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WO1996007421A2 - Medicament anti-ulcereux comprenant une proteine ayant une activite de facteur de croissance cellulaire et un inhibiteur de la pompe a protons - Google Patents

Medicament anti-ulcereux comprenant une proteine ayant une activite de facteur de croissance cellulaire et un inhibiteur de la pompe a protons Download PDF

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Publication number
WO1996007421A2
WO1996007421A2 PCT/JP1995/001772 JP9501772W WO9607421A2 WO 1996007421 A2 WO1996007421 A2 WO 1996007421A2 JP 9501772 W JP9501772 W JP 9501772W WO 9607421 A2 WO9607421 A2 WO 9607421A2
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Prior art keywords
growth factor
medicine
factor activity
groups
protein possessing
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WO1996007421A3 (fr
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Hiroshi Satoh
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to AU33991/95A priority Critical patent/AU3399195A/en
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Publication of WO1996007421A3 publication Critical patent/WO1996007421A3/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1825—Fibroblast growth factor [FGF]
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • the present invention relates to a medicine which comprises a combination of a protein possessing cell growth factor activity with a proton pump inhibitor. More specifically, the present invention relates to an antiulcer medicine effective in the prevention and treatment of ulcers, particularly peptic ulcers in mammals.
  • Ulcers occur by various causes. Peptic ulcers are thought to occur due to deterioration of the balance between aggressive factors (factors that adversely affect the gastrointestinal mucosal membrane), such as gastric juice, pepsin, bile and food, and protective factors, such as mucosal membrane blood flow, mucus secretion and carbonate ion secretion. Based on this idea, there is need for peptic ulcer therapy involving the suppression of aggressive factors or enhancement of protective factors; many drugs exhibiting such actions have been developed and are now in wide use.
  • aggressive factors factors that adversely affect the gastrointestinal mucosal membrane
  • protective factors such as mucosal membrane blood flow, mucus secretion and carbonate ion secretion.
  • Well-known aggressive factor suppressors are acid secretion suppressors, such as histamine H 2 receptor blockers (e.g., cimetidine, ranitidine, famotidine, loxatidine), muscarine receptor blockers (e.g. pirenzepine) and proton pump inhibitors (e.g. omeprazole, lansoprazole) .
  • histamine H 2 receptor blockers e.g., cimetidine, ranitidine, famotidine, loxatidine
  • muscarine receptor blockers e.g. pirenzepine
  • proton pump inhibitors e.g. omeprazole, lansoprazole
  • well-known protective factor enhancers include prostaglandin derivatives (e.g., misoprostol, ornoprostil) and sucralfate.
  • intractable ulcers remain refractory to treat using these drugs. Ulcerative lesions caused by oral intake of non-steroidal anti-inflammatory agents, such as indomethacin and aspirin, pose another major problem as intractable diseases. In addition, it is known that ulcers, even once healed with the above-described drugs, often recur after medication is discontinued. There is need for new drugs or advanced therapies offering solutions to these problems.
  • the suppressors and enhancers are thought to indirectly promote ulcer healing by providing favorable healing conditions, rather than by directly promoting mucosal cell growth.
  • Gastroenterology 100 Gastroenterology 100, A155(1991) and Gastroenterology 102, A159(1992)).
  • Gastroenterology 102 Gastroenterology 102, A159(1992)
  • the present inventors found that when a proton pump inhibitor and a fibroblast growth factor are used in combination, the antiulcer effect is definitely better than with either drug alone. The inventors made further investigations based on this finding, and developed the present invention.
  • the present invention relates to: (1) A medicine which comprises a combination of a protein possessing cell growth factor activity with a proton pump inhibitor,
  • bFGF basic fibroblast growth factor
  • the bFGF mutein is the recombinant human bFGF mutein CS23 in which cysteine residues at the 70- and 88- positions are replaced by serine residues,
  • R 1 , R3 and R* are, the same or different, hydrogen, or an alkyl or alkoxy group
  • R 2 is a hydrocarbon group which may optionally be substituted
  • n is 0 or 1, or a salt thereof
  • a medicine of term (1) which is a kit which comprises a protein possessing cell growth factor activity and a proton pump inhibitor,
  • a medicine of term (1) which is a pharmaceutical composition which comprises a protein possessing cell growth factor activity and a proton pump inhibitor,
  • a method of producing a pharmaceutical composition which comprises admixing a protein possessing cell growth factor activity with a proton pump inhibitor,
  • a method for preventing or treating a ulcerative disease of a mammal which comprises administering an effective amount of a protein possessing cell growth factor activity in combination with an effective eimount of a proton pump inhibitor to the mammal, and
  • a cell growth factor is defined as a non-nutrient substance that promotes animal cell growth in ⁇ i ⁇ o or in vitro; the term "protein possessing cell growth factor activity" as used herein includes all proteins possessing such activity, as long as they are of low toxicity.
  • cell growth factors include fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), epithelial cell growth factor (EGF), a- and / ⁇ -transforming growth factors (TGF ⁇ , TGF?) , insulin-like growth factor (IGF) and platelet-derived angiogenesis factor (PD-ECGF).
  • proteins possessing cell growth factor activity may be isolated from animal bodies and purified, or produced by gene engineering, and as long as they retain their cell growth factor activity, may be muteins resulting from appropriate modifications of constituent amino acids of natural proteins, such as deletion and replacement of some constituent amino acids, and addition of other amino acids.
  • Proteins possessing fibroblast growth factor (FGF) activity include proteins possessing acidic fibroblast growth factor (aFGF) activity and proteins possessing basic fibroblast growth factor (bFGF) activity, with preference given to proteins possessing bFGF activity. Proteins possessing bFGF activity is preferably acid- resistant.
  • FGF fibroblast growth factor
  • aFGF acidic fibroblast growth factor
  • bFGF basic fibroblast growth factor
  • muteins thereof include those described in Japanese Patent Unexamined Publication No. 193/1990 and Japanese Publication of translations of International patent application No. 505736/1991.
  • Preferable muteins are (1) muteins resulting from replacement of at least one bFGF- constituting amino acid with another amino acid, (2) the muteins of term (1) above, wherein said bFGF-constituting amino acid is cysteine, (3) the muteins of term (1) above, wherein said other amino acid is a neutral amino acid, and (4) the muteins of term (1) above, wherein at least one cysteine, as a constituent amino acid, is replaced with serine.
  • the muteins include a modified bFGF such as a purified recombinant human basic FGF (rhbFGF) protein in which a mutation is induced by changing one or more of the four cysteines present at amino acid residues 25, 69, 87 and 92 of the mature protein to serine.
  • rhbFGF human basic FGF
  • the N- terminal Pro comprises the first amino acid.
  • muteins those showing enhanced acid stability, in comparison with the natural basic fibroblast growth factor, as a result of replacement of at least one bFGF- constituting cysteine with another amino acid, are preferred, with greater preference given to the mutein (CS23) resulting from serine replacement of the cysteine residues (70- and 88-positions) at the second and third positions from the N-terminal side, among the four cysteine residues in the amino acid sequence of human bFGF.
  • the structure of the mutein CS23 is more fully described in Senoo et al.. Biochemical and Biophysical Communications, Vol.151, No.2, 702-708 (1988) and in EP-281,822.
  • proton pump inhibitor as used herein is defined as a drug that suppresses acid secretion by directly or indirectly inhibiting H/K-ATPase, which functions as a proton pump in gastric mucosal acid secreting cells (parietal cells).
  • Examples of such drugs include omeprazole, lansoprazole, pantoprazole, pariprazole sodium, leminoprazole, TY-11345, TU-199, FP -65372, BY-686, Tannic acid, Ellagic acid, Ebselen, AHR-9294, Cassigarol-A, Bafilomycin, Y-25942, Xanthoangelol E, SK&F-96356, (-)- Epigallocatechin gallate, WY-27198, T-330 and KF-20054.
  • proton pump inhibitors include benzimidazole compounds, which possess proton pump inhibitory activities and are of low toxicity.
  • benzimidazole compounds include 2-[ (pyridyl)-methylsulfinyl or -methylthio]benzimidazole derivatives and salts thereof.
  • a compound (or salt thereof) represented by formula (I) below is more preferred.
  • R b is a hydrogen atom, an alkyl group, an acyl group, a carboalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkylsulfonyl group;
  • R d is a hydrogen atom, an alkyl group or a group represented by -OR f in which Rf represents a hydrocarbon group which may optionally be substituted;
  • q is 0 or 1.
  • Benzimidazole compounds above are described in USP 4,045,563, USP 4,255,431, USP 4,359,465, USP 4,472,409, USP 4,508,905, JP-A-59181277, USP 4,628,098, USP 4,738,975, USP 5,045,321, USP 4,786,505, USP 4,853,230, USP 5,045,552, EP- A-295603, USP 5,312,824, EP-A-166287, EP-A- 519365, and other publications.
  • the substituent that may optionally be present on ring A includes halogen atoms, alkyl groups which may be substituted for, cycloalkyl groups which may be substituted for, alkenyl groups which may be substituted for, alkoxy groups which may be substituted for, cyano groups, carboxy groups, carboalkoxy groups, carboalkoxyalkyl groups, carbamoyl groups, carbamoylalkyl groups, hydroxy groups, hydroxyalkyl groups, acyl groups, carbamoyloxy groups, nitro groups, acyloxy groups, aryl groups, aryloxy groups, alkylthio groups and alkylsulfinyl groups, and the like.
  • Halogen atoms include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred, with greater preference given to fluorine.
  • the alkyl group in the alkyl group which may be substituted is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl).
  • Straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, with greater preference given to straight-chain or branched alkyl groups having 1 to 3 carbon atoms.
  • Substituents on the substituted alkyl group include halogens, nitro, cyano groups, hydroxy groups, carboxy groups, amidino groups, guanidino groups , carbamoyl groups, amino groups which may have 1 to 2 alkyl groups, acyl groups or other substituents, and the like.
  • the cycloalkyl group in the cycloalkyl group which may be substituted is exemplified by cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl etc..
  • the cycloalkyl group may be substituted by, for example, halogens, nitro, cyano groups, hydroxy groups, carboxy groups, amidino groups, guanidino groups , carbamoyl groups, amino groups which may have 1 to 2 alkyl groups, acyl groups or other substituents, and the like.
  • alkenyl group in the alkenyl group which may be substituted is exemplified by straight-chain or branched alkenyl groups having 2 to 16 carbon atoms.
  • alkenyl groups include allyl, vinyl, crotyl, 2-penten-l-yl, 3- penten-1-yl, 2-hexen-l-yl, 3-hexen-l-yl, 2-methyl-2-propen- 1-yl and 3-methyl-2-buten-l-yl.
  • Straight-chain or branched alkenyl groups having 2 to 6 carbon atoms are preferred, with greater preference given to straight-chain or branched alkenyl groups having 2 to 4 carbon atoms.
  • the alkenyl group may be substituted by, for example, halogens, nitro, cyano groups, amidino groups , guanidino groups amino groups which may have 1 to 2 alkyl groups, acyl groups or other substituents, and the like .
  • the alkenyl group mentioned above includes isomers (E- and Z-configurations) with respect to double bond.
  • alkoxy group in the alkoxy group which may be substituted is exemplified by alkoxy groups having 1 to 10 carbon atoms.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy and cyclohexyloxy.
  • Alkoxy groups having 1 to 6 carbon atoms are preferred, with greater preference given to alkoxy groups having 1 to 3 carbon atoms.
  • the alkoxy group may be substituted by, for example, halogens, nitro, amidino groups , guanidino groups amino groups which may have 1 to 2 alkyl groups, acyl groups or other substituents, and the like .
  • halogen as a substituent on the above-described alkyl, cycloalkyl, alkenyl or alkoxy group is exemplified by chlorine, bromine, fluorine and iodine.
  • alkyl group in the alkylamino group as a substituent on the above-described alkyl, cycloalkyl, alkenyl or alkoxy group is preferably exemplified by straight-chain or branched alkyl groups having 1 to 6 carbon atoms.
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec- butyl, n-pentyl, isopentyl, n-hexyl and isohexyl.
  • straight-chain or branched alkyl groups having 1 to 4 carbon atoms are preferred.
  • the acyl group in the acylamino group as a substituent on the above-described alkyl, cycloalkyl, alkenyl or alkoxy group is exemplified by acyl groups derived from organic carboxylic acids, with preference given to alkanoyl groups having 1 to 6 carbon atoms.
  • alkanoyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, with greater preference given to alkanoyl groups having 1 to 4 carbon atoms.
  • the number of substituents on the above-described alkyl, cycloalkyl, alkenyl or alkoxy group is 1 to 6, preferably 1 to 3.
  • the substituted alkyl groups include trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2-methoxyethyl, 2,2-dimethoxyethyl, 2,2-diethoxyethyl and 2- diethylphosphorylethyl, among others.
  • Difluoromethyl, trifluoromethyl and hydroxymethyl are preferred, with greater preference given to trifluoromethyl.
  • the substituted cycloalkyl groups include 2- aminocyclopropan-1-yl, 4-hydroxycyclopentan-l-yl and 2,2- difluorocyclopentan-1-yl, among others.
  • the substituted alkenyl groups include 2,2- diclorovinyl, 3-hydroxy-2-propen-l-yl and 2-methoxyvinyl, among others.
  • the substituted alkoxy groups include difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy and 2-(3,4-dimethoxyphenyl)ethoxy, among others. Difluoromethoxy is preferred.
  • the alkoxy group in the carboalkoxy group is exemplified by alkoxy groups having 1 to 7 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy) .
  • the alkoxy group in the carboalkoxyalkyl group is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy).
  • the alkyl group in the carboalkoxyalkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • Such carboalkoxyalkyl groups include carbomethoxymethyl, 2- carbomethoxyethyl, 2-carbomethoxypropyl, carboethoxymethyl. 2-carboethoxyethyl, 1-carbomethoxypropyl, carbopropoxymethyl and carbobutoxymethyl.
  • the alkyl group in the carbamoylalkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • the alkyl group in the hydroxyalkyl group is exemplified by alkyl groups having 1 to 7 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl).
  • the acyl group as such or the acyl group in the acyloxy group is exemplified by alkanoyl groups having 1 to 4 carbon atoms such as formyl, acetyl, propionyl, butyryl and isobutyryl.
  • aryl group as such or the aryl group in the aryloxy group is exemplified by aryl groups having 6 to 12 carbon atoms (e.g., phenyl, naphthyl).
  • alkyl in the alkylthio group or alkylsulfinyl group is exemplified by alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl).
  • the number of substituents on substituted ring A is preferably 1 to 4, more preferably 1 to 2.
  • Such substituents on the benzene ring may be present at 4- and 5-positions, with preference given to 5-position.
  • Ring A is preferably A ring which may optionally be substituted by i) a halogen atom ii), an alkyl group which may be substituted, iii) a cycloalkyl group which may be substituted, iv) an alkenyl group which may be substituted, or v) an alkoxy group which may be substituted.
  • the alkyl group for Rb is exemplified by alkyl groups having 1 to 5 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl).
  • the acyl group for Rb is exemplified by acyl groups having 1 to 4 carbon atoms, such as alkanoyl groups having 1 to 4 carbon atoms.
  • the alkoxy in the carboalkoxy group is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl).
  • the alkyl in the alkylcarbamoyl group and dialkylcarbamoyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • the alkyl in the alkylsulfonyl group is exemplified by the above-mentioned alkyl groups having 1 to 4 carbon atoms.
  • Rt> is preferably hydrogen.
  • the alkyl group for Re, Re or R9 is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl).
  • Straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, with greater preference given to straight-chain or branched alkyl groups having 1 to 3 carbon atoms.
  • the alkoxy group for Re, R ⁇ or Rg is exemplified by alkoxy groups having 1 to 10 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec- butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy).
  • Alkoxy groups having 1 to 6 carbon atoms are preferred, with greater preference given to alkoxy groups having 1 to 3 carbon atoms.
  • alkoxy in the alkoxyalkoxy group for Re, Re or R9 is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy).
  • Re is preferably a hydrogen atom, an alkyl group or an alkoxy group. Re is preferably a hydrogen atom, an alkyl group or an alkoxy group. R9 is preferably a hydrogen atom.
  • the alkyl group for R* is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • hydrocarbon group in the hydrocarbon group which may optinally be substituted, for Rf is exemplified by hydrocarbon groups having 1 to 13 carbon atoms, such as straight-chain or branched alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl), alkenyl groups having 2 to 6 carbon atoms (e.g., vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4- pentenyl, 5-hexenyl), alkinyl groups having 2 to 6 carbon atoms (e.g., ethynyl, propargyl, 2-butyn-l-yl, 3-butyn-2- yl, l-pentyn-3-yl, 3-pentyn-l-yl
  • Straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, with greater preference given to straight-chain or branched alkyl groups having 1 to 4 carbon atoms.
  • the substituent group in the substituted hydrocarbon group is exemplified by C ⁇ -io aryl groups (e.g., phenyl, naphthyl), amino, Ci- ⁇ alkylamino groups (e.g., methylamino, ethylamino, isopropylamino) , di-Ci- ⁇ alkylamino groups (e.g., dimethylamino, diethylamino) , N- aralkyl-N-cycloalkylamino groups (e.g., N-benzyl-N- cyclohexylamino) , N-aralkyl-N-alkylamino groups (e.g., N- (l-naphthylmethyl)-N-ethylamino) , azide, nitro, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, C ⁇ _ alkoxy groups (e.
  • the heterocyclic thio group may condense with the benzene ring to form a bicyclic condensed thio group (e.g., 2-benzothiazolylthio, 8-quinolylthio) .
  • Halogens e.g., fluorine, chlorine, bromine, iodine
  • hydroxyl and C1-4 alkoxy groups e.g., methoxy, ethoxy, propoxy, butoxy
  • the number of substituents is normally 1 to 5, preferably 1 to 3.
  • Rd is preferably an alkoxy group which may be substituted, or an alkoxyalkoxy group which may be substituted.
  • the alkoxy in the alkoxy group which may be substituted is exemplified by alkoxy groups having 1 to 8 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy).
  • alkoxy in the alkoxyalkoxy group which may be substituted is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy).
  • R ⁇ * is more preferably an alkoxy group having 1 to 8, preferably 1 to 4 carbon atoms, which may be halogenated, or an alkoxyalkoxy group which may be halogenated.
  • Preferred alkoxy groups which may be halogenated include 2,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, 1-(trifluoromethyl)-2,2,2- trifluoroethoxy, 2,2,3,3-tetrafluoropropoxy, 2,2,3,3,4,4,4- heptafluorobutoxy, 2,2,3,3,4,4,5,5-octafluoropentoxy and methoxy.
  • Preferred alkoxyalkoxy groups which may be halogenated include 3-methoxypropoxy. q is preferably 0.
  • benzimidazole compound for the present invention is exemplified by a compound represented by formula (II) :
  • R 1 , R 3 and R 4 are, the same or different, hydrogen, or an alkyl or alkoxy group;
  • R 2 is a hydrocarbon group which may optionally be substituted;
  • n is 0 or 1.
  • ring A is exemplified by the same rings as those mentioned for ring A of formula (I) above.
  • the alkyl group for Ri, R3 or R* is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms.
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl.
  • Straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, with greater preference given to straight-chain or branched alkyl groups having 1 to 3 carbon atoms.
  • the alkoxy group for Ri, R3 or R* is exemplified by alkoxy groups having 1 to 10 carbon atoms.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy and cyclohexyloxy.
  • Alkoxy groups having 1 to 6 carbon atoms are preferred, with greater preference given to alkoxy groups having 1 to 3 carbon atoms.
  • R 1 is preferably C ⁇ _ ⁇ alkyl or Ci- ⁇ alkoxy, more preferably C 1 - 3 alkyl.
  • R3 is preferably hydrogen or C ⁇ -6 alky, more preferably hydrogen.
  • R 2 is preferably C 1 - 4 alkoxy which may optionally be substituted by i) halogen, ii) hydroxyl or iii) C 1 - 4 alkoxy, more preferably, C 1 -.3 alkyl which may optionally be substituted by i) halogen or ii) C 1 - 4 alkoxy.
  • R* is preferably hydrogen.
  • Example benzimidazole compounds for the present 5 invention include 2-[2-[3-methyl-4-(2,2,3,3- tetrafluoropropoxy)pyridyl]methylthio] benzimidazole, 2-[2- [ 3-methyl-4-( 2, 2, 2- trifluoroethoxy)pyridyl]methylsulfinyl]benzimidazole (lansoprazole) , 2-[ (2-pyridyl)methylsulfinyl]benzimidazole (timoprazole) , 2-[2-(3,5-dimethyl-4- methoxypyridyl)methylsulfinyl]-5-methoxy-lH-benzimidazole (omeprazole) , sodium salt of 2-[2-[4-(3-methoxypropoxy)-3- methylpyridyl]methylsulfinyl]-lH-benzimidazole and 2-[2- (3,4-dimethoxy)pyridyl]methyls
  • a benzimidazole compound (or salt thereof) for the present invention is produced by, for example, the above- described known methods described in Japanese or European Patent Publications and U.S. Patents, or modifications thereof.
  • the salt of a benzimidazole compound is preferably used as a physiologically acceptable salt.
  • Physiologically acceptable salts include salts with inorganic bases, salts with organic bases and salts with basic amino acids.
  • Useful inorganic bases include alkali metals (e.g., sodium, potassium) and alkaline earth metals (e.g., calcium, magnesium).
  • Useful organic bases include trimethylamine, triethylamine, pyridine, picoline, N,N- dibenzylethylenediamine, ethanolamine, diethanolamine, trishydroxymethylaminomethane and dicyclohexylamine.
  • Useful basic amino acids include arginine and lysine. These salts are produced by known methods such as those described in EP-A-295603 and USP 4,738,974, or modifications thereof.
  • the medicine of the present invention is applicable to the prevention and treatment of animal ulcers, and is particularly effective in the prevention and treatment of digestive ulcers in mammals, including humans.
  • digestive ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis, anastomotic ulcer, acute and chronic gastritis.
  • the medicine of the present invention characterized by combined use of a protein possessing cell growth factor activity and a proton pump inhibitor, is not subject to limitation as to dosage form.
  • a protein possessing cell growth factor activity and a proton pump inhibitor may be prepared as individual preparations of ordinary dosage form, or as a composition incorporating both.
  • a protein possessing cell growth factor activity (the active ingredient A) and a proton pump inhibitor (the active ingredient B) may be mixed to a single preparation, as desired, using pharmaceutically acceptable diluents, excipients and other additives by a known method of pharmaceutical production.
  • Each active ingredient may be prepared as a separate preparation, as desired, using pharmaceutically acceptable diluents, excipients and other additives.
  • the medicine of the present invention may be prepared in a set (kit) in which each component constitutes a separate preparation.
  • the medicine of the present invention can be used in a form of (1) a kit comprising a protein possessing cell growth factor activity and a proton pump inhibitor or (2) in a form of a composition containing a protein possessing cell growth factor activity and a proton pump inhibitor.
  • oral administration is preferable, but non-oral administrations (e.g., intravenous administration, subcutaneous administration, intramuscular administration) are also possible.
  • Proton pump inhibitors in particular, permit both oral and non-oral administrations.
  • the route of administration is determined in consideration of target ulcer site etc. - 19 -
  • a protein possessing cell growth factor activity and a proton pump inhibitor When used as separate preparations, they may be administered to the same individual at the same time or at time intervals via the same route or different routes.
  • the protein possessing cell growth factor activity and the proton pump inhibitor can be administered in individual dosage forms prepared by conventional methods.
  • preparations in such dosage forms can, for example, be manufactured by the method described in Japanese Publication of translations of International patent application No. 505736/1991.
  • tablets and capsules are prepared using pharmacologically acceptable carriers (e.g., lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g., alpha-starch, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone), disintegrating agents (e.g., carboxymethyl cellulose, starch, low-substitutional hydroxypropyl cellulose), surfactants [e.g., Tween 80 (Kao-Atlas), Prullonic F68 (Asahi Denka, Japan), polyoxyethylene-polyoxypropylene copolymer], antioxidants (e.g., L-cysteine, sodium sulfite, sodium ascorbate), lubricants (e.g., magnesium stearate,.
  • pharmacologically acceptable carriers e.g., lactose, corn starch, light
  • An aqueous solution for injection is prepared by a conventional method using an aqueous solvent (e.g., distilled water, physiological saline, Ringer's solution) or an oily solvent (e.g., sesame oil, olive oil).
  • an aqueous solvent e.g., distilled water, physiological saline, Ringer's solution
  • an oily solvent e.g., sesame oil, olive oil.
  • One or more than one additive can be used as necessary.
  • Such additives include dissolution aids (e.g., sodium salicylate, sodium acetate), buffers (e.g., sodium citrate, glycerol), isotonizing agents (e.g., glucose, inverted sugar), stabilizers (e.g., human serum albumin, polyethylene glycol), antiseptics (e.g., benzyl alcohol, phenol) and analgesics (e.g., benzalkonium chloride, procaine hydrochloride) .
  • dissolution aids e.g., sodium salicylate, sodium acetate
  • buffers e.g., sodium citrate, glycerol
  • isotonizing agents e.g., glucose, inverted sugar
  • stabilizers e.g., human serum albumin, polyethylene glycol
  • antiseptics e.g., benzyl alcohol, phenol
  • analgesics e.g., benzalkonium chloride, procaine hydrochlor
  • a solid preparation for injection is prepared by a conventional method using, for example, a diluent (e.g., distilled water, physiological saline, glucose), an activator (e.g., carboxymethyl cellulose, sodium alginate), an antiseptic (e.g., benzyl alcohol, phenol) and an analgesic (e.g., benzalkonium chloride, procaine hydrochloride).
  • a diluent e.g., distilled water, physiological saline, glucose
  • an activator e.g., carboxymethyl cellulose, sodium alginate
  • an antiseptic e.g., benzyl alcohol, phenol
  • an analgesic e.g., benzalkonium chloride, procaine hydrochloride
  • the same method as above can normally be used. It is preferable, however, that the proton pump inhibitor be administered in the form of nucleated granules coated with a powder comprising the inhibitor and low-substitutional hydroxypropyl cellulose, according to the method described in Japanese Patent Application Unexamined Publication No. 301816/1988, or a solid composition stabilized with a stabilizer comprising a basic inorganic salt of magnesium and/or calcium, according to the method described in Japanese Patent Application Unexamined Publication No. 163018/1991.
  • Example compositions comprising a protein possessing cell growth factor activity and a proton pump inhibitor for oral administration include tablets, pills, granules, powders, capsules, syrups, emulsions and suspensions. These compositions are produced by known methods, using lactose, starch, sucrose, magnesium stearate and other substances as carriers or excipients.
  • compositions for non-oral administration can be prepared as suppositories or external preparations.
  • Suppositories include rectal suppositories and vaginal suppositories.
  • External preparations include ointments (including creams), vaginal preparations, transnasal preparations and percutaneous preparations.
  • a composition of the present invention may be prepared as an oily or aqueous solid, semi-solid or liquid suppository by a known method.
  • the contents of the protein possessing cell growth factor activity and proton pump inhibitor in the medicine of the present invention may be chosen as appropriate depending on the situation; for example, the concentration of the protein is normally about 0.0001 to 10% by weight, preferably about 0.001 to 1% by weight, and more preferably about 0.01 to 0.2% by weight.
  • the concentration of the proton pump inhibitor is normally about 0.1 to 90% by weight, preferably about 1 to 50% by weight, and more preferably about 2 to 20% by weight.
  • the ratio of the protein possessing cell growth factor activity used to the proton pump inhibitor is normally about 0.0001 to 1 times (by weight), preferably about 0.001 to 0.1 times (by weight), of the proton pump inhibitor content, although it varies depending on combinations.
  • a protein possessing fibroblast growth factor activity and a proton pump inhibitor may be administered to the same subject at the same time, or they may be administered to the same subject at a time interval.
  • the components may have different administration frequencies.
  • the administration frequency of the proton pump inhibitor is preferably one or two per day, more preferably one per day.
  • the administration frequency of the protein possessing fibroblast growth factor activity is preferably 1 to 4 per day, more preferably 3 or 4 per day.
  • the protein possessing cell growth factor activity be in a state in which acid secretion is suppressed by proton pump inhibitor administration (normally after about 30 - 60 minutes following oral administration of the proton pump inhibitor). If acid secretion is continuously suppressed by daily administration of a proton pump inhibitor, the protein can be administered concomitantly with the proton pump inhibitor.
  • the protein possessing cell growth factor activity is administered at 0.01 - 1,000 g/kg/day, preferably 0.1 - 300 g/kg/day more preferably 0.1 - 10 .g/kg/day, and the proton pump inhibitor at 0.01 mg/kg/day - 10 mg/kg/day, preferably 0.1 - 3 mg/kg/day, more preferably 0.1 - 1 mg/kg/day.
  • the dosage volume per administration is determined in consideration of such daily dose, dosage form etc.
  • the medicine of the present invention may include, besides a protein possessing cell prowth factor activity and a proton pump inhibitor, an active ingredient such as an antiulcer substance (ex. H 2 blockers).
  • an active ingredient such as an antiulcer substance (ex. H 2 blockers).
  • mice Male Jcl:SD rats (weighing about 220 g) at 7 weeks of age were used in the experiment after being fasted for 24 hours. Each rat received oral administration of lansoprazole suspended in vehicle ⁇ containing 1% aHC ⁇ 3 and 0.5% methyl cellulose, or vehicle alone. Thirty minutes later, aspirin suspended in 0.5% methyl cellulose (vehicle D ) was orally administered at 200 mg/kg. From 1 hour after aspirin administration, ordinary solid food was given for 2 hours. In experiment 1, CS23 (a human basic fibroblast growth factor mutein) dissolved in vehicle containing no NaHC ⁇ 3, or the vehicle alone, was orally administered three hours later to subject animals. In experiment 2, CS23 dissolved in vehicle containing 1%
  • NaHCC-3 NaHCC-3, or the vehicle alone, was orally administered three hours later to subject animals.
  • animals were sacrificed with gaseous carbon dioxide; the stomach, together with the lower esophagus and duodenum, was excised from each animal.
  • 10 ml of 1% formalin was injected into the stomach via the duodenum, the whole stomach being immersed in 1% formalin.
  • the stomach was incised along the greater curvature, and the contents removed.
  • the length (mm) of each lesion in the gastric body was measured under a dissecting microscope (xlO). For each rat, the length of each lesion was summed, and used as lesion index.
  • the results of experiments 1 and 2 are shown in Tables 1 and 2 , respectively.
  • Drug (1) was orally administered 30 minutes before aspirin administration, and drug (2) 6 hours after aspirin administration.
  • Veh- Solution containing 1% NaHCOs and 0.5% methyl cellulose
  • Drug (1) was orally administered 30 minutes before aspirin administration, and drug (2) 6 hours after aspirin administration.
  • Veh- ⁇ Solution containing 1% aHCOs and 0.5% methyl cellulose LPZ : Lansoprazole ( ) : Dose (mg/kg, p.o.) a: p ⁇ 0.01 vs group 1; b: p ⁇ 0.05 vs group 2; c: p ⁇ 0.05 vs group 4
  • lansoprazole (1 and 3 mg/kg) dose-dependently decreased the gastric mucosal lesion index in both experiments, the index for the 3 mg/kg group being significantly lower than that for the control group, which received vehicle alone.
  • CS23 (0.1 mg/kg) showed no action in experiment 1, in which it was administered with vehicle ⁇ not containing 1% NaHC ⁇ 3 , but caused a 40% reduction in experiment 2 , in which it was administered with vehicle ⁇ , containing 1% NaHCO ⁇ .
  • the medicine of the present invention can be, for example, produced with the following formulations.
  • Components (1), (2), (3) and (4) and a half portion of component (5) are mixed and granulated. To these granules, the remaining portion of component (5) is added, and the whole mixture is packed in a gelatin capsule.
  • kits in which each component constitutes a separate preparation is prepared with the capsules A and B.
  • capsule A (1) lansoprazole 10 mg
  • Components (1), (2) and (3) and a half portion of component (4) are mixed and granulated. To these granules, the remaining portion of component (4) is added, and the whole mixture is packed in a gelatin capsule.
  • Components (1), (2) and (3) and a half portion of component (4) are mixed and granulated. To these granules, the remaining portion of component (4) is added, and the whole mixture is packed in a gelatin capsule.
  • kits in which each component constitutes a separate preparation is prepared with the capsules B and C.
  • capsule B (1) CS23 0.1 mg
  • Components (1), (2) and (3) and a half portion of component (4) are mixed and granulated. To these granules. the remaining portion of component (4) is added, and the whole mixture is packed in a gelatin capsule.
  • Nonpareils (Trade-mark), 1650 g, [sugar core prepared by coating sucrose (75 weight parts) with corn starch (25 weight parts) according to a per se known method, 20 to 28 mesh] are brought into the CF (Trade-mark) granulator (CF- 360, Freund Industrial Co., Ltd., Japan), and coated, while being sprayed with 1050 m* of a hydroxypropylcellulose solution [2% (w/v)] at 30 m*?/min., first with the spraying powder 1 and then with the spraying powder 2, both of which are prepared by mixing the ingredients listed below, at the rate of 60 g/min. at room temperature with a rotor rotating at 200 rpm, dried in vacuo at 40 ⁇ C for 16 hours, and sieved through round sieves, to give spherical granules (14 to 32 mesh) having a core.
  • L-HPC 354 g [degree of substitution with hydroxypropaxyl group: 10.0 to 13.0% (w/w), mean particle size : not more than 30 ⁇ ] [spraying powder 2] granulated sugar 300 g corn starch 246 g
  • the granules obtained as above, 3,800 g, are brought into a fluidized-bed coating vessel (Ohkawara Co., Japan), subjected to enteric coating by spraying the enteric coating film solution described below at the rate of 50 ml/min. under the controlled conditions of inlet air at 65°C and material temperature at 40°C, to give enteric coated spherical granules having a core.
  • a fluidized-bed coating vessel Ohkawara Co., Japan
  • the said granules are mixed with talc and light anhydrous silicic acid, then the mixture is filled into No. 1 hard capsules with a capsule filling machine (Parke-Davis & Co., USA) to give capsules.
  • a capsule filling machine Parke-Davis & Co., USA
  • composition in one capsule enteric coated granules 368.8 g lansoprazole 30.0 mg magnesium carbonate 22.4 mg
  • Combined use of a protein, possessing cell growth factor activity, and a proton pump inhibitor for ulcer therapy, according to the present invention provides rapid and effective therapy, surpassing that of conventional treatments.
  • doses can be reduced, in comparison with administration of either drug alone.

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Abstract

Médicament renfermant une combinaison d'une protéine possédant une activité de facteur de croissance cellulaire et d'un inhibiteur de pompe à protons, qui renforce l'effet préventif ou curatif de n'importe quel médicament utilisé seul contre les ulcères, notamment contre les ulcères gastroduodénaux.
PCT/JP1995/001772 1994-09-09 1995-09-06 Medicament anti-ulcereux comprenant une proteine ayant une activite de facteur de croissance cellulaire et un inhibiteur de la pompe a protons Ceased WO1996007421A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU33991/95A AU3399195A (en) 1994-09-09 1995-09-06 An antiulcer medicine comprising a protein possessing cell growth factor activity and a proton pump inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP6/215717 1994-09-09
JP21571794 1994-09-09

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WO1996007421A2 true WO1996007421A2 (fr) 1996-03-14
WO1996007421A3 WO1996007421A3 (fr) 1996-04-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047320A3 (fr) * 2006-10-17 2008-06-19 Ranbaxy Lab Ltd Composition de comprimés à multiples unités de composés de benzimidazole
EP4356904A1 (fr) * 2022-10-19 2024-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Capsule comprenant du lansoprazole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GASTROENTEROLOGY, 106 (4 SUPPL.). 1994. A818., KASUGAI K ET AL 'H2-receptor antagonist and proton pump inhibitor augment an EGF action in gastric juice of rats' *
NIPPON RINSHO, JAN 1992, 50 (1) P39-44, JAPAN, IMAI S ET AL 'Effect of proton pump inhibitor, in combination with epidermal growth factor, on the healing of chronic gastric ulcer in submandibular gland removed rats' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008047320A3 (fr) * 2006-10-17 2008-06-19 Ranbaxy Lab Ltd Composition de comprimés à multiples unités de composés de benzimidazole
EP4356904A1 (fr) * 2022-10-19 2024-04-24 Sanovel Ilac Sanayi Ve Ticaret A.S. Capsule comprenant du lansoprazole

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AU3399195A (en) 1996-03-27

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