WO2007126039A1 - Préparation antibiotique macrolide enrobée - Google Patents

Préparation antibiotique macrolide enrobée Download PDF

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Publication number
WO2007126039A1
WO2007126039A1 PCT/JP2007/059144 JP2007059144W WO2007126039A1 WO 2007126039 A1 WO2007126039 A1 WO 2007126039A1 JP 2007059144 W JP2007059144 W JP 2007059144W WO 2007126039 A1 WO2007126039 A1 WO 2007126039A1
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group
macrolide antibiotic
substituted
atom
coated preparation
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PCT/JP2007/059144
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English (en)
Japanese (ja)
Inventor
Tatsumori Yoshida
Takeshi Funaki
Yurie Kobayashi
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Shionogi & Co., Ltd.
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Priority to JP2008513281A priority Critical patent/JPWO2007126039A1/ja
Publication of WO2007126039A1 publication Critical patent/WO2007126039A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

Definitions

  • the present invention relates to a stable coating preparation of a macrolide antibiotic effective for the treatment of various infectious diseases caused by bacteria, mycoplasma, fungi, protozoa and the like.
  • Macrolide antibiotics are known to be useful for the treatment of a wide variety of infectious diseases caused by bacteria, mycoplasma, fungi (breasts), protozoa, etc. in mammals, fish and birds.
  • erythromycin As a representative macrolide antibiotic, erythromycin (Patent Documents 1 and 2) has many advantages such as its characteristic antibacterial activity, good tissue migration, and few side effects, and has been a clinically useful antibiotic for many years. Has been used. Since then, various macrolide antibiotics have been promoted, in clinical development, or in research and development.
  • macrolide antibiotics examples include 14- to 16-membered macrolide antibiotics such as erythromycin (Patent Documents 1 and 2), oleandomycin (Patent Documents 3 and 4), and clarithromycin.
  • Patent document 5 roxithromycin (patent document 6), adithromycin (patent document 7), dirithromycin (patent document 8), tethromycin (patent document 9), sesulomycin (patent document 10), flurithromycin Mycetyl succinate (patent document 11), compounds described later (patent documents 12, 13), L-701677 (patent document 14), mycinamicin (non-patent document 1), and many other derivatives are known.
  • erythromycin Patent Documents 1 and 2
  • Patent Documents 3 and 4 examples include clarithromycin.
  • Patent document 5 roxithromycin (patent document 6), adithromycin (patent document 7), dirithromycin (patent document 8), tethromycin (patent document 9), sesul
  • Patent Document 15 a hard capsule that can be filled with a solvent for dissolving poorly soluble medicinal components (polyethylene glycol or the like) that cannot be filled with a conventional hard capsule.
  • Patent Document 15 uses a polyvinyl alcohol copolymer as a coating component of a hard capsule, and the polyvinyl alcohol copolymer is a main agent or a solid substance containing the same. It is not intended to be used as a coating material.
  • Patent Document 16 a rosin composition useful as a coating agent for pharmaceuticals, veterinary drugs, agricultural chemicals, fertilizers, foods, etc., mainly composed of a polyvinyl alcohol copolymer is known.
  • Patent Document 16 a rosin composition useful as a coating agent for pharmaceuticals, veterinary drugs, agricultural chemicals, fertilizers, foods, etc., mainly composed of a polyvinyl alcohol copolymer.
  • Patent Document 1 US2653899
  • Patent Document 2 US24.7
  • Patent Document 3 US2757123
  • Patent Document 4 US 2842481
  • Patent Document 5 US4331803
  • Patent Document 6 US4349545
  • Patent Document 7 US4517359
  • Patent Document 8 EP511799
  • Patent Document 9 US literature
  • Patent Document 10 US5866549
  • Patent Document 11 EP56291
  • Patent Document 12 WO2003Z097659 Al
  • Patent Document 13 WO2005Z ⁇ 81821 A2
  • Non-patent document 1 J. Antibiot 45 (1), 1 (1992)
  • Patent Document 14 EP508699
  • Patent Document 15 WO2002Zl7848
  • Patent Document 16 WO2005Z019286
  • R represents a hydrogen atom or a protecting group for a hydroxyl group
  • a macrolide antibiotic having the partial structural formula shown below, a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solid containing the same is added to polybulal alcohol (PVA) It was found that a coated preparation of a stabilized macrolide antibiotic can be obtained by coating with a coating containing a coalescent as a main component, and the present invention has been completed.
  • PVA polybulal alcohol
  • R represents a protecting group for a hydrogen atom or a hydroxyl group
  • a macrolide antibiotic having a group represented by the formula: pharmaceutically acceptable salt thereof, or a hydrate thereof;
  • a coated preparation of a macrolide antibiotic which is coated with a coating agent containing vinyl alcohol or a polyvinyl alcohol copolymer.
  • Macrolide antibiotics have the following partial structural formula (I): [Chemical 4]
  • a macrolide antibiotic having the group represented by the formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • Item 2 A coated preparation of a macrolide antibiotic according to Item 1.
  • Item 3 The coated preparation of a macrolide antibiotic according to Item 1, wherein the macrolide antibiotic is a 14- to 16-membered ring macrolide antibiotic.
  • Macrolide antibiotics have the general formula ( ⁇ ):
  • R 1 represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),
  • R 2 is (1) hydrogen atom, (2) a halogen atom, (3) optionally containing hetero atom oxygen atom, 0-3 of the selected sulfur atom and nitrogen Nuclear
  • substituents optionally containing 0 to 3 heteroatoms selected from atoms, sulfur atoms and nitrogen atoms, and also selected from the group consisting of a norogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group C— C alkell, optionally substituted with
  • A represents —R 1 or —R 2 , or A and B are bonded together with carbon atoms!
  • R 1 has the same meaning as described above
  • R 1 has the same meaning as described above
  • heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C
  • (f) represents a substituted heterocycloalkylene group
  • Halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl base force may also be selected, which may be substituted with one or more substituents, C—C termination
  • R 4 and R 5 together with the nitrogen atom to which they are bonded contain 3 to 10 heteroalkyls containing 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
  • aryl groups substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, which are also selected C 1 -C alkyl optionally substituted with one or more substituents
  • 1 12 represents a group, an aryl group or a substituted aryl group.
  • R 6 is as defined above, provided that R 6 is a C (O) -C 1 -C alkyl group, C (0 ) —C—C cycloalkyl group or C (0) —R
  • a C 1 -C alkyl group which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups,
  • e a C 1 -C alkyl group, which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;
  • c) represents a halogen atom
  • R 2a represents a hydrogen atom or a hydroxyl-protecting group.
  • Item 4 A coated preparation of a macrolide antibiotic according to Item 3, wherein the compound is a compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  • Macrolide antibiotics may have the following formula ( ⁇ ):
  • Macrolide antibiotic power 2 0 14.3, 14.5, 15.1, 18.8, 20.5, 23.2, 24.9, in powder X-ray diffraction pattern Having at least one peak selected from 25. 6, 29.0, 34.1, 37.7, 38.1, 38.9 and 40.4 (unit: degrees), (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-3-dimethylamino 13-D-xylohexopyranosyloxy) 3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl-1,5,7 Dioxo13— [(E) — [6— ( Pyrazole-1-yl) pyridine-3-yl] methoxyimino]-4, 11, 15-trioxabicyclo [8, 5, 4] nonade force-17E-ylidene] acetamide
  • Item 8 The coated preparation of a macrolide antibiotic according to Item 7, wherein the type 1 is an anhydrous crystal.
  • Item 9 The coated preparation of a macrolide antibiotic according to Item 1, wherein the coated preparation is a solid preparation.
  • Item 10 The coated preparation of macrolide antibiotics according to Item 9, wherein the solid preparation is a tablet or a granule.
  • Item 11 Coating power obtained by copolymerization of polybulle alcohol having an average degree of polymerization of 1300 or less and at least one polymerizable bule monomer in a weight ratio of 6: 4 to 9: 1.
  • Item 2. The coated preparation of macrolide antibiotics according to Item 1, characterized in that it comprises a polybutyl alcohol copolymer.
  • Item 12 The coated preparation of a macrolide antibiotic according to Item 11, wherein the average degree of polymerization of the polybulal alcohol is 900 or less.
  • Item 13 The coated preparation of a macrolide antibiotic according to Item 12, characterized in that the average degree of polymerization of polybulal alcohol is 200 to 600.
  • Item 14 The coated preparation of a macrolide antibiotic according to Item 11, wherein the polybulal alcohol is a partially saponified polybulal alcohol.
  • Item 15 Polymerizable Bull Monomer Strength Unsaturated Carboxylic Acids, Unsaturated Carboxylic Acid Esters, Unsaturated-Tolyls, Unsaturated Amides, Aromatic Bulls, Aliphatic Bulls, Unsaturated Bonds Item 12.
  • Item 16 A copolymer obtained by copolymerizing polybulal alcohol and two or more polymerizable bur monomers, and at least one of the two or more polymerizable vinyl monomers is an unsaturated carboxylic acid or Item 12.
  • the coated preparation of macrolide antibiotics according to Item 11, which is a salt thereof and at least one of them is an ester of an unsaturated carboxylic acid.
  • Item 17 Unsaturated carboxylic acids or their salt strength Acrylic acid, methacrylic acid, chloro Tonic acid, fumaric acid, maleic acid, itaconic acid, and their salt strengths are selected from the group of unsaturated carboxylic acid esters such as acetyl metatalylate, methyl acrylate, ethyl acetate, ethyl.
  • R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms
  • Item 19 The macrolide according to Item 16, which is an unsaturated carboxylic acid or a salt thereof, acrylic acid or a salt thereof, and is an ester of an unsaturated carboxylic acid, such as butyl methacrylate. Coated antibiotics.
  • Item 20 Item 19, wherein the weight ratio of acrylic acid or a salt thereof to methyl methacrylate is from 3: 7 to 0.5: 9.5 in the copolymerization.
  • a macrolide antibiotic coating formulation A macrolide antibiotic coating formulation.
  • Item 21 Obtained by copolymerizing a partially saponified polyvinyl alcohol having an average polymerization degree of 300 to 500 and a polymerizable vinyl monomer in a weight ratio of 6: 4 to 9: 1, and The polymerizable bulle monomer is acrylic acid and methyl methacrylate, and the weight ratio of acrylic acid to methyl methacrylate is 3: 7 to 0.5: 9.5 when copolymerized.
  • Item 14 A coated preparation of a macrolide antibiotic according to Item 11, characterized by.
  • Item 22 Partially saponified polybutyl alcohol having an average degree of polymerization of 300 to 500, methyl methacrylate Item 23.
  • Item 23 Content of coating agent
  • the coated preparation of the macrolide antibiotic according to Item 10 which is 2% (weight ratio) or more with respect to the uncoated tablet or elementary granule.
  • Item 24 The total amount of related substances after storage for 3 months at 25 ° C and 60% relative humidity in a macrolide antibiotic coated preparation is 3% or less, characterized in that A coated preparation of a macrolide antibiotic described in 1.
  • Macrolide antibiotics are (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-trideoxy-1, 3-dimethylamino j8—D—Hydroxysilano) 1-3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl 5, 7 Dixo 13— [(E) — [6 (Pyrazole 1 yl) Pyridine 3-yl] methoxyimino] — 4, 11, 15 trioxabicyclo [8, 5, 4] nonade force—17E-ylidene] is a type 1 crystal of acetamide with a coating containing acid titanium.
  • the macrolide antibiotic is (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-trideoxy-1, 3-dimethylamino j8—D—Hydroxysilano) 1-3 Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl 5, 7 Dixo 13— [(E) — [6 (Pyrazole 1 yl) Pyridine 3-yl] methoxyimino] — 4, 11, 15 trioxabicyclo [8, 5, 4] nonade force—17E—ylidene] Acetamide type 1 crystals at 25 ° C and 60% relative humidity. Macrolide antibiotic coated preparation, characterized in that the total amount of related substances after storage for 3 months is 1.5% or less
  • Item 27 The coated preparation of a macrolide antibiotic according to Item 26, which is packaged in PTP (press-through package) or bottle packaging.
  • R 2a represents a protecting group for a hydrogen atom or a hydroxyl group
  • a macrolide antibiotic having the group represented by the formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof or a compound thereof.
  • a method for suppressing the formation of a related substance of the macrolide antibiotic which comprises coating a solid substance to be coated with a coating agent containing polybulal alcohol or a polybulal alcohol copolymer.
  • R represents a protecting group for a hydrogen atom or a hydroxyl group.
  • a macrolide antibiotic having a group represented by the formula: a pharmaceutically acceptable salt thereof, a hydrate thereof, or a substance thereof The macrolide antibiotic, its pharmaceutically acceptable salt, or a hydrate thereof, characterized in that a solid is coated with a coating agent containing polybulal alcohol or a polybulal alcohol copolymer. Stable way.
  • the coating preparation of a macrolide antibiotic coated with a coating agent containing polybulualcohol or polybulualcohol copolymer of the present invention has excellent antibacterial activity and is used for treatment of various infectious diseases. It can be used, is pharmaceutically stable for a long period of time, and is easy to take. Therefore, it is very useful as a medicine for humans, veterinary medicine for mammals other than humans, fish, birds and the like.
  • polybulal alcohol or polybulal alcohol copolymer as a coating agent can be coated on the active ingredient microparticles and small solids, which prevents the size of the dosage formulation from increasing, and patients such as the elderly and children
  • solid preparations such as tablets, granules, capsules and pills that are easy to take.
  • FIG. 1 shows a production flow chart of a coated preparation of the macrolide antibiotic of Example 1.
  • FIG. 2 shows a chromatograph of liquid chromatography performed on the coated preparation stored in Example 1 performed in Example 1.
  • FIG. 3 is a graph showing the evaluation results of the stability of the macrolide antibiotic-coated preparation conducted in Example 1.
  • ⁇ indicates uncoated tablets
  • ⁇ indicates tablets coated with polybulal alcohol copolymer.
  • the vertical axis shows the total amount of related substances relative to the main drug in the coated preparation at 0.5 ° C, 1 month, 2 months, and 3 months after 25 ° C, 60% relative humidity and no packaging (w / w%).
  • FIG. 4 shows the ratio (wZw%) of polybulal alcohol copolymer to uncoated tablets, and the affinity for the main drug after storage for 1 week under the conditions of 40 ° C, relative humidity 75%, and no packaging. The relationship with the total amount of substances (wZw%) is shown.
  • FIG. 5 shows a production flow chart of the macrolide antibiotic coated preparation of Example 2.
  • FIG. 6 is a graph showing the evaluation results of the stability of the macrolide-based coated preparation of Example 2.
  • the circles indicate uncoated tablets, and the circles indicate tablets coated with acid-titanium-containing polyvinyl alcohol copolymer.
  • the vertical axis represents the total amount of related substances relative to the active ingredient in the coated preparation at 0.5 and 1 month at 25 ° C, 60% relative humidity, and no packaging (wZw%) Indicates.
  • FIG. 7 shows a production flowchart of a coated preparation of the macrolide antibiotic of Example 3.
  • FIG. 8 is a graph showing the evaluation results of the stability of the macrolide antibiotic-coated preparation of Example 3.
  • ⁇ indicates an uncoated tablet
  • a thumbprint indicates a polybulal alcohol-coated tablet.
  • the total amount of related substances (wZw%) relative to the main drug in the coated preparations after 0.5 months, 1 month, 2 months and 3 months under the conditions of 25 ° C, 60% relative humidity and no packaging is shown.
  • the macrolide antibiotic is preferably a 14- to 16-membered macrolide antibiotic.
  • the following partial structural formula is preferred:
  • R represents a hydrogen atom or a protecting group for a hydroxyl group
  • R represents a hydrogen atom or a protecting group for a hydroxyl group
  • R 2a represents a hydrogen atom or a protecting group for a hydroxyl group
  • a macrolide antibiotic having a group hereinafter also collectively referred to as “Q”
  • Q a macrolide antibiotic having a group
  • the partial structure is stabilized by the coating agent. Therefore, as long as it is a macrolide antibiotic having a group represented by the above general formula (I) in its structural formula, it can be used as a pharmaceutically active ingredient in the preparation of the present invention.
  • the bonding site of the partial structural formula is not necessarily limited in the macrolide ring, but is preferably bonded to the macrolide ring in the manner exemplified below.
  • Ra and Rb together represent oxo, or one represents a hydrogen atom and the other represents an —O sugar residue.
  • Ra and Rb together represent oxo. Represents the remaining partial structure of the McLide ride ring.
  • Examples of the 14-membered macrolide antibiotics include compounds represented by the following general formula ( ⁇ ) having the following crosslinking structure described in WO2003Z097659, pharmaceutically acceptable salts thereof, or hydration thereof. Things are more preferred.
  • R 1 represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),
  • R 2 is (1) hydrogen atom, (2) a halogen atom, (3) optionally containing hetero atom oxygen atom, 0-3 of the selected sulfur atom and nitrogen Nuclear , Halogen, ary Group, substituted aryl group, heteroaryl group and substituted heteroaryl group
  • a C 1 -C alkyl group optionally substituted with one or more substituents, (4) oxygen atom
  • substituents optionally containing 0 to 3 heteroatoms selected from atoms, sulfur atoms and nitrogen atoms, and also selected from the group consisting of a norogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group C— C alkell, optionally substituted with
  • A represents one R 1 or one R 2 and is Or A and B are combined! /, Together with the carbon atom,
  • R 1 has the same meaning as above
  • heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom
  • halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C
  • d) optionally containing 0 to 3 heteroatoms selected from an oxygen atom, sulfur atom and nitrogen atom, and halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl forces are also selected 1 or 2 or more Optionally substituted with a substituent of C— C
  • (f) represents a substituted heterocycloalkylene group
  • One of X and Y represents a hydrogen atom and the other is
  • R 4 and R 5 are each independently (1) hydrogen atom
  • Halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl base force may also be selected, which may be substituted with one or more substituents, C—C termination
  • R 4 and R 5 together with the nitrogen atom to which they are bonded contain 3 to 10 heteroalkyls containing 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms.
  • aryl groups substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, which are also selected C 1 -C alkyl optionally substituted with one or more substituents
  • 1 12 represents a group, an aryl group or a substituted aryl group.
  • R 6 is as defined above, provided that R 6 is a C (O) -C 1 -C alkyl group, C (0 ) —C—C cycloalkyl group or C (0) —R R and R together with the carbon atom to which they are attached form a C -C cycloalkyl group
  • a C 1 -C alkyl group which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups,
  • e a C 1 -C alkyl group, which may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;
  • c) represents a halogen atom
  • R 2a represents a hydrogen atom or a hydroxyl-protecting group.
  • M is preferably a bond
  • Ar 2 preferably represents (d) a substituted heteroaryl group.
  • the heteroaryl group is preferably an aromatic heterocyclic group which may contain 1 to 4 heteroatoms selected from 5 or 6-membered N, S, O forces. Pyridyl.
  • Examples of the substituent on the heteroaryl group include the same aromatic heterocyclic group (eg, pyrazole) which may be substituted with amino-substituted lower alkylami-substituted hydroxy, halogen, lower alkyl, lower alkoxy or the like.
  • X and Y are preferably bonded together with a carbon atom
  • (3) — represents a group represented by C (O) R 11 (R 11 is preferably lower alkyl)).
  • L is preferably CI—C6 lower alkyl, more preferably b) —CH 2 CH.
  • Z is preferably a) a hydrogen atom.
  • Examples of more specific macrolide antibiotics include erythromycin (14-membered ring), 6-deoxyerythromycin (14-membered ring), oleandomycin (14-membered ring), claris mouth mycin (14-membered ring), roxithromycin (14-membered ring), dirithromycin (14-membered ring), terisromycin (14-membered ring, compound (IV)), cesromycin (14-membered ring, compound (IX)) , Flurithromycin (14-membered ring), flurithromycin ethyl succinate (14-membered ring), GW7 73546 (14-membered ring, compound (V)), TEA— 0769 (14-membered ring)), TEA— 0777 (14-membered ring, compound (VI)), TEA— 0929 (14-membered ring), JNJ—17069546 (14-
  • telithromycin GW773546, TEA-0777, CP-544372, JNJ-17069546 and sesromycin, or a pharmaceutically acceptable salt or hydrate thereof. is there.
  • compound (III) which is one embodiment of compound ( ⁇ ), a pharmaceutically acceptable salt thereof or a hydrate thereof.
  • the partial structural formula (I Q) is bonded to the 9-position, and the chemical name of the compound (III) is (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9 (3, 4, 6-Trideoxy-1-3-dimethylamino-1- ⁇ -D-Xyloxyhexopyranosyl Xy) -3 ethyl-2 hydroxy 2, 6, 8, 10, 16, 18 hexamethyl-5, 7- dixo 1 13- [(E) [6- (pyrazole 1-yl) pyridine 1-yl] Methoxyimino] 4, 11, 15 Trioxabicyclo [8,5,4] nonade 17E-ylidene] acetamide.
  • the present inventors have found that the storage stability of compound (III), particularly its crystal (eg, type 1 crystal described in WO2005Z081821, particularly its anhydrous crystal) is extremely poor. In particular, it was found to be unstable to humidity and oxygen under long-term storage. It was also discovered from HPLC inspection, NMR analysis, etc. that the instability of compound (III) was caused by the partial structure shown in (I) above. It was also confirmed that by using the coating agent, the stability of the partial structure was improved and the production of related substances caused by the change in the partial structure was remarkably suppressed. Therefore, the stabilizing effect of the present invention is widely applied to various drugs having the same partial structure, particularly macrolide antibiotics. In addition, the stability of preparations containing them as the main drug, particularly various solid preparations, preferably tablets, granules, capsules, etc., is also improved.
  • various solid preparations preferably tablets, granules, capsules, etc.
  • the related substance produced by the change in the partial structure is typically the peak of the macrolide antibiotic as the main drug in HPLC analysis, as shown in Fig. 2 of the Examples below. Means two types of degradation products that appear before and increase over time in the stability test.
  • This type 1 crystal shows a powder X-ray diffraction pattern substantially the same as the type I polymorph described in WO2005Z081821.
  • the water content can be varied in the range of 0 to 2 hydrates.
  • These macrolide antibiotics are known compounds, and can be produced based on the prior literature described in the background section or by a method analogous thereto.
  • any salt can be used as long as it is a pharmaceutically acceptable salt, and it is not particularly limited.
  • hydrohalic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid
  • inorganic such as sulfuric acid, nitric acid, phosphoric acid, perchloric acid, carbonic acid, boric acid Salts with acids
  • acetic acid, trichlorodiacetic acid trifluoroacetic acid, hydroxyacetic acid, lactic acid, succinic acid, succinic acid, tartaric acid, succinic acid, malonic acid, oxalic acid, benzoic acid, mandelic acid, butyric acid, valeric acid, maleic acid
  • Salts with organic carboxylic acids such as propionic acid, heptanoic acid, formic acid, malic acid, lauric acid, palmitic acid
  • salts with amino acids such as arginine, aspartic
  • the type of solvent in the solvate of the macrolide antibiotic is not particularly limited, and examples thereof include water; alcohols such as methanol, ethanol and isopropanol; ethers such as tetrahydrofuran and the like.
  • the coated preparation of the present invention comprising these as main ingredients is It is very effective in the treatment of bacterial infections such as mammals including humans, fish and birds, mycoplasma infections, fungal (branch) infections, and protozoal infections.
  • Streptococcus pneumoniae Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptost Pneumonia, otitis media, sinusitis, bronchitis, tonsillitis, and mastoiditis due to Peptostreptococcus, etc .
  • Streptococcus pyogenes Streptococcus C and G groups, Clostridium diptheria Or pharyngitis, rheumatic fever, and glomerulonephritis caused by Actinobacillus haemolyticum
  • Mycoplasma pneumoniae ⁇ Legionella pneumophilaophil Streptococcus.
  • Respiratory tract infections caused by Pneumoniae Streptococcus pneumoniae
  • Hemphinoles' inf Norenze Hemphinoles' inf Norenze
  • Chlamydi a pneumoniae Staphylococci! Stadiolococci! . epidermidis
  • Streptococcus' Piokenes Streptococcus pyogenes ;, Streptococcus agalactiae), Streptococcus group (Group C to F Streptococcus), Streptococcus Uncomplicated skin and soft tissue infections, abscesses and osteomyelitis due to viridans (Streptococcus viridans, Corynebacterium minutissimum), Clostridium or Bartonella hensela e, and postpartum fever; Acute urinary tract infection caused by Staphylococcus saprophyticus or Enterococcus; urethritis and cervicitis; Chlamydia trachomatis, Haemophilus ducreyi, Man's Ritamu (Trep sexually transmitted diseases caused by onema pallidum), Ureaplasma urealyticum, or Neiserria gonorrheae; S.
  • Tococcus pneumoniae stafiroko Conjunctivitis, keratitis, and lacrimal inflammation caused by Staphylococcus pyogenes, Haemophiles' Infnoreenze (Haemophilus influenzae), or Listeria; Mycobacterium avium, or Myconocterium 'Disseminated mycobacterial abum complex (MAC) disease due to Mycobacterium intracellulare; gastro-meningitis due to Campylobacter jejuni; cliff.
  • Staphylococcus pyogenes Haemophiles' Infnoreenze (Haemophilus influenzae), or Listeria
  • Mycobacterium avium or Myconocterium 'Disseminated mycobacterial abum complex (MAC) disease due to Mycobacterium intracellulare
  • gastro-meningitis due to Campylobacter jejuni
  • cliff cliff.
  • Intestinal protozoa caused by the genus Cryptosporidium; odontogenic infection caused by Streptococcus pyridans; persistent cough caused by Bordetella pertussis; CI ostridium perfringens or Bacteroides ) Gas destruction by genus bacteria 3 ⁇ 4
  • Bacterial and protozoal infections that can be treated or prevented in animals, and diseases associated with such infections include: Pasteurella hemolytica, Pasteurella hemolytica ( Pasteurella mult ocida, Mycoplasma bovis or Bordetel la pulmonary respiratory disease; E.
  • Urinary bowel disease related to: Staphylococcus aureus, Streptococcus uberis, Streptococcus agalac tiae, Streptococcus dysococcus dysococci Klebsiella), Coryne Mastitis in dairy cows associated with infection by the genus Corynebacterium or Enterococcus; A porcine respiratory disease associated with infection by A. pleuro, P.
  • Ushi rot ubiquitinitis associated with infection by Escherichia coli
  • Fusoba kuterium 'non-chromophorome Fusobacterium necrophorumj or nocterote
  • Urushi hairy warts associated with infection by Bacteroides nodosus
  • Pink eyes of Ussi associated with infection by Moraxella bovis Protozoa (ie neosporium) Urinary tract infections in nu and cats related to infection by colon bacteria; Staphylococcus epidermidis, Staphylococcus intermedius (S.
  • Polyvinyl alcohol or a copolymer thereof used as a coating agent in the present invention can preferably use those described in WO02 / 17848 and WO2005 / 019286.
  • a polyvinyl alcohol copolymer is easy to coat in terms of adhesion and the like.
  • the polyvinyl alcohol copolymer used in the present invention is polybulal alcohol or a derivative thereof (for example, esters), a salt, and at least one polymerizable bulle monomer known per se. It can be produced by copolymerization by a method.
  • Examples of methods for producing such a polyvinyl alcohol copolymer include methods known per se such as radical polymerization, for example, solution polymerization, suspension polymerization, emulsion polymerization, and bulk polymerization. Can be carried out under the usual polymerization conditions. This polymerization reaction is usually carried out in the presence of a polymerization initiator, if necessary, as a reducing agent (for example, sodium erythorbate, sodium metabisulfite, ascorbic acid), a chain transfer agent (for example, 2-merca).
  • a polymerization initiator for example, sodium erythorbate, sodium metabisulfite, ascorbic acid
  • a chain transfer agent for example, 2-merca
  • the polybulal alcohol used as the raw material for the polybulal alcohol copolymer has an average degree of polymerization of about 200 to 1500, preferably an average degree of polymerization of about 200 to 1300, more preferably an average degree of polymerization of about 200 to 900, and even more preferably. May have an average degree of polymerization of about 200 to 600, and most preferably an average degree of polymerization of about 300 to 500.
  • the average degree of polymerization of from 300 to 500 parts only do poly Bulle alcohol preferably fixture average polymerization degree of about 300 to 500 degree of saponification of about 60 to: LO 0 mole 0/0, preferably from 78 to 96 mole 0/0 Partially saponified polybutyl alcohol is more preferred.
  • a saponified polybutyl alcohol can be produced by radical polymerization of vinyl acetate and appropriately saponifying the obtained vinyl acetate. This is achieved by controlling the degree of saponification in a manner known per se.
  • Such partially saponified polyvinyl alcohol may be a commercially available product, and examples of preferable commercially available polybutyl alcohol include Gohsenol EG05, EG25 (manufactured by Nippon Gosei Kagaku), and PVA203 (manufactured by Kurarene).
  • PVA204 manufactured by KURARENE
  • PVA2 05 manufactured by KURARENE
  • JP-04 manufactured by Nippon Vinegar Pover Co., Ltd.
  • JP-05 manufactured by Nippon Vinegar Pover Co.
  • a coating agent used in the present invention not only a polyvinyl copolymer but also polyvinyl alcohol can be used alone, and for the purpose of two or more kinds of polybulal alcohols having different degrees of polymerization and saponification. It can be used in combination as appropriate.
  • polybutyl alcohol having an average degree of polymerization of 300 and polyvinyl alcohol having an average degree of polymerization of 1500 can be mixed and used as a coating agent. It is also possible to use a commercially available premitas coating agent containing polyvinyl alcohol.
  • polybulal alcohol various modified polybulal alcohols can be used, for example, amine-modified polybulal alcohol, ethylene-modified polybulal alcohol, carboxylic acid-modified polybulal alcohol, diacetone-modified polybulal alcohol, thiol. Examples thereof include denatured polybulal alcohol.
  • modified polybulal alcohols commercially available products or those produced by methods known in the art can be used.
  • the polymerizable vinyl monomers to be polymerized with poly (vinyl alcohol) include acrylic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, Unsaturated carboxylic acids such as itaconic acid or salts thereof (for example, alkali metal salts, ammonium salts, alkylamine salts), esters thereof (for example, substituted or unsubstituted alkyl esters, cyclic alkyl esters, polyalkylene groups) (Recall esters), unsaturated-tolyls, unsaturated amides, aromatic vinyls, aliphatic vinyls, unsaturated bond-containing heterocycles, and the like.
  • Unsaturated carboxylic acids such as itaconic acid or salts thereof (for example, alkali metal salts, ammonium salts, alkylamine salts), esters thereof (for example, substituted or unsubstituted alkyl esters, cyclic alkyl esters, polyalkylene groups
  • acrylates for example, methyl acrylate, ethyl acrylate, butyl acrylate, isobutyl acrylate, cyclohexyl acrylate, 2-ethyl hexyl acrylate, hydroxy Powers such as ethyl acrylate, polyethylene glycol acrylate, polypropylene glycol acrylate, etc.
  • Examples of methacrylic acid esters include methyl methacrylate, ethyl methacrylate, butyl methacrylate, isobutyl methacrylate, Cyclohexyl methacrylate, 2-ethylhexyl methacrylate, hydroxyethyl methacrylate, polyethylene glycol methacrylate, etc.
  • Examples of unsaturated-tolyls include acrylonitrile, methacrylonitrile, etc.
  • Examples of saturated amides include acrylamide, dimethylacrylamide, and methacrylamide.
  • Aromatic beers include styrene, ⁇ -methylstyrene, and (6)
  • Aliphatic vinyls include butyl acetate.
  • Examples of unsaturated bond-containing heterocycles include ⁇ -vinylpyrrolidone, acryloylmorpholine, and the like.
  • R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms
  • These polymerizable vinyl monomers are capable of being copolymerized with polyvinyl alcohol in combination of one or more, preferably acrylic acid and methacrylic acid ester.
  • a mixture with (e.g. methyl metatalylate) may be copolymerized with polyvinyl alcohol.
  • the weight ratio of the polybulal alcohol to the polymerizable bur monomer is about 6: 4 to 9: 1, preferably about 8: 2.
  • acrylic acid and methyl methacrylate are used as the polymerizable vinyl monomer, the weight ratio is about 3: 7 to about 0.5: 9.5, preferably about 1.25: 8.75. is there.
  • a preferred polybulal alcohol copolymer used as a main component of the coating agent is composed of polybulal alcohol (average degree of polymerization of about 200 to less than 1300), methyl methacrylate and acrylic acid, and the composition ratio is about 60 to 90: 7 to 38: 0.5 to 12 is preferable, about 70 to 90:15 to 20: 2 to 3 is more preferable, and about 80: 17.5: 2.5 force S is more preferable.
  • polymerization initiator those used in this field can be used.
  • inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide
  • organic peroxides such as peracetic acid, t-butylhydride peroxide, and di-propylperoxydicarbonate
  • Azobis compounds such as 2-azobis (2-amidinopropane) hydride chloride and 2,2, -azobis (2,4 dimethylvale-tolyl) can be mentioned.
  • the coating agent used for coating macrolide antibiotics in the present invention is capable of taking various forms. In general, in the application, an aqueous solution, an aqueous dispersion, an organic solvent solution, or an organic solvent dispersion It is preferably carried out by a means such as spraying or spraying known per se. Alternatively, a method may be used in which a tablet sprayed with a solid coating agent or a granule containing the coating agent is prepared, and then heated and melted to coat the surface.
  • the coating amount of polyvinyl alcohol or the copolymerizable amount thereof is, for example, about 2 to 30% by weight, preferably about 5 to 20% by weight, more preferably about 7. 5 to 15% by weight. In the case of coating elementary granules, it is generally about 5 to: LOO% by weight, preferably about 30 to 80% by weight, based on the elementary granules.
  • the coating conditions of the macrolide antibiotic uncoated tablets and uncoated condyles with a polybulualcohol copolymer are generally as follows.
  • Spray gun caliber About 0.8mm
  • a weight ratio of a partially saponified polybulle alcohol having an average degree of polymerization of 300 to 500 and a polymerizable bur monomer is 6: 4 to 9: 1. It is obtained by copolymerization, and the polymerizable vinyl monomer is acrylic acid and methyl methacrylate, and the weight ratio of acrylic acid to methyl methacrylate in the copolymerization is from 3: 7 to 0.5: 9.
  • Macrolide antibiotics characterized in that they are coated with macrolide antibiotics or solids containing them (for example, uncoated tablets, elementary granules) using polybulal alcohol copolymer as a coating agent. A stable coating formulation is provided.
  • the uncoated tablet containing a macrolide antibiotic includes: a) the macrolide antibiotic as it is, or as an excipient, binder, disintegrant or other suitable additive.
  • the mixture is mixed evenly into granules (elementary granules) by an appropriate known method, and then added with a lubricant, etc., and compression-molded, or b)
  • the macrolide antibiotic granules are left as is or added.
  • Macroscopic antibiotics that are produced by direct compression molding, or mixed with the addition of a form, binder, disintegrant or other suitable additive, are mixed.
  • a preferred example is a method in which macrolide antibiotics are added to granules not contained as they are or together with appropriate additives and mixed uniformly, and then compression-molded.
  • the elementary granules can also be produced by means known in the art.
  • a pre-coating layer can be applied to the uncoated tablet before coating with the polyvinyl alcohol copolymer.
  • coating agents those known in the art are used. Examples thereof include hydroxypropylmethylcellulose and sucrose.
  • a solid formulation of maculaide, such as tablets, granules, capsules, and pills, coated with the polybulal alcohol or polybulal alcohol copolymer can be produced by a conventional method.
  • the tablet may preferably contain a disintegrant in order to enhance its disintegration property.
  • a disintegrant those well known in the art can be used, for example, partially pregelatinized starch, sodium carboxymethyl starch, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose (L—HPC), Examples include croscarmellose sodium (for example, Ac-Di-Sol, Asahi Kasei Co., Ltd.), polybulu polypyrrolidone and the like, and preferably carboxymethyl starch sodium.
  • the disintegrant content should be sufficient to disintegrate the tablet quickly.
  • the disintegrant should disintegrate within a few tens of minutes, preferably within a few minutes, in the first or second liquid prescribed by the Japanese Pharmacopoeia.
  • the amount is about 0.5 to 30 parts by weight, preferably about 1 to 20 parts by weight, more preferably about 2 to: LO parts by weight based on 100 parts by weight of the tablet.
  • Tablets containing macrolide antibiotics optionally further include pharmaceutically acceptable additives such as excipients, binders, lubricants, and colorants (eg, acid titanium).
  • pharmaceutically acceptable additives such as excipients, binders, lubricants, and colorants (eg, acid titanium).
  • the content of titanium oxide is about 0.05 to 5 parts by weight, preferably about 0.1 to 2 parts by weight per 100 parts by weight of the tablet.
  • excipients known in the art can be used as the excipient, such as lactose, sucrose, mannitol, crystalline cellulose, corn starch, potato starch, hydroxypropyl starch, and the like.
  • the exemplified force is preferably mannitol or crystalline cellulose.
  • the content of the excipient may be appropriately set in consideration of the main drug content, the target tablet size, etc., but is usually about 5 to 60 parts by weight, preferably about 10 to 100 parts by weight with respect to 100 parts by weight of the tablet. 40 parts by weight.
  • binder those widely known in the art can be widely used.
  • methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol, gelatin, dextrin and the like are preferable.
  • the binder content is usually about 0 with respect to 100 parts by weight of the tablet. 5 to 5 parts by weight, preferably about 1 to 3 parts by weight.
  • Examples of the lubricant include magnesium stearate, talc, sucrose fatty acid ester and the like, and the content thereof is usually a trace amount, for example, about 1 to 3 parts by weight with respect to 100 parts by weight of the tablet.
  • the tablet containing a macrolide antibiotic is subjected to operations such as mixing, granulation, granulation drying, granulation, lubricant blending, tableting and the like using the above raw materials. And can be produced according to a known method.
  • an apparatus such as an agitation granulator, a fluidized bed granulator, a Brabender, or a twin screw granulator may be used. It is preferable to use a granulator.
  • tableting may be performed using a commercially available tableting machine, usually with a tableting pressure of about 0.2 to 1.5 t.
  • a preferred embodiment of the tablet composition of the present invention is as follows.
  • Disintegrant preferably sodium carboxymethyl starch: about 2-10%;
  • Excipients preferably total amount of D-mann-tol and crystalline cellulose: about 10-40%; Binder, preferably hydroxypropylcellulose: about 1-3%;
  • Lubricant preferably magnesium stearate: about 1-3%
  • the coating agent preferably polyvinyl alcohol copolymer, is about 5-20% by weight.
  • the coated preparation of the macrolide antibiotic of the present invention may be administered to humans or animals in an effective amount for treating the above-mentioned diseases.
  • the dose may vary depending on the age, weight, symptom, sex, etc. of the patient or animal to be treated, but usually the above macrolide antibiotics and their pharmacologically acceptable in 1 or several times.
  • 0.01 to 50 mgZkg can be orally administered in terms of a salt or a hydrate thereof.
  • the total amount of related substances after storage for 3 months at 25 ° C and a relative humidity of 60% is preferably 3% or less, more preferably 1.5% or less.
  • the preparation of the present invention is preferably PTP (press-through) in order to further improve the stability.
  • PTP press-through
  • One package or bottle packaging eg, plastic bottles, glass bottles, aluminum cans.
  • the coated preparation of the macrolide antibiotic of the present invention may contain an antibacterial agent other than the macrolide antibiotic.
  • the main component of the coating agent may contain a coating force or other coating components which are polybulal alcohol or polyvinyl alcohol copolymer.
  • R represents a protecting group for a hydrogen atom or a hydroxyl group.
  • a macrolide antibiotic having a group represented by the formula: a pharmaceutically acceptable salt thereof, a hydrate thereof, or a substance thereof Provided is a method for inhibiting the formation of a related substance of the macrolide antibiotic, in which a solid substance is coated with a coating agent containing polybulualcohol or polybulualcohol copolymer. Macrolide antibiotics, their salts, their hydrates, coating agents, coating methods, etc. are as described above.
  • the present invention relates to a macrolide antibiotic having a group represented by the above partial structural formula, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solid containing them, polyvinyl alcohol or polybule.
  • a method for stabilizing the macrolide antibiotic, its pharmaceutically acceptable salt, or hydrate thereof characterized in that it is coated with a coating containing an alcohol copolymer.
  • Macrolide antibiotics, salts thereof, hydrates thereof, coating agents, coating methods, etc. are as described above.
  • a coated tablet of the above uncoated tablet with a polyvinyl alcohol copolymer was produced through the following steps (1) to (1).
  • a polyvinyl alcohol copolymer having a polymerization degree of 500 is gradually added to purified water with stirring, thereby preparing an aqueous solution of 8-: LO wt% polybula alcohol copolymer.
  • the acid is stirred and dispersed with TK Robotics (Special Machine Industries).
  • TK Robotics Specific Machine Industries
  • a titanium bromide-containing polybutyl alcohol copolymer aqueous solution is prepared.
  • the stability of the macrolide-coated preparation (Formulation 1) obtained as described above was compared with that of an uncoated tablet.
  • the evaluation method is as follows.
  • One coating agent and one uncoated tablet were stored for 3 months under conditions of 25 ° C, 60% relative humidity, no packaging, and shading. 0.5. After 5 months, 1 month, 2 months, and 3 months, the residual amount of compound (ii), the main drug, and the amount of related substances produced were measured by liquid chromatography. For the coating agent and the uncoated tablet, the same production lot of macrolide antibiotic (I compound ( ⁇ )) was used.
  • the drug substance of compound (III) in the same production lot used for the coating and uncoated tablets was accurately weighed by about 10 mg. This was dissolved in 70% acetonitrile to make exactly 10 mL. o o
  • the peak areas due to the main drug and related substances were measured by the automatic calculation method.
  • the amount of each related substance (%) and the total amount of related substances (%) were calculated from the following formulas.
  • ⁇ A Sum of peak areas other than system peaks
  • Figure 2 shows the chromatogram of the coated preparation after storage for 1 month.
  • Table 3 shows the retention time, area, and height of each peak.
  • Peak number Retention time Peak area Peak area Peak height
  • Peak 6 is a peak derived from the main compound ( ⁇ ). All peaks other than peak 6 are derived from related substances. In particular, peaks 1 and 2 are the main by-products that increase upon storage.
  • Figure 3 shows the change in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparation and uncoated tablet.
  • ⁇ indicates uncoated tablet
  • ⁇ indicates a coated tablet made of polyvinyl alcohol copolymer.
  • the amount of the related substance in the coated preparation of the present invention hardly changed even after 3 months, whereas the undegraded uncoated tablet rapidly decomposed the active ingredient, and after 3 months.
  • the related substance amount reached about 9%. This proved the stability of the coated preparation of the present invention.
  • the coating preparation was prepared by variously changing the ratio of the coating agent to the entire coating preparation within the range of 5 to 15% by weight.
  • the macrolide coating formulation of the present invention was particularly stable when the coating amount of the polyvinyl alcohol copolymer as the coating agent was in the range of about 7.5 to 15% (wZw). .
  • coated preparations (formulations 2, 3 and 5) having the compositions shown in Table 4 below were obtained.
  • the coating conditions were the same as those shown in Example 1, except that titanium oxide (1% by weight concentration) was used in the coating agent.
  • Crystalline cellulose 5.0 mg 1.5 mg 1 0.0 mg Magnesium stearate 4.0 mg 6. 0 mg 8. 0 mg Constant 1 60. 0 mg 240. 0 mg 320. 0 mg Coating Polyvinyl alcohol Copolymer 1 8. 0 mg 1 8. 0 mg 22.5 mg Titanium oxide 2. 0 mg 2. 0 mg 2.5 m Talc Trace Trace Trace Magnesium stearate Trace Trace mist Trace Coverage meter 20. 0 mg 20 0 mg 25. 0 mg Total 1 80. 0 mg 260. 0 mg 345. 0 mg Coverage ratio (%) (Uncoated tablet) 1 2. 5% 8. 3% 7.8% Copolymer ratio (% ) (Comparative tablet) 1 1. 3% 7. 5% 7. 0% [0111] The stability of the macrolide-based coated preparation (Preparation 2) obtained as described above was compared with that of an uncoated tablet. The evaluation method is as follows.
  • each of the coating agent and the uncoated tablet was stored for 1 month under the conditions of 25 ° C, 60% relative humidity, no packaging, and shading. 0.5. After 5 months and 1 month, the residual amount of the main compound ( ⁇ ) and the amount of related substances produced were measured by liquid chromatography. The same production lot of macrolide antibiotic (compound ( ⁇ )) was used for the coating and uncoated tablets.
  • Figure 6 shows the changes in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparations and uncoated tablets.
  • ⁇ indicates an uncoated tablet
  • ⁇ indicates a coated tablet made of acid-titanium-containing polyvinyl alcohol copolymer.
  • the coated preparation of the present invention has almost the same amount of the related substance after one month, whereas it is coated. One month later, the amount of related substances reached about 4%, confirming the stability of the coated preparation of the present invention.
  • each of the coating agent and the uncoated tablet was stored for 3 months under the conditions of 25 ° C, 60% relative humidity, no packaging, and shading. After 0.5 months, 1 month, 2 months, and 3 months, the residual amount of the compound (ii) as the main drug and the amount of related substances produced were measured by liquid chromatography. For the coating agent and the uncoated tablet, the same production lot of macrolide antibiotic (I compound ( ⁇ )) was used.
  • Figure 8 shows the change in the ratio (%) of the total amount of related substances to the active ingredient in the coated preparation and uncoated tablet.
  • ⁇ indicates an uncoated tablet and ⁇ indicates a coated tablet made of polyvinyl alcohol.
  • the coated preparation of the macrolide antibiotic of the present invention coated with polyvinyl alcohol was stable with almost no related substances formed in the preparation even after storage for 3 months.
  • the ratio (%) of the total amount of related substances to the active ingredient is about 9% (w / w).
  • the macrolide antibiotic-coated preparation coated with polybulal alcohol or a copolymer thereof according to the present invention can be applied to bacteria, mycoplasma, fungi (brietles), protozoa, etc. in mammals including humans, fish, and birds. Can be used to treat a wide range of infectious diseases

Abstract

L'invention concerne une préparation antibiotique macrolide enrobée, laquelle comprend un antibiotique macrolide ayant un groupe représenté par la formule structurelle partielle (I): [où R2a représente un atome d'hydrogène ou un groupe protecteur d'un groupe hydroxyle] ou un sel pharmaceutiquement acceptable ou un hydrate de l'antibiotique ou le sel et lequel est enrobé avec un enrobant comprenant principalement un alcool polyvinylique ou un copolymère d'alcool polyvinylique.
PCT/JP2007/059144 2006-04-28 2007-04-27 Préparation antibiotique macrolide enrobée WO2007126039A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011077843A1 (fr) 2009-12-25 2011-06-30 沢井製薬株式会社 Préparation enrobée contenant de l'atrovastatine
JP2012193175A (ja) * 2011-03-02 2012-10-11 Daiichi Sankyo Healthcare Co Ltd 速溶性防湿フィルムコーティング製剤及びその製造方法

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JPS5428812A (en) * 1977-08-09 1979-03-03 Yoshitomi Pharmaceut Ind Ltd Preparation of coated tablet
JPS5942325A (ja) * 1982-09-03 1984-03-08 Dai Ichi Seiyaku Co Ltd コ−テイング用組成物及びコ−テイング製剤
EP0208971A2 (fr) * 1985-07-10 1987-01-21 Dr. Karl Thomae GmbH Formes galéniques solides pour application orale contenant de la 9-déoxo-11-déoxy-9,11-(imino(2-(2-méthoxyéthoxy)éthylidène)-oxy-)-(9S)-érythromycine et leur procédé de préparation
WO1988003795A1 (fr) * 1986-11-24 1988-06-02 Nortec Development Associates, Inc. Compositions pharmaceutiques avec dissimulation du gout
JPS63215620A (ja) * 1987-03-03 1988-09-08 Nippon Soda Co Ltd 徐放性製剤
JPH092976A (ja) * 1995-06-20 1997-01-07 Lion Corp 被覆組成物
WO1998046239A1 (fr) * 1997-04-11 1998-10-22 Abbott Laboratories Formulations a liberation prolongee de derives d'erythromycine
WO2001004195A1 (fr) * 1999-07-09 2001-01-18 Berwind Pharmaceutical Services, Inc. Pellicules d'enrobage et compositions de pellicules d'enrobage a base de poly(alcool de vinyle)
EP1302205A1 (fr) * 2001-10-01 2003-04-16 Ind-Swift Limited Composition pharmaceutique à libération contrôlée comprenant citrate de macrolide
WO2005019286A1 (fr) * 2003-08-20 2005-03-03 Shionogi & Co., Ltd. Nouvelle composition pour revetements

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5428812A (en) * 1977-08-09 1979-03-03 Yoshitomi Pharmaceut Ind Ltd Preparation of coated tablet
JPS5942325A (ja) * 1982-09-03 1984-03-08 Dai Ichi Seiyaku Co Ltd コ−テイング用組成物及びコ−テイング製剤
EP0208971A2 (fr) * 1985-07-10 1987-01-21 Dr. Karl Thomae GmbH Formes galéniques solides pour application orale contenant de la 9-déoxo-11-déoxy-9,11-(imino(2-(2-méthoxyéthoxy)éthylidène)-oxy-)-(9S)-érythromycine et leur procédé de préparation
WO1988003795A1 (fr) * 1986-11-24 1988-06-02 Nortec Development Associates, Inc. Compositions pharmaceutiques avec dissimulation du gout
JPS63215620A (ja) * 1987-03-03 1988-09-08 Nippon Soda Co Ltd 徐放性製剤
JPH092976A (ja) * 1995-06-20 1997-01-07 Lion Corp 被覆組成物
WO1998046239A1 (fr) * 1997-04-11 1998-10-22 Abbott Laboratories Formulations a liberation prolongee de derives d'erythromycine
WO2001004195A1 (fr) * 1999-07-09 2001-01-18 Berwind Pharmaceutical Services, Inc. Pellicules d'enrobage et compositions de pellicules d'enrobage a base de poly(alcool de vinyle)
EP1302205A1 (fr) * 2001-10-01 2003-04-16 Ind-Swift Limited Composition pharmaceutique à libération contrôlée comprenant citrate de macrolide
WO2005019286A1 (fr) * 2003-08-20 2005-03-03 Shionogi & Co., Ltd. Nouvelle composition pour revetements

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011077843A1 (fr) 2009-12-25 2011-06-30 沢井製薬株式会社 Préparation enrobée contenant de l'atrovastatine
JP2012193175A (ja) * 2011-03-02 2012-10-11 Daiichi Sankyo Healthcare Co Ltd 速溶性防湿フィルムコーティング製剤及びその製造方法

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