WO2007126039A1 - Coated macrolide antibiotic preparation - Google Patents

Abstract

Disclosed is a coated macrolide antibiotic preparation which comprises a macrolide antibiotic having a group represented by the partial structural formula (I): [wherein R2a represents a hydrogen atom or a protecting group for a hydroxyl group] or a pharmaceutically acceptable salt thereof or a hydrate of the antibiotic or the salt, and which is coated with a coating agent comprising mainly a polyvinyl alcohol or a polyvinyl alcohol copolymer.

Description

 Specification

 Macrolide antibiotic coatings

 Technical field

 [0001] 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.

 Background art

 [0002] 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. 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. Examples of such macrolide antibiotics 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. Yes.

[0003] Also, a polymer obtained by polymerizing or copolymerizing at least one polymerizable vinyl monomer in the presence of polyvinyl alcohol and Z or a derivative thereof, or a hard capsule mainly composed of the copolymer should be used. Therefore, 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 is known (Patent Document 15). However, the invention disclosed in 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. [0004] Furthermore, 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). In the invention described in this Patent Document 16, there is no specific description about the stability of a macrolide antibiotic preparation in which a medicine as an object to be coated is described. Moreover, there is a description and suggestion of the long-term storage stability of macrolide antibiotics having specific groups described below.

 [0005] Until now, various formulations for oral administration or parenteral administration have been developed and used for these known macrolide antibiotic preparations. However, when these macrolide antibiotic preparations were stored for a long period of time, decomposition of the active ingredient could be observed in the preparations, which was not necessarily satisfactory stability. In addition, in order to improve stability, if a large amount of additives such as stabilizers, excipients, binders, lubricants, disintegrants, and coating agents are used in the formulation, it is manufactured. Oral preparations generally have a tendency to become large dosage forms, with the disadvantage that they are difficult to take for patients such as the elderly and children.

 [0006] As a known formulation of these macrolide antibiotics, polyvinyl alcohol or a copolymer thereof is used as a coating agent for macrolide antibiotics or uncoated tablets and granules containing the macrolide antibiotics. The prior art regarding coated formulations has not been known so far.

 [0007] Patent Document 1: US2653899

 Patent Document 2: US2 „

 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 „5

Patent Document 10: US5866549 Patent Document 11: EP56291

 Patent Document 12: WO2003Z097659 Al

 Patent Document 13: WO2005Z〇81821 A2

 Non-patent document 1: J. Antibiot 45 (1), 1 (1992)

 Patent Document 14: EP508699

 Patent Document 15: WO2002Zl7848

 Patent Document 16: WO2005Z019286

 Disclosure of the invention

 Problems to be solved by the invention

[0008] In view of the above circumstances, there is an urgent need in the art to develop a stable preparation of a macrolide antibiotic that can withstand long-term storage, particularly a 13-16 membered macrolide antibiotic preparation. In particular, there is a demand for improving the stability of solid preparations such as tablets, granules, capsules and pills.

 Means for solving the problem

[0009] Therefore, as a result of various studies on the stability of macrolide antibiotic preparations, the following formula:

 [Chemical 1]

(Wherein R represents a hydrogen atom or a protecting group for a hydroxyl group), preferably the following formula:

(I)

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.

 That is, the present invention

Item 1. The following partial structural formula:

[Chemical 3]

(In the formula, R represents a protecting group for a hydrogen atom or a hydroxyl group) and 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.

Item 2. Macrolide antibiotics have the following partial structural formula (I): [Chemical 4]

(I)

(Wherein 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. Item 2. A coated preparation of a macrolide antibiotic according to Item 1.

 [0012] 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.

 [0013] Item 4. Macrolide antibiotics have the general formula (Π):

 [Chemical 5]

 {Where A is

a) -OH, b) OR ^p (wherein R ^P represents a protecting group for a hydroxyl group),

c) —R ¹ (wherein R ¹ represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),

d) -OR ¹ (wherein R ¹ has the same meaning as above),

e) - R ² (wherein, 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 A halogen atom, an aryl group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group, a C 1 -C alkyl group optionally substituted with one or more selected substituents, (4) an oxygen atom

 1 12

1 to 2 or more 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

 2 12

Group, or (5) Oxygen atom, sulfur atom and nitrogen nuclear power optionally containing 0 to 3 heteroatoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl forces selected 1 Or a CC alkynyl group which may be substituted with two or more substituents. ),

 2 12

f) —OR ² (R ² is as defined above),

g) -S (O) R ¹¹ (wherein n represents 0, 1 or 2, R ¹¹ independently represents a hydrogen atom, R ¹ or R ² and R ¹ and R ² are as defined above) Having)

h) NHC (0) RU (wherein R ¹¹ has the same meaning as above),

i) —NHC (0) NHRU (wherein R ¹¹ has the same meaning as described above),

j) -NHS (O) R ¹¹ (wherein R ¹¹ has the same meaning as described above),

 2

^{k) -. NR 14 R 15} ( wherein, R ¹⁴ and R ¹⁵ are each independently, represent R ^11, R ¹¹ have the same meaning as defined above), and

1) — NHR ³ (wherein R ³ represents an amino group protecting group)

Represents a group selected from:

 B is

 a) a hydrogen atom,

b) deuterium, c) a neurogenic atom,

 d) OH,

e) R ¹ (R ¹ is as defined above),

f) R ² (R ² is as defined above), or

g) —OR ^p (R ^p is as defined above;

Provided that when B is halogen, OH or —OR ^P , A represents —R ¹ or —R ² , or A and B are bonded together with carbon atoms!

 a) C = 0

b) C (OR ² ) (R ² is as defined above),

 2

c) C (SR ² ) (R ² is as defined above),

 2

 d) C [O (CH)] (m is 2 or 3),

 2 m 2

 e) C [-S- (CH)] (m is as defined above),

 2 m 2

^ ¹¹ ^ ¹¹ has the same meaning as above. ),

g) C = N—O—R ¹¹ ^ ¹¹ has the same meaning as described above. ), Or

h) C = N-0-Ar ¹ -M-Ar ²

[Where

1) - Ar ¹ represents R ^31, R ³¹ is independently

a) a divalent group formed by removing a hydrogen element from R ¹ (R ¹ has the same meaning as described above), b) 0 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom Optionally containing atoms, halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C

 1 12 Norylene group,

 c) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group forces also being selected 1 or 2 or more Optionally substituted with a substituent of C— C

 2 12 Norekenylene group, or

d) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, halogen, aryl, substituted aryl, heteroaryl and substituted hetero; May also be substituted with one or more substituents, also selected as aryl base

 2 12 represents a norequinylene group;

 2) —M is the bond or

 (a) Oxygen atom, sulfur atom and nitrogen nuclear power selected 0 to 3 heteroatoms and — C = N—, — N = N— and — C (O) —force selected from 0 to 3 A c 1 -c anolylene group, optionally containing a group,

 12

 (b) Oxygen atom, sulfur atom and nitrogen nuclear power 0 to 3 selected hetero atoms and — C = N—, — N = N— and — C (O) —force, 0 to 3 selected A C—C canorekenylene group, optionally containing a group,

 2 12

 (c) Oxygen atom, sulfur atom and nitrogen nuclear power 0 to 3 selected hetero atoms and — C = N—, — N = N— and — C (O) —force, 0 to 3 selected A C—C anolenylene group, optionally containing a group,

 2 12

 (d) a substituted arylene group,

 (e) a substituted heteroarylene group or

 (f) represents a substituted heterocycloalkylene group; and

3) Ar ² is

 (a) Allele group,

 (b) a substituted aryl group,

 (c) heteroaryl group, or

 (d) represents a substituted heteroaryl group];

c: ^^^ ¹¹ ^ ¹¹ has the same meaning as above. ),

j) C = NNHC (0) R ¹¹ (R ¹¹ is as defined above),

k) C = NNHC (O) NHR ¹¹ (R ¹¹ is as defined above),

1) C = NNHS (0) R ¹¹ ^ ¹¹ has the same meaning as described above. ),

 2

m) C = NNHR ³ (R ³ has the same meaning as above),

r CzNR ¹¹ ^ ¹¹ has the same meaning as described above. ),

CzNR ¹¹ ^ ¹¹ has the same meaning as described above. ), Or

p) C═N—N—CHR ¹¹ (wherein R ¹¹ has the same meaning as above); One of X and Y represents a hydrogen atom and the other is

 a) a hydrogen atom,

 b) deuterium,

 c) OH,

d) OR ^P (R ^P is as defined above),

e) — NR ⁴ R ⁵ (R ⁴ and R ⁵ are each independently

 (1) hydrogen atom,

 (2) 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

 1 12 alkyl groups, or

(3) 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. Represents a ring, or X and Y are bonded together with a carbon atom,

 (a) C = 0 or

 (b) C = N-Q

(Where Q is

(1) —R ^ R ¹¹ has the same meaning as described above. ),

 (2) an amino protecting group,

(3) —. (. ^ " ¹¹ has the same meaning as above),

( ⁴ ) — OR ⁶ (R ⁶ is independently

 (a) a hydrogen atom,

 (b) -CH 0 (CH) OCH

 2 2 2 3,

 (c) -CH 0 (CH 2 O) 2 CH (n is as defined above),

 2 2 n 3

 (d) 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 units,

 (e) -C 1 -C cycloalkyl group,

 3 12

(f) -c (o) -c -c alkyl group, ( _g ) -c (o) -c 3 -c cycloalkyl group,

 12

(h) -C (O) — ^ (R ¹ is as defined above) or

(i) —Si (R ^a ) (R ^b ) (R ^c ) (R ^a , R ^b and R ^c are each independently C—C alkyl

 1 12 represents a group, an aryl group or a substituted aryl group. ); Or

(5) 0-C (R ⁷ ) (R ⁸ ) — O—R ⁶ (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

1 12 3 12 1

 R and R together with the carbon atom to which they are attached form a C -C cycloalkyl group

7 8 3 12

Or (1) a hydrogen atom or (2) a C 1 -C alkyl group. );

 1 12

 L is

 a) —CH,

 Three

 b) —CH CH,

 twenty three

 c) -CH (OH) CH,

 Three

 d) 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,

 1 6

 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;

 2 6

Or

 f) a C C alkyl group which may be substituted with one or more substituents selected from an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;

 2 6

Representation;

 z is

 a) a hydrogen atom,

 b) methyl group or

 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.

Item 5. Macrolide antibiotics (1) The following formula (ΠΙ):

[Chemical 6]

(1R, 2R, 3R, 6R, 8R, 9R, lOR, 16S, 18R) —N— [9— (3, 4, 6— Trideoxy-1-3-dimethylamino-1-13-D Ranosyloxy)-3-ethyl-2-hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dixo 1 3- [(E)-[6- (pyrazole-1-yl) pyridine-3 —Yl] methoxyimino] -4, 11, 15 trioxabicyclo [8,5,4] nonade force 17E—ylidene] acetamide,

(2) The following formula (IV):

[Chemical 7]

Terithromycin represented by

(3) The following formula (V):

[Chemical 8]

(4) The following formula (VI):

[Chemical 9]

TEA—0777 represented by (5) Formula (VII) below:

[Chemical 10]

CP— 544372 represented by (6) Formula (VIII): [Chemical 11]

Cesromycin represented by, or

(8) (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-1-3-dimethylamino-1-13-D xyloxopyranosyloxy ) 3-Ethyl 2 Hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dioxo 13— [(E) [6- (2-Aminoviridine 6-yl) pyridine 3- 3-yl] Methoxyimino] — 4, 11, 15 trioxabicyclo [8, 5, 4] nonade force 17E—ylidene] acetamide, Item 5. A coated preparation of a macrolide antibiotic according to Item 4, which is a pharmaceutically acceptable salt thereof or a hydrate thereof.

 Item 6. Macrolide antibiotics may have the following formula (ΠΙ):

(1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) —N— [9— (3, 4, 6— Trideoxy-1-3-dimethylamino-1-13-D Ranosyloxy)-3-ethyl-2-hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dixo 1 3- [(E)-[6- (pyrazole-1-yl) pyridine-3 —Yl] methoxyimino] -4, 11, 15 Trioxabicyclo [8,5,4] nonade force— 17E—ylidene] acetamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof The coated preparation of macrolide antibiotics according to Item 5.

Item 7. 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 The coated preparation of macrolide antibiotics according to Item 1.

[0017] Item 8. The coated preparation of a macrolide antibiotic according to Item 7, wherein the type 1 is an anhydrous crystal.

 [0018] Item 9. The coated preparation of a macrolide antibiotic according to Item 1, wherein the coated preparation is a solid preparation.

 [0019] Item 10. The coated preparation of macrolide antibiotics according to Item 9, wherein the solid preparation is a tablet or a granule.

 [0020] 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.

 [0021] 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.

 [0022] 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.

 [0023] 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. The coated preparation of a macrolide antibiotic according to Item 11, characterized in that it is selected from the group consisting of a heterocyclic compound containing the ring and a salt power thereof.

 [0025] 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.

[0026] 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. Atalylate, Butylmetatalylate, Butyl Atalylate, Isobutyl Metatalylate, Isobutyl Atalylate, Cyclohexyl Metatalylate, Cyclohexyl Atalylate, 2-Ethylhexyl Metatalylate, 2-Ethyl Hexyl It is selected from the group consisting of acrylate, hydroxyethyl methacrylate, hydroxyethyl acrylate, esters of polyethylene glycol and methacrylic acid, esters of polyethylene glycol and acrylic acid, and esters of polypropylene glycol and acrylic acid This thing And wherein the coating formulation of the macrolide antibiotics according to claim 16.

Item 18. The unsaturated carboxylic acids, their salts, and esters of the unsaturated carboxylic acid are represented by the general formula (X)

 (Chemical 14)

 H C = C (R) -COOR (X)

 2 1 2

 (Wherein R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms)

 1 2

 An alkyl group having a child is shown. 16. A coated preparation of a macrolide antibiotic according to Item 15, wherein the compound is a compound represented by the formula:

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.

[0029] 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.

 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.

[0031] Item 22. Partially saponified polybutyl alcohol having an average degree of polymerization of 300 to 500, methyl methacrylate Item 23. The macrolide antibiotic coating according to Item 21, wherein the weight ratio of copolymerized relate benzoic acid is 60 to 90: 7 to 38: 0.5 to 12. Formulation.

 [0032] 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.

 [0033] 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.

 Item 25. 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. Polybulal alcohol or polybulal alcohol copolymer with or without inclusion, and the total amount of related substances after storage for 3 months at 25 ° C and 60% relative humidity shall be 1.5% or less Item 2. A coated preparation of a macrolide antibiotic according to Item 1, characterized by:

 [0035] Item 26. 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

[0036] Item 27. The coated preparation of a macrolide antibiotic according to Item 26, which is packaged in PTP (press-through package) or bottle packaging.

[0037] Item 28. The following partial structural formula:

[Chemical 15]

(Wherein 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.

 Item 29. The following partial structural formula:

[Chemical 16]

 (In the formula, 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.

About. The invention's effect

 [0039] 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. In addition, 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 In addition, it is possible to provide solid preparations such as tablets, granules, capsules and pills that are easy to take.

 Brief Description of Drawings

 [0040] 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. In the figure, ◯ indicates uncoated tablets, and 參 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%).

 [Figure 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. In the figure, 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. In the figure, ◯ indicates an uncoated tablet, and 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.

BEST MODE FOR CARRYING OUT THE INVENTION

 In the coated preparation of the macrolide antibiotic of the present invention, the macrolide antibiotic is preferably a 14- to 16-membered macrolide antibiotic. Among these macrolide antibiotics, the following partial structural formula is preferred:

 [Chemical 17]

 (Wherein R represents a hydrogen atom or a protecting group for a hydroxyl group), and more preferred is the partial structural formula (I) below:

[Chemical 18]

(Wherein 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”), and a pharmaceutically acceptable salt thereof. Or their hydrates.

[0042] According to the study by the present inventors, it has been found that 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.

 [0043] 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.

 [Chemical 19]

(In the formula, Ra and Rb together represent oxo, or one represents a hydrogen atom and the other represents an —O sugar residue. Preferably, Ra and Rb together represent oxo. Represents the remaining partial structure of the McLide ride ring.)

[0044] The above numbering is given according to a typical case. In such a case, the partial structure represented by "-Q" is bonded to the 5-position of the macrolide ring. However, depending on the type of macrolide ring, the Nanno << ring can vary.

[0045] Examples of the 14-membered macrolide antibiotics include compounds represented by the following general formula (Π) having the following crosslinking structure described in WO2003Z097659, pharmaceutically acceptable salts thereof, or hydration thereof. Things are more preferred.

 [Chemical 20]

 {Where A is

 a) —OH,

b) OR ^P (wherein R ^P represents a hydroxyl-protecting group),

c) —R ¹ (wherein R ¹ represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group),

d) -OR ¹ (wherein R ¹ has the same meaning as above),

e) - R ² (wherein, 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

 1 12

1 to 2 or more 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

 2 12

Group, or (5) Oxygen atom, sulfur atom and nitrogen nuclear power optionally containing 0 to 3 heteroatoms, halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl forces selected 1 Or a CC alkynyl group which may be substituted with two or more substituents. ),

 2 12

f) —OR ² (R ² is as defined above),

g) -S (O) R ¹¹ (wherein n represents 0, 1 or 2, R ¹¹ independently represents a hydrogen atom, R ¹ or R ² and R ¹ and R ² are as defined above) Having)

h) NHC (0) RU (wherein R ¹¹ has the same meaning as above),

i) —NHC (0) NHRU (wherein R ¹¹ has the same meaning as described above),

j) -NHS (O) R ¹¹ (wherein R ¹¹ has the same meaning as described above),

 2

^{k) -. NR 14 R 15} ( wherein, R ¹⁴ and R ¹⁵ are each independently, represent R ^11, R ¹¹ have the same meaning as defined above), and

1) — NHR ³ (wherein R ³ represents an amino group protecting group)

Represents a group selected from:

 B is

 a) a hydrogen atom,

 b) deuterium,

 c) a neurogenic atom,

 d) OH,

e) R ¹ (R ¹ is as defined above),

f) R ² (R ² is as defined above), or

g) —OR ^P (is as defined above;

Provided that when B is halogen, OH or one OR ^P , A represents one R ¹ or one R ² and is Or A and B are combined! /, Together with the carbon atom,

 a) C = 0

b) C (OR ² ) (R ² is as defined above),

 2

c) C (SR ² ) (R ² is as defined above),

 2

 d) C [—O— (CH 2)] (m is 2 or 3),

 2 m 2

 e) C [-S- (CH)] (m is as defined above),

 2 m 2

^ ¹¹ ^ ¹¹ has the same meaning as above. ),

g) C = N—O—R ¹¹ ^ ¹¹ has the same meaning as described above. ), Or

h) C = N-0-Ar ¹ -M-Ar ²

[Where

¹⁾ - Ar 1 - represents R ^31, R ³¹ is independently

a) a divalent group formed by removing a hydrogen element from R ¹ (R ¹ has the same meaning as above), b) 0 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom Optionally containing atoms, halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups also selected, optionally substituted with one or more substituents, C—C

 1 12 Norylene group,

 c) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group forces also being selected 1 or 2 or more Optionally substituted with a substituent of C— C

 2 12 Norekenylene group, or

 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

 2 12 represents a norequinylene group;

 2) —M— is the bond or

(a) Oxygen atom, sulfur atom and nitrogen nuclear power selected 0 to 3 heteroatoms and — C = N—, — N = N— and — C (O) —force selected from 0 to 3 A c-c anoalkylene group, optionally containing a group, (b) Oxygen atom, sulfur atom and nitrogen nuclear power 0 to 3 selected heteroatoms and — C = N—, — N = N and — C (O) —force, 0 to 3 selected groups Optionally containing a C—C canorekenylene group,

 2 12

 (c) Oxygen atom, sulfur atom and nitrogen nuclear power 0 to 3 heteroatoms selected and optionally 0 to 3 groups selected from C = N—, 1 N = N and C (O) — , C -c anolenylene group,

 2 12

 (d) a substituted arylene group,

 (e) a substituted heteroarylene group or

 (f) represents a substituted heterocycloalkylene group; and

3) Ar ² is

 (a) Allele group,

 (b) a substituted aryl group,

 (c) heteroaryl group, or

 (d) represents a substituted heteroaryl group];

c: ^^^ ¹¹ ^ ¹¹ has the same meaning as above. ),

j) C = NNHC (O) R ¹¹ (R ¹¹ is as defined above),

k) C = NNHC (O) NHR ¹¹ (R ⁿ is as defined above),

1) C = NNHS (0) R ^U (R "is as defined above),

 2

m) C = NNHR ³ (R ³ has the same meaning as above),

r CzNR ¹¹ ^ ¹¹ has the same meaning as described above. ),

CzNR ¹¹ ^ ¹¹ has the same meaning as described above. ), Or

p) C = N—N—CHR ¹¹ (R ¹¹ is as defined above);

 One of X and Y represents a hydrogen atom and the other is

 a) a hydrogen atom,

 b) deuterium,

 c) OH,

d) OR ^P (R ^P is as defined above),

e) — NR ⁴ R ⁵ (R ⁴ and R ⁵ are each independently (1) hydrogen atom,

 (2) 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

 1 12 alkyl groups, or

(3) 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. Represents a ring, or X and Y are bonded together with a carbon atom,

 (a) C = 0 or

 (b) C = N-Q

(Where Q is

(1) —R ^ R ¹¹ has the same meaning as described above. ),

 (2) an amino protecting group,

(3) —. (. ^ " ¹¹ has the same meaning as above),

( ⁴ ) — OR ⁶ (R ⁶ is independently

 (a) a hydrogen atom,

 (b) -CH 0 (CH) OCH

 2 2 2 3,

 (c) -CH 0 (CH 2 O) 2 CH (n is as defined above),

 2 2 n 3

 (d) 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 units,

 (e) -C 1 -C cycloalkyl group,

 3 12

 (f) -c (o) -c -c alkyl group,

 1 12

( _g ) -c (o) -c 3 -c cycloalkyl group,

 12

(h) -C (O) — ^ (R ¹ is as defined above) or

(i) —Si (R ^a ) (R ^b ) (R ^c ) (R ^a , R ^b and R ^c are each independently C—C alkyl

 1 12 represents a group, an aryl group or a substituted aryl group. ); Or

(5) 0-C (R ^? ) (R ⁸ ) — O—R ⁶ (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

7 8 3 12

Or (1) a hydrogen atom or (2) a C 1 -C alkyl group. );

 1 12

 L is

 a) —CH,

 Three

 b) —CH CH,

 twenty three

 c) -CH (OH) CH,

 Three

 d) 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,

 1 6

 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;

 2 6

Or

 f) a C C alkyl group which may be substituted with one or more substituents selected from an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;

 2 6

Representation;

 z is

 a) a hydrogen atom,

 b) methyl group or

 c) represents a halogen atom;

R ^2a represents a hydrogen atom or a hydroxyl-protecting group. }

 The detailed definition of each group in the above compound (Π) is as described in WO2003Z097659. Preferred embodiments of the compound (Π) are as follows.

 A and B together with the bonded carbon atoms

h) C = N— 0— Ar ¹ — M— Ar ²

[Where

1) - Ar ¹ represents R ^31, R ³¹ is preferably

b) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl forces also being selected 1 or 2 or more Optionally substituted with a substituent of C— C A alkylene group, more preferably a c-c alkylene group,

 13

 2) M is preferably a bond,

3) 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. The

 [0047] X and Y are preferably bonded together with a carbon atom,

 (b) C = N-Q

 (Where Q is preferably

(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.

 twenty three

 Z is preferably a) a hydrogen atom.

[0048] 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-membered ring, compound (VIII) above), CP—279107 (14-membered ring), A—185684 (14-membered ring), A— 63483 (14-membered ring), A— 70310 (14-membered ring), A— 75729 (14-membered ring), CP— 544372 (14-membered ring, compound (VII) ), CP— 642959 (14 membered ring), CP— 654743 (14 membered ring), RU— 00 4 (14 membered ring), PL— 1. 2. 9 (14 membered ring), RWJ— 415663 (14 membered ring) ), RWJ—415667 (14-membered ring), GI—448 (14-membered ring), LY—281389 (14-membered ring), the above compound (ΠΙ) (14-membered ring bridge structure), azithromycin (15-membered ring), PL — 1. 1. 3 (15-membered ring), L 701677 (1 5-membered ring), PL— 1. 4. 18 (16-membered ring), PL— 1. 4. 2 (16-membered ring), PL— 1369 (16-member ring) YM—17K (16-membered ring), A—74950 (16-membered ring), Mycinamicin (16-membered ring), (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 Dioxo 13— [(E) — [6— (2 —Aminoviridine 6-yl) pyridine 1 3-yl] methoxyimino] — 4, 11, 15 Trioxy Sabicyclo [8, 5, 4] Nonade force— 17E—Iridene] And acetamide.

 Of these, particularly preferred is

 (1) The following formula (ΠΙ):

 [Chemical 21]

 Or the above-mentioned telithromycin, GW773546, TEA-0777, CP-544372, JNJ-17069546 and sesromycin, or a pharmaceutically acceptable salt or hydrate thereof. is there.

 [0050] Particularly preferred is compound (III) which is one embodiment of compound (Π), a pharmaceutically acceptable salt thereof or a hydrate thereof.

In the compound (III), 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-β-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.

 [0052] As preferred examples of macrolide antibiotics, (1R, 2R, 3R, 6R, 8R, 9R, 1 OR, 16S, 18R) — N— [9— (3, 4, 6 trideoxy— 3 Dimethylamino- j8-D- Xylohexoxolanoxy) 3 Ethyl-2-hydroxy 2, 6, 8, 10, 16, 18 -Hexamethyl 5, 7 Dioxo 13— [(E) — [6— (2 Aminoviridine 1-yl) pyridine 1-yl] methoxyimino] —4, 11, 15 trioxabicyclo [8,5,4] nonadeca-17E-ylidene] acetamide.

 [0053] In particular, 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.

 [0054] 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.

[0055] This type 1 crystal shows a powder X-ray diffraction pattern substantially the same as the type I polymorph described in WO2005Z081821. Preferably, the diffraction angle 2 0 = 14.3, 14.5, 15.1, 18.8, 20.5, 23.2, 24.9, 25.6, 29.0, 34.1, 37. 7, 38.1, 38.9, and 40. 4 at least one strong peak selected. Depending on the storage conditions, the water content can be varied in the range of 0 to 2 hydrates. [0056] 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. Also, Xpert Opin. Ther. Patents (2003) 13 (6), p. 787—805 or “Tomorrow's New Drug” (Technomic) https: // / asushin. Com / shinyaku6 / ssearch etc. It can also be produced by a similar method.

 [0057] As a salt of a macrolide antibiotic, any salt can be used as long as it is a pharmaceutically acceptable salt, and it is not particularly limited. Specifically, salt with 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 acid, glutamic acid; methanesulfonic acid, benzenesulfonic acid, paratoluene sulfone Acid, salts with organic sulfonic acids such as 2-naphthalenesulfonic acid; alkali metals such as lithium, sodium, potassium, calcium, magnesium, or alkaline earth metals Salts with; or ammoxidation - quaternary ammonium such © unsalted - © beam salts.

 [0058] 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.

 [0059] Since these known macrolide antibiotics are effective against various bacteria, mycoplasma, fungi (fungi), protozoa, and resistant bacteria thereof, 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.

 Here, the following can be exemplified as the causative bacteria and disease names of such diseases.

Streff. 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 (Haemophilus influenzae), or Chlamydi a pneumoniae; Staphylococci! Stadiolococci! . epidermidis ), S. hemolyticus, 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. aureus,), or food poisoning caused by streptococci A, B, and C, toxic shock syndrome Toxic diseases; Ulcers caused by Helicobacter pylori; Systemic febrile syndrome caused by Borrelia recurrentis; Laim disease caused by Borrelia burgdorferi; Chlamydia trachomatis Neisseria gonorrhoeae, Staphylococcus aure us, Stref. 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. 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 ¾ | [; and atherosclerosis by Helicobacter pylori or Chlamydia pneumoniae.

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. coli or protozoa (ie, Coccidium, Cryptosporidia, etc.) 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. maltoside, or Mycoplasma ; Porcine intestinal disease associated with infection by Escherichia coli, Lawsonia intracellularis, Salmonella, or Serpulina hyodyisin teriae; related to infection with Fusobacterium spp. 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. intermedius) or skin and soft tissue infections in dogs and cats caused by Pasteurella multocida; Alcaligenes spp., Bacteroides spp., Clostridiumn spp., Enterobacter Genus, Eubacterium, Peptostreptococ (Peptostreptococ) Tooth or oral infections in dogs and cats due to genus cus), genus Po / Porphyromonas, or genus Prevotella. Other bacterial and protozoan infections that can be treated or prevented with macrolide antibiotics and diseases associated with such infections are described in JP Sanford Ci. P. Sanford), etc. Sanford Guidelines against "The The"

Sanford Guide To Antimicrobial Therapy "ゝ 26th Edition, Antimicrobial Therapy Inc., 1996".

 [0062] 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.

 [0063] That is, 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.

[0064] 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). Water, organic solvents (for example, methanol) in the presence of p-ethanol, _α -methylstyrene dimer, 2-ethylhexylthioglycolate, lauryl mercaptan) or dispersants (for example, surfactants such as sorbitan esters and lauryl alcohol). , Ethanol, cassava sorb, carbitol) or a mixture thereof. Also, there are no particular limitations on the method for removing unreacted monomers, drying, pulverization and the like using known methods.

[0065] 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. In particular, 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. Such 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.

 [0066] 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. Ltd.) As 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. For example, 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.

[0067] Further, as the 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. As these modified polybulal alcohols, commercially available products or those produced by methods known in the art can be used.

 [0068] For the production of a polyvinyl alcohol copolymer used as a coating agent, 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. Specifically, as (1) 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. (2) 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. (3) Examples of unsaturated-tolyls include acrylonitrile, methacrylonitrile, etc. (4) Examples of saturated amides include acrylamide, dimethylacrylamide, and methacrylamide. (5) Aromatic beers include styrene, α-methylstyrene, and (6) Aliphatic vinyls include butyl acetate. (7) Examples of unsaturated bond-containing heterocycles include Ν-vinylpyrrolidone, acryloylmorpholine, and the like.

 [0069] Further, unsaturated carboxylic acids and their esters as the polymerizable vinyl monomer in the production of the polyvinyl alcohol copolymer are represented by the following general formula (X):

 (Chemical 22)

 H C = C (R) -COOR (X)

 2 1 2

 (Wherein R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms)

 1 2

An alkyl group having a child is shown. ). [0070] 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. Here, the weight ratio of the polybulal alcohol to the polymerizable bur monomer is about 6: 4 to 9: 1, preferably about 8: 2. When 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.

 [0071] As the polymerization initiator, those used in this field can be used. For example, inorganic peroxides such as potassium persulfate, ammonium persulfate, and hydrogen peroxide, organic peroxides such as peracetic acid, t-butylhydride peroxide, and di-propylperoxydicarbonate, or 2, 2, Azobis compounds such as 2-azobis (2-amidinopropane) hydride chloride and 2,2, -azobis (2,4 dimethylvale-tolyl) can be mentioned.

 [0072] 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.

 [0073] The coating conditions of the macrolide antibiotic uncoated tablets and uncoated condyles with a polybulualcohol copolymer are generally as follows.

• Degree of polymerization of polyvinyl alcohol copolymer: about 500 • Polyvinyl alcohol copolymer liquid concentration: about 8-10% by weight

 'Coating machine: High coater HCT-48 (Freund industry)

 • Spray gun caliber: About 0.8mm

 'Tablet charge: approx. 1 ~ 1.5kg

 • Pan rotation speed: about 20rpm

 • Spraying air volume: About 65-70 L / min

 • Air temperature: approx. 60 ° C

 • Airflow: About 2.5 mVmin

 'Discharge rate: approx. 4.5 mVmin

[0074] According to one more preferred embodiment of the present invention, 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.

[0075] In the present invention, 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.

[0076] A pre-coating layer can be applied to the uncoated tablet before coating with the polyvinyl alcohol copolymer. As coating agents, those known in the art are used. Examples thereof include hydroxypropylmethylcellulose and sucrose.

[0077] 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.

 [0078] The tablet may preferably contain a disintegrant in order to enhance its disintegration property. As the 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.For example, 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. Usually, 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.

 [0079] Tablets containing macrolide antibiotics optionally further include pharmaceutically acceptable additives such as excipients, binders, lubricants, and colorants (eg, acid titanium). Can do. 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.

 [0080] A wide variety of 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.

[0081] As the binder, those widely known in the art can be widely used. For example, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol, gelatin, dextrin and the like are preferable. Propyl cellulose (HPC). 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.

[0082] 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.

 [0083] In the present invention, 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. Regarding the granulation operation, for example, 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. In addition, tableting may be performed using a commercially available tableting machine, usually with a tableting pressure of about 0.2 to 1.5 t.

 [0084] A preferred embodiment of the tablet composition of the present invention is as follows.

 In total tablet weight,

 Compound (ΠΙ), a pharmaceutically acceptable salt, or a hydrate thereof, which is the active ingredient: about 40 to 70%;

 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%

 And against uncoated tablet weight

 The coating agent, preferably polyvinyl alcohol copolymer, is about 5-20% by weight.

[0085] 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. For example, 0.01 to 50 mgZkg can be orally administered in terms of a salt or a hydrate thereof.

[0086] Further, in the preparation of the present invention, for example, 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.

[0087] The preparation of the present invention is preferably PTP (press-through) in order to further improve the stability. One package) or bottle packaging (eg, plastic bottles, glass bottles, aluminum cans).

 [0088] The coated preparation of the macrolide antibiotic of the present invention may contain an antibacterial agent other than the macrolide antibiotic. Further, the main component of the coating agent may contain a coating force or other coating components which are polybulal alcohol or polyvinyl alcohol copolymer.

 [0089] Further, the present invention provides the following partial structural formula:

 [Chemical 23]

 (In the formula, 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.

Further, 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. There is also provided 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. [0091] Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples.

 Example

[0092] Example 1

 Investigate the effect of polyvulcoalcohol blended coating on the stability of tablets.

 According to the production flowchart shown in FIG. 1, a coated preparation (formulation 1) having the composition shown in Table 1 below was obtained.

[0093] [Table 1]

 [0094] A coated tablet of the above uncoated tablet with a polyvinyl alcohol copolymer was produced through the following steps (1) to (1).

 (1) Using the granules granulated by wet granulation with an agitation granulator, produce tablets with φ8mm and φ9mm 2-stage R using a rotary tableting machine.

(2) 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. When compounding titanium oxide, the acid is stirred and dispersed with TK Robotics (Special Machine Industries). A titanium bromide-containing polybutyl alcohol copolymer aqueous solution is prepared.

 (3) Charge 1 ~ 1.5kg of tablets into HCT-48, a breathable coating machine with two fluid nozzles.

(4) blast temperature 60 ° C, air volume 2. 5 m ³ Z min, fixed time heating at Haifuryou 4. 5 m ³ Z component, to maintain the above product temperature 40 ° C.

 (5) Spray gun caliber 0.8mm, spray air volume 65-70LZ min., Pan rotation speed 20rpm, 8-10wt% polybulualcohol copolymer to keep tablet temperature above 40 ° C Spray the aqueous solution in a range of 5 to: LOg / min to coat the tablet with the polyvinyl alcohol copolymer.

 (6) After coating the specified amount of polyvinyl alcohol copolymer, talc and / or magnesium stearate are sprayed onto the tablet surface, and the tablet is discharged from the air-permeable coating machine, iCoater HCT-48.

 (7) Dry the coated tablets prepared using a shelf dryer (fan temperature 65 ° C, drying time 90 minutes).

 [0095] (2) Evaluation of the stability of the macrolide gargle preparation

 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.

 [0096] 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 (ΠΙ)) was used.

 [0097] <Preparation of sample solution for liquid chromatography>

 (1) Each of the coating and uncoated tablets were wrapped in medicine wrapping paper and pulverized quickly, and the whole amount was put into a lOOmL volumetric flask.

 (2) Acetonitrile Z water mixture for liquid chromatography (7: 3) 70 mL was collected. Acetonitrile was used for high performance liquid chromatography (hereinafter the same) o

(3) Shake for 10 minutes. (4) Aceticonitrile Z water mixture for liquid chromatography (7: 3) was prepared to make exactly lOOmL.

(5) Filter the solution in (4) with a 0.45 μm membrane filter (Kurabo Co., Ltd., Chromatodisc non-aqueous 13N), remove 2 mL of the first filtrate, and use the remaining filtrate as the sample solution. .

 [0098] <Preparation of standard solution>

 For use as a standard substance, 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

[0099] <Liquid chromatography conditions> o

 o

 The peak areas due to the main drug and related substances were measured by the automatic calculation method.

 Detector: UV absorption photometer

 (Measurement wavelength range: 195 400nm, extraction wavelength: 210nm)

 Column: L-column ODS, 5 m, 4.6 X 250 mm (National Institute for Chemical Evaluation) Column temperature: Constant temperature around 40 ° C

 Mobile phase A: 0.008 mol ZL potassium dihydrogen phosphate buffer with pH 8.0, Z-acetonitrile (3,2) mixture

 Mobile phase B: acetonitrile ΖρΗ8.0 in 0.012 molZL potassium dihydrogen phosphate buffer (3,1)

 Gradient program:

[0100] [Table 2] Time after sample injection Mobile phase A (%) Mobile phase B (%) (min)

 0 5 7 0 3 0

 5 4 0 3 0 → 1 0 0

4 0 6 5 0 1 0 0

 6 5 6 5. 0 1 1 0 0 → 3 0

6 5. 0 1 8 0 7 0 3 0 Flow rate: 1. OmLZ min. (Main component retention time at setting is about 30 min.)

 Injection volume:

 Sample cooler temperature: 25 ° C

 Needle cleaning solution: Acetonitrile

 Area measurement range: 65 minutes after sample injection

[0101] <Check system compatibility>

 System suitability was confirmed by performing liquid chromatography on 10 L of the standard solution in the same manner as described above and holding the main component for about 30 minutes.

[0102] <Measuring method of street margin ratio>

 The amount of each related substance (%) and the total amount of related substances (%) were calculated from the following formulas.

 Individual related substances (%) = (Ai / ΣΑ) X 100

 Total related substances (%) = (∑ AiZ∑ A) X 100

 Ai: Peak area of each related substance

 ∑ Ai: Sum of peak areas of individual related substances

 ∑ 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 below shows the retention time, area, and height of each peak.

[0103] [Table 3]

Peak number Retention time (min) Peak area Peak area Peak height

 (%)

 1 10. 68 6346 0. 05 548

2 18. 01 35 181 0. 26 2099

3 22. 96 3650 0. 03 247

4 25. 81 3946 0. 03 269

5 26. 95 4038 0. 03 258

6 29. 52 13691722 99. 35 606508

7 30. 41 12922 0. 09 915

8 34. 86 8124 0. 06 439

9 36. 68 3448 0. 03 198

1 0 39. 73 3643 0. 03 205

1 1 49. 01 8722 0. 06 368

[0104] Peak 6 is a peak derived from the main compound (ΠΙ). 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.

 [0105] 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. In Fig. 3, ◯ indicates uncoated tablet, and 參 indicates a coated tablet made of polyvinyl alcohol copolymer. As is clear from FIG. 3, 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.

 [0106] Example 2

 Influence of the cocoon candy on the stability of cocoon

 In the preparation method of the macrolide-based coating preparation of Example 1, 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.

[0107] Each one of these coated preparations, 40 ° C, 75% relative humidity, unwrapped, protected from light Stored for 1 week. Subsequently, in the same manner as in Example 1, the ratio (%) of the total amount of the related substances to the main drug was calculated.

 The results are shown in FIG. As is apparent from FIG. 4, 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). .

 [0109] Example 3

 Review of the effects of titanium oxide-containing polyvinyl alcohol copolymer coating on the stability of the active ingredient

 According to the production flowchart shown in FIG. 5, 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.

[0110] [Table 4] Formulation 2 Formulation 3 Formulation 5 Intragranular compound (I I I) (Type 1 crystal) 00.0 mg 1 50.0 mg 200.0 mg

D-mannil mono 38.4 mg 5 7. 6 mg 76. 8 mg Hydroxypropi / resenolerose 4. D mg 6. 9 mg 9.2 mg Extra-granular canoleboxymethyl starch 8.0 mg 1 2. 0 mg 16. 0 mg Ryumu

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.

 [0112] 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 (ΠΙ) and the amount of related substances produced were measured by liquid chromatography. The same production lot of macrolide antibiotic (compound (ΠΙ)) was used for the coating and uncoated tablets.

 [0113] 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. In Fig. 6, ◯ indicates an uncoated tablet, and 參 indicates a coated tablet made of acid-titanium-containing polyvinyl alcohol copolymer. As is clear from FIG. 6, 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.

 [0114] Example 4

 Review of the effect of polyvinyl alcohol gargle on the ffi

 According to the production flowchart shown in FIG. 7, a coated preparation (formulation 4) having the composition shown in Table 5 below was obtained.

[0115] [Table 5]

Formulation 4 Intragranular Compound (I I I) (Type 1 crystal) 100. 0 mg

 D-manni] ^ 1ul 38.4 mg Hydroxypropylcellulose 4.6 mg Extragranular carboxymethyl cinnatrium 15.0 mg Magnesium stearate 4.0 mg

^? ¾hd 162. 0 mg Coating material Polyvinyl alcohol 15.5 mg Talc Trace amount 15.5 mg

A 177. 5 mg Covering ratio (%) (Uncoated tablet) 9.6%

[0116] The stability of the macrolide-based coated preparation (Preparation 4) obtained as described above was compared with that of an uncoated tablet. The evaluation method is as follows.

 [0117] 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 (ΠΙ)) was used.

 [0118] 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. In FIG. 8, ◯ indicates an uncoated tablet and 參 indicates a coated tablet made of polyvinyl alcohol. Figure

As apparent from FIG. 8, 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. In contrast, when stored as an uncoated tablet, similar substances are rapidly formed, and after 3 months of storage, the ratio (%) of the total amount of related substances to the active ingredient is about 9% (w / w). The Industrial applicability

 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

Claims

Claims Macrolide antibiotics having a group represented by the following partial structural formula: (wherein R represents a protective group for a hydrogen atom or a hydroxyl group), pharmaceutically acceptable salts thereof, or their A coated preparation of a macrolide antibiotic comprising a hydrate and coated with a coating agent containing polyvinyl alcohol or a polyvinyl alcohol copolymer. [2] A macrolide antibiotic is a macromolecule having a group represented by the following partial structural formula (I): [Chemical Formula 2] (I) (wherein R2a represents a protecting group for a hydrogen atom or a hydroxyl group). 2. The coated preparation of a macrolide antibiotic according to claim 1, which is a oral ride antibiotic, a pharmaceutically acceptable salt thereof, or a hydrate thereof. The coated preparation of a macrolide antibiotic according to claim 1, wherein the macrolide antibiotic is a 14 to 16-membered ring macrolide antibiotic. Macrolide antibiotics have the general formula (式): [wherein A is a) —OH, b) ORP (wherein RP represents a hydroxyl protecting group), c) — R1 (wherein R1 represents (1) aryl group, (2) substituted aryl group, (3) heteroaryl group or substituted heteroaryl group), d) -OR1 (wherein R1 is as defined above) ), E) — R2 (wherein R2 is (1) a hydrogen atom, (2) a halogen atom, (3) an oxygen atom, a sulfur atom and a nitrogen atom) 0 to 3 heteroatoms selected A C 1 -C alkyl group optionally substituted with one or more substituents selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group, (4) oxygen Optionally containing 0 to 3 heteroatoms selected from the group consisting of atoms, sulfur atoms and nitrogen atoms, a norogen, aryl group, substituted aryl group, The aryl group and the substituted heteroaryl group are also selected. The C—C alkenyl group, which may be substituted with one or more substituents, or (5) an oxygen atom, a sulfur atom and a nitrogen atom are selected 0 CC alkynyl group optionally containing up to 3 heteroatoms, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl ), 2 12 f) -OR2 (R2 is as defined above), g) -S (O) R11 (wherein n is 0, 1 or 2, R11 is independently A hydrogen atom, R1 or R2, wherein R1 and R2 have the same meaning as above, h) NHC (0) RU (wherein R11 has the same meaning as above), i) — NHC (0 ) NHRU (wherein R11 has the same meaning as above), j) -NHS (O) Rn (wherein R11 has the same meaning as above), 2 k) —NR14R15 (wherein R14 and R15 each independently represent R11, R11 has the same meaning as described above), and 1) —NHR3 (wherein R3 represents an amino group-protecting group.) B represents a group selected from: a) a hydrogen atom, b) deuterium, c) a halogen atom, d) OH, e) —R1 (R1 has the same meaning as described above. F) —R2 (R2 is as defined above), or g) —ORp (wherein RP is as defined above; provided that when B is halogen, OH or —ORP, A Represents —R1 or —R2, or A and B are bonded together with a carbon atom, and a) C = 0 b) C (OR2) (R2 has the same meaning as above. ), 2 c) C (SR2) (R2 has the same meaning as above), 2 d) C [O— (CH 2)] (m is 2 or 3), 2 m 2 e) C [—S— (CH 2)] (m is as defined above), Jinji! ^ 11 ^ 11 is as defined above. ), G) C = N—O—R11 ^ 11 has the same meaning as described above. ), Or h) C = N-0-Ar1-M-Ar2 [wherein 1) —Ar1— represents R31, R31 is independently a) formed by removing hydrogen from R1 2 A valent group (R1 has the same meaning as described above), b) optionally containing 0 to 3 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, a halogen, an aryl group, a substituted aryl group, A heteroaryl group and a substituted heteroaryl group force may also be selected, which may be substituted with one or more substituents, C—C 0 1 12 norylene group, c) selected from an oxygen atom, a sulfur atom and a nitrogen atom 0 to Optionally containing 3 heteroatoms, halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl forces also selected, optionally substituted with one or more substituents, C-C 2 12 Norekenylene group or d) oxygen atom, sulfur atom and nitrogen atom Optionally containing 0 to 3 heteroatoms selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl may be substituted with one or more substituents. , C—C represents 2 12 norequinylene group; 2) —M— is a bond or (a) 0-3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom and —C = N—, — N = N— and — C (O) —Force, optionally containing 0 to 3 groups, c-c Ananolylene group, 1 12 (b) Oxygen atom, sulfur atom and nitrogen nuclear power 0 ~ 3 heteroatoms and — C = N—, — N = N— and — C (O) — force, optionally containing 0 to 3 groups, C—C anolenokenylene group, 2 12 (c) Oxygen atom, sulfur atom and nitrogen nuclear power 0 to 3 selected hetero atoms and — C = N—, — N = N— and — C (O) — C—C anolenoquinylene group, (d) a substituted arylene group, (e) a substituted heteroarylene group or (f) a substituted heterocycloalkylene group, optionally containing 0 to 3 groups selected from 3) Ar2 represents (a) an aryl group, (b) a substituted aryl group, (c) a heteroaryl group, or (d) a substituted heteroaryl group]; i) C = NHHRU (R11 has the same meaning as above) . ), J) C = NNHC (O) R11 (R11 is as defined above), k) C = NNHC (O) NHR11 (R11 is as defined above), 1) C = NNHS ( 0) R11 ^ 11 has the same meaning as above. ), 2 m) C = NNHR3 (R3 is as defined above), n) C = NR11 (Ru is as defined above), o) C = NR11 (R11 is as defined above) Or p) C = N—N—CHR11 ^ 11 has the same meaning as described above. One of X and Y represents a hydrogen atom, the other represents a) a hydrogen atom, b) deuterium, c) OH, d) —ORp (RP has the same meaning as above), e ) — NR4R5 (R4 and R5 are each independently (1) a hydrogen atom, (2) a halogen, an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, one or more substituents selected. C 3 -C 1 12 alkyl group, which may be substituted with, or (3) R4 and R5 together with the nitrogen atom to which they are attached are also selected as oxygen atom, sulfur atom and nitrogen nuclear atom 0 Represents 3 to 10 heteroalkyl rings containing 2 heteroatoms, or X and Y are bonded together with a carbon atom, (a) C = 0 or (b) C = NQ (wherein Q

(1) —R ^ R ¹¹ has the same meaning as described above. ),

 (2) an amino protecting group,

(3) —. (. ^ " ¹¹ has the same meaning as above),

( ⁴ ) — OR ⁶ (R ⁶ is independently

 (a) a hydrogen atom,

 (b) -CH 0 (CH) OCH

 2 2 2 3,

 (c) -CH 0 (CH 2 O) 2 CH (n is as defined above),

 2 2 n 3

 (d) 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 units,

 (e) -C 1 -C cycloalkyl group,

 3 12

 (f) -c (o) -c -c alkyl group,

 1 12

( _g ) -c (o) -c-c cycloalkyl group,

 3 12

(h) -C (O) —R ^ R ¹ has the same meaning as described above. Or

(i) —Si (R ^a ) (R ^b ) (R ^c ) (R ^a , R ^b and R ^c are each independently C—C alkyl

 1 12 represents a group, an aryl group or a substituted aryl group. ); Or

(5) 0-C (R ⁷ ) (R ⁸ ) — O—R ⁶ (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

1 12 3 12 1

R and R together with the carbon atom to which they are attached form a C -C cycloalkyl group

7 8 3 12

Or (1) a hydrogen atom or (2) a C 1 -C alkyl group. );

 1 12

 U

 a) -CH,

 Three

 b) —CH CH,

 twenty three

c) -CH (OH) CH, d) 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,

 1 6

 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;

 2 6

Or

 f) a C C alkyl group which may be substituted with one or more substituents selected from an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group;

 2 6

Representation;

 z is

 a) a hydrogen atom,

 b) methyl group or

 c) represents a halogen atom;

R ^2a represents a hydrogen atom or a hydroxyl-protecting group. }

4. A coated preparation of a macrolide antibiotic according to claim 3, wherein the compound is a compound represented by the formula: pharmaceutically acceptable salt thereof or a hydrate thereof.

 Macrolide antibiotics

 (1) The following formula (ΠΙ):

[Chemical 4]

(1R, 2R, 3R, 6R, 8R, 9R, lOR, 16S, 18R) —N— [9— (3, 4, 6— Trideoxy-1-3-dimethylamino-1-13-D Ranosyloxy)-3-ethyl-2-hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dixo 1 3- [(E)-[6- (pyrazole-1-yl) pyridine-3 —Yl] methoxyimino] -4, 11, 15 trioxabicyclo [8,5,4] nonade force 17E—ylidene] acetamide,

(2) The following formula (IV):

[Chemical 5]

TEA—0777 represented by (5) Formula (VII) below:

[Chemical 8]

CP— 544372 represented by (6) Formula (VIII): [Chemical 9]

Cesromycin represented by, or

(8) (1R, 2R, 3R, 6R, 8R, 9R, lOR, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-1-3-dimethylamino-1-13-D xylohhexopyranosyl Xy) 3-ethyl 2-hydroxy 2, 6, 8, 10, 16, 18 hexamethyl-5, 7 dixo 13— [(E) [6- (2-aminoviridine-6-yl) pyridine 3-yl ] Methoxyimino] — 4, 11, 15 Trioxabicyclo [8, 5, 4] Nonade Rikiichi 17E—Iridene] acetamide, The coated preparation of a macrolide antibiotic according to claim 4, wherein the coated preparation is a pharmaceutically acceptable salt or a hydrate thereof.

 Macrolide antibiotics have the following formula (ΠΙ):

[Chemical 11]

(1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) —N— [9— (3, 4, 6— Trideoxy-1-3-dimethylamino-1-13-D Ranosyloxy)-3-ethyl-2-hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dixo 1 3- [(E)-[6- (pyrazole-1-yl) pyridine-3 —Yl] methoxyimino] -4, 11, 15 trioxabicyclo [8, 5, 4] nonade force—17E—ylidene] acetamide, a pharmaceutically acceptable salt thereof, or a hydrate thereof 6. A coated preparation of a macrolide antibiotic according to claim 5.

 Macrolide antibiotic power 2 0 = 14.3, 14.5, 15.1, 18.8, 20.5, 23.2, 24.9, 25.6, 29. Having at least one peak selected from 0, 34.1, 37.7, 38.1, 38.9 and 40.4 (unit: degree), (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-3 Dimethylamino 1 13-D Xoxyhexanopyranosyloxy) 3 Ethyl 2 Hydroxy 1, 2,

6, 8, 10, 16, 18 Hexamethyl 1,5

7 Dioxo 13— [(E) [6— (Virazo 1-yl) pyridine-3-yl] methoxyimino] —4, 11, 15-trioxabicyclo [8, 5, 4] nonade force—17E—ylidene] acetamide A coated preparation of a macrolide antibiotic according to claim 1, characterized by the above.

8. The coated preparation of a macrolide antibiotic according to claim 7, wherein the type 1 is an anhydrous crystal.

 [9] The coated preparation of a macrolide antibiotic according to claim 1, wherein the coated preparation is a solid preparation.

 [10] The coated preparation of a macrolide antibiotic according to claim 9, wherein the solid preparation is a tablet or a granule.

[11] A polyvinyl alcohol obtained by copolymerizing a polybulal alcohol having an average degree of polymerization of 1300 or less and at least one polymerizable bur monomer in a weight ratio of 6: 4 to 9: 1. The coated preparation of a macrolide antibiotic according to claim 1, characterized in that it comprises a call copolymer.

 12. The coated preparation of a macrolide antibiotic according to claim 11, wherein the average degree of polymerization of polyvinyl alcohol is 900 or less.

 13. The coated preparation of macrolide antibiotics according to claim 12, wherein the average degree of polymerization of polybulal alcohol is 200 to 600.

 14. The coated preparation of a macrolide antibiotic according to claim 11, wherein the polyvinyl alcohol is a partially saponified polybulal alcohol.

 [15] Polymerizable butyl monomer power Unsaturated carboxylic acids, esters of unsaturated carboxylic acids, unsaturated nitriles, unsaturated amides, aromatic bulls, aliphatic bulls, unsaturated bonds containing unsaturated bonds 12. The coated preparation of a macrolide antibiotic according to claim 11, wherein the preparation is selected from the group consisting of a salt strength thereof.

 [16] Polyvinyl alcohol and two or more polymerizable vinyl monomers are copolymerized, and at least one of the two or more polymerizable butyl monomers is an unsaturated carboxylic acid or a salt thereof. 12. The coated preparation of a macrolide antibiotic according to claim 11, wherein at least one other is an ester of an unsaturated carboxylic acid.

[17] Unsaturated carboxylic acids or salts thereof Acrylic acid, methacrylic acid, crotonic acid, Fumaric acid, maleic acid, itaconic acid and their salt strength group power are selected, esters of unsaturated carboxylic acids such as catecholate, methyl acrylate, ethyl methacrylate, ethyl acrylate and butyl. Metatalylate, Butyl Atalylate, Isobutyl Metatalylate, Isobutyl Atalylate, Cyclohexyl Metatalylate, Cyclohexyl Atalylate, 2-Ethylhexyl Metatalylate, 2-Ethyl Hexyl Atalylate, Hydroxy Group power consisting of tilmetatalylate, hydroxyethyl acrylate, esters of polyethylene glycol and methacrylic acid, esters of polyethylene glycol and acrylic acid, and esters of polypropylene glycol and acrylic acid. The features and A coated preparation of a macrolide antibiotic according to claim 16.

[18] Unsaturated carboxylic acids, their salts and esters of unsaturated carboxylic acids General formula (X)

 (Chemical 12)

 H C = C (R) -COOR (X)

 2 1 2

 (Wherein R represents a hydrogen atom or a methyl group, R represents a hydrogen atom or 1 to 4 carbon atoms)

 1 2

 An alkyl group having a child is shown. 16. A coated preparation of a macrolide antibiotic according to claim 15, wherein the compound is a compound represented by the following formula:

[19] The macrolide antibiotic according to claim 16, wherein the macrolide antibiotic is an unsaturated carboxylic acid or a salt thereof, which is acrylic acid or a salt thereof, and is an ester of an unsaturated carboxylic acid, butyl methacrylate. A coated formulation of the substance.

[20] The weight ratio of acrylic acid or salt thereof to methyl methacrylate is 3 when copolymerizing.

 The coated preparation of a macrolide antibiotic according to claim 19, wherein the formulation is 7 to 0.5: 9.5.

 [21] The polymerizable vinyl obtained by copolymerizing a partially saponified polybutyl 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. The 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: 9.5, A coated preparation of the macrolide antibiotic according to claim 11.

[22] Partially saponified polybulal alcohol with an average degree of polymerization of 300 to 500, methyl metatalylate The weight ratio of the macrolide antibiotic according to claim 21, wherein the weight ratio of copolymerization of benzoic acid is 60-90: 7-38: 0.5-12. Coating formulation.

 23. The coated preparation of a macrolide antibiotic according to claim 10, wherein the content of the coating agent is 2% (weight ratio) or more with respect to the uncoated tablet or elementary granule.

 [24] The coated preparation of macrolide antibiotics according to claim 1, wherein the total amount of related substances after storage for 3 months at 25 ° C and 60% relative humidity is 3% or less. Macrolide antibiotic coating.

 [25] Macrolide antibiotics are (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) N— [9- (3, 4, 6-trideoxy-1-3-dimethylamino-13-D— Hexamethylhexohexanoyloxy) -3 Ethyl-2 hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 —Dioxo13— [(E) [6- (Pyrazole 1-yl) pyridine 1 3—yl] methoxyimino] 4, 11, 15 trioxabicyclo [8,5,4] nonade force 1E-ylidene] acetamide type 1 crystal, the coating agent containing acid titanium Polyvinyl alcohol or polybulal alcohol copolymer, and the total amount of related substances after storage for 3 months at 25 ° C and 60% relative humidity is 1.5% or less. A coated preparation of a macrolide antibiotic according to claim 1, characterized in that:

 [26] Macrolide antibiotics are (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) N— [9- (3, 4, 6-trideoxy-1-3-dimethylamino-13-D— Hexamethylhexohexanoyloxy) -3 Ethyl-2 hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 —Dioxo13— [(E) [6- (Pyrazole 1-yl) pyridine 1 3—yl] Methoxyimino] 4, 11, 15 Trioxabicyclo [8, 5, 4] Nonade Chiichi 17E—ylidene] acetamide, a type 1 crystal at 25 ° C and 60% relative humidity A coated preparation of macrolide antibiotics, characterized in that the total amount of related substances after storage for months is 1.5% or less.

 [27] The coated preparation of a macrolide antibiotic according to claim 26, wherein the coated preparation is a PTP (press-through package) package or a bottle package.

 [28] Partial structural formula:

[Chemical 13]

 (In the formula, 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 A method for suppressing the formation of a related substance of the macrolide antibiotic, comprising coating a solid substance with a coating agent containing polybulal alcohol or a polybulal alcohol copolymer.

 The following partial structural formula:

 [Chemical 14]

(Wherein 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. The macrolide antibiotic, its pharmaceutically acceptable salt, or a hydrate thereof, characterized in that the solid substance to be coated is coated with a coating agent containing polybulualcohol or a polybulualcohol copolymer. Stable way.