WO1996038175A1 - Composition stabilisee comprenant un benzimidazole anti-ulcereux - Google Patents

Composition stabilisee comprenant un benzimidazole anti-ulcereux Download PDF

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WO1996038175A1
WO1996038175A1 PCT/JP1996/001427 JP9601427W WO9638175A1 WO 1996038175 A1 WO1996038175 A1 WO 1996038175A1 JP 9601427 W JP9601427 W JP 9601427W WO 9638175 A1 WO9638175 A1 WO 9638175A1
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group
composition according
groups
cyclodextrin
acid
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PCT/JP1996/001427
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English (en)
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Toshihiro Ishiguro
Masanari Nakamichi
Yasuaki Ogawa
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Takeda Chemical Industries, Ltd.
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Priority to AU57806/96A priority Critical patent/AU5780696A/en
Publication of WO1996038175A1 publication Critical patent/WO1996038175A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • the present invention relates to a stabilized composition containing an antiulcerative benzimidazole compound with enhanced water-solubility. Specifically, it relates to a stabilized composition containing an antiulcerative benzimidazole compound useful as medicaments or veterinary drugs, particularly antiulcerative agents, the stability of the composition and the water-solubility of the compound being enhanced by combining it with a branched cyclodextrin-carboxylic acid which is a cyclodextrin derivative.
  • Cyclodextrins have been used as effective means to solve this problem. Cyclodextrins have been used for providing suitable volatility or improving taste or smell, or for emulsification, powdering or stabilization, as well as for enhancing solubility of medicaments, etc. It is believed that these effects of cyclodextrins are produced by the formation of complexes containing active ingredients of pharmaceutical compositions, etc., in the cyclodextrins.
  • cyclodextrins Various homologs of such cyclodextrins are known. Their water solubilities vary with their kinds. For example, ⁇ -, ⁇ - and ⁇ -cyclodextrins consist of six, seven and eight glucose units, respectively, that are joined in such a way as to form a ring, and it is reported that the water-solubilities of ⁇ -, ⁇ - and ⁇ -cyclodextrins are about 15%, about 2% and about 23%, respectively.
  • the present inventors have intensively studied how to enhance the water-solubility of antiulcerative benzimidazole compounds and the stability of the compositions containing the compounds. As a result, it has been found that use of a cyclodextrin having certain improved characteristics can achieve the above objects. Thus, the present invention has been completed.
  • the present invention provides a stabilized composition comprising an antiulcerative benzimidazole compound and a branched cyclodextrin-carboxylic acid or a salt thereof.
  • the present invention also provides a method of enhancing stability of a composition containing an antiulcerative benzimidazole compound, which comprises combining an antiulcerative benzimidazole compound with a branched cyclodextrin-carboxylic acid or a salt thereof.
  • the present invention also provides a method of enhancing solubility in water of an antiulcerative benzimidazole compound, which comprises combining the antiulcerative benzimidazole compound with a branched cyclodextrin-carboxylic acid or a salt thereof.
  • the antiulcerative benzimidazole compound is preferably a proton pump inhibitor, in particular lansoprazole or omeprazole.
  • the composition further comprises a pH adjusting agent, preferably meglumine.
  • the composition is preferably an injectable composition, and is preferably miscible with a transfusion solution.
  • composition of the present invention is particularly stable in a solid form, in particular a lyophilized form.
  • the branched cyclodextrin-carboxylic acid to be used in the present invention is intended to include its free carboxylic acid, and a salt thereof with an alkali metal (e.g., lithium, sodium, potassium, etc.), alkaline earth metal (e.g., calcium, magnesium, etc.), etc.
  • alkali metal e.g., lithium, sodium, potassium, etc.
  • alkaline earth metal e.g., calcium, magnesium, etc.
  • the branched cyclodextrin-carboxylic acid is a cyclodextrin having an organic group containing at least one carboxyl group at the 6-0-position of at least one glucose unit of the cyclodextrin ring.
  • the cyclodextrin ring in the branched cyclodextrin- carboxylic acid has, for example, 6, 7 or 8 glucose units.
  • the cyclodextrin ring has 7 glucose units.
  • Examples of the cyclodextrin include ⁇ -cyclodextrin, ⁇ - cyclodextrin and ⁇ -cyclodextrin. It is preferred that the organic group containing at least one carboxyl group has 1 to 3 glucose units, and that at least one of the hydroxymethyl groups of the glucose units in the organic group is oxidized to a carboxyl group.
  • Examples of the branched cyclodextrin-carboxylic acidin include 6-0-cyclomaltohexaosyl-(6-l)- ⁇ -D-glucosyl-(4-l)- O- ⁇ -D-glucuronic acid (cyclomaltohexaosyl-(6-1)-0- ⁇ -D- glucopyranosyl-(4-1)-O- -D-glucopyranosiduronic acid) (hereinafter also abbreviated as c_-CyD-G 2 -C00H; the abbreviations of the following compounds are likewise shown in the parentheses), 6-0-cyclomaltoheptaosyl-(6-1)- -D- glucosyl-(4-l )-0- -D-glucuronic acid (cyclomaltoheptaosyl- ( 6-1 ) -O- ⁇ -D-glucopyranosyl- ( 4-1 ) -O- ⁇ -
  • CyD-Gj-COOH 6-0-cyclomaltooctaosyl-( 6-1 ) - ⁇ -D-glucuronic acid ( cyclomaltooctaosyl- ( 6-1 ) -O- ⁇ -D-glucopyranosiduronicacid ) ( ⁇ - CyD-Gj-COOH) , 2-0- (6-cyclomaltohexaosyl) -acetic acid ( ⁇ -CyD- CH 2 C00H), 2-0- (6-cyclomaltoheptaosyl) -acetic acid ( ⁇ -CyD- CH 2 C00H), 2-0- (6-cyclomaltooctaosyl) -acetic acid ( ⁇ -CyD-
  • 6-0-cyclomaltohexaosyl-(6-1)- ⁇ -D- glucosyl-(4-l)-0- ⁇ -D-glucuronic acid ⁇ -CyD-G 2 -COOH
  • 6-0- cyclomaltoheptaosyl-(6-1)- ⁇ -D-glucosyl-(4-1)-O- ⁇ -D-glucuronic acid ⁇ -CyD-G 2 -C00H
  • 6-0-cyclomaltooctaosyl-(6-1)- ⁇ -D- glucosyl-(4-1)-O- ⁇ -D-glucuronic acid ⁇ -CyD-G 2 -C00H
  • branched cyclodextrin-carboxylic acids containing ⁇ - cyclodextrin (containing 6 glucose units), ⁇ -cyclodextrin (containing 7 glucose units) and ⁇ -cyclodextrin (containing 8 glucose units), respectively.
  • maltose is attached to one of the glucose units of the cyclodextrin ring through an ⁇ -(l-6) linkage, and the hydroxymethyl group (-CH 2 0H) at the 6- position of the terminal glucose unit of the maltose is oxidized to a carboxyl group to give glucuronic acid.
  • Eachof 6-0-cyclomaltohexaosyl-(6-1)- ⁇ -D-glucuronic acid ( ⁇ -CyD-G i -COOH) , 6-0-cyclomaltoheptaosyl-(6-l)- ⁇ -D- glucuronic acid ( ⁇ -CyD-G ⁇ COOH) and 6-O-cyclomaltooctaosyl- (6-1)- ⁇ -D-glucuronic acid ( ⁇ -CyD-G.-COOH) is a branched cyclodextrin-carboxylic acid in which glucose is attached to one of the glucose units of the cyclodextrin ring through an ⁇ -(l-6) linkage, and the hydroxymethyl group (-CH 2 0H) at the 6-position of the branched glucose is oxidized to a carboxyl group to give glucuronic acid.
  • 2-0-(6-cyclomaltohexaosyl)-acetic acid ( ⁇ - CyD-CH 2 C00H)
  • 2-0-(6-cyclomaltoheptaosyl)-acetic acid ( ⁇ -CyD- CH 2 C00H)
  • 2-0-(6-cyclomaltooctaosyl)-acetic acid ( ⁇ -CyD- CH 2 C00H) are preferable branched cyclodextrin-carboxylic acid wherein a carboxymethyl group is attached as a branch to one of the glucose units of the cyclodextrin ring.
  • the water-solubility of an antiulcerative benzimidazole compound and the stability of the compositions containing the compound can be enhanced by formulating the compound together with a branched cyclodextrin-carboxylic acid.
  • the antiulcerative benzimidazole compound to be used is normally a proton pump inhibitor having a water-solubility of not more than 10 mg/ml.
  • 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).
  • Such drugs include omeprazole, lansoprazole, pantoprazole, pariprazole sodium, leminoprazole, TY-11345, TU-199, FPL-65372, BY-686, Tannic acid, Ellagic acid, Ebselen, AHR-9294, Cassigarol-A, Bafilomycin, Y-25942, Xanthoangelol E, SK&F-96356, (-)- Epigallocatechin gallate, Y-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 salt thereof.
  • a compound (or salt thereof) represented by formula (I) below is more preferred.
  • R 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 c , R ⁇ , and R 8 are, the same or different, a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkoxy group;
  • R is a hydrogen atom, an alkyl group or a group represented by -OR in which R 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, USP 5,039,806 (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, carba oyloxy groups, nitro groups, acyloxy groups, aryl groups, aryloxy groups, alkylthio groups and alkylsulfinyl groups, and the like.
  • the above substituents are hereinafter described.
  • Halogen atoms include fluorine, chlorine, bromine and iodine. Fluorine and chlorine are preferred, with greater preference given to fluorine.
  • 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 10 carbon atoms e.g., methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, h
  • 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-l-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.
  • the 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
  • the halogen as a substituent on the above-described alkyl, cycloalkyl, alkenyl or alkoxy group is exemplified by chlorine, bromine, fluorine and iodine.
  • the 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.
  • 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 trifluoro- ethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethy, 1-methoxyethyl, 2-methoxyethyl, 2,2-dimethoxy- ethyl, 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- dichlorovinyl, 3-hydroxy-2-propen-l-yl and 2-methoxyvinyl, among others.
  • the substituted alkoxy groups include difluoromethoxy, trifluoro ethoxy, 2,2,2-trifluoroethoxy, 2- methoxyethoxy, 4-chlorobenzyloxy and 2-(3,4-dimethoxypehnyl)- 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, hexyloxyl, 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 carba oylalkyl 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.
  • the 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).
  • the 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- ⁇ osition.
  • 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 R b 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 R 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.
  • R is preferably hydrogen.
  • the alkyl group for R c , R ⁇ or R 8 is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g.
  • the alkoxy group for R c , R e or R 8 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.
  • the alkoxy in the alkoxyalkoxy group for R c , R e or R 8 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 c is preferably a hydrogen atom, an alkyl group or an alkoxy group.
  • R ⁇ is preferably a hydrogen atom, an alkyl group or an alkoxy group.
  • R 8 is preferably a hydrogen atom.
  • the alkyl group for R d 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 hydrocarbon group in the hydrocarbon group which may optionally be substituted, for R f 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.
  • alkenyl groups having 2 to 6 carbon atoms e.g., vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl
  • alkynyl 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-1-yl, 4-pentyn-2-yl, 3-hexyn-l-yl)
  • cycloalkyl groups having 3 to 6 carbon atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclo
  • 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 6 _ 10 aryl groups (e.g., phenyl, naphthyl), amino, C j . ⁇ alkylamino groups (e.g., methylamino, ethylamino, isopropylamino) , di-Cj.g 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-(1-naphthylmethyl)-N-ethylamino) , azide, nitro, halogens (e.g., fluorine, chlorine, bromine, iodine), hydroxyl, C ⁇ alkoxy groups (e
  • alkoxycarbonyl groups e.g., methoxycarbonyl, ethoxycarbonyl
  • C 7 _ u aryloxycarbonyl groups e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxy- carbonyl
  • carboxy-C ⁇ _ 4 alkoxy groups e.g., carboxymethoxy, 2-carboxyethoxy
  • 6 alkanoyl groups e.g., formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, haxanoyl
  • C 7 _ n alloyl groups e.g., benzoyl, 1-naphthoyl, 2-naphthoyl
  • C 6 _ 10 arylsulfonyl groups e.g., benzenesulfonyl, 1-naphthyl- sulfonyl, 2-naphthylsulfonyl
  • C ⁇ alkylsulfinyl groups e.g., methylsulfinyl, ethylsulfinyl
  • C 6 _ 10 arylsulfinyl groups e.g., benzenesulfinyl, 1-naphthylsulfinyl, 2-naphth
  • heterocyclic thio groups e.g., 4-pyridylthio, 2- pyrimidylthio, l,3,4-thiadiazol-2-ylthio, l-methyl-5- tetrazolylthio
  • the heterocyclic thio group may condense with the benzene ring to form a bicyclic condensed thio group
  • Halogens e.g., fluorine, chlorine, bromine, iodine
  • hydroxyl and C ⁇ alkoxy groups e.g., methoxy, ethoxy, propoxy, butoxy
  • the number of substituents is normally 1 to 5, preferably 1 to 3.
  • R 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-trifluoroethox , 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) :
  • ring A may optionally be substituted;
  • R , R 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.
  • ring A is exemplified by the same rings as those mentioned for ring A of formula (I) above.
  • the alkyl group for R 1 , R 3 or R A 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 R 1 , R 3 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.
  • hydrocarbon group which may optionally be substituted, for R 2 is exemplified by the same hydrocarbon groups as those mentioned for R above.
  • R 1 is preferably C ⁇ alkyl or C ⁇ alkoxy, more preferably C ⁇ .
  • R is preferably hydrogen or C ⁇ alkyl, more preferably hydrogen.
  • R is preferably C ⁇ alkoxy which may optionally be substituted by i) halogen, ii) hydroxyl or iii) alkoxy, more preferably, C ⁇ _ 3 alkyl which may optionally be substituted by i) halogen or ii) C w alkoxy.
  • R is preferably hydrogen.
  • benzimidazole compounds for the present invention include 2-[2-[3-methyl-4-(2,2,3,3-tetrafluoro- propoxy)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)methyl- sulfinyl]-5-methoxy-lH-benzimidazole (omeprazole), sodium salt of 2-[2-[4-(3-methoxypropoxy)-3-methyl]pyridyl]methylsulfinyl- lH-benzimidazole and 2-[2-(3,4-dimethoxy)pyridyl]methyl-
  • lansoprazole and omeprazole are preferably applied to the present invention.
  • 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-dibenzylethylene- diamine, ethanolamine, diethanolamine, trishydroxymethyl- aminomethane and dicyclohexylamine.
  • Useful basic amino acids include arginine and lysine.
  • the mixing ratio of the branched cyclodextrin-carboxylic acid to the antiulcerative benzimidazole compounds is not limited and can be selected from wide ranges.
  • the amount of the branched cyclodextrin- carboxylic acid to be used is 0.1 to 20 mol, preferably 0.1 to 10 mol, more preferably 0.2 to 5 mol, particularly preferably 2 to 5 mol, per mol of the antiulcerative benzimidazole compound.
  • composition of the present invention can be prepared by mixing the branched cyclodextrin-carboxylic acid with the antiulcerative benzimidazole compound according to known methods. Roughly speaking, the inclusion compound of the antiulcerative benzimidazole compound included in the branched cyclodextrin-carboxylic acid can be prepared, for example, by the following four methods:
  • the inclusion compound can be prepared as follows: (1) A compound to be included in the inclusion compound is added to an aqueous solution of the branched cyclodextrin-carboxylic acid (hereinafter sometimes referred to as the cyclodextrin). The mixture is stirred (shaken), if necessary, under warming. The remaining unreacted compound to be included is removed by filtration, centrifugation, etc., to obtain an inclusion compound.
  • the cyclodextrin branched cyclodextrin-carboxylic acid
  • the cyclodextrin is dissolved in water, and a compound to be included is added thereto. The two are mixed for 10 minutes to several hours, followed by lyophilization (M. Kurozumi et al., Chem. Pharm. Bull., 23, 142 (1975)) to give powder. This powder is dissolved in water, and the unreacted compound to be included is removed to obtain an aqueous solution of an inclusion compound.
  • a compound to be included is dissolved in an appropriate water-soluble organic solvent in advance. This solution is contacted with cyclodextrin in an aqueous solution.
  • a compound to be included is dissolved in a lipophilic organic solvent (e.g., ethyl ether, etc.), and the solution is mixed with a saturated aqueous solution of the cyclodextrin. The mixture is shaken vigorously for 10 minutes to several hours and then allowed to stand in a cold place overnight to precipitate an inclusion compound. The precipitate is separated by centrifugation or filtration. The resulting powder is dissolved in water to give an aqueous solution of an inclusion compound.
  • a lipophilic organic solvent e.g., ethyl ether, etc.
  • a powdered compound to be included and powdered cyclodextrin are mixed, and a small amount of water is added thereto.
  • the mixture is kneaded (Y. Nakai et al., Chem. Pharm. Bull., 26, 2419 (1978)) and then, if necessary, lyophilized.
  • An aqueous solution of the cyclodextrin and an aqueous solution of a compound to be included are mixed to give an aqueous solution of an inclusion compound.
  • the above method (3) is useful for solubilization of antiulcerative benzimidazole compounds.
  • the aqueous solution or powder thus obtained by the known methods giving inclusion compounds contains an inclusion compound or a complex formed by electrostatic or hydrophobic interactions or hydrogen bonds, etc. Therefore, the term "inclusion compound” used in the present invention means not only an inclusion compound or a complex per se but also a mixture of an inclusion compound, a complex, a free compound to be included and/or a free cyclodextrin. That is, the powder and aqueous solution obtained may contain, other than an inclusion compound or a complex, a water-insoluble or slightly water-soluble compound that is not included or complexed, and/or free cyclodextrin.
  • the inclusion compound per se and powder and an aqueous solution like this have extremely high water-solubilities and dissolve in water instantly.
  • composition of the present invention may be the aqueous solution or powder per se thus obtained, or it may be a pharmaceutical composition in an appropriate dosage form, a veterinary composition, etc. , prepared using known additives such as excipients, binders or lubricants.
  • saccharides for example, to improve properties of the powder obtained above (packing capacity into a storage bottle or a vial, specific volume, destaticizing, etc.), saccharides, antiseptics, stabilizers, antistatic agents, etc., can be added.
  • the powder obtained by this operation readily dissolves in an aqueous isotonic solution prepared using distilled water or sodium chloride and saccharides (e.g., glucose, mannitol, inositol, etc.).
  • the resulting injectable preparation containing an active ingredient can be administered intravenously, intramuscularly, subcutaneously, into organs, or directly to foci such as tumor or excised parts of tumor, in a drug concentration effective in vivo against the diseases to be treated.
  • oral preparations tablets, capsules, granules, fine granules, enveloped preparations, drops, liquids, etc., can be prepared.
  • known excipients, lubricants, binders, dispersers, stabilizers, colorants and absorption-improving (promoting) agents, etc. can normally be used.
  • the above powder can also be formulated into preparations other than injectable or oral preparations according to conventional methods.
  • preparations are preparations administered to mucous membranes such as nose, the rectum.
  • Each of the above preparations can be molded into various controlled-release preparations or preparations for targeting therapies, and the composition of the present invention can be used as a raw material of such preparations.
  • the composition is preferably an injectable composition, especially intravenously injectable solution.
  • the composition preferably further contains a pH adjusting agent, such as meglumine, sodium hydroxide, potassium hydroxide, ammonia water, sodium bicarbonate, sodium carbonate, triethanolamine , monoethanolamine , diisopropanolamine, triisopropanolamine and L-arginine.
  • the amount of the pH adjusting agent to be used is 0.01 to 10 mol, preferably 0.1 to 5 mol, per mol of the antiulcerative benzimidazole compound.
  • the composition is miscible with a transfusion solution, and can be used as a mixture of the composition and a transfusion solution.
  • transfusion solution examples include glucose injection, xylitol injection, D-mannitol injection, fructose injection, isotonic sodium chloride solution, dextran 40 injection, dextran 70 injection, amino acid injection, Ringer's injection, lactated Ringer's injection.
  • the ratio of the composition to the transfusion solution is 1/1 (v/v) to 1/500 (v/v), preferably 1/20 (v/v) to 1/100 (v/v).
  • the composition 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 (e.g., humans, monkeys, cattle, dogs, swine, etc.).
  • digestive ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis, anastomotic ulcer, acute and chronic gastritis.
  • compositions comprising lansoprazole as the antiulcerative benzimidazole compound can be used in accordance with the manner described in EP 0174726.
  • the composition of the present invention can be administered in an appropriate dosage form such as injections, oralpreparations, syrups, preparations externally administered to skin, pernasal preparations, rectal suppositories or preparations applied to mucous membranes.
  • compositions of the present invention are chosen as appropriate, according to ulcer type, symptoms, age and the other factors, for example, in the case of the compositions of proton pump inhibitors, the compositions are administered at the dose of 0.01 mg/kg/day -
  • the daily dose of lansoprazole is 0.01 - 30 mg/kg, more preferably 0.1 - 3 mg/kg.
  • lansoprazole alone was added to water. The mixture was shaken at room temperature, and filtered through a membrane filter (0.22 ⁇ m) . The lansoprazole in the above homogeneous aqueous solution and filtrate was determined by high performance liquid chromatography (HPLC) . HPLC conditions:
  • the lyophilized composition comprising ⁇ -CyD-G 2 - COONa and lansoprazole of the present invention was an inclusion compound which was stable at room temperature without decomposition of the lansoprazole.
  • Example 3
  • Example 4 The lyophilized powder obtained in Example 3 was filled into vials (150 mg powder per vial) and dried over phosphorus pentaoxide, and each vial was sealed under an atmosphere of nitrogen gas. A preparative stability test was carried out at 40°C for 4 weeks. The water content was 0.5% after drying over phosphorus pentaoxide, and the amount of the residual lansoprazole was not less than 95% after 4 weeks.
  • the lyophilized powder obtained in Example 3 was dissolved in water for injection (150 mg powder per ml of the water for injection).
  • the solution was mixed with isotonic sodium chloride solution (Otsuka Seishoku Chu (Otsuka Pharmaceutical Co., Ltd.)), glucose injection (Ohtsuka Toeki 5% (Otsuka Pharmaceutical Co., Ltd.)), Ringer's solution containing low molecular weight dextran and lactic acid (Low Molecular Weight Dextran L Injection (Otsuka Pharmaceutical Co., Ltd.)) and an electrolyte solution for transfusion (Solita T No. 3 (Shimizu Pharmaceutical Co., Ltd.)).
  • the stability of lansoprazole after the addition of transfusion solution was tested.
  • composition ratio of the aqueous lyophilized powder solution to the transfusion solution was 1/99 (v/v) .
  • the amount of the residual lansoprazole was not less than 98% in the isotonic sodium chloride solution and glucose injection until 8 hours after the addition, not less than 97% in the Ringer's solution until 4 hours after the addition, and not less than 93% in the electrolyte solution for transfusion until 4 hours after the addition.
  • Example 3 The lyophilized powder obtained in Example 3 was dissolved in water for injection (150 mg powder per ml of the water for injection). The solution was added to each of Ringer's solution containing low molecular weight dextran and lactic acid (Low Molecular Weight Dextran L Injection (Otsuka Pharmaceutical Co., Ltd.)) and an electrolyte solution for transfusion (Solita T No. 3 (Shimizu Pharmaceutical Co., Ltd.)).
  • Ringer's solution containing low molecular weight dextran and lactic acid Low Molecular Weight Dextran L Injection (Otsuka Pharmaceutical Co., Ltd.)
  • an electrolyte solution for transfusion Solita T No. 3 (Shimizu Pharmaceutical Co., Ltd.)
  • the stability of lansoprazole after the addition of the transfusion solution was compared with that in a formulation containing no cyclodextrin-carboxylic acid [the formulation being a solution of lyophilized powder of lansoprazole (30 mg) containing mannitol (60 mg) and meglu ine (10 mg) in an aqueous 30% polyethylene glycol 400 solution (5 rol)]- Tne composition ratio of the aqueous lyophilized powder solution to the transfusion solution was 1/99 (v/v) .
  • the composition ratio of the formulation containing no cyclodextrin-carboxylic acid to the transfusion solution was 1/99 (v/v).
  • the amounts of the lansoprazole remaining 1 hour, 4 hours and 18 hours after the addition of the electrolyte solution for transfusion were 98.2%, 93.3% and 62.3%, respectively, in the case of the composition of Example 3, compared with 60.1%, 12.8% and 0%, respectively, in the case of the formulation containing no cyclodextrin-carboxylic acid.
  • the composition of the present invention is very stable, and the antiulcerative benzimidazole compound combined with a branched cyclodextrin-carboxylic acid according to the present invention has a much higher water- solubility compared with that of the antiulcerative benzimidazole compound alone.
  • the branched cyclodextrin-carboxylic acid has less effect (e.g., destruction of erythrocytes) on the living body than ⁇ - cyclodextrin, and therefore is highly safe for blood.
  • ⁇ -CyD-G 2 -COOH is hardly decomposed with acids or enzymes, and therefore the composition of the present invention is highly safe to mammals including humans.

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Abstract

Cette invention concerne une composition stabilisée comprenant un composé de benzimidazole anti-ulcéreux, notamment un inhibiteur de la pompe à protons, ainsi qu'un acide cyclodextrin-carboxylique ramifié.
PCT/JP1996/001427 1995-06-02 1996-05-28 Composition stabilisee comprenant un benzimidazole anti-ulcereux WO1996038175A1 (fr)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998040069A2 (fr) * 1997-03-13 1998-09-17 Hexal Ag Stabilisation de benzimidazoles sensibles aux acides avec des combinaisons amino-cyclodextrine
EP1018340A1 (fr) * 1999-01-06 2000-07-12 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes d'inclusion de sels d'aminoacides de dérivés du benzimidazol et de cyclodextrines, leur préparation et formulations pharmaceutiques les contenant
US6147103A (en) * 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
WO2002055076A1 (fr) * 2001-01-04 2002-07-18 Daiichi Pharmaceutical Co., Ltd. Preparation pharmaceutique contenant de la cyclodextrine
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
WO2003059393A1 (fr) * 2002-01-15 2003-07-24 Altana Pharma Ag Complexes d'inclusion de pantoprazole cyclodextrine
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
WO2004093875A1 (fr) * 2003-04-22 2004-11-04 Dr. Reddy's Laboratories Limited Formulations pharmaceutiques orales à base de principes actifs labiles en milieu acide et de dérivés glucides hydrosolubles, utilisation de ces formulations, et procédé de fabrication approprié
US6951885B2 (en) 2000-08-10 2005-10-04 Takeda Pharmaceutical Company Limited Pharmaceutical composition
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
WO2006082490A1 (fr) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Formulations injectables de composes de benzimidazole
EP1903039A1 (fr) * 2005-06-13 2008-03-26 Takeda Pharmaceutical Company Limited Produit d injection
RU2481830C2 (ru) * 2007-01-16 2013-05-20 Бипар Сайенсиз, Инк. Лекарственные препараты для лечения рака
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

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EP0657176A2 (fr) * 1993-12-06 1995-06-14 Takeda Chemical Industries, Ltd. Composition à hydrosolubilité accrue contenant un composé insoluble ou légèrement soluble dans l'eau

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DE3427786A1 (de) * 1984-07-27 1986-01-30 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Inklusionskomplexe von benzimidazolderivaten mit cyclodextrinen, deren herstellung und arzneimittel
DE3427785A1 (de) * 1984-07-27 1986-01-30 Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz Einschlussverbindungen von benzimidazolderivaten mit cyclodextrinen, deren herstellung und arzneimittel
WO1986000913A1 (fr) * 1984-07-27 1986-02-13 Byk Gulden Lomberg Chemische Fabrik Gesellschaft M Nouveaux complexes de substances actives
WO1993013138A1 (fr) * 1991-12-31 1993-07-08 Sunkyong Industries Co., Ltd. Medicaments enterosolubles administrables par voie orale contenant des composes instables en milieu acide
WO1995007263A1 (fr) * 1993-09-09 1995-03-16 Schering Aktiengesellschaft Derives de 1,2-di(het)aryl-benzimidazol, leur preparation et leur utilisation comme substances mimetiques de la prostacycline (pgi2)
EP0657176A2 (fr) * 1993-12-06 1995-06-14 Takeda Chemical Industries, Ltd. Composition à hydrosolubilité accrue contenant un composé insoluble ou légèrement soluble dans l'eau

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
WO1998040069A3 (fr) * 1997-03-13 1998-12-17 Hexal Ag Stabilisation de benzimidazoles sensibles aux acides avec des combinaisons amino-cyclodextrine
US6248758B1 (en) * 1997-03-13 2001-06-19 Hexal Ag Pharmaceutical antacid
WO1998040069A2 (fr) * 1997-03-13 1998-09-17 Hexal Ag Stabilisation de benzimidazoles sensibles aux acides avec des combinaisons amino-cyclodextrine
US6576258B1 (en) 1997-07-14 2003-06-10 Lek, Tovarna Farmacevtskih In Kemicnih Izdelkov, D.D. Pharmaceutical formulation with controlled release of active substances
US6147103A (en) * 1998-08-11 2000-11-14 Merck & Co., Inc. Omeprazole process and compositions thereof
EP1018340A1 (fr) * 1999-01-06 2000-07-12 Tecnimede-Sociedade Tecnico-Medicinal, S.A. Complexes d'inclusion de sels d'aminoacides de dérivés du benzimidazol et de cyclodextrines, leur préparation et formulations pharmaceutiques les contenant
US6951885B2 (en) 2000-08-10 2005-10-04 Takeda Pharmaceutical Company Limited Pharmaceutical composition
US7247653B2 (en) 2000-08-10 2007-07-24 Takeda Pharmaceutical Company Limited Pharmaceutical composition
US6989381B2 (en) 2000-08-22 2006-01-24 Pharmacia Corporation Solution composition of an oxazolidinone antibiotic drug having enhanced drug loading
WO2002055076A1 (fr) * 2001-01-04 2002-07-18 Daiichi Pharmaceutical Co., Ltd. Preparation pharmaceutique contenant de la cyclodextrine
EP1348432A4 (fr) * 2001-01-04 2005-08-10 Daiichi Seiyaku Co Preparation pharmaceutique contenant de la cyclodextrine
EP1348432A1 (fr) * 2001-01-04 2003-10-01 Daiichi Pharmaceutical Co., Ltd. Preparation pharmaceutique contenant de la cyclodextrine
WO2002098423A1 (fr) * 2001-06-06 2002-12-12 Cipla Limited Compose d'inclusion de s-omeprazole (esomeprazole) avec des cyclodextrines
WO2003059393A1 (fr) * 2002-01-15 2003-07-24 Altana Pharma Ag Complexes d'inclusion de pantoprazole cyclodextrine
WO2004093875A1 (fr) * 2003-04-22 2004-11-04 Dr. Reddy's Laboratories Limited Formulations pharmaceutiques orales à base de principes actifs labiles en milieu acide et de dérivés glucides hydrosolubles, utilisation de ces formulations, et procédé de fabrication approprié
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
WO2006082490A1 (fr) * 2005-02-02 2006-08-10 Ranbaxy Laboratories Limited Formulations injectables de composes de benzimidazole
EP1903039A1 (fr) * 2005-06-13 2008-03-26 Takeda Pharmaceutical Company Limited Produit d injection
EP1903039A4 (fr) * 2005-06-13 2010-09-22 Takeda Pharmaceutical Produit d injection
RU2481830C2 (ru) * 2007-01-16 2013-05-20 Бипар Сайенсиз, Инк. Лекарственные препараты для лечения рака

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