid, L-tartaric acid, mesylic acid, and tosylic acid.
  • Another embodiment is an acid addition salt with hydrobromic acid.
  • various hydrates, solvates and crystal polymorphs of the compound represented by the formula (I) or a salt thereof may be used.
  • the known compound A or a pharmaceutically acceptable salt thereof can be used alone or in combination of two or more.
  • the known compound A or a pharmaceutically acceptable salt thereof has an inhibitory activity against JAK3 and is caused by unwanted cytokine signaling (for example, rejection in living transplants, autoimmune diseases, asthma, atopic) Dermatitis, Alzheimer's disease, atherosclerosis), or useful as an active ingredient of a therapeutic or prophylactic agent for diseases (for example, cancer, leukemia) caused by abnormal cytokine signaling.
  • unwanted cytokine signaling for example, rejection in living transplants, autoimmune diseases, asthma, atopic
  • Dermatitis for example, Alzheimer's disease, atherosclerosis
  • diseases for example, cancer, leukemia
  • the dose of the known compound A or a pharmaceutically acceptable salt thereof is appropriately determined according to individual cases in consideration of the administration route, the symptoms of the disease, the age, race, sex, etc. of the administration subject.
  • the daily dose of the known compound A or a pharmaceutically acceptable salt thereof is about 0.001 to about 100 mg / kg in one embodiment, about 0.1 to about 100 mg / kg in another embodiment. From about 30 mg / kg to about 0.1 to about 10 mg / kg is suitable, and this is administered once or divided into multiple doses such as 2 to 4 times.
  • the daily dose is suitably about 0.0001 to about 10 mg / kg per body weight, and is administered once to several times a day.
  • a transmucosal agent about 0.001 to about 100 mg / kg per body weight is administered once to several times a day.
  • the addition amount of the known compound A or a pharmaceutically acceptable salt thereof is 10 mg or more and 200 mg or less as a certain embodiment and 15 mg or more and 150 mg or less as another embodiment per unit preparation.
  • the addition amount of the known compound A or a pharmaceutically acceptable salt thereof is 5% by weight or more and 70% by weight or less as a certain embodiment and 7% by weight or more and 50% by weight or less as another embodiment per unit preparation.
  • the “acidic substance” used in the present invention is not limited as long as it is pharmaceutically acceptable and maintains the solubility of Compound A in a neutral pH range. Moreover, as another aspect, if the supersaturated state of the compound A is maintained, it will not be restrict
  • citric acid, malic acid, tartaric acid, fumaric acid, ascorbic acid, succinic acid, maleic acid and the like can be mentioned.
  • Other embodiments include citric acid, tartaric acid, malic acid, and ascorbic acid.
  • Yet another embodiment is citric acid or tartaric acid, and another embodiment is tartaric acid.
  • acidic substances can be used alone or in combination of two or more.
  • the addition amount of the acidic substance is not limited as long as it is an amount that maintains the solubility of Compound A in the neutral pH range.
  • it is 10% by weight or more and 200% by weight or less as one aspect, 50% or more and 150% by weight or less as another aspect, and 100 as another aspect.
  • % By weight or more and 120% by weight or less.
  • it is 5% by weight or more and 50% by weight or less per unit preparation, in another embodiment, it is 10% by weight or more and 40% by weight or less, and in another embodiment, it is 20% by weight or more and 40% by weight or less. .
  • the “supersaturation maintaining agent” used in the present invention is a “substance that maintains the solubility of Compound A (dissolution maintenance agent)” as one embodiment, and the “substance that maintains the supersaturation of Compound A (supersaturation maintenance) as another embodiment.
  • a substance that is pharmaceutically acceptable and maintains the solubility of Compound A it is not limited.
  • the substance is not limited as long as it is pharmaceutically acceptable and maintains the supersaturation of Compound A.
  • Another embodiment is a pharmaceutically acceptable water-soluble polymer.
  • hypromellose hydroxypropylcellulose, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer and the like
  • Other embodiments include hypromellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose acetate succinate.
  • Another embodiment is hypromellose.
  • TC-5E viscosity: 3 mPa ⁇ s (2% aqueous solution 20 ° C.)
  • TC-5M viscosity: 4.5 mPa ⁇ s (2% aqueous solution 20 ° C.)
  • TC-5R viscosity: 6 mPa ⁇ s (2% aqueous solution 20 ° C.)
  • TC-5S viscosity: 15 mPa ⁇ s (2% aqueous solution 20 ° C.)).
  • Hydroxypropyl cellulose can be obtained under the trade names HPC-L (Nippon Soda), KLUCEL LF (Hercules), KLUCEL JF (Hercules). Further, hydroxypropylmethylcellulose acetate succinate can be obtained as a trade name AQOAT (Shin-Etsu Chemical Co., Ltd.).
  • “solubility maintenance agent” or “supersaturation maintenance agent” can be used alone or in combination of two or more.
  • the addition amount of the “solubility maintenance agent” or the “supersaturation maintenance agent” is not limited as long as the solubility of the compound A is maintained. Or it will not restrict
  • the weight of the known compound A for example, in one embodiment, it is 10 wt% or more and 200 wt% or less, in another embodiment, 20 wt% or more and 200 wt% or less, and in another embodiment, 40 wt% or more and 150 wt% or less. It is 50 weight% or less and as a further aspect, it is 50 weight% or more and 120 weight% or less.
  • Per unit preparation it is 5% by weight or more and 50% by weight or less as one embodiment, 10% by weight or more and 40% by weight or less in another embodiment, and 10% by weight or more and 30% by weight or less in another embodiment. Moreover, as another aspect, it is 20 to 30 weight%.
  • the “release control base” used in the present invention is not limited as long as it is a polymer that forms a hydrogel (hydrogel-forming polymer). Moreover, as another aspect, if it is a base which controls the discharge
  • the properties of the polymer substance depend on its molecular weight, and higher molecular weight is preferable.
  • One embodiment includes a viscosity average molecular weight of 2 million or more, and another embodiment includes a viscosity average molecular weight of 4 million or more.
  • polyethylene oxide for example, trade name Polyox WSR-303 (average molecular weight: 7 million, viscosity: 7500-10000 cps (1% aqueous solution 25 ° C.))
  • Polyox WSR Coagulant average molecular weight 5 million, viscosity: 5500-7500 cps (same)
  • Polyox WSR-301 average molecular weight: 4 million, viscosity: 1650-5500 cps (same)
  • Polyox WSR-N-60K Average molecular weight: 2 million, viscosity: 2000-4000 cps (2% aqueous solution at 25 ° C.)
  • Polyox WSR-N-12K average molecular weight: 1 million, viscosity: 400-800 cps (2% aqueous solution at 25 ° C.)
  • Polyox WSR- 1105 average Amount: 900
  • Another embodiment includes PEO having an average molecular weight of 2 million or more.
  • a higher molecular weight in one embodiment, an average molecular weight of 4 million or higher or higher viscosity, preferably a viscosity of 1% aqueous solution at 25 ° C. is 3000 cps or higher.
  • the polymer which is is preferable.
  • These polymer substances forming the hydrogel can be used alone or in combination of two or more. Also, a mixture comprising two or more kinds of polymer substances and having properties suitable for the present invention as a whole can be suitably used as the polymer substance forming the hydrogel of the present invention.
  • Another embodiment is a hydrogel-forming polymer having a viscosity average molecular weight of 2 million to 7 million.
  • polyethylene oxide, hypromellose, sodium carboxymethyl cellulose, hydroxyethyl cellulose, carboxyvinyl polymer and the like can be mentioned as certain embodiments.
  • Other embodiments include polyethylene oxide.
  • the addition amount of the hydrogel-forming polymer is 5% by weight or more and 500% by weight or less as an aspect with respect to the weight of the known compound A, and 10% by weight or more and 80% by weight or less as another aspect. As another aspect, it is 10 to 60 weight%. Per unit preparation, it is 3% by weight or more and 60% by weight or less as an aspect, in another aspect, it is 5% by weight or more and 30% by weight or less, and in another aspect, it is 5% by weight or more and 20% by weight or less. .
  • a hydrophilic base may be further added to the controlled-release pharmaceutical composition of the present invention.
  • the “hydrophilic base” used in the present invention the amount of water necessary for dissolving 1 g of the hydrophilic base in one embodiment is 5 mL or less at 20 ⁇ 5 ° C., and in another embodiment, 4 mL or less. belongs to. The higher the solubility in water, the higher the effect of allowing water to enter the preparation.
  • polyethylene glycol PEG; for example, trade names PEG400, PEG1500, PEG4000, PEG6000, PEG20000; manufactured by NOF Corporation
  • polyvinylpyrrolidone PVP; for example, trade name PVP K30 manufactured by BASF Corporation
  • Water-soluble polymers Sugar alcohols such as D-sorbitol and xylitol, sucrose, anhydrous maltose, D-fructose, dextran (eg, dextran 40), sugars such as glucose and sucrose, polyoxyethylene Surfactants such as polyoxypropylene glycol (for example, Pluronic F68; manufactured by Asahi Denka Co., Ltd.), salts such as sodium chloride and magnesium chloride, organic acids such as citric acid and tartaric acid, glycine, ⁇ -alanine, lysine hydrochloride and the like Ami Examples include amino acids such as noic acids and meglumine.
  • PEG6000 PVP
  • D-sorbitol Preferably PEG8000, a citric acid, sucrose, etc. are mentioned.
  • a hydrophilic base can be used 1 type or in combination of 2 or more types.
  • the addition amount of the hydrophilic base is 5% by weight or more and 100% by weight or less as an aspect with respect to the weight of the known compound A, and is 10% by weight or more and 80% by weight or less as another aspect. As another certain aspect, they are 100 weight% or more and 120 weight% or less. In one embodiment, it is 3% by weight or more and 50% by weight or less per unit preparation, and in another embodiment, it is 5% by weight or more and 30% by weight or less. *
  • various pharmaceutical additives are appropriately used as necessary, and formulated.
  • a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable.
  • excipients, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, buffers, antioxidants, surfactants, fluidizing agents, etc. are used. .
  • Examples of the excipient include D-mannitol and lactose hydrate.
  • Examples of the binder include gum arabic, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose and the like.
  • Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.
  • Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
  • Examples of the foaming agent include baking soda.
  • Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
  • Examples of the fragrances include lemon, lemon lime, orange and menthol.
  • Examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid, sodium lauryl sulfate and the like.
  • Examples of the colorant include yellow ferric oxide, red ferric oxide, black iron oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3, and the like.
  • Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid , Boric acid or its salts.
  • Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
  • surfactant examples include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
  • fluidizing agent examples include light anhydrous silicic acid.
  • an appropriate amount can be appropriately added by combining one or more kinds. As for the addition amount, any excipient is used in an amount within the range in which the desired effect of the present invention is achieved.
  • a preferable dosage form is an oral solid preparation that can be easily taken by a patient and is convenient for storage and carrying.
  • it is a tablet, a capsule, a powder, a granule, a fine granule, a dry syrup, etc., and it is a tablet as another aspect.
  • controlled-release pharmaceutical composition of the present invention can be produced by a known method such as pulverization, mixing, granulation, molding (tablet), film coating and the like.
  • the method for pulverizing the pulverizing step is not particularly limited as long as it can be pharmaceutically pulverized.
  • the pulverizer include a hammer mill, a ball mill, a jet mill, and a pin mill.
  • the grinding conditions are not particularly limited as long as they are appropriately selected.
  • the apparatus As a method of mixing in the mixing step , there is no particular limitation on the apparatus and means as long as it is a method that can generally mix each component uniformly pharmaceutically.
  • the mixing apparatus include a V-type mixer, a ribbon-type mixer, a container mixer, and a high-speed stirring mixer.
  • the mixing conditions are not particularly limited as long as they are appropriately selected.
  • Examples of the granulating step granulator include a high speed stirring granulator and the like.
  • Examples of the granulation method include, for example, a fluidized bed granulation method, a melt granulation method, a high-speed stirring granulation method, a crushing (pulverization) granulation method, an extrusion granulation method, a rolling granulation method, and a spray granulation method. Examples thereof include a granulation method and a dry granulation method.
  • Another embodiment is a high-speed stirring granulation method.
  • the binder solution is prepared by dissolving or dispersing in a solvent such as water, ethanol or methanol. Further, these solvents can be appropriately mixed and used.
  • the conditions for preparing the binder solution are not particularly limited as long as they are appropriately selected.
  • the drying method is not particularly limited as long as it is usually a pharmaceutically drying method, and examples thereof include ventilation drying and drying under reduced pressure.
  • sizing may be performed to remove coarse particles having a certain size or more.
  • a solid dispersion containing Compound A and a supersaturation maintaining agent may be prepared before granulation, and an acidic substance and various additives may be mixed into the solid dispersion for granulation.
  • a granulated product or a mixture of granulated products mixed with various pharmaceutical additives is filled into capsules to make capsules, or compressed into tablets using a rotary tableting machine. be able to.
  • the compression step is not particularly limited as long as it is a method for molding the controlled-release pharmaceutical composition of the present invention. Examples thereof include a direct tableting method in which a drug and an appropriate pharmaceutical additive are mixed and then compression-molded to obtain a tablet, and a method in which a lubricant is further mixed with the granulated product and then compression-molded to produce a tablet.
  • the tableting device include a rotary tableting machine, a single tableting machine, and an oil press. Tableting conditions such as tableting pressure are not particularly limited as long as the tablet can be molded and the tableting pressure does not damage the tablet during the production process.
  • Film coating may be applied to the tablet surface after tableting as appropriate.
  • the method is not particularly limited as long as it is usually a pharmaceutically film coating method. Examples thereof include pan coating and dip coating.
  • the film coating agent include hypromellose, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, iron sesquioxide (red, yellow), titanium oxide, polyethylene glycol, triethyl citrate and the like.
  • the film coating agent can be appropriately added in an appropriate amount by combining one kind or two or more kinds.
  • a film coating rate will not be restrict
  • the method is not particularly limited as long as it can be usually pharmaceutically dried.
  • the drying conditions are not particularly limited as long as they are appropriately set in consideration of, for example, the stability of the preparation.
  • Reference Examples 1-6 Based on the formulation shown in Table 1, Compound A hydrobromide (manufactured by Astellas Pharma, the same applies hereinafter), acidic substance (anhydrous citric acid: manufactured by Komatsuya Co., Ltd., malic acid: manufactured by Kanto Chemical Co., Inc., tartaric acid: manufactured by Komatsuya Co., Ltd.) , Fumaric acid: manufactured by Kanto Chemical Co., Inc., ascorbic acid: manufactured by Kanto Chemical Co., Ltd., succinic acid: manufactured by Wako Pure Chemical Industries, Ltd., hereinafter the same unless otherwise specified, polyethylene oxide (molecular weight: 7 million, Polyox WSR-303, Dow Made by Chemical Co., unless otherwise noted, and magnesium stearate (Parteck (registered trademark) LUB MST, Merck Co., Ltd.) were mixed using a mortar pestle and compression molded using an oil press tableting machine. And tablets (diameter 9 mm) were produced.
  • acidic substance
  • Comparative Example 1 In order to make the size of the preparations the same without adding the acidic substance in the present invention, polyethylene glycol (PEG 8000 (Polyglycol 8000, manufactured by Clariant Co., Ltd., hereinafter the same unless otherwise specified)) was added for comparison. A pharmaceutical composition (tablet) was prepared.
  • PEG 8000 Polyglycol 8000, manufactured by Clariant Co., Ltd., hereinafter the same unless otherwise specified
  • Examples 1 to 4 and Comparative Examples 2 to 4 Based on the formulation shown in Table 2, various additives were mixed using a mortar pestle. The mixture was compression-molded using an oil press tableting machine to produce a controlled release pharmaceutical composition (tablet) of the present invention and a comparative pharmaceutical composition (tablet).
  • the polyethylene oxide having a molecular weight of 2 million is Polyox WSR N-60K manufactured by Dow Chemical Co. (hereinafter, unless otherwise specified), and the hypromellose is manufactured by TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.
  • Ceolus PH101 manufactured by Asahi Kasei (hereinafter, the same unless otherwise specified), as sodium lauryl sulfate, NIKKOL SLS, manufactured by Nikko Chemicals (hereinafter, The same applies hereinafter unless otherwise specified.
  • Examples 5-8 Based on the formulation shown in Table 3, 299.7 g of Compound A hydrobromide, 320.0 g of anhydrous citric acid (manufactured by Mallinckrodt Baker), 129.1 g of crystalline cellulose (Ceolous PH101), 304. hypromellose (TC-5E). After mixing 0 g using a high-speed stirring granulator (PMA 1 High Shear Granulator, manufactured by GEA), purified water was added and wet granulation was performed.
  • PMA 1 High Shear Granulator manufactured by GEA
  • Examples 15, 19 and 20 In the same manner as in Examples 9 to 14 and 16 to 18, based on Tables 4 and 5, Compound A hydrobromide, anhydrous citric acid, crystalline cellulose (Ceolous PH101), hypromellose (TC-5E) were stirred at high speed. After mixing using a granulator, purified water was added to perform wet granulation. This granulated product was dried using a fluidized bed granulator, and then granulated using a granulator to obtain a granulated product.
  • Hypromellose (Methocel K100LV, manufactured by Dow Chemical), polyethylene oxide (molecular weight: 7 million or molecular weight: 2 million), magnesium stearate, sodium lauryl sulfate (manufactured by Stepan), and light anhydrous silicic acid (AEROSIL 200) It mixed and compression-molded using the rotary tableting machine, and manufactured the controlled release pharmaceutical composition (tablet) of this invention.
  • Examples 21-25 Based on the formulation shown in Table 6, various additives were mixed using a mortar pestle. The mixture was compression-molded using an oil press tableting machine to produce a controlled release pharmaceutical composition (tablet) of the present invention.
  • Test example 1 The drug dissolution properties of the preparations of Reference Examples 1 to 6 and the control preparation (preparation of Comparative Example 1) were evaluated. Using 900 mL (37 ° C.) of a test solution obtained by adding 1% sodium lauryl sulfate to a USP pH 6.8 phosphate buffer as a test solution, an elution test was performed according to the Japanese Pharmacopoeia Dissolution Test Method 2 (paddle rotation speed: 100 rpm) ). After starting the dissolution test, the dissolution rate was calculated by sampling over time and measuring the absorbance using a spectrophotometer. In addition, about the control formulation, 0.1N hydrochloric acid was used as a test solution, and the drug dissolution property was similarly evaluated.
  • Test example 2 Regarding the supersaturation maintaining agent, hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd., unless otherwise specified), hypromellose (TC-5E), and a mixture of hydroxypropylcellulose and hypromellose, Compound A bromide The supersaturation ability of hydrates was evaluated. USP pH 6.8 phosphate buffer 488 mL (37 ° C.) was used as a test solution, and hydroxypropylcellulose and hypromellose in the amounts shown in Table 7 were added to the dissolution tester vessel and completely dissolved.
  • Test example 3 Dissolution (supersaturation) was evaluated using a dissolution test method (paddle method).
  • the test solution system was subjected to a dissolution test in accordance with the Japanese Pharmacopoeia dissolution test method 2 under the same conditions as in Test Example 2.
  • Various additives shown in Table 8 polyvinyl alcohol: PVA, manufactured by Nippon Synthetic Chemical Co., Ltd., hydroxypropyl cellulose: HPC-L, hypromellose: TC-5E, hydroxypropyl methylcellulose acetate succinate: HPMC-AS, manufactured by Shin-Etsu Chemical Co., Ltd.
  • PVA polyvinyl alcohol
  • HPC-L hypromellose
  • HPMC-AS hydroxypropyl methylcellulose acetate succinate
  • the drug concentrations when hydroxypropylcellulose, hypromellose, and hydroxypropylmethylcellulose acetate succinate were added were 85.1 ⁇ g / mL, 80.5 ⁇ g / mL, and 78.5 ⁇ g / mL, respectively, and no supersaturation maintenance agent was added.
  • the drug concentration of the product was significantly higher than the drug concentration of 20.3 ⁇ g / mL, and it was revealed that the supersaturation was maintained even after 14 hours (Table 8).
  • polyvinyl alcohol was added, the drug concentration was 23.7 ⁇ g / mL, which was similar to that of the product without the addition of the supersaturation maintenance agent.
  • Test example 4 The tablets of Comparative Examples 2, 3, 4, and Example 1 were evaluated for drug dissolution.
  • a test solution 900 mL (37 ° C.) of 0.1N hydrochloric acid or pH 6.8 phosphate buffer was used, 5 tablets were added per vessel, and a dissolution test was conducted according to the second method of the Japanese Pharmacopoeia Dissolution Test Method.
  • shaft 100% in a figure corresponds to 133.3 microgram / mL as a well-known compound A density
  • In 0.1N hydrochloric acid solution all tablets showed sustained drug dissolution and released 85-100% of the drug in 5 hours (FIG. 2).
  • the drug elution rate is 40% (drug concentration 53.3 ⁇ g / mL) or more even at 5 hours from the start of the test, greatly improves the drug solubility at pH 6.8, and can maintain the supersaturation of the solubility even after 5 hours. It became clear.
  • Test Example 5 The oral absorbability of the tablet of Comparative Example 2 was evaluated. As an evaluation system, a dog fasted for 18 hours or more after administration was used. In order to forcibly control the dog's gastric pH to be acidic, treatment with pentagastrin (intra thigh muscle administration; 30 minutes before tablet administration, 30 minutes after tablet administration, 90 minutes after administration) is performed before tablet administration. did. Six tablets of Comparative Example 2 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the plasma drug concentration was measured. As a result, a continuous plasma drug concentration pattern was shown (FIG. 4). The maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration transition curve (AUC) up to 24 hours after administration were 1346 ng / mL and 11102 ng ⁇ h / mL, respectively.
  • Cmax maximum plasma drug concentration
  • AUC area under the plasma drug concentration transition curve
  • Test Example 6 The oral absorbability of the tablet of Comparative Example 2 was evaluated. As an evaluation system, a dog fasted for 18 hours or more after administration was used. In order to force the canine gastric pH to be neutrally controlled, famotidine (intramuscular thigh administration; 90 minutes before tablet administration, 30 minutes before administration) was administered before tablet administration. Six tablets of Comparative Example 2 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured. As a result, the plasma drug concentration was remarkably low (FIG.
  • Cmax and AUC were 268 ng / mL and 3096 ng ⁇ h / mL, respectively. They were 0.20 times and 0.28 times lower than Cmax and AUC, respectively, when administered to the dogs subjected to the pentagastrin treatment evaluated in Test Example 5.
  • Test Example 7 The oral absorbability of the tablet of Comparative Example 3 was evaluated. The same evaluation system as in Test Example 6 was used. Six tablets of Comparative Example 3 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured. As a result, the plasma drug concentration transition up to 1 hour after administration showed a pattern similar to that during the pentagastrin treatment in Test Example 5, but did not continue thereafter (FIG. 4). Cmax and AUC were 464 ng / mL and 3377 ng ⁇ h / mL, respectively, which were 0.34 times and 0.30 times lower than those of the pentagastrin treatment of Comparative Example 2 evaluated in Test Example 5, respectively.
  • Test Example 8 The oral absorbability of the tablet of Example 1 was evaluated. The same evaluation system as in Test Example 5 was used. Six tablets of Example 1 (150 mg as known compound A hydrobromide) were orally administered with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured. As a result, a sustained plasma drug concentration pattern was shown, and Cmax and AUC were 2326 ng / mL and 15285 ng ⁇ h / mL, respectively.
  • Test Example 9 The oral absorbability of the tablet of Example 1 was evaluated. The same evaluation system as in Test Example 6 was used. Six tablets of Example 1 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs with neutral gastric pH by famotidine treatment, and the plasma drug concentration was measured. As a result, a continuous increase in plasma drug concentration was observed (FIG. 4), Cmax and AUC were 1746 ng / mL and 14879 ng ⁇ h / mL, respectively, and during the pentagastrin treatment of Example 1 evaluated in Test Example 8. They were 0.75 times and 0.97 times, respectively.
  • Test Example 10 The oral absorbability of the tablet of Example 2 was evaluated. The same evaluation system as in Test Example 5 was used. Eight tablets of Example 2 (150 mg as known compound A hydrobromide) were orally administered with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured. The results showed a sustained plasma drug concentration profile, with Cmax and AUC being 1942 ng / mL and 12927 ng ⁇ h / mL, respectively.
  • Test Example 11 The oral absorbability of the tablet of Example 3 was evaluated. The same evaluation system as in Test Example 5 was used.
  • One tablet of Example 3 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog whose gastric pH was acidified by treatment with pentagastrin, and the drug concentration in plasma was measured. The results showed a sustained plasma drug concentration profile, with Cmax and AUC being 2232 ng / mL and 16452 ng ⁇ h / mL, respectively.
  • Test Example 12 The oral absorbability of the tablet of Example 4 was evaluated. The same evaluation system as in Test Example 5 was used. As a result of oral administration of one tablet of Example 4 (150 mg as known compound A hydrobromide) with 50 mL of water to a dog whose stomach pH was acidified by pentagastrin treatment, a sustained plasma drug concentration profile was obtained. The indicated Cmax and AUC were 2091 ng / mL and 16081 ng ⁇ h / mL, respectively.
  • the drug can be continuously maintained even in the neutral pH environment of the digestive tract. It is considered that the PK parameter variation due to the release and the pH variation in the digestive tract was reduced.
  • Test Example 13 The oral absorbability of the tablet of Example 5 was evaluated. The same evaluation system as in Test Example 5 was used. As a result of orally administering 8 tablets (150 mg as known compound A hydrobromide) of Example 5 together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, a sustained plasma drug concentration profile was obtained. Cmax and AUC shown were 1942 ng / mL and 12927 ng ⁇ h / mL, respectively (FIG. 5).
  • Test Example 14 The oral absorbability of the tablet of Example 22 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 22 (150 mg as known compound A hydrobromide) was orally administered together with 50 mL of water to a dog whose stomach pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile. Cmax and AUC shown were 2332 ng / mL and 16452 ng ⁇ h / mL, respectively (FIG. 5).
  • Test Example 15 The oral absorbability of the tablet of Example 23 was evaluated. The same evaluation system as in Test Example 5 was used.
  • One tablet of Example 23 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog whose stomach pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile.
  • the indicated Cmax and AUC were 2091 ng / mL and 16081 ng ⁇ h / mL, respectively (FIG. 5).
  • Test Example 16 The oral absorbability of the tablet of Example 6 was evaluated. The same evaluation system as in Test Example 5 was used. Four tablets of Example 6 (150 mg as known compound A hydrobromide) were orally administered together with 50 mL of water to dogs whose gastric pH was acidified by treatment with pentagastrin, resulting in a sustained plasma drug concentration profile. Cmax and AUC shown were 1329 ng / mL and 9749 ng ⁇ h / mL, respectively.
  • Test Example 17 The oral absorbability of the tablet of Example 17 was evaluated. The same evaluation system as in Test Example 5 was used. One tablet of Example 17 (150 mg as known compound A hydrobromide) was orally administered with 50 mL of water to a dog that had been treated with pentagastrin for acidification of the gastric pH. As a result, a sustained plasma drug concentration profile was obtained. Cmax and AUC shown were 1635 ng / mL and 11439 ng ⁇ h / mL, respectively.
  • Test Example 18 For the tablets of Example 5, Examples 22 and 23, drug dissolution was evaluated. In addition, about the tablet of Example 5, 8 tablets were injected
  • Example 18 both the tablets of Example 5, Examples 22 and 23 showed sustained and stable dissolution up to 6 hours from the start of the dissolution test, and the dissolution rate was 60% (drug concentration 80.0 ⁇ g / The elution rate was 30% (drug concentration 40.0 ⁇ g / mL) or more at 14 hours. Compared with the drug solubility (10.9 ⁇ g / mL) at pH 6.8, it showed a very high value, and it was revealed that supersaturation can be maintained for a long time.
  • Compound A has excellent JAK3 inhibitory activity and is useful as an active ingredient of a therapeutic and / or prophylactic agent for various immune diseases including autoimmune diseases, inflammatory diseases, and allergic diseases.
  • high bioavailability can be imparted to a controlled-release pharmaceutical composition containing a pharmaceutically acceptable salt thereof.

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Abstract

Cette invention concerne une composition pharmaceutique à libération contrôlée contenant le composé 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]- amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide, dont la solubilité à pH acide est extrêmement différente de la solubilité à pH neutre, comme agent médicinal, la solubilité de l'agent médicinal pouvant être maintenue à pH neutre dans le tube digestif après vidange gastrique (intestin grêle par exemple). La composition pharmaceutique à libération contrôlée présente une bonne absorption orale et présente une biodisponibilité élevée. La composition pharmaceutique à libération contrôlée comprend le composé 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H- pyrrolo[2,3-b]pyridine-5-carboxamide ou un sel pharmaceutiquement acceptable, une substance acide, un agent de maintien de la sursaturation et un ingrédient de base à libération contrôlée.
PCT/JP2013/059487 2012-03-30 2013-03-29 Composition pharmaceutique à libération contrôlée WO2013147135A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2979698A4 (fr) * 2013-03-29 2016-11-16 Astellas Pharma Inc Composition pharmaceutique pour administration orale
JP7459458B2 (ja) 2018-06-28 2024-04-02 ライオン株式会社 内服組成物及びその製造方法

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JPS62242615A (ja) * 1986-04-16 1987-10-23 Fujisawa Pharmaceut Co Ltd マトリツクス錠
WO1994006414A1 (fr) * 1992-09-18 1994-03-31 Yamanouchi Pharmaceutical Co., Ltd. Preparation d'hydrogel a liberation prolongee
JP2004518676A (ja) * 2000-12-20 2004-06-24 シャイア ラボラトリーズ，インコーポレイテッド 最小化ｐＨ依存性溶解プロフィールを有する徐放性薬学的剤形
JP2009504796A (ja) * 2005-08-22 2009-02-05 ノバルティス アクチエンゲゼルシャフト ｐＨ依存性薬剤化合物、ｐＨ調整剤および遅延剤を含む医薬組成物
JP2009522206A (ja) * 2005-12-28 2009-06-11 アステラス製薬株式会社 へテロ環ヤヌスキナーゼ３阻害剤
WO2010038690A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique à libération contrôlée

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JPS62242615A (ja) * 1986-04-16 1987-10-23 Fujisawa Pharmaceut Co Ltd マトリツクス錠
WO1994006414A1 (fr) * 1992-09-18 1994-03-31 Yamanouchi Pharmaceutical Co., Ltd. Preparation d'hydrogel a liberation prolongee
JP2004518676A (ja) * 2000-12-20 2004-06-24 シャイア ラボラトリーズ，インコーポレイテッド 最小化ｐＨ依存性溶解プロフィールを有する徐放性薬学的剤形
JP2009504796A (ja) * 2005-08-22 2009-02-05 ノバルティス アクチエンゲゼルシャフト ｐＨ依存性薬剤化合物、ｐＨ調整剤および遅延剤を含む医薬組成物
JP2009522206A (ja) * 2005-12-28 2009-06-11 アステラス製薬株式会社 へテロ環ヤヌスキナーゼ３阻害剤
WO2010038690A1 (fr) * 2008-09-30 2010-04-08 アステラス製薬株式会社 Composition pharmaceutique à libération contrôlée

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2979698A4 (fr) * 2013-03-29 2016-11-16 Astellas Pharma Inc Composition pharmaceutique pour administration orale
JP7459458B2 (ja) 2018-06-28 2024-04-02 ライオン株式会社 内服組成物及びその製造方法

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