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WO2010107040A1 - Préparation solide contenant un antagoniste du récepteur y5 du npy - Google Patents

Préparation solide contenant un antagoniste du récepteur y5 du npy Download PDF

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WO2010107040A1
WO2010107040A1 PCT/JP2010/054488 JP2010054488W WO2010107040A1 WO 2010107040 A1 WO2010107040 A1 WO 2010107040A1 JP 2010054488 W JP2010054488 W JP 2010054488W WO 2010107040 A1 WO2010107040 A1 WO 2010107040A1
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solid preparation
optionally substituted
weight
salt
acid
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Japanese (ja)
Inventor
岳二 清中
有紀 村上
見奈子 藤井
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to CN2010800225081A priority Critical patent/CN102438623A/zh
Priority to SG2011068038A priority patent/SG174488A1/en
Priority to JP2011504851A priority patent/JPWO2010107040A1/ja
Publication of WO2010107040A1 publication Critical patent/WO2010107040A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

Definitions

  • the present invention relates to a preparation for improving the water solubility of an NPYY5 receptor antagonist.
  • trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxy is characterized by containing carboxymethylethylcellulose as an amorphous stabilizer. It relates to solid formulations of amides.
  • Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals. In previous reports, NPY has been found to have a feeding promoting action, an anticonvulsant action, a learning promoting action, an anxiolytic action, an antistress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders.
  • the NPY receptor antagonist may be a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
  • Y1, Y2, Y3, Y4, Y5 and Y6 subtypes have been discovered for NPY receptors (Trends in Pharmacological Sciences, Vol. 18, 372 (1997)).
  • the Y5 receptor is involved in at least the feeding function, and its antagonist has been suggested to be an anti-obesity drug (Peptides, Vol. 18, 445 (1997)).
  • NPYY5 receptor antagonist examples include compounds described in International Publication Pamphlets WO01 / 37826 and WO03 / 076374, and in particular, trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tersal Butylsulfonylamino) cyclohexanecarboxamide exhibits a high anti-obesity effect.
  • this drug is administered orally, according to the study by the present inventors, it was revealed that the water solubility is low and the amount of absorption decreases because the drug is not sufficiently dissolved in the digestive tract.
  • the absorption rate of the drug decreases as the dose increases, and digestive activity during feeding (mechanical stimulation due to contraction of the digestive tract, increase in digestive juice secretion, prolonged digestive tract residence time, etc.) ),
  • the absorption rate is more likely to fluctuate than when fasting, and the expected therapeutic effect may not be obtained or unexpected adverse events may occur.
  • increasing the dissolution rate of a drug from a solid preparation is important in developing an oral administration preparation.
  • Patent Document 1 is characterized by heating or mechanochemically treating a preparation containing nicardipine hydrochloride, 15% by weight of urea as an amorphization inducer, and hydroxypropylmethylcellulose as an amorphization stabilizer.
  • a solid dispersion is disclosed.
  • Patent Document 2 discloses that a preparation containing ephonidipine hydrochloride, 11% by weight of urea as an amorphization inducer, and hydroxypropylmethylcellulose acetate succinate as an amorphous stabilizer is heated or mechanochemically treated. A featured solid dispersion is disclosed. Further, Non-Patent Document 1 discloses a solid dispersion containing nifedipine, polyvinylpyrrolidone and 7% by weight of urea.
  • Patent Documents 1 and 2 are methods in which the manufacturing method gives an excessive load to the drug such as high-temperature heating or mechanochemical treatment, and the drug may be decomposed.
  • Patent Document 3 efonidipine hydrochloride, Patent Document 4, Cyclosporin A, Patent Document 5, Bicalutamide, Patent Document 6, Amifostine, Patent Document 7, Itconazole, Patent Document 8, 6-Hydroxy-5 , 7-Dimethyl-2-methylamino-4- (3-pyridylmethyl) benzothiazole, Nifedipine in Non-Patent Document 1, and 4 ′′ -O- (4-methoxyphenyl) acetyltyrosine in Non-Patent Document 2
  • the solubility is increased, the optimal amorphous stabilizer, the kind of the amorphousization inducing agent, and the optimal blending amount are not always the same depending on the drug.
  • CMEC carboxymethylethylcellulose
  • the present invention (1) Formula (I): [Wherein, R1 is optionally substituted lower alkyl, optionally substituted cycloalkyl or optionally substituted aryl, R2 is hydrogen or lower alkyl, R1 and R2 together may form a lower alkylene, n is 1 or 2, X is a lower alkylene which may have a substituent, Lower alkenylene which may have a substituent, -CO-lower alkylene which may have a substituent, -CO-lower alkenylene which may have a substituent or Wherein R3, R4, R5 and R6 are each independently hydrogen or lower alkyl; Is an optionally substituted cycloalkylene, an optionally substituted cycloalkenylene, an optionally substituted bicycloalkylene, an optionally substituted arylene or a substituent And p and q are each independently 0 or 1) And -NR2-X- (Where Is piperidinediyl, piperazinediyl, pipe
  • the blending ratio of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose is 1: 1 to 1:19.
  • the blending ratio of trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose is 1: 2.33 to 1: 5.
  • Amorphization inducer is an amino acid or a salt thereof, aspartame, erythorbic acid or a salt thereof, ascorbic acid or a salt thereof, stearic acid ester, aminoethylsulfonic acid, inositol, ethylurea, citric acid or a salt thereof, glycyrrhizin Acid or salt thereof, gluconic acid or salt thereof, creatinine, salicylic acid or salt thereof, tartaric acid or salt thereof, succinic acid or
  • a method for improving the solubility of the drug, (27) Amorphization inducer in a solid preparation containing trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide and carboxymethylethylcellulose A method for improving the solubility of the drug, characterized in that (28) By containing carboxymethylethylcellulose, trans-N- (5-trifluoromethylpyridin-2-yl) -4-one 60 minutes after the start of the test in the second dissolution solution of the Japanese Pharmacopoeia dissolution test method A method of controlling the elution rate of (tertiarybutylsulfonylamino) cyclohexanecarboxyamide to 60% or more and controlling the elution rate to 70% or more after 180 minutes, About.
  • the solid formulation of the present invention increases the elution of NPYY5 receptor antagonists, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide, from the formulation Can be made.
  • the solid preparation of the present invention is preferably a stable preparation that is maintained in an amorphous state even after long-term storage. More preferably, the size of the preparation (eg, tablet) is reduced, and the ingestion is improved.
  • the main NPYY5 receptor antagonist used in the present invention is preferably a compound represented by the above formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, WO01 / 37826 It is described in an international publication pamphlet, WO03 / 076374 international publication pamphlet.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • fluorine and chlorine are preferable.
  • “Lower alkyl” includes linear or branched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, Examples thereof include n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl and n-decyl.
  • “Lower alkyl” in R 1 is preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, and most preferably isopropyl or t-butyl. “Lower alkyl” in other cases preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms.
  • substituent of “optionally substituted lower alkyl” in Z include (1) halogen; (2) cyano; (3) (i) hydroxy, (ii) lower alkoxy, (iii) mercapto, (iv) lower, each optionally substituted with one or more substitutable groups selected from the substituent group ⁇ defined below.
  • Examples of the substituent of “lower alkyl optionally having a substituent” other than Z include one or more groups selected from the substituent group ⁇ , and an arbitrary position is It may be substituted with these substituents.
  • Substituent group ⁇ is halogen, optionally protected hydroxy, mercapto, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl, cyano, A group consisting of cycloalkyl, phenyl, phenoxy, lower alkylphenyl, lower alkoxyphenyl, halogenophenyl, naphthyl and heterocyclic groups.
  • substituents examples include one or more groups selected from substituent group ⁇ , preferably phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl or heterocyclic ring Formula group.
  • Cycloalkyl includes cyclic alkyl having 3 to 8, preferably 5 or 6, carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • substituent of “optionally substituted cycloalkyl” include one or more groups selected from the substituent group ⁇ , and any position may be substituted.
  • “Bicycloalkyl” includes a group formed by removing one hydrogen from an aliphatic ring having 5 to 8 carbon atoms in which two rings share two or more atoms. Specific examples include bicyclo [2.1.0] pentyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl and bicyclo [3.2.1] octyl. “Lower alkenyl” is a straight or branched alkenyl having 2 to 10, preferably 2 to 8, more preferably 3 to 6 carbon atoms having one or more double bonds at any position. Is included.
  • the substituent of “optionally substituted lower alkenyl” includes halogen, lower alkoxy, lower alkenyl, amino, lower alkylamino, lower alkoxycarbonylamino, lower alkylthio, acyl, carboxy, lower alkoxycarbonyl, carbamoyl. , Cyano, cycloalkyl, phenyl, lower alkylphenyl, lower alkoxyphenyl, naphthyl and / or heterocyclic group.
  • “Acyl” means (1) straight or branched alkylcarbonyl or alkenylcarbonyl having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, most preferably 1 to 4 carbon atoms, and (2) carbon number.
  • Cycloalkylcarbonyl having 4 to 9, preferably 4 to 7 carbon atoms and (3) arylcarbonyl having 7 to 11 carbon atoms are included. Specific examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioyl, methacryloyl, crotonoyl, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.
  • the acyl part of “acyloxy” is the same as above.
  • Cycloalkenyl includes those having one or more double bonds at any position in the cycloalkyl ring, specifically cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cyclohexenyl. Sadienyl and the like can be mentioned.
  • substituent of “optionally substituted cycloalkenyl” include one or more groups selected from substituent group ⁇ .
  • substituent of the “optionally substituted amino” examples include the substituent group ⁇ , the optionally substituted benzoyl and / or the optionally substituted heterocyclic carbonyl (here And the substituent includes hydroxy, lower alkyl, lower alkoxy and / or lower alkylthio).
  • Aryl is a monocyclic or polycyclic aromatic carbocyclic group, and includes phenyl, naphthyl, anthryl, phenanthryl and the like.
  • aryls fused with other non-aromatic hydrocarbon cyclic groups include indanyl, indenyl, biphenylyl, acenaphthyl, tetrahydronaphthyl and fluorenyl. Particularly preferred is phenyl.
  • phenyl Particularly preferred is phenyl.
  • the “optionally substituted aryl” and the “optionally substituted phenyl” in Z are one or more substitutable groups selected from the substituent group ⁇ and the substituent group ⁇ . It includes “aryl” and “phenyl” which may be substituted with lower alkyl which may be substituted.
  • Examples of the substituent of “optionally substituted aryl” and “optionally substituted phenyl” other than Z include one or more groups selected from the substituent group ⁇ .
  • the “hydrocarbon cyclic group” includes the above “cycloalkyl”, “cycloalkenyl”, “bicycloalkyl” and “aryl”.
  • the “non-aromatic hydrocarbon cyclic group” includes the above “cycloalkyl”, “cycloalkenyl” and “bicycloalkyl”.
  • hydrocarbon cyclic group which may have a substituent means the above “cycloalkyl which may have a substituent”, “cycloalkenyl which may have a substituent”, “substitution” It includes “bicycloalkyl which may have a group” and “aryl which may have a substituent”.
  • “Heterocyclic group” includes a heterocycle having one or more heteroatoms arbitrarily selected from O, S and N, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl.
  • a tricyclic fused heterocyclic group of: dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazole Includes non-aromatic heterocyclic groups such as linyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl .
  • a condensed heterocyclic group condensed with a ring other than a heterocyclic ring may have a bond on any ring.
  • the substituent of the “heterocyclic group optionally having substituent (s)” is the same as the above-mentioned “aryl optionally having substituent (s)”.
  • the heterocyclic group moiety of “heterocyclic carbonyl”, “heterocyclic oxy”, “heterocyclic thio” and “heterocyclic substituted phenyl” is the same as the above “heterocyclic group”.
  • “Lower alkylene” includes a divalent group in which 1 to 6, preferably 2 to 6 and more preferably 3 to 6 methylenes are continuous. Specifically, methylene, ethylene, trimethylene, tetra Examples include methylene, pentamethylene and hexamethylene. Particularly preferred is tetramethylene.
  • the lower alkylene part of “lower alkylenedioxy” is the same as the above “lower alkylene”, preferably methylenedioxy or ethylenedioxy.
  • “Lower alkenylene” is a divalent group of 2 to 6, preferably 3 to 6, more preferably 4 to 5 consecutive methylenes, wherein at least one of the carbon-carbon bonds is a double bond. Is included.
  • Cycloalkylene is a divalent group formed by removing one hydrogen atom from the above “cycloalkyl”.
  • the “cycloalkylene” in X is preferably 1,4-cyclohexanediyl.
  • the “cycloalkenylene” includes a group having at least one double bond in the ring of the cycloalkylene.
  • Bicycloalkylene includes a group formed by removing one hydrogen from the above “bicycloalkyl”. Specific examples include bicyclo [2.1.0] pentylene, bicyclo [2.2.1] heptylene, bicyclo [2.2.2] octylene, bicyclo [3.2.1] octylene.
  • the “heterocyclic diyl” includes a divalent group formed by removing one hydrogen atom from the above “heterocyclic group”. Preferred are piperidine diyl, piperazine diyl, pyridine diyl, pyrimidine diyl, pyrazine diyl, pyrrolidine diyl or pyrrole diyl, and more preferred is piperidine diyl.
  • “Arylene” includes a divalent noble formed by removing one hydrogen atom from the above “aryl”. Preferable is phenylene.
  • the “heteroarylene” includes those having the aromatic attribute among the above “heterocyclic diyl”.
  • pyrrole diyl imidazole diyl, pyrazole diyl, pyridine diyl, pyridazine diyl, pyrimidine diyl, pyrazine diyl, triazole diyl, triazine diyl, isoxazole diyl, oxazole diyl, oxadiazole diyl, isothiazole diyl, thiazole diyl, thiadiazole diyl , Flangedyl and thiophenediyl.
  • “Pharmaceutically acceptable salts” include, for example, salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid; salts of organic acids such as paratoluenesulfonic acid, methanesulfonic acid, oxalic acid or citric acid; ammonium, Examples include salts of organic bases such as trimethylammonium or triethylammonium; salts of alkali metals such as sodium or potassium; and salts of alkaline earth metals such as calcium or magnesium.
  • the “solvate” is preferably a hydrate, and one molecule of the compound according to the present invention may be coordinated with an arbitrary number of water molecules.
  • prodrug is a derivative of a compound according to the invention having a chemically or metabolically degradable group and is pharmaceutically active in vivo by solvolysis or under physiological conditions It is the compound which becomes.
  • Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985.
  • compound (I) according to the present invention has carboxy, an ester derivative produced by reacting carboxy of compound (I) with an appropriate alcohol, or carboxy of compound (I) and an appropriate amine
  • prodrugs such as amide derivatives produced by reacting.
  • the compound (I) according to the present invention when the compound (I) according to the present invention has a hydroxy, a compound such as an acyloxy derivative produced by reacting the hydroxy of the compound (I) with an appropriate acyl halide or an appropriate acid anhydride, for example.
  • Drugs are exemplified.
  • the compound (I) according to the present invention has an amino, such as an amide derivative produced by reacting the amino of the compound (I) with an appropriate acid halide or an appropriate mixed acid anhydride
  • Prodrugs are exemplified.
  • compound (I) according to the present invention has an asymmetric carbon atom, it includes racemates, both enantiomers, and all stereoisomers (geometric isomers, epimers, enantiomers, etc.).
  • both of the E-form and the Z-form can be present.
  • X is cycloalkylene
  • both cis and trans isomers are included.
  • the compound represented by the formula (I) is preferably trans-N- (4-((2S, 6R) -2,6-dimethylmorpholino) phenyl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide, Trans-N- (6- (5,6-dihydropyridin-1 (2H) -yl) pyridin-3-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide, trans-N- (6- (4 -Trifluoromethyl) phenyl) pyridin-3-yl) -4- (tertiarybutylsulfonylamino) cyclohexan
  • a particularly preferred compound is trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide (S-2367).
  • the compound is a crystal at room temperature.
  • the content of the NPYY5 receptor antagonist, in particular S-2367, in the preparation of the present invention is preferably a content that can improve solubility and produce a medicinal effect. 5 to 50% by weight, (2) preferably 10 to 40% by weight, (3) more preferably 15 to 30% by weight, (4) more preferably 20 to 30% by weight, (5) particularly preferred Is from 25 to 30% by weight. If the amount is less than this amount, sufficient drug efficacy may not be obtained, or the preparation may be enlarged, and if it is more than this amount, the solubility may not be sufficiently improved.
  • the NPYY5 receptor antagonist in the preparation of the present invention is not particularly limited as long as it is an orally administrable drug, but is preferably a so-called poorly water-soluble drug having low water solubility.
  • the water solubility of the drug refers to a buffer solution and water having a pH range of 1 to 8 which can be considered as an environment in the digestive tract, typically the first solution of dissolution test, the second solution of dissolution test of the Japanese Pharmacopoeia,
  • the solubility of a drug at 37 ° C. in any one of water is 100 ⁇ g / mL or less, further 50 ⁇ g / mL or less, and further 10 ⁇ g / mL or less.
  • Amorphous stabilizers preferably stabilize the amorphous state by loosening the crystal structure of a poorly water-soluble drug with an amorphization inducer and interacting with the rocking state of the crystal lattice. It is to become.
  • an amorphous stabilizer that can convert the crystal of the compound into an amorphous state by itself without blending an amorphization inducer is also included.
  • carboxymethyl ethyl cellulose (CMEC) is preferable.
  • CMEC is a mixed ether of cellulose carboxymethyl and ethyl.
  • the CMEC is not limited as long as it is listed in the Pharmaceutical Additives Standard, but preferably, carboxymethyl group (—CH 2 COOH) 8.9 to 14.9% and ethoxyl group ( -OC 2 H 5 ) 32.5 to 43.0% may be used.
  • CMEC manufactured by Sanyo Chemical Industries, Ltd.
  • CMEC is exemplified.
  • the content of CMEC in the preparation of the present invention is preferably a content capable of improving the solubility of the active ingredient, and is (1) usually 50 to 95% by weight, (2) preferably, based on the total amount of the preparation. 60 to 90% by weight, (3) more preferably 70 to 85% by weight, (4) more preferably 70 to 80% by weight, and (5) particularly preferably 70 to 75% by weight. If the amount is less than this amount, the CMEC crystal precipitation suppression effect is reduced, so that the drug may crystallize in the production process, and an amorphous preparation may not be obtained. The content of the active ingredient may be reduced, and the dosage of the whole preparation may be increased.
  • the NPYY5 receptor antagonist is usually 5 to 50% by weight and the CMEC is 50 to 95% by weight with respect to the total amount of the preparation.
  • the NPYY5 receptor antagonist is 10 to 40% by weight and the CMEC is 60 to 90% by weight.
  • the NPYY5 receptor antagonist is 15 to 30% by weight, and the CMEC is 70 to 85% by weight.
  • the NPYY5 receptor antagonist is 20 to 30% by weight, and the CMEC is 70 to 80% by weight.
  • the NPYY5 receptor antagonist is 25 to 30% by weight and the CMEC is 70 to 75% by weight.
  • S-2367 is usually 5 to 50% by weight and CMEC is 50 to 95% by weight with respect to the total amount of the preparation.
  • S-2367 is 10 to 40% by weight and CMEC is 60 to 90% by weight.
  • S-2367 is 15 to 30% by weight and CMEC is 70 to 85% by weight.
  • S-2367 is 20 to 30% by weight and CMEC is 70 to 80% by weight.
  • S-2367 is 25 to 30% by weight and CMEC is 70 to 75% by weight.
  • the amorphization inducer used in the present invention is a compound having a function / property that changes the crystal lattice energy of a poorly water-soluble drug in a lower energy direction and increases fluctuation of the crystal lattice at the same temperature. It is.
  • amino acids or salts thereof amino acids or salts thereof (aspartic acid and its sodium salt, magnesium salt, etc., glycine, alanine, glutamic acid and glutamic acid hydrochloride, etc.), aspartame, erythorbic acid or its salt, ascorbic acid or its salt (sodium salt) , Stearic acid ester, aminoethylsulfonic acid, inositol, ethylurea, citric acid or its salt (trisodium, disodium, sodium dihydrogen salt, calcium salt, etc.), glycyrrhizic acid or its salt (trisodium, disodium) Sodium salts such as diammonium and monoammonium, potassium salts, etc.), gluconic acid or salts thereof (sodium salts, calcium salts, magnesium salts etc.), creatinine, salicylic acid or salts thereof (sodium) ), Tartaric acid or its salts (sodium salt, potassium
  • an amorphization inducer preferably, an amino acid or a salt thereof (aspartic acid and its sodium salt, magnesium salt, etc., glycine, alanine, glutamic acid, glutamic acid hydrochloride, etc.), ascorbic acid or a salt thereof (sodium salt, etc.), Stearic acid ester, aminoethylsulfonic acid, ethylurea, citric acid or salts thereof (salts such as trisodium, disodium and sodium dihydrogen, calcium salts), glycyrrhizic acid or salts thereof (sodium salts such as trisodium and disodium) , Ammonium salts such as diammonium and monoammonium, potassium salts, etc.), creatinine, tartaric acid or salts thereof (sodium salts, sodium / potassium salts, hydrogen / potassium salts, etc.), succinic acid or salts thereof (disodium, monosodium, etc.)
  • the amorphization-inducing agent is an amino acid or a salt thereof (aspartic acid and its sodium salt, magnesium salt, etc., glycine, alanine, glutamic acid, glutamic acid hydrochloride, etc.), ethyl urea, glycyrrhizic acid or a salt thereof (three Sodium, sodium salts such as disodium, ammonium salts such as diammonium and monoammonium, potassium salts, etc.), tartaric acid or salts thereof (sodium salts, sodium / potassium salts, hydrogen / potassium salts, etc.), succinic acid or salts thereof ( Sodium salts such as disodium and monosodium), sodium saccharin, nicotinamide and urea, maltose, maltol, mannitol and meglumine. Particularly preferred is urea.
  • the content of the amorphization-inducing agent in the preparation of the present invention is a content that can improve solubility, and is (1) usually less than 8% by weight, (2) preferably 0, based on the total amount of the preparation. 1 to 6% by weight, (3) more preferably 0.5 to 5% by weight, (4) more preferably 1 to 4.5% by weight, and (5) particularly preferably 2 to 4% by weight. is there.
  • Two or more types of amorphization inducers may be used in combination, but when used in combination, the combined amount may be within the range of the content. If the amount is less than this amount, it may not be possible to increase the solubility of the drug.
  • the solubility of the drug may be reduced and side effects of the amorphization inducer may occur.
  • the effect of suppressing the crystal precipitation of the amorphous stabilizer (particularly water-soluble polymer) in the production process is reduced, the drug is easily crystallized when the solvent is removed, and an amorphous preparation is obtained. It is likely to be difficult.
  • One of the preferred embodiments of the solid preparation of the present invention is that (1) the NPYY5 receptor antagonist is usually 5% by weight or more, the CMEC is 50% by weight or more, and the amorphization inducer is 8% relative to the total amount of the preparation.
  • NPYY5 receptor antagonist is 10 to 30% by weight
  • CMEC is 65 to 89.5% by weight
  • amorphization inducer is 0.5 to 5% by weight
  • CMEC is 75.5 to 89% by weight
  • amorphization inducer is 1 to 4.5% by weight
  • NPYY5 receptor antagonist is 15 to 20% by weight, 76 to 83% by weight of CMEC, 2 to 4% by weight of amorphization inducer A.
  • S-2367 is 5% by weight or more, CMEC is 50% by weight or more, urea is less than 8% by weight
  • S-2367 is 10 to 40% by weight
  • CMEC is 54 to 89.9% by weight
  • urea is 0.1 to 6% by weight
  • S-2367 is 10 to 30% by weight
  • CMEC is 65-89.5 wt%, urea 0.5-5 wt%
  • S-2367 is 10-20 wt%
  • CMEC is 75.5-89 wt%
  • urea is 1-4.
  • S-2367 is 15 to 20% by weight
  • CMEC is 76 to 83% by weight
  • urea is 2 to 4% by weight.
  • the dissolution of the active ingredient (especially S-2367) is sufficiently improved, but depending on the content of the active ingredient, it may It may be preferred that a crystallization inducer is included. In particular, when S-2367 is 20%, dissolution is improved by adding an amorphization inducer.
  • the preparation method of the present invention preferably comprises NPYY5 receptor antagonist (especially S-2367), CMEC, and optionally an amorphization inducer dissolved in a solvent, the solvent is removed, and the resulting solid product To a suitable particle size.
  • the solvent may be any solvent that can dissolve these raw materials. Specific solvents are water, alcohol, acetone, carbon halide and mixtures thereof.
  • a heating pressure reduction and spray drying spray drying
  • a spray dryer is preferably used.
  • Production conditions may be any conditions that allow the preparation of the present invention to be obtained in good yield.
  • a liquid containing a main ingredient having a solid content concentration of about 1 to 20% is sprayed under conditions of an outlet temperature of 50 to 110 ° C.
  • CMEC and an amorphization inducer in the solid preparation of the present invention affects the solubility and stability of the NPYY5 receptor antagonist.
  • the stability of the active ingredient in the preparation of the present invention was evaluated by confirming the amorphous state by powder X-ray diffraction measurement.
  • the solid preparation of the present invention can be obtained in the form of a solid powder, granules, lumps or the like. Even if the preparation of the present invention is obtained in the form of a lump, powder can be obtained by pulverization or the like. The powder can also be contained in granules or tablets.
  • excipients, binders, lubricants and the like used in granules and tablets those conventionally used in pharmaceutics can be used. For example, excipients such as D-mannitol, disintegrants such as carmellose calcium, binders such as hydroxypropylcellulose, lubricants such as magnesium stearate, coating agents such as hydroxypropylmethylcellulose, and the like.
  • the dissolution property of the solid preparation of the present invention is that of the second method (paddle method, 50 rpm, dissolution test second solution, 900 mL) of the Japanese Pharmacopoeia for a preparation in which the content of the main drug (eg, S-2367) is 20 mg.
  • the dissolution rate 60 minutes after the start of the dissolution test was (1) usually 4% or more in 30 minutes, 7% or more in 60 minutes, 15% or more in 180 minutes, (2) preferably 30 10% or more in minutes, 15% or more in 60 minutes, 30% or more in 180 minutes, (3) More preferably, 30% or more in 30 minutes, 40% or more in 60 minutes, 50% or more in 180 minutes, (4 ) More preferably, 40% or more in 30 minutes, 50% or more in 60 minutes, 60% or more in 180 minutes, (5) Particularly preferably, 50% or more in 30 minutes, 60% or more in 60 minutes, 180 minutes 70% or more.
  • a stable preparation is a preparation that is maintained in an amorphous state even after storage over time.
  • S-2367 is a solid preparation maintaining the amorphous state.
  • the dissolution of the active ingredient can be increased by using the solid preparation of the present invention, for example, the amount of the active ingredient in the tablet can be reduced, and as a result, the tablet can be miniaturized.
  • the weight per tablet containing S-2367 before using the solid preparation of the present invention was about 840 mg, whereas the result of using the solid preparation of the present invention was that per tablet.
  • the weight was about 450 to 550 mg, preferably about 500 mg, and the ingestion was improved.
  • CMEC-containing preparation As an NPYY5 receptor antagonist, trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxyamide (S-2367) is used as an amorphization inducer.
  • Urea manufactured by Wako Pure Chemical Industries, Ltd.
  • CMEC carboxymethyl ethyl cellulose
  • S-2367 was produced based on the method described in WO01 / 37826 International Publication Pamphlet. A prescribed amount of S-2367 and CMEC shown in Table 1 were added to acetone and dissolved. Next, when adding urea, the prescribed amount of urea was added to ethanol and dissolved. These dissolved solutions were mixed and spray-dried at a outlet temperature of about 80 ° C. using a spray dryer B-290 / B-295 (manufactured by Büch) to prepare a solid preparation of the present invention in a powder state.
  • Dissolution test method About the solid formulation of this invention obtained by the said method, the dissolution test was done according to the method prescribed
  • the concentration of S-2367 is determined by using an automatic sampling system (Autosampler W PAS-615 (manufactured by Toyama Sangyo Co., Ltd.), spectrophotometer UV-1700 (manufactured by Shimadzu Corporation)) or spectrophotometer 8453 (manufactured by Agilent). And measured.
  • the dissolution test conditions are as follows.
  • Test method Japanese Pharmacopoeia Method 2 (Paddle Method) Rotation speed 50rpm ⁇ Test solution: second solution for dissolution test (900 mL, 37 ° C.) Test liquid collection time: 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 150, 180 minutes Detection wavelength: 243 nm Layer length: 5mm
  • the powder X-ray diffraction pattern of the solid preparation of the present invention was examined using a powder X-ray diffraction apparatus RINT2000 (manufactured by Rigaku Corporation). The powder X-ray diffraction measurement was carried out on the preparation immediately after production and on the preparation after storage for 1 week at 60 ° C. under glass bottle sealing conditions.
  • Test Example 1 Dissolution Behavior of CMEC-Containing Preparation
  • a solid preparation of the present invention in which urea is not contained in the preparation and the contents of S-2367 and CMEC are as shown in Table 1 was produced by the above method. These preparations were subjected to a dissolution test by the above method.
  • the result of converting the elution concentration of S-2367 into the elution rate is shown in FIG.
  • the content of S-2367 was 15 to 30% by weight, the dissolution rate was changed in substantially the same manner, approximately 60% or more after 60 minutes from the start of the test and 70% or more after 180 minutes.
  • Test Example 2 Storage stability of CMEC-containing preparation
  • powder X-ray diffraction measurement was performed.
  • FIG. 3 immediately after the production, the crystal peak of S-2367 was not detected in any preparation, and S-2367 was amorphized.
  • FIG. 4 when it was stored at 60 ° C. for 1 week under glass bottle sealing conditions, as shown in FIG. 4, in the preparation with S-2367 of 15 to 30% by weight, the crystal peak of S-2367 was not observed, and it was amorphous.
  • Test Example 3 Dissolution Behavior of CMEC and Urea-Containing Preparation As shown in Tables 2 and 3, a preparation containing 15 to 20% by weight of S-2367 and 4% by weight of urea was produced by the above method, and the dissolution behavior was examined.
  • Test Example 4 Storage stability of CMEC and urea-containing preparations
  • the state of the main drug (S-2367) in the urea-containing preparations shown in Tables 2 and 3 powder X-ray diffraction measurement was performed.
  • the crystal peak of S-2367 was not observed immediately after production and after storage for 1 week under the conditions of 60 ° C. and glass bottle sealing, and the amorphous state was maintained. And the formulation was stable.
  • the present invention relates to the water solubility of NPYY5 receptor antagonists, particularly trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide (S-2367).
  • S-2367 trans-N- (5-trifluoromethylpyridin-2-yl) -4- (tertiarybutylsulfonylamino) cyclohexanecarboxamide

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Abstract

La présente invention concerne une préparation qui est capable d'améliorer la solubilité dans l'eau d'un antagoniste du récepteur Y5 du NPY même lorsque l'antagoniste du récepteur Y5 du NPY est contenu dans la préparation en une grande quantité. La présente invention concerne spécifiquement une préparation solide qui contient un antagoniste du récepteur Y5 du NPY, de la carboxyméthyl éthyl cellulose, et au besoin, un inducteur de l'amorphisation. La préparation solide possède une aptitude améliorée à la dissolution de l'antagoniste du récepteur Y5 du NPY.
PCT/JP2010/054488 2009-03-19 2010-03-17 Préparation solide contenant un antagoniste du récepteur y5 du npy Ceased WO2010107040A1 (fr)

Priority Applications (3)

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CN2010800225081A CN102438623A (zh) 2009-03-19 2010-03-17 含有npyy5受体拮抗剂的固体制剂
SG2011068038A SG174488A1 (en) 2009-03-19 2010-03-17 Solid preparation containing npy y5 receptor antagonist
JP2011504851A JPWO2010107040A1 (ja) 2009-03-19 2010-03-17 Ｎｐｙｙ５受容体拮抗剤を含有する固形製剤

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US8697739B2 (en) 2010-07-29 2014-04-15 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof

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US8889716B2 (en) 2011-05-10 2014-11-18 Chdi Foundation, Inc. Transglutaminase TG2 inhibitors, pharmaceutical compositions, and methods of use thereof

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WO1997006781A1 (fr) * 1995-08-11 1997-02-27 Nissan Chemical Industries, Ltd. Procedes permettant de rendre amorphes des medicaments peu solubles
JPH09208459A (ja) * 1996-02-07 1997-08-12 Eisai Co Ltd 溶解性を改良した製剤
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
WO2003076374A1 (fr) * 2002-03-12 2003-09-18 Shionogi & Co., Ltd. Procede de production de derive d'acide trans-4-amino-1-cyclohexanecarboxylique
JP2007517015A (ja) * 2003-12-31 2007-06-28 ファイザー・プロダクツ・インク 低溶解性薬物、ポロキサマーおよび安定化ポリマーの安定化された医薬用固体組成物
WO2007108463A1 (fr) * 2006-03-23 2007-09-27 Shionogi & Co., Ltd. Préparation solide améliorant la solubilité
WO2008047769A1 (fr) * 2006-10-18 2008-04-24 Shionogi & Co., Ltd. Agent améliorant le métabolisme du glucose
JP2008540629A (ja) * 2005-05-19 2008-11-20 ファイザー・インク 非晶形のｖｅｇｆ−ｒ阻害剤を含む医薬組成物
WO2009038112A1 (fr) * 2007-09-21 2009-03-26 Shionogi & Co., Ltd. Préparation solide comprenant un antagoniste du récepteur npyy5
WO2009136617A1 (fr) * 2008-05-08 2009-11-12 塩野義製薬株式会社 Processus pour la production d’un composé présentant une activité antagoniste sur le récepteur npyy5, et cristal utile

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Publication number Priority date Publication date Assignee Title
WO1997006781A1 (fr) * 1995-08-11 1997-02-27 Nissan Chemical Industries, Ltd. Procedes permettant de rendre amorphes des medicaments peu solubles
JPH09208459A (ja) * 1996-02-07 1997-08-12 Eisai Co Ltd 溶解性を改良した製剤
WO2001037826A1 (fr) * 1999-11-26 2001-05-31 Shionogi & Co., Ltd. Antagonistes npyy5
WO2003076374A1 (fr) * 2002-03-12 2003-09-18 Shionogi & Co., Ltd. Procede de production de derive d'acide trans-4-amino-1-cyclohexanecarboxylique
JP2007517015A (ja) * 2003-12-31 2007-06-28 ファイザー・プロダクツ・インク 低溶解性薬物、ポロキサマーおよび安定化ポリマーの安定化された医薬用固体組成物
JP2008540629A (ja) * 2005-05-19 2008-11-20 ファイザー・インク 非晶形のｖｅｇｆ−ｒ阻害剤を含む医薬組成物
WO2007108463A1 (fr) * 2006-03-23 2007-09-27 Shionogi & Co., Ltd. Préparation solide améliorant la solubilité
WO2008047769A1 (fr) * 2006-10-18 2008-04-24 Shionogi & Co., Ltd. Agent améliorant le métabolisme du glucose
WO2009038112A1 (fr) * 2007-09-21 2009-03-26 Shionogi & Co., Ltd. Préparation solide comprenant un antagoniste du récepteur npyy5
WO2009136617A1 (fr) * 2008-05-08 2009-11-12 塩野義製薬株式会社 Processus pour la production d’un composé présentant une activité antagoniste sur le récepteur npyy5, et cristal utile

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8697739B2 (en) 2010-07-29 2014-04-15 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
US9789118B2 (en) 2010-07-29 2017-10-17 Novartis Ag Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof

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