EP1140979A1 - Polyol verbindungen, verfahren zur deren herstellung und verwendung - Google Patents

Polyol verbindungen, verfahren zur deren herstellung und verwendung

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Publication number
EP1140979A1
EP1140979A1 EP00900126A EP00900126A EP1140979A1 EP 1140979 A1 EP1140979 A1 EP 1140979A1 EP 00900126 A EP00900126 A EP 00900126A EP 00900126 A EP00900126 A EP 00900126A EP 1140979 A1 EP1140979 A1 EP 1140979A1
Authority
EP
European Patent Office
Prior art keywords
amino
compound
residue
acid
tetrahydroxyhexanoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00900126A
Other languages
English (en)
French (fr)
Inventor
Keiji Kamiyama
Yuji Nishikimi
Atsushi Hasuoka
Masafumi Nakao
Ken-Ichiro Miyagawa
Yohko Akiyama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Takeda Pharmaceutical Co Ltd
Original Assignee
Takeda Chemical Industries Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries Ltd filed Critical Takeda Chemical Industries Ltd
Publication of EP1140979A1 publication Critical patent/EP1140979A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a polyol, a method of its production, and its use. More particularly, the invention relates to a bioactive compound of use as a medicine, for as a preventing and treating drug for diseases such as gastric ulcer and duodenal ulcer, and an anti-Helicobacter pylori agent containing the said compound.
  • Helicobacter pylori Being a member of the group of bacteria doing harm in the gastrointestinal tract, Helicobacter pylori is a gram-negative microaerophile belonging to the genus Helicobacter and, as suggested, may be a major factor in the recurrences of gastritis, duodenal ulcer and stomach ulcer.
  • chemotherapy such as a two-drug combined therapy using a bismuth drug and an antibiotic or a three-drug combined therapy using a bismuth drug, metronidazole (US Patent 2,944,061), and either tetracycline (e.g. US Patent 2,712,517) or amoxicillin (US Patent 3,192,198) is being practiced today.
  • the ternary therapy consisting of a gastric proton pump inhibitor, amoxicillin, and clarithromycin has also been found to be effective (Gut, 1995, 37 (Supplement 1) : A365) (Gastroenterology, 1996, 110 : A171).
  • the present invention has for its object to provide a novel medicinal agent having high antibacterial activity, particularly against Helicobacter pylori and other bacteria of the genus Helicobacter . and producing clinically rewarding preventing and treating responses with a reduced incidence of adverse reactions.
  • X is L-serine residue, L-asparagine residue or (S)-2- aminobutyric acid residue and Y is ⁇ -L-amino acid residue, and discovered that, because of this unique chemical structure that dipeptide Y-X is bonded directly to nitrogen atom, the above compound displays remarkable inhibitory activity against the bacteria doing harm in the gastrointestinal tract, particularly high anti-Helicobacter activity, with clinically favorable pharmacological characteristics such as a low risk for adverse effects.
  • the present invention has been developed on the basis of the above finding.
  • the inventors of the present invention have discovered that the effectiveness of active ingredients (e.g. anti Helicobacter pylori effect) can be potentiated by administering gastric mucosa adhesive composition containing an active ingredient (e.g. anti Helicobacter pylori substance) , and that the composition has favorable safety characteristics and an enhanced adhesion to the mucosa.
  • active ingredients e.g. anti Helicobacter pylori effect
  • the present invention relates to : (1) A compound of the formula (I) or its salt;
  • a pharmaceutical composition which contains a compound as shown in the above (1) or its pro-drug;
  • a pharmaceutical composition as shown in the above (7) which is an anti-Helicobacter pylori agent;
  • a pharmaceutical composition as shown in the above (8) which is a preventing and treating agent of Helicobacter pylori infectious disease;
  • a pharmaceutical composition as shown in the above (7) which is a gastric mucosa adhesive pharmaceutical composition;
  • a pharmaceutical composition which contains both of a compound as shown in the above (1) and the other antibacterial agent and/or an antiulcerative agent;
  • a method for treating or preventing a mammal suffering from a Helicobacter pylori infectious disease which comprises administering an effective amount of a compound as shown in the above (1) or its pro-drug optionally together with a pharmaceutically acceptable carrier, diluent or excipient, to a patient suffering from the disease;
  • composition is for treating or preventing a Helicobacter pylori infectious disease
  • R 1 , R 2 , R 3 and R 4 are independently a protecting group for hydroxy group or a hydrogen atom, and R 5 is a protecting group for carboxyl group or a hydrogen atom] , its salt or its reactive derivative at the amino group with a compound of the formula :
  • L-serine residue, L-asparagine residue and (S) -2-aminobutyric acid residue each of which is represented by X, respectively mean parts which form by removing a hydroxy group from the carboxyl group and a hydrogen atom from the amino group of L-serine, L-asparagine and (S) -2-aminobutyric acid.
  • these amino acid residues represented by X are bonded with the amino group of 5-amino- 2,3,4, 6-tetrahydroxyhexanoyl group at the carbonyl group which forms by removing a hydroxy group from the carboxyl group, and bond with Y at NH which forms by removing a hydrogen atom from the amino group.
  • the symbol X is preferably (S) -2-aminobutyric acid residue.
  • ⁇ -L-amino acid residue represented by Y means a part which forms by removing a hydroxy group from the carboxyl group of ⁇ -L-amino acid, and bonds to X at the carbonyl group which forms by removing a hydroxy group from the carboxyl group .
  • ⁇ -L-amino acid include such amino acids as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, etc. and such other amino acids as norvaline, norleucine, 2-aminoadipic acid, 2-aminobutyric acid, 2-aminoisobutyric acid, 2-amino-4-pentenoic acid, 1-aminocyclopropanecarboxylic acid,
  • the protecting group for hydroxy group represented by R 1 , R 2 , R 3 and R 4 means one usually known as a protecting group for hydroxy group in the field of peptide chemistry.
  • the protecting group for the hydroxy includes ether-forming protecting groups such as tert-butyl, methoxymethyl, benzyloxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, methylthiomethyl , 2- tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, 2- tetrahydropyranyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, o- nitrobenzyl, 2, 6-dichlorobenzyl, trityl, isopropylidene, cyclohexylidene , benzylidene, p-methoxybenzylidene, etc.; silyl ether-forming protecting groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, isopropyldimethylsilyl, diethylisoprop
  • the carboxyl-protecting group which can be used includes ester-forming protecting groups such as methyl, ethyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, tert-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl, cyclohexyl, cyclopentyl, phenacyl, etc.; silyl ester-forming protecting groups such as trimethylsilyl, triethylsilyl, tert- butyldimethylsilyl, isopropyldimethylsilyl, dimethylphenylsilyl, etc. Among them, benzhydryl, etc. are preferable.
  • L-serine residue which may be protected L-asparagine residue which may be protected and (S)- 2-aminobutyric acid residue, each of which is represented by X', respectively mean parts which form by removing a hydroxy group from the carboxyl group and a hydrogen atom from the amino group of L-serine residue which may be protected, L-asparagine residue which may be protected and (S) -2-aminobutyric acid residue.
  • L-serine residue which may be protected, L- asparagine residue which may be protected and (S) -2-aminobutyric acid residue represented by X' respectively includes, L-serine residue which is not protected, L-asparagine residue which is not protected and (S) -2-aminobutyric acid residue, and also include L-serine residue whose hydroxy group is protected, L-asparagine residue whose carbamoyl group is protected.
  • L-serine residue which is protected is one whose hydroxy group is protected and L- asparagine residue which is protected is one whose carbamoyl group is protected.
  • the protecting group for the hydroxy group of L- serine residue includes those mentioned as the protecting group for the hydroxy group shown by R 1 , R 2 , R 3 and R 4 . Among them, tert- butyl group, etc. is preferable.
  • the protecting group for the carbamoyl group of L-asparagine residue include, for example, xanthyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, benzhydryl group,4,4' -dimethoxybenzhydryl group , etc . Among them, triphenylmethyl group is preferable.
  • L-serine residue which may be protected, L-asparagine residue which may be protected and (S)- 2-aminobutyric acid residue, each of which is represented by X" respectively mean group which forms by removing a hydroxy group from the carboxyl group of L-serine which may be protected, L-asparagine which may be protected and (S) -2-aminobutyric acid.
  • X bond to amino group of 5-amino-2,3 , 4,6- tetrahydroxyhexanoyl group at carbonyl group which forms by removing a hydroxy group from the carboxyl group.
  • L-serine residue which may be protected, L-asparagine residue which may be protected and (S) -2-aminobutyric acid residue each of which is represented by X" include L-serine residue which is not protected, L-asparagine residue which is not protected and (S) -2-aminobutyric acid residue and also include L-serine residue whose hydroxy group is protected, L-asparagine residue whose carbamoyl group is protected.
  • the protecting group for the hydroxy group of L-serine residue and the protecting group for the carbamoyl group of L-asparagine residue include those mentioned for X' .
  • ⁇ -L-amino acid residue which may be protected includes ⁇ -L-amino acid residue which may be protected, represented by Y, and also includes ones whose amino group, carboxyl group, hydroxy group and carbonyl group are partially or entirely protected, when ⁇ -L-amino acid residue has a carboxyl group, a hydroxy group or a carbonyl group.
  • the protection for the amino group, carboxyl group, hydroxy group and carbonyl group means those by the protecting group usually known as the protecting group for amino group, protecting group for carboxyl group, protecting group for hydroxy group and protecting group for carbonyl group in the field of peptide chemistry.
  • the amino-protecting group which can be used includes amide-forming protecting groups such as formyl, acetyl, chloroacetyl , dichloroacetyl, trichloroacetyl , trifluoroacetyl, acetoacetyl, o-nitrophenylacetyl, etc.; carbamate-forming protecting groups such as tert-butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- chlorobenzyloxycarbonyl , 2 , 4-dichlorobenzyloxycarbonyl, benzhydryloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2- trimethylsilylethoxycarbonyl, 1-methyl-1- ( 4- biphenyl)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl , 9- anthrylmethoxycarbonyl, isonicot
  • the carbonyl-protecting group includes acetal-, ketal- , dithioacetal- or dithioketal-forming protecting groups, such as dimethyl, diethyl, dibenzyl, diacetyl, etc.; protecting groups forming optionally substituted 1,3-dioxane or 1,3-dioxolane, protecting groups forming 1,3-dithiane or 1,3-dithiolane, and protecting groups forming hydrazones substituted with N,N-dimethyl, 2, 4-dinitrophenyl, etc. Among them, 1,3-dioxane, etc. are preferable.
  • the protecting group for carboxyl group include those mentioned for the carboxyl group represented by R 5 . Among them, tert-butyl group, benzyl group, etc. are preferable.
  • the protecting group for the hydroxy group include those mentioned for the hydroxy group represented by the above R 1 , R 2 , R 3 and R 4 .
  • the salt of Compound ( I ) according to the invention includes a salt with a pharmacologically acceptable base and a salt with an pharmacologically acceptable acid.
  • the salt with a pharmacologically acceptable base include a salt with an alkali metal (e.g. sodium, potassium, etc.) and a salt with an alkaline earth metal (e.g. calcium, magnesium, etc.).
  • the pharmacologically acceptable acid include a salt with an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.) and a salt with an organic acid (e.g.
  • Examples of the pro-drug of Compound (I) include a compound wherein an amino group of Compound (I) is acylated, alkylated, phosphorylated, etc. (e.g.
  • a compound wherein an amino group of Compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-l,3-dioxolen-4- yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, tert-butylated, etc. ) ; a compound wherein an hydroxy group of Compound ( I ) is acylated, alkylated, phosphorylated, borylated, etc. (e.g.
  • Compound (I) a compound wherein an hydroxy group of Compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated, etc.); a compound wherein a carboxyl group of Compound ( I ) is modified with ester, amide, etc. (e.g.
  • the pro-drug of Compound ( I ) may be a compound which is converted into Compound ( I ) under the physiological conditions as described in "Pharmaceutical Research and Development” , Vol. 7 (Drug Design) , pages 163-198 published in 1990 by Hirokawa Publishing Co. (Tokyo, Japan) .
  • Compound (I) may be hydrated.
  • Compound (I) can be produced, for example, by reacting a compound of the formula (II), its salt or its reactive derivative at the amino group [hereinafter briefly referred to as Compound (II) ] with a compound of the formula (III) , its salt or its reactive derivative at the carboxyl group [hereinafter briefly referred to as Compound (III) ] , or by reacting a compound of the formula (IV) , its salt or its reactive derivative at the amino group [hereinafter briefly referred to as Compound (IV) ] with a compound of the formula (V) , its salt or its reactive derivative at the carboxyl group [hereinafter briefly referred to as Compound (V) ] , if necessary, followed by deprotection.
  • the reacting derivatives at the amino group mean ones capable of forming peptide bond by reacting with compounds (III) or (V) respectively, for example, a compound which forms by the substitution of the amino group of Compound (II) and Compound (IV) etc. with a trimethylsilyl group, a trimethylstannyl group.
  • the reacting derivatives at the carboxyl group mean ones capable of forming peptide bond by reacting with compounds (II) and (IV) respectively, and can be prepared from Compound (III) and (V) respectively, for example, by the acid halide method, azide method, mixed acid anhydride method (the "counterpart acid” which can be used includes isobutyloxycarbonyl chloride, pivaloyl chloride, etc.
  • symmetric acid anhydride method the method using a condensing agent such as N,N' -carbodiimidazole, N,N' -dicyclohexylcarbodiimide, N,N'- diisopropylcarbodiimide, 1-ethyl-3- ( 3- dimethylaminopropyl)carbodiimide , N-ethoxycarbonyl-2-ethoxy- 1,2-dihydroquinoline, diethyl phosphorocyanidate , diphenylphosphoryl azide, 2-(lH-benzotriazol-l-yl) -1, 1,3,3- tetramethyluronium tetrafluoroborate, 2-(lH-benzotriazol-l-yl) - 1,1,3,3-tetramethyluronium hexafluorophosphate, benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafluorophosphate, benzo
  • the solvent which can be used includes aromatic hydrocarbons such as benzene, toluene , xylene , etc . ; halogenated hydrocarbons such as dichloromethane , chloroform, etc., saturated hydrocarbons such as hexane, heptane, cyclohexane, etc.; ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.; nitriles such as acetonitrile etc.; sulfoxides such as dimethyl sulfoxide etc.; amides such as N,N-dimethylformamide etc.; esters such as ethyl acetate etc. , and water.
  • aromatic hydrocarbons such as benzene, toluene , xylene , etc .
  • halogenated hydrocarbons such as dichloromethane , chloroform, etc., saturated hydrocarbons such as hexane,
  • Each amount of Compounds (III) and (IV) is 0.5 to 10 equivalents relative to one equivalent of Compounds (IV) and (V) , respectively.
  • the reaction temperature is usually about-80 to 100° C and preferably about-50 to 50" C.
  • the reaction time may range from about 1 to 96 hours, preferably about 1 to 72 hours.
  • the compound when amino group, carboxyl group, hydroxy group or carbonyl group each of which is not concerned with the reaction is protected, the compound can be subjected to deprotection reaction to convert to Compound ( I ) .
  • hydroxy-protecting, carbonyl-protecting, and carboxy-protecting groups includes the method using an acid, the method using a base, the reduction method, the ultraviolet method, the hydrazine method, the phenylhydrazine method, the sodium N-methyldithiocarbamate method, the tetrabutylammonium fluoride method, the palladium acetate method, the mercury chloride method, and the Lewis acid method.
  • Those routine methods and/or other known methods can be selectively used.
  • the method using an acid is one of the common methods for hydrolyzing an amide, ester, silyl ester, or silyl ether, and is applied to elimination of the corresponding type of protecting group .
  • the method is commonly used for deprotection of an amino group protected by tert-butoxycarbonyl, p- methoxybenzyloxycarbonyl , benzhydryloxycarbonyl, 9- anthrylmethoxycarbonyl, 1-methyl-l- ( 4-biphenyl)ethoxycarbonyl, adamantyloxycarbonyl , or trityl and the deprotection of a hydroxy group protected by methoxymethyl, tert-butoxymethyl, 2- tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, 2- tetrahydrofuranyl, or trityl.
  • the preferred acid includes organic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • the method using a base is one of the common methods for hydrolyzing an amide, ester, or the like bond and is applied to elimination of the corresponding type of protecting group.
  • organic bases can be used with advantage for deprotection of an amino group protected by 9-fluorenylmethoxycarbonyl.
  • the preferred base includes such inorganic bases as alkali metal hydroxides , e . g. lithium hydroxide, sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides, e.g. magnesium hydroxide, calcium hydroxide, etc.; alkali metal carbonates , e.g.
  • alkaline earth metal carbonates e.g. magnesium carbonate, calcium carbonate, etc.
  • alkali metal hydrogencarbonates e.g. sodium hydrogencarbonate , potassium hydrogencarbonate , etc.
  • alkali metal acetates e.g. sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphates e.g. calcium phosphate, magnesium phosphate, etc.
  • alkali metal hydrogenphosphate e.g.
  • disodium hydrogenphosphate dipotassium hydrogenphosphate, etc.; and aqueous ammonia; and such organic bases as trimethylamine , triethylamine, diisopropylethylamine , pyridine, picoline, N- methylpyrrolidine, piperidine, N-methylpiperidine, N- methylmorpholine, l,5-diazabicyclo[4.3.0]non-5-ene, 1,4- diazabicyclo[2.2.2]octane, 1 , 8-diazabicyclo [ 5.4.0 ] -7-undecene, etc.
  • organic bases as trimethylamine , triethylamine, diisopropylethylamine , pyridine, picoline, N- methylpyrrolidine, piperidine, N-methylpiperidine, N- methylmorpholine, l,5-diazabicyclo[4.3.0]non-5-ene, 1,4- diazabicyclo[
  • the reduction method is used typically for the deprotection of an amino group protected by trichloroacetyl, trifluoroacetyl, o-nitrophenylacetyl, 2 , 2 , 2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4- dichlorobenzyloxycarbonyl, isonicotinyloxycarbonyl, trityl, or the like; the deprotection of a hydroxy group protected by benzyl, p-nitrobenzyl, or the like; and the protection of a carboxyl group protected by benzyloxymethyl, benzyl, p-nitrobenzyl, phenacyl, 2,2,2-trichloroethyl, benzhydryl, or the like.
  • the preferred mode of reduction includes reduction with sodium borohydride, reduction with zinc/acetic acid, and catalytic reduction.
  • the ultraviolet method is applied typically to the deprotection of a hydroxy or carboxyl group protected by o-nitrobenzyl.
  • the hydrazine method is typically applied to the deprotection of an amino group protected by phthaloyl (e.g. phthalimide group) .
  • phthaloyl e.g. phthalimide group
  • phenylhydrazine method is typically applied to the deprotection of an amino group protected by acetoacetyl.
  • the sodium N-methyldithiocarbamate method is typically applied to the deprotection of a chloroacetyl-protected amino or hydroxy group.
  • the tetrabutylammonium fluoride method is typically used for deprotecting a 2-trimethylsilylethylcarbamate, silyl ether, or silyl ester to regenerate an amino group, a hydroxy group or a carboxyl group as the case may be.
  • the palladium acetate method is typically used for deprotecting an allyl ester to regenerate a carboxyl group.
  • the mercury chloride method is typically applied to the deprotection of a hydroxy group protected by methylthiomethyl .
  • the Lewis acid method is typically applied to the deprotection of a hydroxy group protected by 2-methoxyethoxymethyl.
  • the preferred Lewis acid includes zinc bromide and titanium tetrachloride, among other compounds.
  • the intermediates, reaction products, and end products as produced by the above series of reactions can be isolated and purified as necessary by known purification procedures or procedures analogous thereto, for example by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, redistribution, and chromatography.
  • the above Compound (III) can be produced by reacting ⁇ -L-amino acid whose functional group such as amino group, hydroxy group, carbonyl group, etc.
  • the above Compound (IV) can be produced, for example, by reacting Compound (II) obtained by the method shown above with L-serine whose amino group is protected and whose hydroxy group may be protected, with L-asparagine whose amino group is protected and whose carbamoyl group may be protected or with (S) -2-aminobutyric acid whose amino group is protected and then removing the protecting group for amino group.
  • Compound ( I ) according to the present invention is less toxic and has laudable pharmacobiological activities , for example high antibacterial activity against Helicobacter bacteria represented by Helicobacter pylori . so that it is effective in the prevention or treatment of diseases associated with Helicobacter pylori infection and/or an ammonium produced by Helicobacter pylori (e.g. , duodenal ulcer, gastric ulcer, gastritis (inclusive of chronic gastritis), cancer of the stomach, gastric MALT lymphoma, hepatic encephalopathy, diabetes mellitus , urticaria), especially duodenal ulcer, gastritis, gastric MALT lymphoma.
  • diseases associated with Helicobacter pylori infection and/or an ammonium produced by Helicobacter pylori e.g. , duodenal ulcer, gastric ulcer, gastritis (inclusive of chronic gastritis), cancer of the stomach, gastric MALT lymphoma,
  • compound (I) or its salt can be used in combination with other antibacterial agents and antiulcer agents.
  • antibacterial agents that can be used in combination with compound (I) include, for example, nitroimidazole antibiotics (e.g. , tinidazole and metronidazole) , tetracyclines (e.g., tetracycline, doxycycline and minocycline) , penicillins (e.g., amoxicillin, ampicillin and mezlocillin) , cephalosporins (e.g., cefaclor, cefadroxil, cefazolin, cefuroxime, cefuroxime axetil, cephalexin, cefpodoxime proxetil, ceftazidime and ceftriaxone), carbapenems (e.g., imipenem and meropenem) , aminoglycosides (e.g., paromomycin) , macrolide antibiotics (e.g., erythromycin, clarithromycin and azithromycin) ,
  • Antiulcer agents that can be used in combination with compound (I) include, for example, proton pump inhibitors (e.g., lansoprazole, omeprazole, pantoprazole, rabeprazole, leminoprazole, etc.) and Histamine H 2 antagonists (e.g., ranitidine, cimetidine and famotidine) .
  • the above-described other antibacterial agents and antiulcer agents may be used in combination of two or more kinds .
  • the dose of the antibacterial agent is normally 1 to 500 mg, preferably 5 to 200 mg, per adult per day in oral administration; the dose of antiulcer agent is normally 0.5 to 1,000 mg, preferably 1 to 500 mg, per adult per day in oral administration.
  • the medicinal composition comprising Compound (I) according to the invention can be administered as a safe antibacterial agent or as a safe antiulcerative drug to man and other mammals (e.g. human, canine, feline, monkey, rat, mouse, equine, bovine, etc.), alone or together with a pharmaceutically acceptable carrier, either orally or parenterally.
  • a pharmaceutically acceptable carrier e.g. human, canine, feline, monkey, rat, mouse, equine, bovine, etc.
  • the oral route of administration is preferred.
  • the dosage form which can be used for oral medication includes but is not limited to tablets (inclusive of dragees and film-coated tablets ) , pills , granules , fine granules , powders , capsules
  • the dosage form for parenteral administration includes but is not limited to injections, infusions, drip infusions, and suppositories .
  • the oral medication is preferably administered as the gastric mucosa-adhesive composition (the gastric mucosa-adhesive agent).
  • the gastric mucosa-adhesive composition according to the present invention is, for instance, a composition comprising (a) a compound ( I ) having anti-Helicobacter pylori activity, (b) a lipid and/or a polyglycerol fatty acid ester and (c) a viscogenic agent (a material which becomes sufficiently viscous with water to attach itself to the gastric mucosa) .
  • the composition is at least adapted to attach itself to the gastric mucosa and/or otherwise stay in the stomach and release the active ingredient such as anti-Helicobacter pylori substance contained therein at a suitable rate and thereby display a potentiated pharmaceutical effect (e.g. anti-
  • the composition is preferably be a composition further comprising (d) a material which swells a viscogenic agent (e.g. a curdlan and/or a low-substituted hydroxypropylcellulose as a swelling material) .
  • a viscogenic agent e.g. a curdlan and/or a low-substituted hydroxypropylcellulose as a swelling material
  • the composition is preferably a solid composition and particularly a composition containing a matrix.
  • the matrix may, for example, be a gastric mucosa-adhesive matrix comprising (a) , (b) a polyglycerol fatty acid ester and (c) , or a gastric mucosa-adhesive matrix comprising (a), (b) a lipid and (c).
  • the preferred matrix is a gastric mucosa-adhesive matrix comprising (b) a polyglycerol fatty acid ester.
  • the preferable example of the gastric adhesive composition of the present invention is a composition further comprising (d) a material which swells a viscogenic agent .
  • the gastric mucosa-adhesive matrix comprising said four components (a), (b), (c), and/or (d) is preferably a matrix such that the viscogenic agent is dispersed in the matrix which comprises the polyglycerol fatty acid ester or lipid or a matrix which is covered with the viscogenic agen .
  • the melting point of the gastric mucosa-adhesive matrix may, for example, be about 30° to about 120° C and preferably about 40° to about 120° C.
  • the polyglycerol fatty acid ester for use in the present invention is esters of polyglycerols with fatty acids and may be a mono- or poly-ester (diester, triester, etc.).
  • the polyglycerol fatty acid ester is characterized in that it does not undergo polymorphic transition or any material interaction with the active ingredient, allowing those coexisting ingredients to remain undeactivated and stable for an extended period of time.
  • Polyglycerol by definition is "a polyhydric alcohol containing n (cyclic form) to (n+2) (straight-chain form or branched form) hydroxy groups and (n-1) (straight-chain form or branched form) to n (cyclic) ether bonds per molecule"
  • Polyglycerin Esters (ed.) Sakamoto Yakuhin Kogyo Co., Ltd., published October 4, 1994]
  • any straight-chain ester or branched-chain ester can be used in the present invention.
  • compounds of the following formula (VI) can be employed.
  • n represents a degree of polymerization which is an integer of not less than 2 .
  • the value of n is generally about 2 to about 50, preferably about 2 to about 20, and for still better results, about 2 to about 10.
  • the polyglycerol includes but is not limited to diglycerol, triglycerol, tetraglycerol, pentaglycerol, hexaglycerol, heptaglycerol, octaglycerol, nonaglycerol , decaglycerol, pentadecaglycerol, eicosaglycerol, and triacontaglycerol.
  • tetraglycerol, hexaglycerol or decaglycerol is used in many cases .
  • the fatty acid includes but is not limited to saturated or unsaturated fatty acids each containing about 8 to about 40, preferably about 12 to about 25, and more preferably about 15 to about 22 carbon atoms.
  • the preferred fatty acid is stearic acid, oleic acid, lauric acid, linoleic acid, linolenic acid, ricinoleic acid, caprylic acid, capric acid, or behenic acid.
  • the polyglycerol fatty acid ester includes but is not limited to behenic acid hexa( tetra)glyceride, caprylic acid mono(deca)glyceride, caprylic acid di( tri)glyceride, capric acid di(tri)glyceride, lauric acid mono( tetra)glyceride, lauric acid mono(hexa)glyceride, lauric acid mono(deca)glyceride, oleic acid mono(tetra)glyceride, oleic acid mono(hexa)glyceride, oleic acid mono(deca)glyceride, oleic acid di( tri)glyceride, oleic acid di(tetra)glyceride, oleic acid sesqui(deca)glyceride, oleic acid penta(tetra)glyceride, oleic acid penta(hexa)glyceride, oleic acid
  • the preferred polyglycerol fatty acid ester includes , for instance, behenic acid hexa( tetra) glyceride (e.g. HB-310TM, Sakamoto Yakuhin Kogyo Co. , Ltd. , ; Poem J-46BTM, Riken Vitamin Co. ) , stearic acid penta(tetra) glyceride (e.g. PS-310TM, Sakamoto Yakuhin Kogyo Co. , Ltd. ) , stearic acid mono(tetra)glyceride (e.g.
  • polyglycerol fatty acid esters can be used each alone or as a mixture of two or more species , preferably about 2 or about 3 species .
  • the molecular weight of the polyglycerol fatty acid ester is generally about 200 to about 5000, preferably about 300 to about 3000, preferably about 2000 to about 3000.
  • the hydrophile- lipophile balance (HLB) number of the polyglycerol fatty acid ester is generally about 1 to about 22, preferably about 1 to about 15, more preferably about 1 to about 9 , for still better results , about 1 to about 4.
  • Two or more polyglycerol fatty acid esters differing in HLB number from each other may be used in combination to provide for the designed HLB number.
  • the proper polyglycerol fatty acid ester can be selected with reference to the particular active ingredient (e.g. anti- Helicobacter pylori agent, etc.), viscogenic agent, swelling material (e.g. curdlan, and/or low-substituted hydroxypropylcellulose, etc.), the particular combination thereof , and the objective form of the composition.
  • active ingredient e.g. anti- Helicobacter pylori agent, etc.
  • viscogenic agent e.g. anti- Helicobacter pylori agent, etc.
  • swelling material e.g. curdlan, and/or low-substituted hydroxypropylcellulose, etc.
  • a suitable polyglycerol fatty acid ester is selected according to the species of active ingredient used and the intended dosage form. Generally, polyglycerols with degrees of polymerization in the range of about 2 to about 16 are preferred. The particularly preferred range is about 2 to about 10. Preferred are esters such that the fatty acid has formed an ester bond with at least one of the (degree of polymerization +2) hydroxy groups, preferably such that the fatty acid or acids have formed ester bonds with not less than about 60%, more preferably not less than about 80%, of the total number of hydroxy groups in the polyglycerol. The fatty acid or acids are preferably saturated acids each containing about 6 to about 22, more preferably about 15 to about 25, and for still better result, about 18 to about 22 carbon, atoms.
  • the fatty acid involved in the formation of the ester bonds may be of the same kind or different kinds .
  • a liquid polyglycerin fatty acid ester may be included in the mixture as long as the final composition is solid at atmospheric temperature.
  • the amount of the polyglycerol fatty acid ester relative to the total weight of the composition is generally about 5 to about 98 weight %, preferably about 20 to about 95%, more preferably about 40 to about 95% and to the active ingredient in the composition may, for example, be about 0.01 to about 15000 times by weight, preferably about 0.1 to about 1000 times by weight, and for still better result, about 0.1 to about 100 times by weight.
  • the lipid for use in the present invention is one having a melting point of about 40 to about 120° C, preferably about 40 to about 90° C.
  • the lipid includes but is not limited to saturated fatty acids of about 14 to about 22 carbon atoms (e.g. myristic acid, stearic acid, palmitic acid, behenic acid, etc.) or salts (sodium salt, potassium salt, etc. ) thereof; higher alcohols of about 16 to about 22 carbon atoms (e.g. cetyl alcohol, stearyl alcohol, etc.); fatty acid glycerol esters such as the monoglycerides , diglycerides , triglycerides , etc. of the above-mentioned fatty acids (e.g. 1-monostearin, 1-monopalmitin, etc.); oils (e.g. castor oil, cottonseed oil, beef tallow, etc.
  • saturated fatty acids of about 14 to about 22 carbon atoms e.g. myristic acid, stearic acid, palmitic acid, behenic acid, etc.
  • salts sodium salt, potassium salt, etc.
  • oils e.g. beeswax, camauba wax, sperm wax, etc.
  • hydrocarbons e.g. paraffin, microcrystalline wax, etc.
  • phospholipids e.g. hydrogenated lecithin etc.
  • oils, waxes, C ⁇ 4 _ 22 saturated fatty acids, C ⁇ 6 - 22 higher alcohols, and hydrocarbons are preferred.
  • the more preferred are hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, carnauba wax, stearic acid, stearyl alcohol, and microcrystalline wax.
  • the most preferred is hydrogenated castor oil or carnauba wax.
  • the amount of the lipid relative to the total weight of the composition is generally about 5 to about 98 weight %, preferably about 20 to about 95 weight %, more preferably about 40 to about 95 weight %, and to the active ingredient in the composition is about 0.01 to about 15000 times by weight, preferably about 0.1 to about 1000 times by weight , and for still better resul , about 0.1 to about 100 times by weight.
  • the above-mentioned polyglycerol fatty acid ester and lipid may be used as a mixture.
  • the combination of a polyglycerol fatty acid ester with a wax or the combination of a polyglycerol fatty acid ester with a hydrogenated oil can be mentioned.
  • the total amount of the polyglycerol fatty acid ester and lipid relative to the total weight of the composition is generally about 5 to about 98 weight % , preferably about 20 to about 95 weight % , more preferably about 40 to about 95 weight %, and to the active ingredient in the composition is about 0.01 to about 15000 times by weight , preferably about 0.1 to about 1000 times by weight , and for still better result , about 0.1 to about 100 times by weight.
  • a lipid may be incorporated in a matrix comprising the polyglycerol fatty acid ester.
  • the lipid is a pharmaceutically acceptable water-insoluble substance capable of regulating the dissolution kinetics of the active ingredient.
  • the lipid includes those species mentioned hereinbefore.
  • the amounts of the lipid and polyglycerol fatty acid ester need only be within the range not detracting from the adhesion to the gastrointestinal mucosa and can be selected from said range of total amount , and the amount of the lipid relative to the polyglycerol fatty acid ester may be about 0.01 to about 1000 times by weight, preferably about 0.1 to about 200 times by weight, and for still better results, about 0.1 to about 100 times by weight.
  • the swelling material used in the present invention is a material which swells a viscogenic agent or accelerates the swell of a viscogenic agent caused by water.
  • Any type of swelling material can be used in the present invention as long as it has the characteristics described above and is pharmaceutically acceptable.
  • a curdlan and/or a low-substituted hydroxypropylcellulose can be used.
  • the amount of the swelling material in the gastric mucosa- adhesive composition of the present invention is about 0.5 to about 50 weight %, preferably about 1 to about 40 weight %, and for still better results, about 1 to about 30 weight %, relative to the total weight of the composition.
  • the curdlan for use in the present invention is a linear water-insoluble polysaccharide (b-1, 3-glucan) produced by microorganisms (such as Alcaligenes faecalis var. myxogenes etc. ) , which includes such species as curdlan 10C3K, 13140, 12607, 12665, 13127, 13256, 13259, and 13660 [New Food Industry, 20, No. 10, p. 49 (1978)] .
  • curdlan N a food additive.
  • the amount of the curdlan in the gastric mucosa-adhesive composition of the invention relative to the total weight of the composition is about 0.5 to about 50 weight %, preferably about 1 to about 40 weight % , and more preferably about 1 to about 30 weight % .
  • the low-substituted hydroxypropylcellulose for use in the present invention is a cellulose derivative available upon substitution of hydroxypropoxy for some of the hydroxy groups of cellulose, which has a hydroxypropoxy content of 5.0 to 16.0% (as specified in the Japanese Pharmacopoeia Twelfth Edition).
  • the low-substituted hydroxypropyl cellulose mentioned above is useful, in particular, one which has a hydroxypropoxy content of 7.0 to 13.0% (e.g. L-HPCTM, Shin-Etsu Chemicals . , Co. , Ltd. is preferred.
  • those derivatives with a degree of substitution within the above range and varying in particle diameter such as LH-11TM (Shin-Etsu Chemicals., Co., Ltd. hydroxypropoxy content 10.0 to 12.9%, particle size distribution ⁇ 98% under 150 ⁇ m sieve and - ⁇ O.5% on 180 ⁇ m sieve), LH-20TM (Shin-Etsu Chemicals., Co., Ltd., hydroxypropoxyl content 13.0-16.0%, particle size distribution ⁇
  • LH-22 or LH-31 is utilized.
  • the amount of the low-substituted hydroxypropylcellulose in the gastric mucosa adhesive composition of the present invention is about 0.5 to about 50 weight %, preferably about 1 to about 40 weight % , and for still better results , about 1 to about 30 weight % , relative to the total weight of the composition.
  • viscogenic agent any type of viscogenic agent can be used in the present invention as long as it becomes sufficiently viscous with water to attach itself to the gastrointestinal mucosa and is pharmaceutically acceptable. Preferred, however, are those substances which are markedly swollen by water and develop high degrees of viscosity.
  • the viscogenic agent thus , includes synthetic polymers and naturally-occurring viscogenic materials.
  • the preferred synthetic polymer is a polymer such that the viscosity of a 2% aqueous solution thereof at 20° C is about 3 to about 50000 cps. , preferably about 10 to about 30000 cps. , and for still better results, about 15 to about 30000 cps.
  • the preferred polymer is such that the viscosity of a 0.2% solution thereof after neutralization at 20° C is about 100 to about 500000 cps , preferably about 100 to about 200000 cps, and for still better results, about 1500 to about 100000 cps.
  • the value of the viscosity is measured with a Brookfield viscometer at about 20° C.
  • the above-mentioned polymer is an acidic polymer which includes but is not limited to carboxyl-or sulfo-containing polymers and the corresponding salt-containing polymers. Particularly preferred are carboxyl-containing polymers and carboxylate salt-containing polymers.
  • the carboxyl (inclusive of its salt ) -containing polymer is preferably an acrylic homopolymer or copolymer containing acrylic acid as a monomer unit or its salt.
  • the salt includes monovalent metal salts such as the sodium salt, potassium salt, etc. , divalent metal salts such as the magnesium salt, calcium salt, etc. , ammonium salt, etc.
  • the acrylic polymer, inclusive of its salt includes polymers containing carboxyl groups in a proportion of about 58 to about 63 weight % and having a molecular weight of about 20 X 10 4 to about 600 X 10 4 , preferably about 100 X 10 4 to about 600 X 10 4 , and more preferably about 100 10 4 to about 500 X ION
  • the preferred acrylic polymer, inclusive of its salt includes acrylic acid homopolymers and their salts. Such polymers are listed under the heading of carboxyvinyl polymer in Japanese Standards of Pharmaceutical Ingredients (October 1986).
  • carbomer [CarbopolTM (hereinafter referred to as Carbopol), The B.F. Goodrich Company] 940, 934, 934P, 941, 1342, 974P, 971P ( ⁇ F XVIII), EX214 etc., HIVISWAKOTM 103, 104, 105, and 204 (Wako Pure Chemical Industries) , ⁇ OVEO ⁇ AA1TM (The B.F. Goodrich Company), and calcium polycarbophil (US Patent XXIII)).
  • CarbopolTM hereinafter referred to as Carbopol
  • the B.F. Goodrich Company 940, 934, 934P, 941, 1342, 974P, 971P ( ⁇ F XVIII), EX214 etc.
  • HIVISWAKOTM 103, 104, 105, and 204 Wako Pure Chemical Industries
  • ⁇ OVEO ⁇ AA1TM The B.F. Goodrich Company
  • calcium polycarbophil US Patent XXIII
  • the naturally-occurring viscogenic agent includes but is not limited to mucin, agar, gelatin, pectin, carrageenin, sodium alginate, locust bean gum, xanthan gum, tragacanth gum, chitosan, pullulan, waxy starch, sucralfate, curdlan, and cellulose and its derivatives (e.g. cellulose sulfate) and preferably hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.).
  • mucin agar, gelatin, pectin, carrageenin, sodium alginate, locust bean gum, xanthan gum, tragacanth gum, chitosan, pullulan, waxy starch, sucralfate, curdlan, and cellulose and its derivatives (e.g. cellulose sulfate) and preferably hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.).
  • the most preferred viscogenic agent is an acrylic polymer or its salt. Those viscogenic agents can be used alone or in combination. Referring to the amount of the viscogenic agent for use in the composition of the invention, its amount in the gastric mucosa adhesive matrix may for example be about 0.005 to about 99 weight %, preferably about 0.5 to about 45 weight %, more preferably about 1 to about 30 weight %, furthermore preferably about 1 to about 25 weight %, and for still better result, about 1 to about 20 weight %.
  • the amount of the viscogenic agent is about 0.005 to about 95 weight %, preferably about 0.5 to about 30 weight % , and more preferably about 1 to about 25 weight %, and for still better result, about 1 to about 20 weight % based on the total weight .
  • the proportion of the viscogenic agent is also about 0.005 to about 95 weight %, preferably about 0.5 to about 30 weight %, and more preferably about 1 to about 25 weight %, and for still better result, about 1 to about 20 weight based on the total weight .
  • the composition of the present invention contains a curdlan as a swelling material
  • the composition is capable of attaching itself to the gastrointestinal mucosa even without addition of said viscogenic agent, for the curdlan acts as a viscogenic agent by itself.
  • the curdlan may be formulated in an amount beyond the range defined hereinbefore for imparting the necessary adherent effect.
  • the gastric mucosa adhesive composition comprising the viscogenic agent dispersed in a matrix comprising a polyglycerol fatty acid ester and/or lipid may be any dispersion of the polyglycerol fatty acid ester and/or lipid, viscogenic agent, curdlan and/or low-substituted hydroxypropylcellulose, and active ingredient. Dispersion can be effected by the analogue to the per se known technology.
  • the amount of Compound ( I ) in the medicinal composition of the invention is generally 2 to 85 weight % and preferably 5 to 70 weight % .
  • the manufacturing technology for the pharmaceutical composition (especially, the gastric mucoa adhesive composition)comprising the compound (I) of the present invention include those known methods which are in common usage in the pharmaceutical field.
  • the composition can be manufactured using suitable amounts of the additives (e.g. dilutions, excipient, binder, disintegrator, lubricant, sweetener, surfactant, suspending agent , emulsifier, etc. ) which are generally used in the pharmaceutical industry.
  • said excipient for the manufacture of tablets containing Compound (I), for instance, said excipient , binder, disintegrator, and lubricant are employed.
  • the excipient, binder, and disintegrator are formulated.
  • the excipient is also used in the manufacture of powders or capsules , while the sweetener is added in the manufacture of a syrup.
  • the suspending agent, surfactant , and/or emulsifier is added.
  • the excipient includes but is not limited to lactose, sucrose, glucose, starch, cane sugar, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogencarbonate, calcium phosphate, and calcium sulfate.
  • the binder includes but is not limited to 5 to 10 wt. % starch solution, 10 to 20 wt. % gum arabic solution or gelatin solution, 1 to 5 wt. % gum tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, and glycerin.
  • the disintegrator includes but is not limited to starch and calcium carbonate.
  • the lubricant includes,but is not limited to magnesium stearate, stearic acid, calcium stearate, and purified talc.
  • the sweetener includes but is not limited to glucose, fructose, inverted sugar, sorbitol, xylitol, glycerin, and simple syrup.
  • the surfactant includes but is not limited to sodium lauryl sulfate, polysorbate 80, sorbitan fatty acid monoesters, and polyoxyl stearate 40.
  • the suspending agent includes but is not limited to gum arabic, sodium alginate. carboxymethylcellulose sodium, methylcellulose , and bentonite.
  • the emulsifier includes but is not limited to gum arabic, gum tragacanth, gelatin, and polysorbate 80.
  • the colorant, preservative, flavorant, corrigent, stabilizer, thickener, and other common additives for pharmaceutical use can be formulated in suitable amounts in the manufacture of said dosage forms containing Compound ( I ) .
  • the gastric mucosa adhesive composition which is solid at atomospheric temperature, can be produced in a similar manner to the per se known technology.
  • a typical process comprises melting the polyglycerol fatty acid ester and/or lipid at a temperature beyond its melting point, adding said viscogenic agent, anti- Helicobacter pylori agent, and curdlan and/or low-substituted hydroxypropylcellulose either at one time or serially to the melt to thereby disperse them in the melt, and cooling the dispersion.
  • the heating temperature may for example be about 40 to about 150° C, preferably about 50 to about 110° C, and more preferably about 50 to about 100° C.
  • This process can be carried out with a conventional granulating machine and the composition is preferably molded into solid beads (e.g. granules, fine granules, etc.) by spray cooling, for example spray chilling.
  • the spray chilling method may typically comprise dripping a mixed dispersion of the viscogenic agent, curdlan and/or low- substituted hydroxypropylcellulose, and active ingredient in a molten polyglycerol fatty acid ester and/or lipid at a constant flow rate onto a rotary disk revolving at a high speed of, for example, about 10 to about 6000 rpm, preferably about 900 to about 6000 rpm, and more preferably about 1000 to about 5000 rpm.
  • the rotary disk may for example be a flat, smooth disk, typically made of aluminum and measuring about 5 to about 100 cm in diameter, preferably about 10 to about 20 cm in diameter.
  • the dripping rate of said molten dispersion can be selected according to the designed particle diameter and is generally about 1 to about 1000 g/min. , preferably about 2 to about 200 g/min., more preferably about 5 to about 100 g/min.
  • the granules thus obtained are true to spheres so that a uniform film can be formed on their surface with good efficiency in the subsequent coating step.
  • An alternative production process comprises kneading the viscogenic agent, curdlan and/or low-substituted hydroxypropylcellulose, and active ingredient into the polyglycerol fatty acid ester and/or lipid and granulating the resulting dispersion.
  • the solvent for use in this process may be a solvent of the common variety (e.g. methanol, acetonitrile, chloroform, etc.).
  • a further alternative process for producing the solid composition comprises the use of the melt granulation technology.
  • a typical melt granulation process comprises heating the polyglycerol fatty acid ester and/or lipid at a temperature near its melting point, for example, a temperature from its melting point to a temperature about 5° C below the melting point, subjecting the resulting melt to granulation, such as the above-mentioned spray chilling, and suspending the resulting fine particles together with the viscogenic agent, anti-Helicobacter pylori agent, and curdlan and/or low-substituted hydroxypropylcellulose under heating at a suitable temperature to provide an adhesive matrix-drug system. In this case, the influence of heat on the active ingredient can be avoided.
  • the solid composition comprising a matrix made up of a polyglycerol fatty acid ester and/or a lipid and coated with a viscogenic agent may be a preparation coated with such a viscogenic agent alone or a mixture of a viscogenic agent and a swelling material (e.g. curdlan and/or a low-substituted hydroxypropylcellulose etc) , preferably with a coating material containing either a viscogenic agent alone or a viscogenic agent plus a curdlan and/or a low- substituted hydroxypropylcellulose.
  • the coating material may be a composition containing at least one member selected from among said polyglycerol fatty acid ester, said lipid, and said water- insoluble polymer.
  • the solid composition can be providedwith a film in which the viscogenic agent has been dispersed.
  • the coating material may further contain the additives mentioned hereinbefore.
  • the water-insoluble (hydrophobic) polymer includes but is not limited to hydroxypropylmethylcellulose phthalate (The Japanese Pharmacopoeia Twelfth Edition) , hydroxypropylmethylcellulose acetate succinate (Shin-Etsu Chemicals Co., Ltd.), carboxymethylethylcellulose (Freund Industries Co., Ltd., CMEC, Japanese Standards of Pharmaceutical Ingredients, 1986) , cellulose acetate trimellitate (Eastman) , cellulose acetate phthalate (The Japanese Pharmacopoeia Twelfth Edition), ethylcellulose (Asahi Chemical Industry Co., Ltd.), aminoalkyl methacrylate copolymer (R ⁇ hm-Pharma, EudragitTM RS-100, RL-100, RL-PO, RS-PO, RS-30D, RL-30D) , methacrylic acid-ethyl acrylate copolymer (R ⁇ hm-Pharma, EudragitTM
  • the proportion of the viscogenic agent in the coating material is about 0.005 to about 100 weight %, preferably about 0.05 to about 95 weight %, more preferably about 0.05 to about 30 weight %, and for still better result, about 1 to about 10 weight % based on the whole solid fraction of the coating material.
  • the proportion of the viscogenic agent based on the total weight of the solid fraction of the coating material is about 0.05 to about 95 weight %, preferably about 0.5 to about 95 weight % , more preferably about 0.5 to about 30 weight % , futhermore preferably about 5 to about 30 weight %, and for still better result, about 5 to about 25 weight %.
  • two or more members selected from the class consisting of the polyglycerol fatty acid ester, lipid, and hydrophobic polymer can be used in combination.
  • the remaining component is used in a proportion of about 0.0001 to about 1000 part by weight, preferably about 0.01 to about 100 part by weight, and more preferably about 0.01 to about 10 part by weight.
  • the coating amount can be selected according to the type of solid composition and the desired strength of adhesion to the mucosa.
  • the coating amount for a solid composition may be about 0.1 to about 30 weight %, preferably about 0.5 to about 20 weight %, for tablets and about 0.1 to about 100 weight %, preferably about 1 to about 50 weight %, for fine granules.
  • the coating material may be supplemented with the common additives such as those mentioned hereinbefore.
  • the coating material and the additive may be added together or separately, etc. applied.
  • the proportion of the additive relative to the solid fraction of the coating material is about 0.1 to about 70 weight %, preferably about 1 to about 50 weight %, and more preferably about 20 to about 50 weight %.
  • the coating technology that can be used includes a variety of per se known methods, such as pan coating, fluidized-bed coating, roll coating, etc.
  • the coating material is a solution or dispersion containing water or an organic solvent
  • the spray coating method can also be employed.
  • the kind of said water or organic solvent there is no particular limitation on the kind of said water or organic solvent.
  • alcohols such as methanol, ethanol, isopropyl alcohol, etc .
  • ketones such as acetone etc.
  • halogenated hydrocarbons such as chloroform, dichloromethane, trichloromethane, etc.
  • the objective coated composition can be produced by melting the polyglycerol fatty acid ester and/or lipid, optionally together, ith other additives, under heating, emulsifying the melt with water, spray-coating the surface of a solid composition with the resulting emulsion, and drying the coat.
  • An alternative procedure comprises adding the coating material to the solid composition preheated in a coating pan or the like and melt- spreading the coating.
  • the solid composition is coated generally at a temperature of about 25 to about 60° C and preferably at about 25 to about 40° C.
  • the coating time can be judiciously selected with reference to the coating method, the characteristics and amount of the coating material, and characteristics of the substrate solid composition. Insofar as a sufficient adhesion to the gastrointestinal mucosa can be assured, the gastric mucosa adhesive solid composition may, if necessary, be further coated with a conventional gastric coating agent or a water-soluble coating agent.
  • the gastric mucosa adhesive composition according to the present invention can generally be administered orally as it is or in a suitable preparation.
  • the solid oral dosage form includes but is not limited to fine granules, granules, pills, tablets manufactured by compressing said fine granules or granules with a tablet machine, and capsules manufactured by filling said fine granules or granules into suitable capsule shells .
  • fine granules and granules are preferred.
  • the particle size distribution of said fine granules may for example be : particles measuring about 10 to about 500 ⁇ m in diameter account for not less than about 75 weight %, particles larger than about 500 ⁇ m account for not more than about 5 weight % , and particles smaller than about 10 ⁇ m account for not more than about 10 weight % .
  • the preferred distribution is about 105 to about 500 ⁇ m accounting for about ⁇ 75 weight %, about ⁇ SOO ⁇ m accounting for not more than about 5 weight %, and about ⁇ 74 ⁇ m accounting for not more than about 10 weight %.
  • the particle size distribution of said granules may for example be about 500 to about 1410 ⁇ m accounting for not less than about 90 weight % and about ⁇ 177 ⁇ m accounting for not more than about 5 weight % .
  • gastric mucosa adhesive composition is to be provided as a liquid composition
  • a liquid composition can be manufactured by the manner similar to the per se known technology.
  • a typical procedure comprises mixing a polyglycerol fatty acid ester and/or a lipid, which is liquid at atmospheric temperature, a viscogenic agent , an active ingredient , and a swelling material (e.g. a curdlan and/or a low-substituted hydroxypropylcellulose etc . ) all at once or serially to provide a dispersion or solution.
  • a swelling material e.g. a curdlan and/or a low-substituted hydroxypropylcellulose etc .
  • the dosage form comprising such a liquid adherent mucosal medication system includes but is not limited to syrups , emulsions , suspensions, and encapsulated versions thereof.
  • the proportion of the active ingredient (e.g. an anti-HP agent etc.) in the composition of the invention is about 0.005 to about 95 weight %, preferably about 1 to about 95 weight %, and more preferably about 10 to about 95 weight % , and for still better result , about 10 to about 50.
  • the medicinal composition (especially, a gastric mucosa adhesive composition) of the present invention comprising Compound (I) or its prodrug is stable and less toxic and can therefore be used safely.
  • the daily oral dosage which depends on the patient's clinical status and body weight , the particular species of compound, and the route of administration, for an adult patient (body weight: ca 60 kg), for example, with gastric ulcer associated with
  • Helicobacter pylori infection is 1 to 500 mg, preferably about 10 to 200 mg, as the active ingredient (Compound (I) or its prodrug).
  • HC-70 (The accession number: IFO- 16098( Institute for Fermentation, Osaka)) sufficiently grown on a slant medium composed of glucose 0.1%, tryptone 0.5%, yeast extract 0.25%, and agar 1.5% was used to inoculate a 2-L Sakaguchi flask containing 500 mL of a seed culture medium (pH 7.0) composed of glucose 2.0%, soluble starch 3.0%, corn steep liquor 0.3%, soybean flour 1.0%, polypeptone 0.5%, yeast extract 0.1%, oatmeal agar 0.2%, sodium chloride 0.3%, and precipitated calcium carbonate 0.5% and incubation was carried out on a reciprocating shaker at 24° C for 2 days.
  • a seed culture medium pH 7.0
  • the culture 500 mL, was transferred to a 200-L fermentor containing 120 L of a production medium (pH 6.5) composed of glucose 0.5%, dextrin 5.0%, soybean meal 3.5%, yeast extract 0.5%, precipitated calcium carbonate 0.7%, ACTOCOLTM 31-56 (Takeda Chemical Industries Ltd.) 0.05%, and silicone oil 0.05% and fermention was carried out at a temperature of 22° C and an internal pressure of 1.0 kg/cm 2 under 120 L/min. aeration and 120 rpm agitation for 42 hours.
  • a production medium pH 6.5
  • a production medium composed of glucose 0.5%, dextrin 5.0%, soybean meal 3.5%, yeast extract 0.5%, precipitated calcium carbonate 0.7%
  • ACTOCOLTM 31-56 Takeda Chemical Industries Ltd.
  • silicone oil 0.05%
  • the resulting culture broth (120 L) was adjusted to pH 7 and filteredwith a filter aid (Radiolite 600 , Showa Chemical Industry) .
  • the filtrate (130 L) was adjusted to pH 7 and subjected to HP-20 ( 7 L) column chromatography. After the column was washed with water (21 L) , elution was carried out with 30% (v/v) isopropyl alcohol/H 2 0 (28 L).
  • the eluate was concentrated and the residue was diluted with water to a volume of 30 L and subjected to CNP-80 (H-form, 15 L) column chromatography. After the column was washed with water (45 L) , elution was carried out with 2N-aqueous ammonia (53 L) .
  • the eluate was concentrated and subjected to PA-412 (OH-form, 2 L) column chromatography.
  • the column was washed with water (6 L) and 1 M sodium chloride/H 2 0 (2 L) in that order and serial elution was carried out with 1 M sodium chloride/H 2 0 (10 L) and lN-hydrochloric acid (4 L) .
  • the eluate was adjusted to pH 7 and subjected to HP-20 (1 L) column chromatography.
  • the column was washed with water (3 L) and elution was carried out with 30% (v/v) isopropyl alcohol/H 2 0 (3.4 L).
  • the eluate was concentrated, adjusted to pH 7, and subjected to HP-20S (400 mL) column chromatography.
  • the eluate was concentrated and allowed to stand at 7° C and the crystal crop was harvested to provide HC-70III (1.3 g) .
  • the 10% (v/v) isopropyl alcohol/H 2 0 eluate from the HP-20S (400 mL) column was concentrated, and after addition of methanol, the concentrate was allowed to stand at 7° C and the resulting crystals (1.7 g) were collected by filtration.
  • This crystal crop was recrystallized twice from water. In this manner, a crystal crop (1.3 g) composed predominantly of HC-70II was obtained. Of this crystal crop, 719 mg was subjected to HP-20S (70 mL) column chromatography.
  • the culture 500 mL, was transferred to a 200-L fermentor containing 120 L of a production medium (pH 7.0) composed of glucose 2.0%, soluble starch 3.0%, corn steep liquor 0.3%, soybean flour 1.0%, polypeptone 0.5%, yeast extract 0.1%, sodium chloride 0.3%, precipitated calcium carbonate 0.5%, ACTOCOLTM 31-56 (Takeda Chemical Industries Ltd.) 0.05%, and silicone oil 0.05% and incubated at a temperature of 24° C and an internal pressure of 1.0 kg/cm 2 under 120 L/min. aeration and 120 rpm agitation for 48 hours .
  • a production medium pH 7.0
  • a production medium composed of glucose 2.0%, soluble starch 3.0%, corn steep liquor 0.3%, soybean flour 1.0%, polypeptone 0.5%, yeast extract 0.1%, sodium chloride 0.3%, precipitated calcium carbonate 0.5%
  • ACTOCOLTM 31-56 Takeda Chemical Industries Ltd.
  • silicone oil 0.05%
  • the culture, 10 L was transferred to a 2000-L fermentor containing 1200 L of a production medium (pH 7.0) composed of glucose 0.5%, myo-inositol 1.0%, soybean meal 5.0%, corn steep liquor 1.0%, ACTOCOLTM 31-56 (Takeda Chemical Industries Ltd.) 0.05%, and silicone oil 0.05% and incubated at a temperature of 28° C and an internal pressure of 1.0 kg/cm 2 under 840 L/min. aeration and 30 rpm agitation for 114 hours.
  • a production medium pH 7.0
  • a production medium composed of glucose 0.5%, myo-inositol 1.0%, soybean meal 5.0%, corn steep liquor 1.0%, ACTOCOLTM 31-56 (Takeda Chemical Industries Ltd.) 0.05%, and silicone oil 0.05%
  • the fermentation broth (1200 L) thus obtained was adjusted to pH 5 and a flocculating agent [0.5 (w/v) Sanfloc C-109P, Sanyo Chemical Industries, Ltd.] was added for flocculation.
  • the broth was then filtered with a filter aid (Radiolite 600) .
  • the filtrate (1200 L) was adjusted to pH 5 and subjected to charcoal [Granular Shirasagi (Takeda Chemical Industries Ltd.) , 25 L] and SP-850 (100 L) column chromatographies , followed by washing with water (300 L) .
  • the SP-850 column alone was serially washed with O.lN-sodium hydroxide/H 2 0 (300 L), water (300 L), 0.
  • the column was washed with water (50 mL) and serial elution was carried out with water (100 mL) and 20% (v/v) isopropyl alcohol/H 2 0 (200 mL) .
  • the eluate was concentrated and freeze-dried to provide crude powders (149 mg) .
  • N-tert-butoxycarbonyl-L-methionine (249mg) in acetonitrile (10ml) was added N-hydroxysuccinimide (115mg) and dicyclohexylcarbodiimide (206mg). The reaction mixture was stirred at room temperature for 3 hours , filtered and concentrated. The residue was dissolved in dimethylformamide ( 5ml) .
  • N ⁇ -benzyloxycarbonyl-N £ -tert- butoxycarbonyl-L-lysine (308mg) in acetonitrile (10ml) were added N-hydroxysuccinimide (102mg) and dicyclohexylcarbodiimide (175mg) .
  • the reaction mixture was stirred at room temperature for 2 hours and filtered.
  • In vitro antibacterial test Antibacterial activity against Helicobacter pylori in vitro Using Helicobacter pylori (NCTC 11637) as the test strain, the antibacterial activity of test compounds was assayed by the agar dilution method as follows . Test compounds were respectively dissolved in dimethyl sulfoxide, and using sterile distilled water, a doubling dilution series was prepared for use as samples. Using 7% horse blood-supplemented Brucella agar as the medium, plates were prepared by mixing 2 mL of each sample with 18 mL of the 7% horse blood-Brucella agar.
  • Mongolian gerbils (MON/Jms/Gbs, male, aged 5 weeks) were deprived of food for 20 hours and 10 7 " 58 CFU/mouse of Helicobacter pylori TN2GF4 was inoculated into the stomach.
  • 50 mg/kg of the test compound suspended in 0.5% methylcellulose/water was administered orally twice daily, in the morning and evening, for 2 consecutive days.
  • the stomach was isolated from the infected gerbils and homogenized and a 10-fold dilution series of the homogenate was inoculated on activated charcoal-modified Skirrow medium. Cultivation was carried out microaerobically at 37° C for 4 days and the eradication rate was determined according to growth of the bacteria.
  • Mongolian gerbils (MON/Jms/Gbs) infected with Helicobacter pylori were orally dosed with the compound of Example 14 containing gastric mucosa adhesive preparation obtained in Formulation Example 2 (the compound of Example 14 AdMMS-1 in Table 2), and a 0.5% methylcellulose suspension containing the compound of Example 14 (the compound of Example 14 suspension in Table 2), respectively at a dose of 3 mg/kg, 10 mg/kg as the compound of Example 14 twice a day for 7 consecutive days.
  • the stomach was excised and the gastric wall was homogenized and serial dilutions were plated on the Helicobacter pylori selective medium.
  • the inoculated medium was incubated for 4 days at 37° C under microaerobic conditions and the number of viable cells was counted. The results are shown in Table 2.
  • Table 2 Table 2
  • the compound or salt of the invention can be administered typically in the following dosage forms .
  • Compound (I) of the invention has specific and high antibacterial activity against Helicobacter bacteria represented by Helicobacter pylori . Therefore, with this Compound (I), the desired anti-Helicobacter pylori efficacy can be achieved at a remarkably reduced dose as compared with the conventional antibacterial agents available for control of Helicobacter bacteria (especially Helicobacter pylori) .
  • Compound (I) is effective in the prevention or treatment of various diseases associated with Helicobacter bacteria, such as duodenal ulcer, gastric ulcer, chronic gastritis, and cancer of the stomach. Moreover, because Helicobacter pylori is a major factor in recurrences of ulcer. Compound (I) is effective in preventing recurrence of ulcers as well.
  • Compound (I) shows no activity against such gram-positive bacteria as those of the general Staphylococcus and Bacillus . or such gram-negative bacteria as those belonging to the general Escherichia, Pseudomonas . Proteus, Klebsiella. Serratia, Salmonella. Citrobacter. Alcali ⁇ enes , etc. Therefore, Compound ( I ) is selectively effective in the prevention or treatment of diseases associated with Helicobacter bacteria, with minimal effects on other bacteria and fungi, and, therefore, can be used as a safe drug.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP00900126A 1999-01-07 2000-01-06 Polyol verbindungen, verfahren zur deren herstellung und verwendung Withdrawn EP1140979A1 (de)

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JP189899 1999-01-07
JP189899 1999-01-07
PCT/JP2000/000023 WO2000040599A1 (en) 1999-01-07 2000-01-06 Polyol compounds, their production and use

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TW420610B (en) * 1994-04-07 2001-02-01 Pfizer A pharmaceutical composition for treating a H. pylori infection or gastric or duodenal ulcers
WO1998042311A1 (en) * 1997-03-25 1998-10-01 Takeda Chemical Industries, Ltd. Gastrointestinal mucosa-adherent pharmaceutical composition
ID20812A (id) * 1997-07-09 1999-03-11 Takeda Chemical Industries Ltd Senyawa polyol, produk dan penggunaannya

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