WO2007148772A1

WO2007148772A1 - Sugar-coated reparation of macrolide antibiotic

Info

Publication number: WO2007148772A1
Application number: PCT/JP2007/062560
Authority: WO
Inventors: Tatsumori Yoshida; Takeshi Funaki; Yurie Kobayashi
Original assignee: Shionogi & Co., Ltd.
Priority date: 2006-06-23
Filing date: 2007-06-22
Publication date: 2007-12-27
Also published as: JPWO2007148772A1

Abstract

A coated preparation of a macrolide antibiotic, comprising: a macrolide antibiotic having a group represented by the partial structural formula below, a pharmaceutically acceptable salt thereof, or a hydrate of the antibiotic or the salt as the main ingredient; and a coating agent mainly comprising a sugar, wherein the macrolide antibiotic is coated with the coating agent. [Formula] wherein R2a represents a hydrogen atom or a protecting group for a hydroxyl group.

Description

Specification

Sugar-coated preparations of macrolide antibiotics

Technical field

[0001] The present invention relates to a stabilized coating preparation of a macrolide antibiotic effective for the treatment of various infectious diseases caused by bacteria, mycoplasma, fungi, protozoa, and the like, and an analogue of a macrolide antibiotic The present invention relates to a method for suppressing the generation of.

Background

[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 clarithro. Mycin (patent document 5), roxithromycin (patent document 6), adisthromycin (patent document 7), dirithromycin (patent document 8), tethromycin (patent document 9), sesulomycin (patent document 10), full Rithromycin ether succinate (Patent Document 11), Compound III (Patent Documents 12 and 13), L-701677 (Patent Document 14), Mycinamicin (Non-Patent Document 1), and many other derivatives are known. ing.

[0003] Up to now, various dosage forms for oral administration or parenteral administration have been developed and used for these known macrolide antibiotic preparations. However, when these macrolide antibiotic preparations are stored for a long period of time, the formation of macrolide antibiotic related substances may be observed in the preparations, which is not always a 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 preparation, Oral preparations generally have a tendency to become large dosage forms. There was a drawback that it was difficult to take.

As known preparations of these macrolide antibiotics, saccharides as a main component are used as coating agents for macrolide antibiotics having a specific chemical structure, such as the present invention, or uncoated tablets, elementary granules, and the like. The prior art used for the stabilized coating formulation was not known so far.

[0004] Patent Document 1: US2653899

Patent Document 2: US2823203

Patent Document 3: US2757123

Patent Document 4: US2842481

Patent Document 5: US4331803

Patent Document 6: US4349545

Patent Document 7: US4517359

Patent Document 8: EP511799

Patent Document 9: US5635485

Patent Document 10: US5866549

Patent Document 11: EP56291

Patent Document 12: WO 2003/097659 A1

Patent Document 13: WO 2005/081821 A2

Non-Patent Document 1: J. Antibiot 45 (1), 1 (1992)

Patent Document 14: EP508699

Disclosure of the invention

Problems to be solved by the invention

[0005] In view of the above circumstances, there is an urgent need in the art to develop a stabilized preparation of a macrolide antibiotic that can withstand long-term storage, particularly a 13- to 16-membered ring macrolide antibiotic preparation. In particular, there is a demand for improving the stability of macrolide antibiotic solid preparations such as tablets, granules, capsules and pills.

Means for solving the problem

[0006] Accordingly, as a result of various studies on the stabilization of macrolide antibiotic preparations, the following formula: [Chemical 1]

(Wherein R represents a hydrogen atom or a hydroxyl-protecting group), preferably:

[Chemical 2]

(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, using a saccharide-based covering agent. It was found that a coated preparation of a stabilized macrolide antibiotic can be obtained by coating, and the present invention was completed.

That is, the present invention

1) As the active ingredient, the following partial structural formula:

(Wherein R ^2a represents a protecting group for a hydrogen atom or a hydroxyl group), a macrolide antibiotic having a group represented by the following formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof: A coated preparation of a macrolide antibiotic, characterized in that it is coated with a coating mainly composed of sugars,

[0008] 2) The main drug is the following partial structural formula (I):

[Chemical 4]

(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. A macrolide antibiotic coating preparation as described in 1) above,

[0009] 3) The macrolide antibiotic coated preparation according to 1) above, wherein the macrolide antibiotic is 14 to 16-membered ring macrolide antibiotic,

[0010] 4) Macrolide antibiotics have the general formula (II):

{Where A is

a)-OH,

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

-Shaku type in the middle! ^ Represents an aryl group, (2) a substituted aryl group, (3) a heteroaryl group or a substituted heteroaryl group. ),

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

_1 ² (wherein, 1 ^2, (1) a hydrogen atom, include (2) a halogen atom, (3) an oxygen atom, optionally 0-3 heteroatom selected from oxygen, sulfur and nitrogen atoms, halogen A C 1 -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, (4) an oxygen atom

1 12

1 to 2 or more substituents optionally selected from a halogen, a aryleno group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group, optionally containing 0 to 3 heteroatoms selected from a silicon atom, a sulfur atom and a nitrogen atom May be substituted with, C-C Alkeninore

2 12

Group, or (5) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group It represents a C 1 -C alkynyl group which may be substituted with one or more substituents. ),

2 12

f) OR ² (R ² is as defined above), g) —S (◯) _n R ″ (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 the same as above. Has significance.),

h) —NHC (O) R ¹¹ (wherein R ¹¹ has the same meaning as described above),

i) -NHC (O) NHR ¹¹ (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) one 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

a) a hydrogen atom,

b) deuterium,

c) a halogen atom,

d) —OH,

e) one R ¹ (R ¹ has the same meaning as above),

f) one R ² (R ² has the same meaning as above), or

g) — represents OR ^p (is as defined above);

Provided that when B is halogen, —OH or —〇R ^P , A represents —R ¹ or —R ² , or A and B together with the bonded 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 [-0- (CH)] (m is 2 or 3),

2 m 2

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

2 m 2

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

Ji: ^^ —. — ^ ¹ ^ ¹¹ has the same meaning as 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 and optionally substituted with one or more substituents selected from halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;

1 12 Norylene group,

c) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, one or more selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group May be 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, one or more selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group Which may be substituted with a substituent of CC

2 12 represents a norequinylene group;

2) —M is the bond or

(a) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms and — C = N—, — N = N— and — C (〇) — selected from forces 0 to 3 A CC anolylene group, optionally containing a group,

1 12

(b) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms and — C = N—, — N = N— and — C (〇) — Forces selected from 0 to 3 A c-c anorekenylene group, optionally containing a group,

2 12

(c) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and — C = N—, — N = N— and — C (〇) —force 0 to 3 groups selected A 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 ¹¹ is as defined above),

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

2

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

n) C = NR "(R ¹¹ has the same meaning as above),

o) C = NR ¹¹ (R ¹¹ has the same meaning as above), or

D ^^^^ — Ji! ! ! ^ 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) 10H,

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) C C -alkyl which may be substituted with one or more substituents selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group

1 12 alkyl groups, or

(3) R ⁴ and R ⁵ together with the nitrogen atom to which they are attached contain 0 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Represents a kill ring, or X and Y, together with carbon atoms,

(a) C = 〇 or

(b) C = N-Q

(Where Q is (1) R ¹¹ (R ¹¹ is as defined above),

(2) an amino protecting group,

(3) —C (O) R ¹¹ (R ¹¹ has the same meaning as described 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) may be substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl groups, C 1 -C alkyl

1 12 units,

(e) -C -C cycloanolenoquinole group,

3 12

(f) -c (o) -c -c alkyl group,

1 12

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

12

(h) -C (O) ^-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 ) —〇—R ⁶ (R ⁶ is as defined above, provided that R ⁶ represents a C (O) -C—C alkyl group, C (〇 ) One C—C cycloalkyl group or C (〇) One 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) represents a hydrogen atom or (2) a C—C alkyl group. );

1 12

L is

a) -CH,

Three

b) -CH CH,

twenty three

c) -CH (OH) CH,

Three

d) may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, C 1 -C alkyl groups,

1 6

e) may be substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl and substituted heteroaryl, C 1 -C alkenyl, or Or

f) a C C alkynyl 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. }

A coated preparation of a macrolide antibiotic as described in 3) above, which is characterized by being a compound represented by the formula:

5) Macrolide antibiotics

(1) The following formula (III):

[Chemical 6]

(1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9 ((3, 4, 6-trideoxy-1-3-dimethylamino-1-β-D Xylohexopyrano Siloxy) 3 Ethyl-2 Hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl-5, 7 Dio Xoxo—13— [(E) — [6— (Pyrazole—1yl) pyridine—3—yl] methoxyimino] — 4, 11, 15—Trioxabicyclo [8, 5, 4] Nonade force 17E —Iridene] acetamide, (2) Formula (IV) below:

[Chemical 7]

Telithromycin, represented by

(3) The following formula (V):

[Chemical 8]

(4) The following formula (VI):

[Chemical 9]

TEA — 0777 (5) The following formula (VII):

[Chemical 10]

CP—544372, indicated by

(6) The following formula (VIII):

[Chemical 11]

Shoulder indicated by 17069546,

(7) The following formula (IX):

[Chemical 12]

Cesromycin represented by, or

(8) (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-Trideoxy _ 3-dimethylaminomino β _D— Ranosyloxy) _ 3 _Ethyl —2-hydroxy-1, 2, 6, 8, 10, 16, 18—hexamethyl-1,5,7-dioxo13— [( E) — [6— (2-Aminoviridine-6-yl) pyridine-3-yl] methoxyimino] — 4, 11, 15-trioxabicyclo [8, 5, 4] Nonade force 17E-ylidene] Acetamide,

Or a coated preparation of macrolide antibiotics according to 1) above, which is a pharmaceutically acceptable salt or hydrate thereof,

[0012] 6) Macrolide antibiotic power Formula (III):

[Chemical 13]

(1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6— Trideoxy _3-dimethylaminomino β _D— Nosyloxy) _3_ Ethyl _2—Hydroxy 1,2, 6, 8, 10, 16, 18—Hexamethyl _5,7-Dioxo _1 3_ [) _ [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, A coated preparation of a macrolide antibiotic as described in 5) above,

[0013] 7) Macrolide antibiotic power In powder X-ray diffraction pattern, 2Θ = 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 at least one peak selected from 40 · 4 (unit: degree), (1R, 2R, 3 R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4 , 6-Trideoxy 1-Dimethyl Noreamino-β-D Xylohexoxolanosyloxy) 3 Ethyl 2 Hydroxyl 1, 2, 6, 8, 10, 16, 18 Hexamethinore 5, 7 Di-satisfied 13- [(E) [6-—Birazo 1-yl) pyridine-3-yl] methoxyimino]-4, 11, 15 trioxabicyclo [8,5,4] nonade force 17E-ylidene] acetamide crystals A coated preparation of a macrolide antibiotic as described in 1) above,

[0014] 8) A coated preparation of a macrolide antibiotic as described in 7) above, wherein the type 1 is an anhydrous crystal,

[0015] 9) The coated preparation of the macrolide antibiotic according to 1) above, wherein the coated preparation is a solid preparation,

[0016] 10) A coated preparation of a macrolide antibiotic as described in 9) above, wherein the solid preparation is a tablet or a granule,

11) A coated preparation of a macrolide antibiotic as described in 1) above, wherein the saccharide is at least one selected from the group consisting of monosaccharides, disaccharides, trisaccharides and sugar alcohols,

[0017] 12) Saccharose is sucrose (sucrose), fructose, glucose, lactose, lactulose, raffinose, trehalose, erythritol, mannitol, sonorebitol, xylitol, maltitol (powder reduced maltose starch syrup), reduced palatinose powder, pullulan And a coated preparation of a macrolide antibiotic as described in 1) above, which is at least one selected from the group consisting of reduced lactose and

[0018] 13) A coated preparation of a macrolide antibiotic as described in 1) above, wherein the content of the coating agent is 5% by weight or more based on the uncoated tablet or elementary granule,

[0019] 14) A coated preparation of a macrolide antibiotic as described in 1) above, wherein the saccharide content is 70% by weight or more based on the coating;

[0020] 15) The total amount of macrolide antibiotics related to macrolide antibiotics is 3% or less of the active ingredient after storage for 2 months at 40 ° C, relative humidity 75%, light-shielding conditions. A coated preparation of a macrolide antibiotic as described in 1) above,

[0021] 16) Main drug power lR, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6— Trideoxy _ 3-dimethylamino 1 β _D— Hexobiranosyloxy) _ 3 _ Ethyl 2 Hydroxy 1, 2, 8, 8, 10, 16, 18 Hexamethyl 1, 5, 7 Dioxo 1 3— [(E) — [6— (Pyrazole 1-yl) pyridine-3- 3-yl] methoxyimino ] — 4, 11, 15 Trioxabicyclo [8, 5, 4] Nonade force — Type 1 crystal of 17E ylidene] acetamide, macrolide after 2 months storage at 40 ° C, relative humidity 75%, shading conditions A macrolide antibiotic coated preparation characterized in that the total amount of the related antibiotics is 3% or less of the main drug,

[0022] 17) PTP (press-through package) packaging or bottle packaging

The macrolide antibiotic coating preparation described in 16) above,

[0023] 18) The macrolide antibiotic described in 1) above, a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solid containing them is coated with a coating containing a saccharide as a main component. A method of inhibiting the formation of macrolide antibiotics, characterized by covering, and

19) The macrolide antibiotic described in 1) above, a pharmaceutically acceptable salt thereof, or a hydrate thereof or a solid containing them is coated with a coating containing saccharide as a main component. A method for stabilizing the macrolide antibiotics, pharmaceutically acceptable salts thereof, or hydrates thereof,

About.

The invention's effect

[0024] The macrolide antibiotic coating preparation coated with a saccharide-based coating agent of the present invention has excellent antibacterial activity and can be used for the treatment of various infectious diseases. Since it is pharmaceutically stable for a long period of time and easy to take, it is very useful as a medicine for humans, non-human mammals, fish and birds. In addition, saccharides as a coating agent can be applied to the active ingredient microparticles and small solids, so tablets, granules, capsules, pills, etc. that are easy to take for patients such as the elderly and children. Solid formulations can be provided.

Brief Description of Drawings

[0025] FIG. 1 shows a production flow chart of a macrolide antibiotic coated preparation of Example 1. FIG. 2 shows the stability test results of the macrolide antibiotic coating preparation (Formulation 1) obtained in Example 1. In the figure, ◯ indicates macrolide antibiotic uncoated tablets, and 秦 indicates sugar-coated tablets. The vertical axis shows the analogs of macrolide antibiotics to the main drug in the coated preparations after 0.5 month, 1 month, and 2 months after 40 ° C, 75% relative humidity, shading, no packaging Indicates the percentage of the total mass.

[Figure 3] shows the macrolide system coated with the coating composition shown in Table 1 (coated with smoothing layer 64.85mg and coloring layer about 0, 20, 40, 70mg). Relationship between the coating amount and the ratio of the total amount of macrolide antibiotic related substances to the main drug when antibiotic preparation (Formulation 1) is stored at 40 ° C, 75% relative humidity, shading, no packaging for 2 weeks Indicate

FIG. 4 shows a production flow chart of a macrolide antibiotic coated preparation of Example 2.

FIG. 5 shows the stability test results of macrolide antibiotic uncoated tablets and sucrose-coated tablets (Product 2) and maltitol-coated tablets (Preparation 3) obtained in Example 2. The vertical axis shows the ratio of the total amount of macrolide antibiotics relative to the main drug after storage for 1 month under the conditions of 40 ° C, 75% relative humidity, shading and no packaging.

BEST MODE FOR CARRYING OUT THE INVENTION

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

(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 15]

(Wherein R represents a protecting group for a hydrogen atom or 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.

[0027] According to the study by the present inventors, it has been found that the partial structure is stabilized by a coating agent containing saccharide as a main component. 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 main drug in the preparation of the present invention.

[0028] In the macrolide ring, the bonding site of the partial structural formula is not necessarily limited, but is preferably bonded to the macrolide ring in the manner exemplified below.

[Chemical 16]

(In the formula, Ra and Rb together represent oxo or one represents a hydrogen atom and the other represents an O sugar residue. The phantom dotted line represents the remaining partial structure of the macrolide ring.)

[0029] 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, the numbering can vary depending on the type of macrolide ring.

[0030] Also, a 14-membered macrolide antibiotic, WO2003Z097659 (Patent Document)

The compound represented by general formula (II) having the following crosslinked structure described in 12), a pharmaceutically acceptable salt thereof or a hydrate thereof is more preferable.

[Chemical 17]

{Where A is

a)-OH,

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

— ^ (Where ゝ! ^ Represents an aryl group, (2) a substituted aryl group, (3) a heteroaryl group or a substituted heteroaryl group),

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

1 12

1 to 2 or more substituents optionally selected from a halogen, a aryleno group, a substituted aryl group, a heteroaryl group, and a substituted heteroaryl group, optionally containing 0 to 3 heteroatoms selected from a silicon atom, a sulfur atom and a nitrogen atom Optionally substituted with C-C alkeninoles

2 12

f) -OR ² (R ² is as defined above),

g) — S (〇) 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 (O) R ¹¹ (wherein R ¹¹ has the same meaning as described above),

—NH ^ C NHR ¹¹ (wherein R ¹¹ has the same meaning as 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 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 represents as defined above;

Provided that when B is halogen, —OH or —OR ^P , A represents —R ¹ or —R ² , or A and B together with the carbon atoms to which they are attached,

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 [-0- (CH)] (m is 2 or 3),

2 m 2

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

2 m 2

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

g) C = N—O—R ″ (R ″ has the same meaning as above), or

h) C = N-0-Ar ¹ -M-Ar ²

[Where

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

1 12 Norylene group,

2 12 Norekenylene group, or d) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, one or more selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group Which may be substituted with a substituent of CC

2 12 represents a norequinylene group;

2) _M—

(a) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and — C = N—, — N = N— and — C (〇) —force 0 to 3 groups selected Optionally containing a c-c anoalkylene group,

1 12

(b) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and — C = N—, — N = N— and — C (〇) —force 0 to 3 groups selected Optionally containing a c-c anolenokenylene group,

2 12

(c) 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms and — C = N—, — N = N— and — C (〇) — selected from forces 0 to 3 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 (O) R ¹¹ (R ¹¹ is as defined above),

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

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

2

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

n) C = NR "(R ¹¹ has the same meaning as above), o) C = NR ¹¹ (R ¹¹ has the same meaning as 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) 10H,

d) _OR ^P (R ^P has the same meaning as above),

e) _NR ⁴ R ⁵ (R ⁴ and R ⁵ are each independently

(1) hydrogen atom,

(2) may be substituted with one or more substituents selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group;

1 12 alkyl groups, or

(3) R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded contain an oxygen atom, a sulfur atom and a nitrogen nuclear atom containing 0 to 2 heteroatoms 3 to 10 heteroalkyls Represents a ring, or X and Y, together with carbon atoms,

(a) C = 〇 or

(b) C = N-Q

(Where Q is

(1) R ¹¹ (R ¹¹ is as defined above),

(2) an amino protecting group,

(3) —C (O) R ¹¹ (R ¹¹ has the same meaning as described 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

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 ¹ (R ¹ is as defined above) or

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

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

(5) O — C (R ⁷ ) (R ⁸ ) —OR ⁶ (R ⁶ has the same meaning as described above, provided that R ⁶ is a C (O) —C—C alkyl group, C (〇) C—C cycloalkyl group or C (〇)

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) represents 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 (〇H) CH,

Three

d) a C C alkyl group that 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,

1 6

e) a C C alkenyl 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

Or

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 compound (II) is described in WO2003 / 097659 (Patent Document 1). As described in 2). Preferred embodiments of compound (II) 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, one or more selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group May be substituted with a substituent of C C

1 12 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, and O, more preferably It is pyridinole. 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. Illustrated.

X and Y are preferably bonded together with the carbon atom,

(b) C = N-Q

(Where Q is preferably

(3) C (O) R ¹¹ (R ¹¹ is preferably lower alkyl)).

L is preferably C—C lower alkyl, more preferably b) —CH 2 CH.

1 6 2 3

Z is preferred a) a hydrogen atom.

More specific examples of macrolide antibiotics include erythromycin (14-membered ring), 6-deoxyerythromycin (14-membered ring), oleandomycin (14-membered ring), clarith mouth mycin (14-membered ring) Ring), roxithromycin (14-membered ring), dirithromycin (14-membered ring), terisromycin (14-membered ring, compound (IV)), cesromycin (14-membered ring, compound (IX)), Thromycin (14-membered ring), Flurithromycin ethylsuccinate (14-membered ring), GW7 75346 (14-membered ring, compound (V)), TEA—0769 (14-membered ring)), TEA—0777 (14 Member ring, compound (VI)), TEA-0929 (14 member ring), JNJ—17069546 (14 member ring, compound (VIII) above), CP—279107 (14 member ring), A—185684 (14 member) Ring), A— 63483 (14 member ring), A— 70310 (14 member ring), A— 75729 (14 member ring), CP— 544372 (14 member 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), Compound (III) (14-membered ring bridge structure), azithromycin (15-membered ring), PL— 1. 1. 3 ( 15-membered ring), L_ 701677 (l 5-membered ring), PL— 1. 4. 18 (16-membered ring), PL—1. 4. 2 (16-membered ring), PL_ 1369 (16-membered 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-β _D-xy 1-hexopyranosyloxy) _ 3_ethyl _ 2—hydroxy 1, 6, 8, 10, 16, 18—hexamethinol 5,7—dioxo 13— [(E) — [6— ( 2—aminoviridine-6-yl) pyridine-3-yl] methoxyimino] —4, 11, 15-trioxabicyclo [8,5,4] nonade force—17E-ylidene] acetamide.

Of these, the following formula (III) is particularly preferable:

[Chemical 18]

Compound (111) represented by the above, or the above-mentioned telithromycin, GW773546, TEA-077 7, CP-544372, JNJ-17069546 and cesromycin, or a pharmaceutically acceptable salt or hydrate thereof.

[0033] Particularly preferred is compound (III) which is one embodiment of compound (II), a pharmaceutically acceptable salt thereof or a hydrate thereof.

In the compound (III), the partial structural formula (1Q) 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-dimethylamino-1-β-D-xy-hexoxypyranosyloxy) _ 3 _ethyl _ 2-hydroxy _2 , 6, 8, 10, 16, 18—Hexamethyl _ 5, Ί—Dioxo 13— [(Ε) — [6— (Pyrazonol 1-yl) Pyridine 1 3-yl] methoxyimino] — 4 , 1 1, 15-trioxabicyclo [8,5,4] nonade 17E-ylidene] acetamide.

[0035] As preferred examples of macrolide antibiotics, (1R, 2R, 3R, 6R, 8R, 9R, 1OR, 16S, 18R) — N— [9— (3, 4, 6 trideoxy 1 3 Dimethylamino 1 D—Xylohexylanosyloxy) -3 Ethyl 2 Hydroxy 2, 6, 8, 10, 16, 18 Hexamethyl 1,5,7 Dioxo 13— [(E) — [6— (2 Aminoviridine Also included are 1-6-nole) pyridine-3-yl] methoxyimino]-4, 1 1, 15 trioxabicyclo [8,5,4] nonadec-17E-ylidene] acetamide.

[0036] In particular, the present inventors have poor storage stability of crystals of compound (III) (eg, type 1 crystals described in WO2005 / 081821 (patent document 13), particularly anhydride crystals thereof), I discovered that. 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 the use of the coating agent improved the stability of the partial structure and significantly suppressed the production of macrolide antibiotic related substances caused by changes in the partial structure. . 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 agent, particularly various solid preparations, preferably tablets, granules, capsules and the like is also improved. The related substances generated by the change in the partial structure are typically the main macrolide antibiotics in HPLC analysis. It means two kinds of degradation products that appear before the peak of and increase over time in the stability test.

[0037] This type 1 crystal exhibits a powder X-ray diffraction pattern that is substantially the same as the type I polymorph described in WO2005 / 081821 (Patent Document 13). Preferably, diffraction angle 2 Θ = 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.

Shows at least one strong peak selected from 9 and 40.4 degrees. Depending on the storage conditions, the water content can vary from 0 to 2 hydrate.

[0038] These macrolide antibiotics are known compounds, and can be produced based on the prior literature described in the Background Art section or by a method analogous thereto. In addition, E Xpert Opin. Ther. Patents (2003) 13 (6), p. 787- 805 Alley f "Tomorrow's New Drug" (Technomic) https: Z asushin. Com / shinyaku6 / ssearch Or it can manufacture also by the method according to it.

[0039] As the salt of the 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, trichloroacetic 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 or alkaline earths such as lithium, sodium, potassium, calcium, magnesium Salts with genus; quaternary Anmoniumu salts such as or Anmoniumu salts.

[0040] 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.

[0041] Since these known macrolide antibiotics are effective against various bacteria, mycoplasma, fungi, protozoa, and their resistant bacteria, etc., these are the main agents of the present invention. The coated preparation is very effective for the treatment of bacterial infections such as mammals including humans, fish and birds, mycoplasma infections, fungal (branch) infections, and protozoal infections.

Here, examples of the causative bacteria and disease names of such diseases are as follows.

Streptococcus pneumoniae, Streptococcus pneumoniae, Hemphinoles Infnorense (Haemophilus influenzae), Moraxella catarrhalis, Staphylococcus aureus, Peptococcus rep Rhinitis, bronchitis, tonsillitis, and mastoiditis; Streptococcus pyogenes, Streptococcus group C and G, Clostridium diptheria e, or Actinobacillus haemolyticum, etc. Pharyngitis, rheumatic fever, and glomerulonephritis; Mycoplasma pneumoniae, Resi innocence ¹ ~~ Mofifu (Legionella pneumophila), Streptococcus pneumoniae, Respiratory tract infection caused by Les 'Inf Norenze (Haemophilus influenzae) or Chlamydi a pneumoniae; Staphylococci! S aureus, Stahirococcus' S. epidermidis, S. epidermidis Streptococcus pyogenes streptococcus agalactiae, Streptococcus agalactiae, Streptococcus streptococcus, Streptococcus, Streptococcus (Streptococcus viridans), Coralbacterium minutissimum, Clostridium or Bartonella hensela e, uncomplicated skin and soft tissue infections, abscesses and osteomyelitis, and postpartum fever Staphylococcus · Staphylococcus saprophyt icus) or enterococcus acute urinary tract infections; urethritis and uterine tractitis; Chlamydia trachomatis, Haemophilus ducreyi, treho non ¹ ^^ (Treponema pallidum), Ureaplasma urealvticum, or Neisseria 'Gonoroje (N Eiserria gonorrheae) sexually transmitted disease; S. aureus, or Streptococcus haematophagia 8, B, and C food poisoning, toxic shock syndrome, toxic disease; Helicobacter pylori ulcer; Borrelia 'Systemic febrile syndrome due to Borrelia rec urrentis; Lyme disease caused by Borrelia burgdorf eri; Chlamydia trachomatis, Neisseria gonorrhoeae, Staphylococcus aureus ), Sutorefutoko' / vinegar New ¹ to Monnier (Streptococcus pneumoniae), Staph Gray Lactococcus 'pyogenes (Staphylococcus pyogenes), to Mofuinoresu' Inn Furuenze (Haemophilus influenzae), or Listeria (Listeria) belonging to the genus via imaging meningitis, keratitis, And lacrimal cystitis; mycobacteria Disseminated mycobacterial and abum complex (MAC) diseases caused by Mycobacterium avium or Mycobacterium intracellulare; Gastric ulceritis due to Campylobacter jejuni Intestinal protozoa caused by the genus Cryptospori dia; Odontogenic infection caused by Streptococcus viridans; persistent cough caused by Bordetella pertussis; Clostridium perfringens or Hacteroites (Bacteroides) gas gangrene; and atherosclerosis caused by Helicobacter pylori or Chlamydia pneumoniae.

Bacterial and protozoan infections that can be treated or prevented in animals and diseases associated with such infections include: Pasteurella hemolytica, Nosullella 'Moretocida' (Pasteurella mult ocida), Mycoplasma bovis or Bordetel la pulmonary respiratory disease; E. coli or protozoa (ie Coccidium, Cryptosporidia, etc.) Intestinal diseases associated with infection; Staphylococcus aureus, St reptococcus uberis, Streptococcus agalac tiae, Streptococcus dygalocci Mastitis in dairy cows associated with infection by the genus Klebsiella, Corynebacterium, or Enterococcus; A. pleuro, P. maltoside, or mycoplasma Porcine respiratory disease associated with infection by genus fungi; associated with infection by Neisseria gonorrhoeae, Lawsonia 'Lawsonia intracellularis, Sanore monella or Serpulina hyodyisin teriae Porcine intestinal disease; ushi rot associated with infection by Fusobacterium spp .; ushi uteritis associated with infection with Escherichia coli; Fusobacterium necrophorum or nocteroites' nodosus ( Busheroides nodosus) associated with infection by lashes; Moratasella bovis Pink eye of ushi associated with infection by urine; early miscarriage of ushi associated with infection with protozoa (ie neosporium); Skin and soft tissue infections in nu and cats caused by Staphylococcus epidermidis, Staphylococcus intermedius, or Pasteurella multocida; Alcaligenes Genus Bacteroides, Clostridiumn, Enterobacter, Eubacterium, Peptostreptococcus, Ponolephyromonas as), or in dogs and cats caused by Prevotella Tooth or oral infection. Other bacterial and protozoal infections that can be treated or prevented with macrolide antibiotics and diseases associated with such infections are described in JP Sanford et al. Ford Guideline "," The

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

[0044] As the saccharide used as the main component of the coating agent in the present invention, a known substance, a commercially available product, or a synthetic product can be used.

[0045] As the saccharide used as the main component of the macrolide antibiotic coating agent in the present invention, a known saccharide generally used in the art can be preferably used. Examples thereof include monosaccharides, disaccharides, trisaccharides and / or sugar alcohols. More specifically, sucrose (sucrose), fructose, glucose, lactose, lactulose, raffinose, trehalose, erythritol, mannitol, sonolebithonole, xylitol, maltitol (powder reduced maltose starch syrup), reduced palatinose powder, pullulan or reduced Lactose and the like are exemplified, but sucrose and maltitol are preferred. Punorelan can also be added as a binder. Saccharides can be used singly or in combination of two or more.

[0046] The coating agent used for coating the macrolide antibiotic in the present invention takes various forms, but generally contains a saccharide when applied. For example, an aqueous solution, an aqueous dispersion, an organic solvent solution or an organic solvent dispersion is applied to the macrolide antibiotics containing, for example, tablets (for example, uncoated tablets), granules (by means known per se, spraying, spraying, etc.). For example, it is preferably carried out by coating with elementary granules). Alternatively, a method may be used in which a tablet obtained by spraying a solid coating agent or a granule containing the coating agent is prepared, and then heated and melted to coat the surface. The amount of saccharide in the coating agent is preferably 5% by weight or more, more preferably about 10 to 100% by weight, further preferably about 20 to 90% by weight, for example, with respect to the macrolide antibiotic uncoated tablet. More preferably, it is about 25 to 65% by weight. In the case of coating the core granules, generally with respect to raw granule, preferably 5 wt% or more, more preferably about 1 0 to 200 wt ^_0/0, more preferably from about 20: a 150 weight ^_0/0.

[0047] The content of saccharide in the coating is preferably 50% by weight or more, more preferably 70 to 100% by weight.

[0048] The coating of macrolide antibiotic uncoated tablets, elementary granules, etc. with saccharides may be carried out in a plurality of liquids if desired. The coating is preferably performed in 2 to 3 times. The coating for forming the smoothing layer and the coloring layer is preferably as follows.

(Smoothing layer-1)

'Coating machine: Noi coater HCT_48 (Freund industry)

• Spray gun caliber: 1.2mm

'Tablet charge: lk500g

'Pan rotation speed: 20rpm

• Spraying air volume: 50L / min • Air temperature: 70 ° C

• Blow rate: 2.5m ³ / min

* Discharge rate: 4.5m ³ / min

(1 smoothing layer, 2 coloring layer)

'Coating machine: sugar-coated bread with a diameter of 47cm (Pier type, Kikusui Seisakusho)

'Tablet charge: lk500g

'Pan rotation speed: 25rpm

• Air temperature: 60 ~ 65 ° C

• Blower damper: 8

-Exhaust damper: Fully open

[0049] In the present invention, the uncoated tablets containing macrolide antibiotics are: a) Macrolide antibiotics as they are, or excipients, binders, disintegrants or other suitable additives are used as a capsule. After the mixture is mixed evenly into granules (elementary granules) by an appropriate known method, an additive such as a lubricant is added and compression molded, or b) The macrolide antibiotic granules are left as is or An excipient, binder, disintegrant, or other suitable additive and mixed evenly is manufactured by direct compression molding, or contains a pre-produced macrolide antibiotic. A preferred example is a method in which a macrolide antibiotic is added to a granule as it is or with an appropriate additive and mixed uniformly and then compression-molded. Elementary granules can also be produced by means known in the art.

[0050] The macrolide antibiotic according to the present invention exhibits an excellent stabilizing effect by being coated with a coating agent containing saccharide as a main component. However, in some cases, polybranol alcohol or its co-polymer is further present. A more stable preparation can be obtained by using in combination a coating agent composed mainly of coalescence. Here, it is possible to use the polybutyl alcohol or a copolymer thereof described in WO2002 / 17848, WO2005Z019286.

[0051] Macrolide solid preparations coated with these saccharides, such as tablets and granules, as well as capsules and pills, can be produced by conventional methods. [0052] 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.), polyvinylpolypyrrolidone, and the like, and preferably carboxymethyl starch sodium. The disintegrant content should be sufficient to quickly disintegrate the tablet.For example, it disintegrates within several tens of minutes, preferably within several 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 10 parts by weight per 100 parts by weight of the tablet.

[0053] As the excipient, those widely known in the art can be widely used. Examples thereof include lactose, sucrose, mannitol, crystalline cellulose, corn starch, potato starch, hydroxypropyl starch and the like. Preferred force is mannitol or crystalline cellulose. The content of the excipient may be appropriately set in consideration of the main drug content, the size of the target tablet, 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.

[0054] As binders, those widely known in the art can be widely used. For example, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, polyvinyl alcohol, gelatin, dextrin, punoreran and the like are preferable. Is hydroxypropylcellulose (HPC). The binder content is usually about 0.5-5 parts by weight, preferably about 1-3 parts by weight, per 100 parts by weight of the tablet.

[0055] Examples of the lubricant include magnesium stearate, talc, sucrose fatty acid ester and the like, and the content thereof is usually a very small amount, for example, about 1 to 3 parts by weight with respect to 100 parts by weight of the tablet.

[0056] In the present invention, the tablet containing a macrolide antibiotic as the active ingredient is subjected to various operations such as mixing, granulation, granulation drying, granulation, lubricant mixing, and tableting using the above raw materials. It can be produced by carrying out according to a method well known in the art. Regarding the granulation operation, for example, an apparatus such as a stirring granulator, a fluidized bed granulator, a Brabender, or a twin screw granulator may be used. However, it is preferable to use a stirring granulator from the viewpoint of obtaining homogeneous granules. Tableting can be performed using a commercially available tableting machine, usually with a tableting pressure of about 0.2 to 1.5 tons.

[0057] One embodiment of a preferred tablet composition of the present invention is as follows.

In total tablet weight,

Compound (III), a pharmaceutically acceptable salt, or a hydrate thereof, which is the active ingredient: about 20 to 50%;

Disintegrant, preferably sodium carboxymethyl starch: about 2 to: 10. / o;

Excipients, preferably D-mannitol and crystalline cellulose total: about 10-40%; binder, preferably hydroxypropylcellulose: about 1-3%;

Lubricant, preferably magnesium stearate: about :! to 3%

And against uncoated tablet weight

The coating, preferably sucrose and / or maltitol, is about 15-75% by weight.

[0058] 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 mg / kg can be administered orally in terms of a salt or a hydrate thereof.

[0059] In addition, the preparation of the present invention has, for example, a total amount of a macrobiotic related substance after storage for 2 months under a light-shielding condition at 40 ° C, a relative humidity of 75%, preferably 3% or less with respect to the active ingredient. is there

[0060] The preparation of the present invention may be preferably packaged in PTP (press-through single package) or bottle packaging (eg, plastic bottle, glass bottle, aluminum can) to further improve the stability. ,.

[0061] Further, the present invention provides the following partial structural formula:

[Chemical 19]

(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 production of a related substance of the macrolide antibiotic, wherein a solid is coated with a coating agent containing saccharide as a main component. Macrolide antibiotics, their pharmaceutically acceptable salts, or their hydrates, coating agents, coating methods, etc. are as described above.

[0062] Further, the present invention provides a macrolide antibiotic having a group represented by the partial structural formula, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solid containing them, a saccharide Provided is a method for stabilizing a macrolide antibiotic, a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is coated with a coating agent having a main component. Macrolide antibiotics, their pharmaceutically acceptable salts, or their hydrates, coating agents, coating methods, etc. are as described above.

[0063] Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example

[0064] Example 1

(1) Manufacture of coated steel II

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

[0065] [Table 1] Formulation 1

Compound (I I I) (Type 1 crystal) 100. 0 mg Intragranular D-mannitol 38.4 mg Hydroxypropylcellulose 4.6 mg Carboxymethyl starch sodium 15.0 mg Extragranular

Magnesium stearate 4.0 mg Uncoated tablet Total 162. 0 mg Smoothing layer Sucrose 34.0 mg Talc 12.8 mg Precipitated calcium carbonate 15.1 mg Pullulan 1. 19 mg Copolyvidone 1.5 mg Coating agent

Polyoxyethylene (105) Polyoxyp

0. 26 mg lopyrene (5) glycol

Coloring layer Sucrose 65.8 mg and Pullulan 0.15 mg Polytushing layer Carnauba wax Trace coating total 130. 8 mg

292. 8 mg coverage (wt%)

80. 8% (uncoated tablet)

[0066] (Detailed conditions)

The above coated preparation (Preparation 1) was produced by the following steps 1 to 7.

0. Tablets with a diameter of 8 mm for sugar coating were produced with a rotary tableting machine using granules granulated by a 10-type stirring granulator (Fukae Patek).

[0067] Smoothing layer 1

1. Weigh 1306 g of purified water.

2. Dissolve 80 g of copolyvidone and 14 g of polyoxyethylene (105) polyoxypropylene (5) glycol in a portion of the purified water weighed in 1 above to make an aqueous binder solution.

3. Prepare syrup solution by dissolving 800 g of sucrose in a portion of purified water weighed at 90 ° C.

4. Add 300g of precipitated calcium carbonate and 300g of talc to the rest of the purified water weighed earlier. Stir and disperse with Robotics (Special Machine Industries). Mix with aqueous binder solution and syrup solution to make smoothing layer 1 coating solution.

5. Charge 1.5 kg of tablets into a high-coater HCT-48 (Freund Industries), a pneumatic coating machine with two fluid nozzles.

6. blast temperature 70 ° C, air volume 2. 5 m ³ / min, a fixed time heating at Haifuryou 4. 5 m ³ / min, and holds the above product temperature 50 ° C.

7. Spray gun caliber 1.2mm, spraying air volume 50LZ min, pan rotation speed 20rpm, smoothing layer _ 1 coating liquid 10 ~ 15g / min to keep the tablet product temperature above 50 ° C Spray while adjusting the range to cover 28 mg.

[0068] Smoothing layer 2

1. Weigh 700 g of purified water.

2. Dissolve 50 g of pullulan in a portion of the purified water weighed earlier to make an aqueous binder solution.

3. Dissolve 800 g of sucrose in a portion of the purified water weighed earlier to make a syrup solution.

4. Agitate and disperse 400g of precipitated calcium carbonate and 300g of talc in the remaining purified water. Mix with aqueous binder solution and syrup solution to make a smoothing layer-2 coating solution.

5. Add 1.5kg of tablets to sugar-coated bread (Pia type, Kikusui Seisakusho).

6. Blowing temperature 60 ~ 65 ° C, blower damper scale 8, exhaust air damper scale fully open, pan rotation speed 25rpm, smoothing layer 2 Add and stir while adjusting coating solution in the range of 15-50g / time ,dry. Coat 37 mg by repeating this cycle 15 times.

[0069] Coloring layer

1. Weigh 900 g of purified water.

2. Dissolve 6 g of pullulan in a portion of the purified water weighed earlier to make an aqueous binder solution.

3. Dissolve 1700 g of sucrose in the remaining weighed purified water to make a syrup solution.

4. Mix with aqueous binder solution and syrup solution to make a coloring layer coating solution.

5. Add 1.5kg of tablets to sugar-coated bread (Pia type, Kikusui Seisakusho).

6. Blower temperature 60 ~ 65 ° C, Blower damper scale 8, Exhaust damper scale fully open, Pan rotation Add, stir, and dry the coloring layer coating solution while adjusting it within the range of 15 to 50 g / time under the condition of several 25 rpm. 66mg is coated by repeating this series of cycles 32 times. Apply an inner lid if necessary.

[0070] Polishing layer

Polishing is performed in a conventional manner using sucrose syrup solution and carnauba roux.

[0071] The uncoated tablets were coated with saccharides under the following conditions.

Covering conditions:

(Smoothing layer-1)

'Coating machine: Noi coater HCT-48

• Spray gun caliber: 1.2mm

'Tablet charge: lk500g

'Pan rotation speed: 20rpm

• Spraying air volume: 50L / min

• Air temperature: 70 ° C

• Blow rate: 2.5m ³ / min

* Discharge rate: 4.5m ³ / min

(Smoothing layer-2, coloring layer)

'Tablet charge: lk500g

'Pan rotation speed: 25rpm

• Air temperature: 60 ~ 65 ° C

• Blower damper: 8

-Exhaust damper: Fully open

[0072] ί2) ¾

Fig. 2 shows the results of a test comparing the stability of a macrolide antibiotic preparation coated with the coating listed in Table 1 with an uncoated uncoated tablet. In the figure, ◯ indicates an uncoated tablet, and a mark indicates a coated preparation (formulation 1) according to the present invention. The stability test was conducted under the conditions of 40 ° C, 75% relative humidity, no packaging, and shading.After the sugar-coated tablets were prepared, 0.5 months, 1 month, 2 months later The total amount of macrolide antibiotics relative to drugs is shown. As is clear from FIG. 2, the coated preparation (Formulation 1) of the present invention is stable, with almost no formation of macrolide antibiotic analogues even after 2 months. In the case of uncoated tablets, the total amount of macrolide antibiotics increased rapidly, and the total amount of macrolide antibiotics exceeded 20% after 2 months. ) Was proved to be stable.

FIG. 3 shows the relationship between the coating amount of the coating agent (coloring layer) used in Example 1 and the total amount of analogs of the macrolide antibiotics to the main drug. At this time, the stability test was conducted for 2 weeks under the conditions of 40 ° C, 75% relative humidity, light shielding and no packaging. Coloring layer Omg, that is, when only the smoothing layer is coated, the total amount of macrolide antibiotics is about 5%, whereas when 20 mg of the coloring layer is coated, it is about 3%. A coating layer of 40-70 mg resulted in a total of approximately 1% of macrolide antibiotic related substances. This indicates that for stabilization of macrolide antibiotic preparations, coating with a saccharide-containing smoothing layer and then coating with a saccharide-containing coloring layer more than a certain amount has a good stabilizing effect. Les.

(3) Evaluation of the stability of the macrolide coating preparation

The stability evaluation method of the macrolide-based coated preparation of the present invention is as follows.

Each coating and uncoated tablet was stored for 3 months under the 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 (III) as the main drug and the amount of related substances produced were measured by liquid chromatography. In addition, the macrolide antibiotic (I compound (III)) of the same production lot was used for the coating agent and the uncoated tablet.

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

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

(3) Shake for 10 minutes. (4) Add the acetonitrile / water mixture for liquid chromatography (7: 3) to make exactly lOOmL.

(5) Filter the solution in (4) with a membrane filter (Kurabo, Chromatodisc non-aqueous 13N) with a pore size of 0 · 45 μΐη, remove the 2 mL of the first filtrate, and use the remaining filtrate as the sample solution. .

For use as a standard substance, approximately 10 mg of the drug substance of compound (III) in the same production lot used for the coating agent and uncoated tablet was accurately weighed. This was dissolved in 70% acetonitrile to make exactly 10 mL.

Liquid chromatography conditions>

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 to 400 nm, extraction wavelength: 210 nm)

Column: L-column ODS, 5 / im, 4.6 X 250mm (Chemicals Evaluation Laboratory) Column temperature: Constant temperature around 40 ° C

Mobile phase A: 0.008 mol / L potassium dihydrogen phosphate buffer / acetonitrile (3/2) pH 8.0

Mobile phase B: Mixture of acetonitrile / pH 8.0, 0.012 mol / L potassium dihydrogen phosphate buffer (3/1)

Gradient program:

[Table 2]

Flow rate: 1. OmLZ min. (Main component retention time at setting is about 30 min.)

Injection volume: 10 L

Sample cooler temperature: 25 ° C Needle cleaning solution: Acetonitrile

Area measurement range: 65 minutes after sample injection

<Systems † Cow.

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

<¾1) ratio, incense + ¾>

The amount of each related substance (%) and the total amount of related substances (%) were calculated from the following formulas. Individual related substance amount (%) = (817 ∑ 8) 100

Total related substances (%) = (∑ Ai / ∑A) XI 00

Ai: Peak area of each related substance

∑ Ai: Sum of peak areas of individual related substances

ΣΑ: Sum of peak areas other than system peaks

Example 2

(1) Manufacture of coated steel II

According to the production flowchart shown in FIG. 4, coated preparations (formulations 2 and 3) having the compositions shown in Table 3 below were obtained.

[Table 3]

Formulation 2 Formulation 3 Compound (III) (Type 1 crystal) 100. Omg 100. Omg Intragranular D-manni! ^ One 38. 4mg 38. 4mg Hydroxypropylcellulose 4.6 mg 4.6 mg Carboxymethyls Chinatrium 12. Omg 12. Omg crystalline cellulose 5. Omg 5. Omg extragranular

Hydrous silicon dioxide 0.3 mg 0.3 0.3 mg Magnesium stearate 4. Omg 4. Omg Uncoated tablet Total 164. 3 mg 164. 3 mg Coating polymer layer Polypinyl alcohol 13. Omg 13. Omg Smoothing layer White sugar 15. Omg 15. Omg Talc 5.6 mg 5. 6 mg Precipitated calcium carbonate 5. 6 mg 5. 6 mg Copolyvidone 1.5 mg 1. 5 mg Polyoxyethylene (105) Polyoxyx 0.26 mg 0.26 mg Cypropylene (5) Glycol

Coloring layer Saccharose 52.9 mg-and Maltitol-52. 9 mg Polishing layer Pullulan 0. 12 mg 0. 12 mg Carnaupalou Trace-Coating agent total 94. Omg 94. Omg

A

α mouth + Τ 258. 3mg 258. 3mg Coverage ratio (wt%) (uncoated tablet) 57. 2% 57. 2%

(2) Results

The results of comparing the stability of the macrolide antibiotic preparations (formulations 2 and 3) coated with the coatings listed in Table 3 with uncoated uncoated tablets are shown in FIG. At this time, the stability test was conducted for one month at 40 ° C, 75% relative humidity, no packaging, and light-shielding conditions. As shown in FIG. 5, it was proved that the macrolide antibiotic preparation coated with the coating agent containing the saccharide of the present invention as a main component is stable for a long period of time compared with the uncoated tablet. In FIG. 5, sucrose-coated tablet means formulation 2 obtained in Example 2, and maltitol-coated tablet means formulation 3 obtained in Example 2.

Industrial applicability

The sugar-coated macrolide antibiotic coating formulation according to the present invention includes humans It can be used for the treatment of a wide range of infectious diseases caused by bacteria, mycoplasma, fungi, protozoa, etc. in mammals, fish and birds.

Claims

Claims As the active ingredient, a macrolide antibiotic having a group represented by the following partial structural formula: (wherein R represents a protective group for a hydrogen atom or a hydroxyl group), a pharmaceutically acceptable salt thereof, Alternatively, a coated preparation of a macrolide antibiotic, characterized in that it contains a hydrate thereof and is coated with a coating containing sugar as a main component. The main drug is a macrolide antibiotic having a group represented by the following partial structural formula (I): [Chemical Formula 2] (wherein R2a represents a protective group for a hydrogen atom or a hydroxyl group), and its pharmaceutically acceptable The coated preparation of a macrolide antibiotic according to claim 1, wherein the salt is a salt or a hydrate thereof. [3] The coated preparation of a macrolide antibiotic according to claim 1, wherein the macrolide antibiotic is 14 to 16-membered ring macrolide antibiotic. [4] Macrolide antibiotics have the general formula (II): [wherein A is a) -OH, b) one ORP (wherein RP represents a hydroxyl protecting group) , — ^ (Where ゝ! ^ Represents an aryl group, (2) a substituted aryl group, (3) a heteroaryl group or a substituted heteroaryl group), d) -OR1 (where R1 is the same as above) ), _1 2 (wherein 1 2 is 0 to 3 heteroatoms selected from (1) hydrogen atom, (2) halogen atom, (3) oxygen atom, sulfur atom and nitrogen atom) A CC 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 atom 1 Optionally containing 0 to 3 heteroatoms selected from 12 atoms, sulfur atoms and nitrogen atoms, including halogens, aryleno groups, substituted aryl groups, hetero atoms; A C 1 -C 3 alkeninole 2 12 group, which may be substituted with one or more substituents selected from a hydrogen group and a substituted heteroaryl group, or (5) selected from an oxygen atom, a sulfur atom and a nitrogen atom CC alkynyl group optionally containing ~ 3 heteroatoms and optionally substituted with one or more substituents selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group ), 2 12 f) -OR2 (R2 has the same meaning as described 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 (O) R11 (wherein R11 has the same meaning as above), —NHC C NHR11 (Wherein R11 has the same meaning as above), j) -NHS (◯) R11 (wherein R11 has the same meaning as above.) 2k) —NR14R15 (wherein R14 and R15 each independently represents R11, R11 has the same meaning as described above), and 1) —NHR3 (wherein R3 is an amino group-protecting group) B represents a) a hydrogen atom, b) deuterium, c) a halogen atom, d) —OH, e) R1 (R1 has the same meaning as described above). ), F) —R2 (wherein R2 has the same meaning as above), or g) — represents ORP (wherein has the same meaning as above); provided that when B is halogen, OH or ORP, A is —R1 or —R2, or A and B together with the carbon atoms to which they are attached, a) C = 0 b) C (OR2) (R2 has the same meaning as above.) 2 c) C (SR2) (R2 is as defined above), 2 d) C [-0- (CH)] (m is 2 or 3), 2 m 2 e) C [ -S-(CH)] (m is as defined above), 2 m 2 ! ! ^ 11 has the same meaning as above. ), G) C = NOR "(R" has the same meaning as above), or h) C = N-0-Ar1-M-Ar2 wherein 1) —Ar1— represents R31, R31 is independently a) a divalent group formed by removing a hydrogen element from R1 (R1 has the same meaning as described above), b) selected from an oxygen atom, a sulfur atom and a nitrogen atom 0-3 Optionally containing one heteroatom and may be substituted with one or more substituents selected from halogen, aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups, C -C 1 12 norylene group, c) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen atoms, from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl May be substituted with one or more selected substituents, C 1 -C 2 12 norekenylene group, Or d) optionally containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, and selected from halogen, aryl, substituted aryl, heteroaryl and substituted heteroaryl 1 or CC represents a 2 12 norequinylene group which may be substituted with two or more substituents; 2) — M is a bond or (a) 0 to 3 selected from an oxygen atom, a sulfur atom and a nitrogen atom Heteroatom and — C = N—, — N = N— and — C (〇) —Arbitrarily containing 0 to 3 groups selected by force, CC anoreylene group, 1 12 (b) Oxygen atom, sulfur 0 to 3 heteroatoms selected from atoms and nitrogen atoms and — C = N—, — N = N— and — C (〇) —force optionally containing 0 to 3 groups selected, c − c Anolekenylene group, 2 12 (c) 0 to 3 heterocycles selected from oxygen, sulfur and nitrogen atoms Atom and — C = N—, — N = N— and — C (〇) — Force optionally containing 0 to 3 groups selected, c-c anolenoquinylene group, 2 12 (d) substituted arylene group, ( e) represents a substituted heteroarylene group or (f) a substituted heterocycloalkylene group; and 3) Ar2 represents (a) an aryl group, (b) a substituted aryl group, (c) a heteroaryl group, or (d) a substituted group. Represents a heteroaryl group]; ! ! ! ^ 11 has the same meaning as above. ), J) C = NNHC (O) R11 (R11 has the same meaning as above), k) C = NNHC (O) NHR11 (R11 has the same meaning as above), 1) C = NNHS ( 0) RU (RU is as defined above), 2 m) C = NNHR3 (R3 is as defined above), n) C = NR "(R11 is as defined above) O) C = NR11 (R11 is as defined above), or p) C = N—N—CHR11 (R11 is as defined above); one of X and Y is hydrogen A) a hydrogen atom, b) deuterium, c) 10H, d) —ORP (RP is as defined above), e) —NR4R5 (R4 and R5 are each Independently,

(1) hydrogen atom,

(2) It may be substituted with one or more substituents selected from halogen, aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group, C 1 C

1 12 alkyl groups, or

(3) R ⁴ and R ⁵ together with the nitrogen atom to which they are attached contain 0 to 2 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atomic energy 3 to 10 Represents a teloalkyl ring, where X and Y are bonded together with the carbon atom, (a) C = 〇 or

(b) C = N— Q

(Where Q is

(1) -R ¹¹ (R ¹¹ is as defined above),

(2) an amino protecting group,

( ³ ) _C (O) R ¹¹ (R ¹¹ is as defined 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

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) ^-1 has the same meaning as described above. Or

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

1 12 3 12 1

7 8 3 12

Or (1) represents 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) From aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups A CC alkyl group, optionally substituted with one or more selected substituents,

1 6

2 6

Or

f) may be substituted with one or more substituents selected from aryl groups, substituted aryl groups, heteroaryl groups and substituted heteroaryl groups;

2 6

Representation;

z is

a) a hydrogen atom,

b) a methyl group, or

c) represents a halogen atom;

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

A coated preparation of a macrolide antibiotic according to claim 3, characterized in that the compound is a compound represented by the following formula, a pharmaceutically acceptable salt thereof, or a hydrate thereof.

Macrolide antibiotics

(1) The following formula (III):

[Chemical 4]

Compounds represented by the formula (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9 ((3, 4, 6-trideoxy-1, 3-dimethylamino-1, β-D) (Xopyranosyloxy) 3 ethyl 2 hydroxy 2, 6, 8, 10, 16, 18 hexamethyl-5, 7 dixo _ 13 _ [(Ε) _ [6— (pyrazole _ 1 _yl) pyridine] 3_yl] methoxyimino] —4, 11, 15 trioxabicyclo [8, 5, 4] nonade 17E ylidene] acetamide, (2) the following formula (IV):

[Chemical 5]

Telithromycin, represented by

(3) The following formula (V):

[Chemical 6]

(4) The following formula (VI):

[Chemical 7]

TEA — 0777 (5) The following formula (VII):

CP— 544372

(6) The following formula (VIII):

[Chemical 9]

JNJ—17069546 represented by (VUI), (7) the following formula (IX):

[Chemical 10]

Cesromycin represented by, or

(8) (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6 Trideoxy-1-3-dimethylamino-1-β-D Xylohexopyranosyl Xy) 3-ethyl _ 2—hydroxy-1,2,6,8,10,16,18—hexamethyl-1,5,7-dioxone 13 _ [(Ε) — [6— (2-aminopyridine 1 6- L) pyridine-3-yl] methoxyimino] -4,11,15-trioxabicyclo [8,5,4] nonade 17E-ylidene] acetamide,

The coated preparation of a macrolide antibiotic according to claim 1, which is a pharmaceutically acceptable salt thereof or a hydrate thereof.

[6] Macrolide antibiotics have the following formula (III):

[Chemical 11]

(1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6— Trideoxy-1-3-dimethylamino-1-β-D Roxy) 3-Ethyl 2 Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethyl 1, 5, 7 Dioxo 1 3_ [) _ [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, 5. A coated preparation of a macrolide antibiotic described in 5.

[7] Macrolide antibiotic power In powder X-ray diffraction pattern, 2Θ = 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 (unit: degree) ) Having at least one peak selected from (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) _3_Ethyl _2—Hydroxy 1, 2, 6, 8, 10, 16, 18 Hexamethinole 5, 7 Di-aged 13- [(E) [6— (Birazo 1-yl) pyridine-3--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.

8. The macrolide system according to claim 7, wherein the type 1 is an anhydrous crystal. Antibiotic coating formulation.

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

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

[11] The coated preparation of a macrolide antibiotic according to claim 1, wherein the saccharide is at least one selected from the group consisting of monosaccharides, disaccharides, trisaccharides and sugar alcohols. .

[12] Sucrose is sucrose (sucrose), fructose, glucose, lactose, lactulose, raffinose, trenorose, erythritol, mannitol, sorbitol, xylitol, maltitol (powder reduced maltose starch syrup), reduced palatinose powder, pullulan and reduced 2. The coated preparation of a macrolide antibiotic according to claim 1, which is at least one selected from the group consisting of lactose.

[13] The coated preparation of the macrolide antibiotic according to claim 1, wherein the content of the coating agent is 5% by weight or more based on the uncoated tablet or elementary granule.

[14] The coated preparation of a macrolide antibiotic according to claim 1, wherein the saccharide content is 70% by weight or more based on the coating.

[15] The total amount of macrolide antibiotic-related substances is less than 3% of the active ingredient after storage for 2 months under the conditions of 40 ° C, 75% relative humidity, and light-shielded conditions. The coated preparation of macrolide antibiotics according to claim 1, characterized in that

[16] Main drug power S (1R, 2R, 3R, 6R, 8R, 9R, 10R, 16S, 18R) — N— [9— (3, 4, 6-trideoxy _ 3-dimethylamino-β _D 1-Hexopyranosyloxy) _ 3—Ethinole 1—Hydroxy 1 2, 6, 8, 10, 16, 18—Hexamethinore 5,7—Dioxo 13 _ [(E) — [6— ( Pyrazole _ 1 _yl) pyridine-3 _yl] methoxyimino] _4, 11, 15 5 trioxabicyclo [8, 5, 4] nonade 17E-ylidene] acetamide crystals, 40 A macrolide antibiotic is characterized by the fact that the total amount of macrolide antibiotics after storage for 2 months under the conditions of ° C, relative humidity of 75% and less than 3% of the main drug Coating formulation.

[17] The coated preparation of a macrolide antibiotic according to claim 16, wherein the coated preparation is a PTP (press-through package) package or a bottle package.

[18] The macrolide antibiotic according to claim 1, a pharmaceutically acceptable salt thereof, a hydrate thereof, or a solid containing them is covered with a coating containing saccharide as a main component. A method for suppressing the formation of a related substance of a macrolide antibiotic, characterized by

[19] The macrolide antibiotic according to claim 1, its pharmaceutically acceptable salt, or a hydrate thereof or a solid containing the same is covered with a coating containing saccharide as a main component. A method for stabilizing the macrolide antibiotic, its pharmaceutically acceptable salt, or hydrate thereof.