TW200800233A - A coated preparation of macrolide antibiotics - Google Patents

Abstract

This invention provides a coated preparation of macrolide antibiotics, the coated preparation comprising macrolide antibiotics having a group presented by the following structural formula: (wherein R2a presents a protective group of a hydrogen atom or a hydroxy group) and pharmaceutically acceptable salts or hydrates thereof. The coated preparation is coated by a coating agent comprising polyvinylalcohol or polyvinylalcohol copolymer as a principal component.

Description

200800233 IX. Description of the Invention: [Technical Field] The present invention relates to a stable formulation of a vinegar-based antibiotic in a macrocyclic ring ^ i I. 8 . # tg (mycoplasma) ^ A ga} various infections caused by protozoa disease. [Prior Art] It is known that macrolide antibiotics are effective for treating various sputum infections caused by bacteria, mold, fungi (mold), protozoa, and the like in mammals, fish, and birds. As a representative macrolide antibiotic, erythromycin (Patent Document 2) has been used for many years because of its unique antibacterial power, good tissue transfer, and few side effects. It is used clinically as an antibiotic with sputum. After that, various macrolide antibiotics are marketed, or are still in clinical development or research and development. As such a macrolide antibiotic, a macrolide antibiotic having 14 to 16 member rings is known, such as erythromycin (Patent Documents 1 and 2), and ampinomycin.

(oleandomycin) (Patent Documents 3 and 4), clarithromycin (Patent Document 5), roxithromycin (Patent Document 6), azithromycin (a patent), and dirithromycin (Patent Document 8), telithromycin (Patent Document 9), cethromycin (Patent Document 10), and fluoroerythromycin ethylsuccirate (Patent Document 11) ), a compound described later] (Patent Documents 12 and 13), L-701677 (Patent Document 14), mycinamicin (Non-Patent Document 1), and various other derivatives. 5 319213 200800233 - At the same time, it is also known that in the presence of polyvinyl alcohol and/or one-line miso 6 / in the presence of at least one type of polymerizable ethylenic organism, the compound or copolymer is the main hard_ The solvent for dissolving the poly-components, which is formed by early-lime polymerization or copolymerization, can not be filled with hard capsules that can be filled with poorly soluble drugs. Auto Show (JJ15), it is clear that Use diligence P : ° The copolymer used as a hard capsule described in Patent Document 15 can be applied as a drug, animal medicine, and farmer's ancestor with polyvinyl alcohol copolymer as the main component.酉 文献 々 々 々 々 16 16 16 16 16 16 16 16 16 16 16 16 The resin composition of the coating agent of the 卜 艮 艮 艮 寺 寺 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂 树脂The development and use of oral or non-oral dosage forms. However, in order to preserve 34 antibiotic preparations in the giant ring, it is necessary to consider the main solution in the preparation, and it does not necessarily meet the necessary stability. For the purpose of formulating a large amount of stabilizer, excipient, binder, lubricant, disintegrant, and coating additive, the prepared oral garment will be prepared. The dosage form is generally larger than the dosage form, and is not suitable for use by the elderly, children, etc. As for the known preparations of these macrolide antibiotics, polyvinyl alcohol or its copolymer is used as the macrolide. It is an antibiotic or a coating agent containing a bare ingot, a bare particle, or the like, and the prior art regarding a stabilized coating preparation is still 319213 6 200800233 ^ [Patent Document 1] US 2653899 [Patent Document 2] US 2823203 [Patent Literature 3]US [Patent Document 4] US Pat. No. 2,842, 481 [Patent Document 5 IUS4331803 [Patent Document 6] US 4349545 [Patent Document 7] US4517359 • [Patent Document δ] ΕΡ 511799 [Patent Document 9] US 5635485 [Patent Document l〇] US 5866549 [Patent Document ^ ^ ^ [^^^^] [Patent Document 12] WO2003/097659 Α1 [Patent Document 13] WO2005/081821 A2 [Non-Patent Document 1] J. Antibiot 45(1), 1 (1992) [Patent Document 14] EP508699 • [Patent [15] WO2002/17848 [Patent Document 16] WO2005/019286 [Disclosure] [Problems to be Solved by the Invention] In view of the foregoing, in the field, development of a macrolide antibiotic capable of long-term preservation is expected In particular, the development of a stable preparation of a 13- to 16-membered ring system macrolide antibiotic preparation, in particular, can improve the stability of solid preparations such as tablets, granules, capsules, pills, etc. 7 319213 200800233 . The means to solve the problem] As a result of various investigations on the stability of the vinegar-based antibiotic-made sword in the king's clothes, it was found to be part of the structural formula shown in the following formula:

(wherein R2a represents a hydrogen atom or a protecting group of a light group), and preferably has a partial structural formula represented by the following formula:

CH,

(I) a macrolide antibiotic, a pharmaceutically acceptable salt thereof or a hydrate thereof or a solid containing a substance of a certain amount, and a coating agent containing a polyvinyl alcohol or a polyvinyl alcohol copolymer as a main component After coating, a coated preparation of a stabilized macrolide antibiotic can be obtained, that is, the present invention is completed. That is, the present invention relates to the following items: Item 1 is a coated preparation of a macrolide-based antibiotic, which is characterized by containing 319213 8 200800233 - having a partial structural formula r H3Cs < %, N human rCH, a pharmaceutically acceptable salt or a hydrate thereof, and coated with a coating agent containing a polyethylene glycol or a polyvinyl alcohol copolymer. Item 2. The coated preparation of the macrolide antibiotic according to the first item, which is characterized by a macrocycle_|Antibiotic I contains a base represented by the following structural formula (1): Γ R2aH3C\ , CH, N, human 0〆

V rCH, (a macrocyclic lactone antibiotic of the formula (wherein fa represents a hydrogen atom or a protecting group of a hydroxyl group), a pharmaceutically acceptable salt thereof or a hydrate thereof. Item 3 as in item 1 A macrolide-based antibiotic preparation, which is a macrolide lactone antibiotic with 14 to 16 members of the ring system macrolide antibiotic. Item 4: Macrolide lactone antibiotic in item 3. The coated preparation, 9 319213 200800233 _ The meal is a macrolide lactone antibiotic represented by the formula (positive), a compound, a pharmaceutically acceptable salt or a hydrate thereof

Wherein A represents a group selected from the following: a) -OH, -' *: - ... b) -OR (wherein 'rp is a protecting group of a radical) c;>-R1 (In the formula, Ri represents (1) aryl, (7) substituted aryl, (3) heteroaryl 5 substituted heteroaryl) e)-R2 (wherein R 2 is desirably selected from (1) hydrogen atom, (2) dentate /, (3) 乳 to 3 heteroatoms Z in the milk atom, sulfur atom and nitrogen atom are selected from the group consisting of fluorene, aryl, substituted aryl, heteroaryl or substituted heteroaryl, f 1 or more The CVCl2 fluorenyl group substituted by the substituent, (4) contains a source selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and may be selected from a self group, an aryl group, a substituted aryl group, a heteroaryl group or a ^: i or more than 2 substituent groups in the anthracene group, or (5) optionally containing an oxygen atom, a sulfur atom and a nitrogen hydrazine 2 319213 10 200800233 ... to 3 heteroatoms. a aryl group, an aryl group, a substituted or substituted heteroaryl group, a heteroaryl (tetra) 2 alkynyl group or a substituent of two or more, f) - 〇R2 (wherein 'R2 has the same meaning as defined above), g) -SWnR^ (where n is 〇, ! or 2, Rn independently The gas atom R1 ^ R 2 ·5 T?1 ^ τ>2 u 4 屌, ^ and R have the same meaning as described above), h) -NHC(〇)Rii (wherein, 妒为.K has and W says the same meaning), ί)-ΝΪΚ:(〇)ΝΗΚιι(where, η士二 has the same meaning as before;), j^NHS(9)2Ru(where, I) k) -NR^RU t , r4 And R independently represent R11, R11 and right in the same sense as above), and ^^^^l) -NHR3 (wherein R3 represents an amine protecting group); B system represents: a) argon atom, b) Heavy hydrogen, c) halogen atom, d) _OH, e: KR2 (wherein R1 has the same meaning as described above), f > R (wherein R2 has the same meaning as described above), or g)-〇R (wherein rp has the same meaning as described above. However, when B is a element, a collar or a singular, A represents A or #, or A and B together with a combined carbon atom represent a) C = Ο b) C ( OR2) 2 (R2 has the same meaning as described above), 319213 11 200800233 .c) C(SR-) 2 (R2 has the same meaning as described above), d) CJ>0-(CH2)m] 2 ( In is 2 or 3), e) C[-S-(CH2)m]2 (m has the same meaning as described above), flC^CHR11®11 has The same meaning as described above), g) C=N_0-Rn (Rii has the same meaning as described above), or 'h) C = Ν-0-Ar1-M-Ar2 [wherein, -Ar〗_ represents R31, R31 Independently representing a) a divalent group formed by removing a hydrogen atom in 攸R (r1 having the same meaning as described above containing 0 to 3 hetero atoms selected from an oxygen atom, a sulfur atom, and a nitrogen atom) may be selected from a halogen a kb-extension group substituted with an aryl group, a substituted aryl group, a heteroaryl group or a substituted aryl-based towel (8) or a substituted silk on the hemp, and C) optionally containing a G selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom Up to 3 hydrazines' may be a C2-C12 extended alkenyl group substituted with one or more substituents selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl or substituted aryl group, or _ . · .... ·. ' ) Ren Si contains 选自 from oxygen, sulfur and nitrogen atoms to 3 impurities f = 'may be selected from arginine, aryl, substituted aryl, heteroaryl The substitution of one or more substituents in the base of the base of the base group is replaced by a ruthenium atom, a sulfur atom, and a nitrogen atom. 〇I 3 in the atom _ atom and selected from _C=N _, and _[(〇)_ in G straight 3 12 319213 200800233 based on CVcI2 alkyl, sulfur atom and nitrogen in the nitrogen to 3 - N = N j_C (0) - in the 〇 to 3 a radical of a radical sulfur atom and a nitrogen atom to three -N=N_&-C(0)- to 3 to 3 groups b) optionally containing a hetero atom selected from oxygen atoms and selected from C2-C12-exene a group, c) optionally containing a hetero atom selected from oxygen atoms and optionally 02<12-alkenyl, d) substituted aryl, e) substituted heteroaryl or f) substituted heterocycloalkyl; and 3> Ar2 represents: - a) aryl, b) substituted aryl, c) heteroaryl, or d) substituted heteroaryl]; i) hNHHRARn has the same meaning as described above) j) C = NNHC(〇) Rll (R11 has the same meaning as described above) k) hNNHC(0)NHRn (RU has the same meaning as described above) l) C NNHSCOLR11^11 is right-handed, > π /, has the same meaning as described above Meaning) m) C = NNHR3 (R3 has the same meaning as described above) ^CtNR'R11 has the same meaning as described above) C = NRii (Rn has the same meaning as described above), or P)C, -CHRn ( Rll has the same meaning as described above); one of X and γ represents The hydrogen atom 5 is further represented by 319213 13 200800233 , a) a hydrogen atom, b) a heavy hydrogen, c) - 〇H, d) - 〇Rp (Rp has the same meaning as described above y, e) -NR4R5 (R4, R5 a Ci_c 2 alkyl group substituted with (1) a hydrogen atom, (7) one or more substituents selected from a halogen, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, respectively, or • (3) R4 and R5 together with the combined nitrogen atom represent a 3 to 1 杂 heteroalkane ring containing 〇 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom; or X and γ are combined The carbon atoms collectively represent (a) C = 〇 or (b) C = NQ (wherein Q is represented by (O-R'Il11 has the same meaning as described above), I (2) is protected by an amine group, (3) ^:0)1111^11 has the same meaning as described above), (4) -〇R6 (R6 independently represents (a) a hydrogen atom, (b) -CH20(CH2)20CH3 v (c) -Cn2〇 ( CH2〇)nCH3 (n has the same meaning as described above) (d) CpCu which can be substituted by one or two or more substituents from the aryl group, the substituted aryl group, the heteroaryl group and the substituted heteroaryl group Base, (e) -C3_Ci2$l base, 319213 14 200800233 alkyl, 仏) {(〇 <3-(:12 cycloalkyl, OO-qCO-RW has the same meaning as described above) or (1)-Si(Ra)(Rb)(RC) (Ra and Rb and rc each independently represent cvCi2 alkyl , aryl or substituted aryl); or C5) 0_C(R7)(R8)-C^r6 (r6 has the same meaning as described above. However, Han 6 non-CCCO-C^Cu alkyl, C(0)-C3_C12 cycloalkyl or c(〇)_Rl, R7 and R8 together with the bonded carbon atom form a 乂3/^ cycloalkyl group, or L system represents a) _CH3 b) -CH2CH3 ^ c) -CH(〇H)CH3, the sentence may be substituted by an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group or two or more substituents 〇 〇 6 alkyl, .. 1 • e) may be selected from a green, substituted aryl, heterochloro or substituted (tetra) group or a substituted C2_C6 alkenyl group, 戋f) may be selected a C2_c6 alkynyl group substituted with one or more substituents of an aryl group, a substituted aryl group, a heteroaryl group or a heterocyclic group, and a z group representing a) a ruthenium atom , b) a methyl group, or c) a halogen atom, and a anatomical group representing a hydrogen atom or a hydroxyl group. } ' 319213 15 200800233 Item 5. The coated preparation of the macrolide antibiotic according to item 4, characterized in that the macrolide antibiotic is the following compound or their pharmaceutically acceptable salt or Hydrate, etc., (1) (1!1, 2115311, 611, 8艮911, 101151685 18R)-N_[9-(3,4,6·trideoxy-3) represented by the following formula (111) -didecylamino-cold-D-wood (xylo)-hexylyrylsyloxy-3-ethyl-2-hydroxy-2,6,8,10,16,18 -hexamethylene-5,7-dione (〇\〇)_13-[(£)-[6-(吼君-1-yl y-acridin-3-yl)nonoxyimino]- 4,11,15·trioxa (0X0)bicyclic φ [855,4]Asian-19-17Ε-yl]acetamide

(2) Telithicin represented by the following formula (IV) 16 319213 200800233

(3) GW773546 represented by the following formula (V)

(4) TEA-0777 17 319213 200800233 represented by the following formula (VI)

(5) CP-544372 represented by the following formula (W)

(6) JNJ-17069546 represented by the following formula (Μ)

18 319213 200800233

10(7) erythromycin represented by the following formula (IX), or

(8) (1R, 2R, 3R, 6R58R, 9R, 10R, 16S, 18: R)-N-[9_(3,4,6·trideoxy-3-didecylamino-indole-wood- Cyclosyloxy)-3-ethyl-2-3⁄4yl-2,6,8,10,16,18 _ hexamethyl-5,7-di-fat-13 _ [ (E) - [6-(2-Aminopyridinium σ -6-yl) acridine-3-yl]nonyloxyimino]-4,11,15-trioxabicyclo[8,5,4] 19-19-17-yl] ethylamine. Item 6. The coated preparation of the macrolide antibiotic according to Item 5, characterized in that the macrolide antibiotic is represented by the following formula (m) 19 319213 200800233

(1R, 2R53R56R58R, 9R, 10R, 16S, 18R)-N-[9-(3,4 6-dideoxy-3-dimethylamino-Wanmu-hexapyloxy) -3_ethyl 2 di- per 2,6,8,10,16,18-hexamethylene-7,7-dione-13-[(5)-[6 ten than sal-1- Kb pyridine-3-yl]nonyloxyimino]_4,11,15-trioxabicyclo[8,5 4] nin-l-yl]acetic acid amine, its acceptable salt Or their water. Item 7. The coated preparation of the macrolide antibiotic according to Item 1, wherein the macrolide antibiotic has a selected from the group consisting of 2 0 = 14.3, 14 in the powder X-ray diffraction pattern. 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) At least _ learning, and is (lR, 2R53R, 6R58R, 9R, 10R, 16S518R> N: [9-(3,4,6_dideoxy-3-didecylamino- cold_D_木-己Piperanosyloxy)_3·ethyl-2_carbyl-256,8,10,16518-hexamethylene-5,7-dioneyl_13_[(£)-[6_(pyrazine-ι _ base) acridine · 3 - yl] oxime imino] trioxabicyclo [8,5,4] arylene 19 Ε yl] acetamide type 1 crystal. 20 319213 200800233 '28 items · The coated preparation of the macrolide-based antibiotic in the seventh item, the type 1 is an anhydride crystal in the bean. ', = 9 items of the ^2 item, the coated preparation of the vinegar-based antibiotic in the giant ring, the bean The coated preparation is a solid preparation. /, = 10 items: a coated preparation of a macrocyclic vinegar-based antibiotic according to item 9, wherein the solid reading agent is a tablet or granule. ^ Item 11 1st From the coated preparations whose death characteristics are 1/ester antibiotics, the shoulders "...after the dosage system contains polyethyl alcohol, which has an average polymerization degree of 1300 or less, and the fish at least _ pick-up factory JK B. Polyvinyl alcohol copolymer obtained by copolymerization of a monomer in a weight ratio of 6: 4 to 9 L. 12 items, such as the average aggregation of vinyl alcohol in the 11th Hall (4) = ^ 10 degrees of difficulty in the range of 200 to 600 Μ ········································································ The coating preparation of vinegar-based antibiotics in the soil, the unsaturated __^2 thin single system is selected from the group consisting of lysine, ethene, acetonitrile, unsaturated acid amines, aromatic salts. Among the group of people. Unsaturated bonded heterocyclics and their sisters are as follows: characterized by: a coating preparation of vinegar-based antibiotics of macrocyclic ring of h ρ, copolymerized by: And two or more kinds of polymerizable ethylenic monomers, at least 319,213 91 200800233; one type of unsaturated acid And a salt thereof, at least one of which is an ester of an unsaturated carboxylic acid. Item 17: The coated preparation of the macrolide antibiotic according to Item 16, characterized in that the unsaturated carboxylic acid or The salt is selected from the group consisting of propyl benzoic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, iiaconic acid, and the like. The ester of an unsaturated carboxylic acid is selected from the group consisting of decyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl propyl acrylate, butyl methacrylate, butyl acrylate, isobutyl methacrylate, Isobutyl acrylate, cyclohexyl methacrylate, propylene cyclohexyl acrylate 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate, methyl propyl J: citric acid via ethyl ester, hydroxy acrylate Ethyl ester, ester of polyethylene glycol and methacrylic acid, ester of polyethylene glycol and acrylic acid, and group of esters of polyacrylic acid and acrylic acid. Item. The coated preparation of the macrolide antibiotic according to Item 15, wherein the uncharacterized carboxylic acid or a salt thereof and the ester of the unsaturated carboxylic acid are a compound represented by the formula (X) or Its salt, H2C=C(R1).C00R2 (X) (wherein R1 represents a hydrogen atom or a methyl group, and R2 represents a halogen atom or an alkyl group having 1 to 4 carbon atoms). = 9 items, such as the macrolide lactone-based antibiotic coating preparation according to item 16, the second unsaturated carboxylic acid or its salt-based acrylic acid or a salt thereof, and the unsaturated carboxylic acid hydrazine-based methyl methacrylate. 319213 200800233 • The weight ratio is 3 :: 7 to 〇.·5: 9.5. Item 21. The coated preparation of the macrolide-type antibiotic according to Item 11, which is characterized in that it is a partially saponified polyvinyl alcohol having an average polymerization degree of 300 to 500 and a polymerizable ethylenic monomer. The ratio of the ratio of 6 ·· 4 to 9 : 1 is 5 and the polymerizable ethylenic monomer is the weight ratio of acrylic acid to decyl methacrylate in the copolymerization. For 3: 7 to 0.5: 9.5. Item 22. The coated preparation of the macrolide antibiotic according to Item 21, which is characterized in that: saponified polyvinyl alcohol, methyl propyl sulfonate having an average polymerization degree of 3 〇〇 to 5 〇〇 The weight ratio of rhodium and propionate copolymerization is from 6 9 to 9 0 : 7 to 38 : 〇·5 to 12. Item 23. The coated preparation of the macrolide-type antibiotic according to the above item, wherein the content of the coating agent is 2% by weight or more based on the bare or bare particles. Item. The coated preparation of the macrolide antibiotic according to Item 1, wherein the Rut's sign is: the coated preparation of the macrolide antibiotic is 25. Under the condition of 〇 and relative humidity of 6〇%, the total amount of the rim-like substance after three months of storage is 3% or less. -, page such as 苐1 item in the macrocyclic vinegar antibiotic coating preparation, characterized by: macrolide antibiotics are (1R, 2R, 3R, 6R, 8R, 9R, 10R, 68'1811) - Team [9-(3,4,6-trideoxy-3-trimethylamino-7/5-0-wood-hexylpyranosyloxy)-3-ethyl·2_yl group·2 , 6, 8, 1 〇, 16, 18_^ 4_5, 7. -isoyl 13 [(Ε)-[6-(pyrazole_;[_yl)pyridine-3-yl]nonyloxyimino]_4, 1U5-trioxabicyclo.[8,5,4]十九 ΐ Ε Ε 基 ] 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 319 After storage for 3 months under conditions, the total amount of the rim material is 1.5% or less.

Item 26. The coated preparation of the macrolide antibiotic according to the above item, characterized in that the macrolide antibiotic is (1R, 2R53R56R, 8R, 9R, 10R, 16S, 18R) good [9_( 3,4,6-trideoxy Ianosyloxy)-3_ethylhydroxy-2,6,8,1〇,16518_hexamethylene-7,7-dione-13-[( EH6-decaazine_1_yl)acridine·3_yl]methoxyimino]_4, ^,15-trioxacyclo- 5,4]-nine-n-nΕ-yl]acetamide > Type crusting, the total 1 of the shellfish after storage for 3 months under conditions of 25 C and relative humidity of 6〇%; [· 5 % or less. Item 27. The coated preparation of the macrolide antibiotic according to Item 26, which is packaged in a blister pack (ΡΤΡ; (4) ss th_gh pa#). = , suppresses the formation of the rim-like substance of the __ antibiotic, and the 〆q is: a macrocycle having the following structural formula: • 3:=, its pharmaceutically acceptable fines, containing polyethylene Alcohol or polyvinyl alcohol copolymer (4)

319213 24 200800233 . (In the formula, R2a is a hydrogen hydrazine ~ # ^ flying atom or a protecting group of a hydroxyl group.) Brother, 29 items. · A kind of inside the giant ring. Wonderful with ", α Procedence.円S antibiotic, its pharmaceutically acceptable salt or the hydrate of the hydrate of the hydrate. The method of surname is characterized by:: will have the following part 癸a, human antibiotics, and its pharmaceutically acceptable The salt or the hydrate of the temple or the solid matter containing the Xi Xi Temple is coated with a coating agent containing a polyvinyl alcohol or a polyethylidene copolymer.

(In the formula, R2a represents a protective group of a hydrogen atom or a hydroxyl group. [Effects of the Invention] / The macrocyclic ring of the present invention is an antibiotic coated preparation which is agglomerated

It can be applied to the treatment of various infectious diseases, and it can be used in the preparation of medicines. It can be used as a human medical rate, and it is a mammal, fish, birds, etc. Animal medicine. At the same time, as: Replicated polyvinyl alcohol or polyethylene glycol copolymer, you can even consider: tiny particles or small solids, can prevent the treatment = ^, can be provided as suitable for the elderly Large size of clothing: solid preparation of agents, capsules, pills, and the like. W [Embodiment] 319213 25 200800233 The macrolide lactone in the cyclohexadelide antibiotic coating preparation of fx is preferably a 14- to 16-membered ring. The macrolide antibiotic. 14 £ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ τ it # # # ^ ^ ^ ^ The base of the macrolide (hereinafter collectively referred to as 'Q") is an antibiotic salt or a hydrate of the same. Good. 4 cities

^2aH3〇^^^CH3

= :1:=subsequent protection base)’

V (I) (wherein R R represents a protective group of a hydrogen atom or a hydroxyl group.) After investigation by the inventors of the present invention, it is judged that a part of the structure can be described by a coating agent. Therefore, the structural towel is as long as it has the above-mentioned macro ring of the base of d! The antibiotics are intended to be used as active ingredients in the present invention as 319213 26 200800233.

Ch3

Rb 'R-like indicates oxygen, or one of the hydrogen groups is -0-sugar residue. The other is stranded. Preferably, the Ra and Rb lines also indicate that the dotted line of oxygen represents the rest of the structure of the ring_ring. ) * The arc is given to the number of ί (ngbedng) according to the typical situation. It can be mentioned above, _Q, and the part of the comrades in the giant ring is from the Μ Λ, Ό • • The younger brother of the clothes is on the 5th. However, the number can vary depending on the type of giant. · The macrolide lactone antibiotic of the 14-membered ring is a chemically acceptable salt of WO20 (b/G97659 which has the crosslinked structure shown below, its pharmaceutically acceptable salt or The hydrate is preferred. 319213 27 200800233

> {wherein, A represents: a) -〇H, b), 〇R (wherein RP is a protecting group for a hydroxyl group) C)-R]U t ^ R1 ^ ^ , (3)# ^ ^ Substituted heteroaryl. )) Heterocyclic group 1 d) OR (wherein R1 has the same meaning as described above), e) _R (wherein R2 represents arbitrarily containing a halogen selected from (1) (7), m-human and shop V ^ (2) halogen 3丨3 has a ruthenium atom, a sulfur atom, and a ruthenium to three hetero atoms in the nitrogen atom, and may be one or more selected from the group consisting of halogen, aryl, substituted aryl, heteroaryl or substituted heteroaryl. Substituent substituted 〇142 alkyl, (4) any: ^ selected from oxygen, sulfur and nitrogen atoms to 3 heteroatoms: remote from the tooth f, aryl S, substituted aryl, material a C2'C12 alkenyl group substituted with two or more substituents of a human diterpene or a substituted heteroaryl group, or (5) optionally, from an oxygen atom, a sulfur atom, and a ruthenium in a nitrogen atom to three hetero atoms, a CyCn alkynyl group substituted with one or two or more substituents selected from a halogen, an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group, 319213 28 200800233, t0R2 (the formula rR2 has the same meaning as described above) Meaning), hydrogen atom rUr2, r1r2^ or 2' and independent surface h) -NHC(0)Rn (in the formula, n right ~ me) i) -NHC (0) traitor (in the formula, R]1 such as 乂, slave ~ me), j) -NHS(0)2R1^(^+ , R Ll^^ *)' k) -NR14R15 (in the formula, Ri4 and 15 ', month" have the same meaning),

The same meaning as described above); independently representing the group selected from the W group to represent an amine protecting group; 'a) a hydrogen atom, b) a heavy hydrogen, c) a halogen atom, d)-OH, €)# ( In the formula, R1 has the same meaning as described above, f> R2 (wherein R2 has the same meaning as described above), or g)-OR (wherein RP has the same meaning as described above); however, when B When it is halogen, _0H or _〇RP, A means _Rl or second, or A and B together with the carbon atom to be bonded, a) C = Ο b) C(OR2)2 (R2 has the same meaning as described above Meaning), c) C(SR2)2 (R2 has the same meaning as before), d) C[-0-(CH2)m]2 (m is 2 or 3), e) C[-S-( CH2)m]2 (m has the same meaning as described above), 319213 29 200800233 g) C = N-〇-Rn(R]] has the same meaning as described above) 乂 or h) G = Ν-0-Ar ^M- Ar2 [wherein, -Ar] represents r3], and r31 independently represents hydrogen removal. (4) Diosin··^^ 14 2 ^, xj, ^^^^^ Ci_Ci2#^ ^ ^ r 卞 原子 原子 原子0 to 3 heteroaryls of the atom t are selected from the group consisting of a aryl group, a substituted aryl group, and a material ^ 1 4 e2-c12#^^. ^ is intended to be selected from an oxygen atom, a sulfur atom and a nitrogen atom.至至3杂^ ΐt 士 can be selected from halogen, aryl, substituted aryl, heteroaryl or substituted • 2^ M ^ 1 ^ C2-C12#^^ ^ 2)-M- is a bond or representation _ means containing from an oxygen atom, a sulfur atom, and a nitrogen atom to three: 隹: a sub- and a selected from _C'..._N=N- and _c(〇)_ to the base

Ci-C12 stretching base, ) any ... 3 have: ^ from the oxygen atom, sulfur atom and nitrogen atom to 3 hetero (hetero) atoms and selected from the heart ν " · Ν, _ and to the base 匕 < 12 extends alkenyl, self-defective to c) optionally contains white #^^ 虱 atom, sulfur atom and nitrogen in the 〇 to 3 319213 30 200800233 and -C(〇)- 0 to 3 a hetero atom and a selected from the group consisting of: (2) alkynyl, d) substituted aryl, e) substituted heteroaryl or f) substituted heterocycloalkyl; and: 3) -Ar2 a) aryl, b) substituted aryl, 丨c) heteroaryl ' or d) substituted heteroaryl];

Oc^nhurAr11 has the same meaning as before, and, male...the same soul j) C=NNHC(0)RH(Ru has the same meaning as 篆立') k) C=NNHC(0)NHR11(R11 , ..., has the same meaning as the description) l) C = NNHSCOhRWR" has * ten, the door is the same as the other meaning) m) c = NNHR \ R3 has the same meaning as above) iOC ^ NR ' R11 has the same enthalpy as above) C = NRn (RH has the same meaning as described above), or P) C = NN - CHR11 (Rl1 has the same meaning as described above.) 一方 One of X and Y represents a hydrogen atom, and One is a) a hydrogen atom, b) a heavy hydrogen, c) -OH, d) -ORp (Rp has the same meaning as described above), and e) -NR4R5 (R4 and R5 independently represent 31 319213 200800233 _ (1) a hydrogen atom, (2) a halogen atom, an aryl group, a substituted aryl group, a heteroaryl group, or a (10) 4 and a " combined with a nitrogen atom in a heteroaryl group substituted with one or more substituents; & a sulfur atom and a ruthenium in a nitrogen atom to 2 heteroatoms 3, a heteroalkane ring represented by a 1 atom, or a X and γ system together with a bonded carbon atom, (a) C = 0 or

(b) C = N, Q • (wherein Q is represented by (lHl 'R11 has the same meaning as described above), (2) an amine protecting group, (SyCCC^R'R11 has the same meaning as described above), (4) -0R6 (R6 independently represents (a) a halogen atom, (b) -CH2〇(CH2)2〇CH3, and (c)-CH2〇(CH2〇)nCH3 (n has the same meaning as described above) ' (4) may be a Ci_Cu alkyl group substituted with one or two or more substituents selected from the group consisting of an aryl group, a substituted aryl group, a heteroaryl group and a substituted heteroaryl group, (e)-C3-Ci2 cycloalkyl group, ( f)-C(〇)-Ci-C12 alkyl, (3)-0(0)-03-^2 cycloalkyl, (hhC^CO-R'R1 has the same meaning as described above) or (i) -Si(in(Rb)(Re) (Ra and Rb and y are each independently represented by Ci-C] 2 $complete, aryl or substituted aryl); or 319213 32 200800233, (5)0-C ( R7)(R8)-0-R6 (R6 has the same alkyl group as above, and the %2 ring group R and R form together with the bonded carbon atom to form _C3_c] 2 cycloalkane, show (!) hydrogen Atom or (2) (: Ί-α2 alkyl); Guangfan soil, or Table L shows a) _CH3 b) -CH2CH3, c) -CH(〇H)CH3 ^ Heterocyclyl or substituted heteroaryl : sentence can be selected from aryl, substituted The base of the soil, %1', or more than 1 or more substituents substituted by the substituent, e) may be selected from an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group 1 or 2 More than one Cr=substituent substituted by a substituent, or CVCV acetylene Z, which may be substituted with one or more substituents selected from an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group Indicates, earth, a) a hydrogen atom, b) a T group, or c) a halogen atom, and R represents a protective group of a hydrogen atom or a hydroxyl group. A detailed definition of each of the above compounds (π), as described in w〇2003/097659. The desirable form of the compound (n) is as follows. A and β are represented together with the bonded carbon atoms. h) C =: Ν· Ο - Ar1 -M-Ar2 [wherein, -Ar1- represents R3i, and the ideal r31 is 33 319213 200800233

And a hydrazine in a nitrogen atom to a 3 aryl group, a heteroaryl group or a substituted cvc12 alkylene group. The heteroaryl group is preferably an aromatic heterocyclic ring of 5 or 6 members, a hetero atom in oxygen. As the substituent on the heteroaryl group, for example, I, a thiol group, a dentate, a lower alkyl group, and a lower-grade scent-free (for example, σ to saliva). Fb/y is preferably a group having the following formula together with a carbon atom to be bonded,

(b) C = N-Q (wherein Q is preferably (3)-C(〇)R11 (r11 is preferably a lower alkyl group). L is preferably a lower alkyl group of c-wide A, and more preferably seven). Z is preferably a) a hydrogen atom. ... / more. For the specific example of antibiotics in the macrocyclic ring, for example, red fluorescein (14-membered ring), 6-deoxyerythromycin (14-membered ring), chlortetracycline (μ-membered ring), and lyophilized (14-membered ring), roxithromycin (14-membered ring), dirithromycin (14 members), telithromycin 04 member ring, the aforementioned compound (IV)), erythromycin (14, ring) The aforementioned compound (κ)), fluoroerythromycin (14-membered ring), ethyl succinic acid fluoroerythromycin (14-membered ring), GW773546 (14-membered ring, the aforementioned compound (v)), TEA-0769 (14 贞) Ring), τεα·〇777 (14 anthracene ring, the aforementioned compound (γι)), TEA-0929 (14 tributary ring), JNJ_17〇69546 (14 tributary ring, the aforementioned compound 319213 34 200800233 (M)), 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, the aforementioned Compound (W)), CP-642959 (14-membered ring), cp-654743 (14-membered ring), RU.4 (14-membered ring), PL-1.2.9 (14-membered ring), RWJ_415663 (14-membered ring) , RWJ-415667 (14-member ring), GI-448 (14-member ring), LY-281389 (14-member ring), the aforementioned compound (melon) (14 Ring cross-linked structure), azithromycin (15-membered ring), PL-: L1.3 (15-membered ring), L-701677 (15-membered ring), PL-1.4.18 (16-membered ring), PL-1.4.2 (16 member ring), PL-1369 (16 member ring), 10YM-17K (16 member ring), A-74950 (16 member ring), mexinmycin (16 member ring), (1 R, 2R, 3R) ,6R'8R,9R,10R,16S,18R)-N-[9-(354,6'trideoxy-3-didecylamino-/5-hexanpyranosyloxy)_3_ Ethyl 2 -yl-yl-256,8,10516,18-hexamethylene-5,7-dione-13-[print]_[6-(2-aminol-pyridyl-6-yl)啦 rid-3-yl]methoxyimino]_4,11,15-trioxabicyclo[8,5,4]heptadecan-17E-yl]acetamide and the like. Among them, the most preferable compound (m) which can be represented by the following formula (melon) 35 319213 200800233

Or the future of telithromycin, GW773546, TEA-0777, CP-544372, JNJ-17069546 and erythromycin, or their pharmaceutically acceptable salts or their hydrates, etc. The best compound is Π a compound of one form (dish), or a pharmaceutically acceptable salt thereof or a hydrate thereof. In the compound (m), the aforementioned partial structural formula (_q) is bonded at the 9th position, and the chemical name of the compound (JH) is (1r, 2r, 3r, 6r, 8R, 9R, 1〇r, 16S,18R)-N-[9-(354,6-Trideoxy-3-trimethylamino-wan_0_mu-hexylpyranosyloxy)-3•ethyl-2-hydroxyl -2,6,8,10,16,18-hexamethyl-5,7-dioneyl_13-[(EK[6-decaazole]-yl)pyridine '3_yl]methoxyimine Base]_4, 11,15_trioxabicyclo[85554] sub-nine _17 £; _ base] acetamidine. Meanwhile, as a preferred example of the macrolide antibiotic, it is also possible to have (1R, 2R, 3R, 6R wind 9R, 10R, 16S5l called dimethylamino U-wood: hexoseranoseoxy)_3 _Ethyl 2 • keel 319223 36 200800233 • 2A8,10,16,18-hexamethylene _5,7·dione-i3_[(EH6_(2•Aminopyridin-6-yl)pyridine-3 -Methoxy]methoxyiminotrioxabicycle p $ 4] Yeptadecan-17E-yl]acetamidamine. ', The inventors have found in particular that the compound (melon), especially its crystal, W: W保存2005/08182i t ^ 1 ^ ^a} The preservation stability is extremely poor. You can record the instability of humidity or oxygen under long-term storage, and also find compounds (m from HPLC detection, NMR analysis, etc.) The instability is due to the part x appeal structure which can be expressed by the above (1), and it is also confirmed that the part can be improved by the above-mentioned coating agent, ^ ^ ^ ^ ^ , g ^ , ρ ^ # ^ ^ ^ ^ ^ # ^ ^ ^ = Qualitative generation. Therefore, the effect of stabilization on this day (four) can be broadly applied to various drugs with the same partial structure. / / It is the antibiotic in the giant ring On. Also can improve the inclusion of these The stability of the preparation of the medicine, especially the various solid preparations, preferably also improves the stability of the tablets, granules, capsules, etc. It is apparent that the partial structure of the substance is caused by a change in the structure of the part. It is intended to mean two kinds of decomposition products which increase in iW time in the edge test before HpLc: the peak of the macrocyclic (four) antibiotic of the main drug, as shown in the second tobacco towel described later. The type 1 crystal essentially exhibits the same powder diffraction pattern as the type 1 polymorph in f〇2〇〇5/〇81821. 'The side exhibits a diffraction angle... selected from 143, 5 and At least - (four) material in the degree. (d) in the range of 319213 37 200800233 0 to 2 hydrates in the combined storage conditions can change the moisture content. These macrolide antibiotics are well-known compounds, according to the prior art Early literature was prepared according to these methods. Also, ^ ^ ® Expert Opin. Ther. Patents (2003) 13(6) 5 p.787-805 or "Technomic" https: //asiishin The methods in .com/shinyaku6/search, etc. are made according to these methods. The salt of the macrolide-based antibiotic may be used as long as it is pharmaceutically acceptable, and any salt may be used, and specific examples thereof include hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, and the like. a salt of a hydrohalic acid; a salt of a mineral acid such as sulfuric acid, nitric acid, acid, perchloric acid, carbonic acid or boric acid; acetic acid, trichloroacetic acid, trifluoroacetic acid, glycolic acid, lactic acid, aromatic acid, citric acid, tartaric acid, - oxalic acid, malonic acid, oxalic acid, benzoic acid, mandelie acid, g acid, valeric acid, maleic acid, propionic acid, heptanoic acid, formic acid a salt of an organic carboxylic acid such as malic acid, lauric acid or palmitic acid; a salt of an amino acid such as arginine, aspartic acid or glutamic acid; sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 2 - salts of organic acids such as naphthoic acid; salts of metals such as sodium, unloading, sulphur, magnesium, etc.; or quaternary ammonium salts such as money salts; The solvate of the macrolide-based antibiotic is not particularly limited, and examples thereof include water; alcohols such as methanol, ethanol, and isopropyl alcohol; and ethers such as tetrahydrofuran. These well-known macrolide antibiotics are effective in combating various bacteria, mycoplasma, fungi (mold), protozoa, and resistant bacteria, etc., and the present invention as a main drug is used. The coated preparation can be used as a very effective treatment for bacterial infections such as mammals, fish and birds including humans, fungal infections, fungal (mold) infections, and protozoal infections, including 38 319213 200800233. Here, the pathogens and disease names of the diseases can be as follows. For example, pneumonia, otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Peptostreptococcus, etc. , 10 pairs of rhinitis, bronchitis, tonsillitis and mastoiditis, Streptococcus pyogenes, Streptococcus (3 and (3 groups, Closridiiim diphtheriae or Actinobacillus haemolyticum) Caused by pharyngitis, rheumatic fever, and glomerulonephritis; Mycoplasma pneumoniae, pulmonaryophilic veterans. 'Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae or Respiratory infections caused by Chlamydia pneumoniae; Staphylococcus aureus, S. epidermidis, S. hemolyticus, Streptococcus pyogenes, Streptococcus agalactiae ), Streptococcus C to F group (Groups C to F Streptococcus), grass green Uncomplicated skin and soft tissue infections caused by Streptococcus viridans, Corynebacterium minutissiinum, Clostridium, or Bartonella henselae; abscesses and osteomyelitis, And puerperal fever; Staphylococcus saprophyticus or Enterococcus 39 319213 200800233 Acute urinary tract infections caused by the stomach; urethritis and cervicitis; Chlamydia trachomatis, Haemophilus ducrei Sexually transmitted diseases caused by (Haemophilus ducreyi), Trepononea pallidum, Ureaplasma urealyticum or Neissera gonorrhoeae; Staphylococcus aureus (S, · aureus), or Streptococcus A, B and Food poisoning, toxic shock syndrome, toxin disease caused by group C; '-·.-ulcer caused by Helicobacter pylori; systemic fragrant febrile syndrome caused by rebrelia recurrentis; Caused by Borrelia burgdorferi Lyme disease; conjunctivitis, cornea caused by Chlamydia trachomatis, gonorrhea, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus pyogenes, Haemophilus influenzae or Listeria * . . . · Inflammation and lacrimal gland inflammation, Mycobacterium avium or Mycobacterium intracellulare caused by disseminated Mycobacterium tuberculosis complex (MAC) disease; Campylobacter Jejuni) gastroenteritis from the bow; intestinal protozoa caused by the genus Cryptaspoddium; odontogenic infection caused by Streptococcus viridans; Haemophilus pertussis (B〇rdeltella pertussis) Sustained cough; gangrene caused by Clostridium perfringens or Bacteroides; and atherosclerosis caused by pyloric helix or Chlamydia pneumoniae Wait. As for the treatment and prevention of bacterial infections and protozoal infections in animals and diseases associated with four infections, for example, the following: hemolytic pasteurized rod 319213 40 200800233 , bacteria (Pasteurellahemolytica), Pasteurella septicum (Pastenrella) Bovine respiratory disease caused by nmtocida), MyC〇plasma b〇vis or Bordetella; coliform or protozoa (ie, Coccidium, cryptosome) Infection-related bovine and intestinal diseases; Staphylococcus aureus, Streptococcus ubeds, Streptococcus agalactiae, Streptococcus dysgalactiae, Klebsiella (5) mastitis of cows caused by (4) bacteria (Corynebacterium) or Enterococcus spp.; A. pleuropneumoniae, Rmult〇cida or Respiratory diseases of pigs infected with Xiangji bacteria; coliform, intracellular intestinal bacteria (Lawsonia intracellularis), Salmonella (Salm〇nella) or Serpulina Infection-related porcine bowel disease caused by hyodysinteriae; infection-related bovine hoof disease caused by Fusobactediim genus; coliform uterus caused by coliform infection; Fusobacterimn necroplionnn or Bacier〇ides nodasus infection-associated bovine ciliary body sputum; infection-related bovine red eye caused by Moraxella bovis; protozoa (ie neosporium) Early abortion of cattle associated with infection; infection of urinary tract infections in dogs and cats caused by coliforms; infection caused by Staphylococcus epidermidis, s. intermedins or Pasteurella septicum Related skin and soft tissue infections of dogs and cats; Alcaiigenes, Bacteroides, Bacillus, Enter〇bacter, fungi 319213 41 200800233 . (Eiibacrterium) Dogs and cat teeth caused by bacteria, Peptostreptococcus, Porphyromonas or Prevotella Oral infections. Other bacterial infections and protozoal infections that can be treated or prevented by macrolide antibiotics and diseases associated with such infections, in "Sanford Guide to Antimicrobial Therapy" by JP Sanford et al., "Sanford Guide to Antimicrobial Therapy", It is described in the 26th edition, Antimicrobial Therapy Inc. 1996". Polyvinyl alcohol or a copolymer thereof as a coating agent of the present invention can be used, and φ is preferably used in WO02/17848 and WO2005/019286. A polyvinyl alcohol copolymer is easy to be coated in terms of adhesion or the like. That is, the polyvinyl alcohol copolymer used in the present invention can be obtained by a known method from polyvinyl alcohol or a derivative thereof (for example, an ester) or A method in which at least one of the polymerizable ethylene monomers of the salt is copolymerized to produce. As a method for producing such a polyvinyl alcohol copolymer, a known method is a radical polymerization method such as solution polymerization, suspension polymerization, emulsion polymerization, and block formation. Polymerization, etc., various polymerization methods can be carried out under usual polymerization conditions. This polymerization reaction is usually carried out in the presence of a polymerization initiator, or Reducing agent (for example, erythorbate sodium, metabisulfite sodium, ascorbic acid), chain transfer agent (such as 2-mercaptoethanol, α-mercaptobenzene) Ethylene dimer, tiii〇glycolate 2_ethylhexyl ester, lauryl mercaptan or dispersant (such as sorbitan ester, lauryl alcohol and other surfactants) Next, in water, an organic solvent (such as decyl alcohol, ethanol, Ceilosolve, carbitol) or a mixture of these 42 319213 200800233, and the removal of unreacted monomers - a method of drying, pulverization, etc., and a well-known method, and rain is not particularly limited. The polyvinyl alcohol which is a raw material of a polyvinyl alcohol copolymer can be used as long as the average degree of polymerization is about 200 to 1,500, and The average degree of polymerization is preferably from about 200 to 1,300, preferably from about 200 to about 900, more preferably from about 200 to about 600, and most preferably from about 300 to about 500. Especially in average Preferably, the partially-polyvinyl alcohol having a degree of mixing of 300 to 500 is used, and the degree of saponification having an average degree of polymerization of about 300 to 500 is about 60 10 to 100 mol%, and the partially saponified polyvinyl alcohol is about 78 to 96 mol%. This kind of saponified polyvinyl alcohol can be obtained by radically polymerizing vinyl acetate and then saponifying the obtained vinyl acetate moderately. In order to manufacture the desired polyvinyl alcohol, it can be moderately prepared. It can be achieved by controlling the degree of polymerization and the degree of saponification by a well-known method. In addition, as a part of the saponified polyvinyl alcohol thus obtained, a commercially available product can be used, and as a commercial product of a polyvinyl alcohol, for example, Gohsenol EG05, EG25 (manufactured by Nippon Synthetic Chemical Co., Ltd.), PVA203 (manufactured by Kiiraray Co., Ltd.), w PVA204 (made by Kuraray Co., Ltd.), PVA205 (made by Kuraray Co., Ltd.), JP-04 (made by Nippon Vinegar V. POVAL Co., Ltd.), etc. Further, the coating agent used in the present invention is not limited to a polyethylene copolymer, and polyethylene may be used alone, and two or more kinds of polyvinyl alcohol having different degrees of polymerization and saponification may be used in combination with the purpose. For example, a polyvinyl alcohol having an average degree of polymerization of 300 and a polyvinyl alcohol having an average degree of polymerization of 1,500 can be used as a coating agent. Further, a commercially available premix coating agent containing polyvinyl alcohol can also be used. 43 319213 200800233 ...It is also possible to use various modified polyvinyl alcohols, for example, for the reduction of polyvinyl alcohol, the extension of ethyl group, the conversion of acetylene, the modification of carboxylic acid, and the modification of diacetone. Polyethylene glycol, thiol oxime ^ two modified g poly (4) can also be used commercially available products, or 制 in the domain of the method.匕 匕 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在(eg, metal salts, ammonium salts, amines), esters of such acids (eg, substituted or unsubstituted alkyl esters, cyclic alkyl vinegar, polyglycol diols), unsaturated nitriles, Unsaturated acid amines, aromatic vinyls, aliphatic vinyls, heterocyclic unsaturated chains, and the like. Specifically, for example, (1) acrylic acid acrylate methyl acrylate, acrylic acid vinegar, propionate butyl s, propionate isobutyl vinegar, alanine hexanoic acid, acrylic acid 2 _ Ethylhexyl ester, acrylic acid by ethyl acetate, polyethylene glycol acrylate vinegar, polypropylene glycol propylene vinegar, etc., (2) methacrylic acid acetonate methyl acetoacetate methyl methacrylate, ethyl methacrylate, Butyl methacrylate, isobutyl methacrylate, cyclohexyl methacrylate, 2-ethylhexyl methacrylate, methacrylic acid, polyethylene glycol methacrylate, etc. (3) Acrylonitrile, mercaptoacrylonitrile, etc. of unsaturated nitriles, (4) Acrylamide, methacrylamide, methacrylamide, etc. of unsaturated amines (5) aromatic Ethylene-based styrene, methyl styrene, etc., (6) aliphatic vinyl-based vinyl acetate, (7) unsaturated bond-containing heterocyclic oxime, ethylene tetrahydroperpenone, acrylic acid, and the like. Further, the polymerizable ethylenic monomer in the production of the polyethylene glycol copolymer 319213 44 200800233 • The unsaturated carboxylic acid and its ester can be represented by the following formula (χ). H2c=C(R〇-CO〇R2 (wherein R! represents a hydrogen atom or a fluorenyl group, and L represents a hydrogen atom or an alkyl group having i to one carbon atom. y can be a hydrazine of these polymerizable ethylenic monomers) The two or more group names are further copolymerized with a polyethylene glycol, and it is desirable to copolymerize a mixture of acrylic acid and mercaptopropyl acid ester (for example, methyl methacrylate) with polyvinyl alcohol. The weight ratio of vinyl alcohol to polymerizable ethylenic monomer is about 6:4 to 9:, and preferably about 8:2, and 'in the use of acrylic acid as a polymerizable monomeric methacrylic acid When vinegar, its weight ratio is about 3:7 to about 〇5:95, every 1.25: 8.75 ^^ 〇, alcohol copolymer, is made of polyvinyl alcohol (average degree of polymerization about 2 〇〇 to 1 = to), A The composition of methyl acrylate and acrylic acid is preferably a composition ratio of about 0 Θ to 90 : 7 5 1 S Π · AC ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ · · · · 12 to 12, preferably about 70 to 9 〇.15 to 2 〇: 2 to 3, and about 8 〇: 175:2.5 is better. Furnace = polymerization agent' is used in this field. For example, persulfate money, chlorine peroxide Wait for her ί or ^^ butyl, peroxydiwei The organic peroxygen of the heart § is intended to be an azo compound such as azobis(2 propylidene) hydrochloride or 2,2' azobis(2,-methylvaleronitrile). The macrocyclic quinones of the present invention are highly resistant to dispersal (iv) and generally, when applicable, it is preferred to carry out the aqueous solution by means of a well-known method of spreading and spraying. Another 3 319213 45 200800233 , in the sprayed solid coating agent a tablet or a method of preparing a particle containing a coating agent and then heating and melting to cover the surface. As for the amount of polyvinyl alcohol or a copolymer thereof in the coating agent, for example, in comparison with a macrolide antibiotic Ingots, preferably from about 2 to 30% by weight, and preferably from about 5 to 20% by weight, more preferably from about 7.5 to 15% by weight, and when coated with bare particles, relative to bare particles The amount is generally from about 5 to 100% by weight, and is preferably from about 30 to 80% by weight. Further, the conditions for coating the naked 10 ingots and the prime particles of the macrolide antibiotic of the polyvinyl alcohol copolymer are generally It is as follows.: 10 Polyvinyl alcohol copolymer polymerization degree: about 500 ginseng polyvinyl alcohol copolymer liquid concentration About 8 to 10% by weight 10 coater: Highcoater HCT_48 (FREUND industry). Spray gun caliber: about 0.8 leg 10 tablet loading: about 1 to 1.5 kg. Pump rotation number: about 20 rpm Φ spray air amount: about 65 to 70 L/min • Supply air temperature: about 60 t: ® air supply amount: about 2 < 5 m 3 /min. Exhaust air volume: about 4.5 m 3 /min According to a preferred embodiment of the present invention, the stability of the macrolide antibiotic can be provided. a coating agent characterized in that a partially saponified polyvinyl alcohol having an average polymerization degree of 300 to 500 is copolymerized with a polymerizable ethylenic monomer in a weight ratio of from 6:4 to 9:1, and The polymerizable ethylene monomer is acrylic acid and decyl decyl acrylate, and the weight ratio of acrylic acid to sulfhydryl group 46 319213 200800233 - methyl acrylate at the time of copolymerization is 3:7 to 0.5: 9: The coating agent is coated in the ring. The sound is broad (for example, bare ingots, bare particles). The heart is made of a bare ingot containing the slaves. As for the rare ingots containing the macrocyclic (four) antibiotics in the present invention, a preferred method of the coating may be, for example, a) directly using a macrocyclic antibiotic, or a formula, a binder. Adding meals to the granules (naked _ after 'adding two ί 形 ' or b) directly to the macrolide antibiotics, or adding excipients, binders, or granules纮 丨 , , 兹 , , , , 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹 兹The human is uniformly mixed and then formed into a shape. The concentric female can also be produced by the well-known method in (4). For the antimony ingot, it can be pre-coated before being coated with the polyvinyl alcohol copolymer. ^#, such as hydroxypropyl methylcellulose, white sugar, etc. The macrocyclic vinegar which can be coated with polyethyl alcohol or polyethylene copolymer can be prepared by a conventional method. As for the tablet, in order to improve it Disintegration and the best person to the right. As for the disintegrant, you can use the section φ, March (four) has been used in the field of violation Knowers, such as partial powder, 竣methyl temple powder, renegade methyl fiber phase, low substitution hydroxy 缄 缄 素 ( (L-HPC), cross-linked cellulose 纳 S 〇 d surface X, for example , Ac Sol Sol, Asahi Kasei (stock)), Polyurethane ketone 319213 47 200800233 /etc., preferably sodium carboxymethyl starch. The amount of disintegrant is 1 mil or the number of dynasties 2 tens of minutes Within, it is better to do the amount of solution in the number of dreams, usually i (10) weight np relative to the tablet

Stone m lost Dan Bali eight days of injury, about Q S

Viia^ l ^ · About 2 to 10 parts by weight. , ^^^^ ^ ^ ^ ^ ^^ ^^^ 叩 叩 疋 疋 疋 锭 锭 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩 叩The content of titanium oxide is relative to _^ is about: Γ by weight, and about 0... "Mammoi. (mammoi), crystalline pheromone, corn 扒 铃 铃 、 、, (4) Preferably, the content of the excipient is as long as it is considered in consideration of the main Huadandan ^'~曰曰 fiber, etc., usually "the size of the tanning agent is about 5 to 6 times.八八, 100 parts by weight of the tincture is a replacement injury 'and preferably about 10 to 4 parts by weight. As for the binding agent, the field-based cellulose, polyethylene, thioglycol, hydroxy in the field can be widely used. Propylcellulose: 肀vinyl: such as: , , ::: and purchased as a (4)-based cellulose as a good '1' pass-on 疋 relative to 100 parts by weight of the tablet is about 〇 并 and about 1 to 3 parts by weight It is better. To 5 liters, etc., such as hard bromate, talc, sucrose fatty acid vinegar is about; very small, for example, relative to ^ 319213 48 200800233 The invention contains 'giant A lozenge that is cool in λ and hunger, using the above-mentioned raw materials and mixing, granulating, drying, granulating, lubricant mixing, and radish according to the well-known ancient dogs in the field.铉笙々~ After the steps of Yihong Temple, you can get it.

Further, the granulation operation is carried out by using, for example, a wiper I, a granulator, a fluidized layer granulator, a brabender, or a biaxial granulator to produce m π. Yes, but it is preferable to use a stirring granulator in order to obtain a uniform granule. Further, the key-making can also be carried out using a commercially available tableting machine 'generally at a spinning pressure of about G 2 to i 5 t · the preferred tablet composition of the present invention - the form can be as follows. In the total weight of the tablet, the compound of the main drug (the salt or the hydrate of the drug of the melon: about 40 to 70; the disintegrant, the excipient, 40%;隹: about 2 to 1 〇 0 / 〇; and D_mannitol and crystalline cellulose is preferred: a total of about 10 to the Lu bond, and preferably hydroxypropyl cellulose: about i to 3%; lubrication And magnesium stearate is preferred: about i to 3%, while the coating agent is preferably about 5 to 2% by weight relative to the weight of the bare ingot. The giant of the present invention. The vinegar-based antibiotic-coated preparation in the ring may be administered to a human or an animal as long as an effective amount for treating the above-mentioned diseases, although the dosage may vary depending on the age, body weight, symptoms, sex, etc. of the patient or the animal to be treated, but usually When it is divided into the above-mentioned macrolide antibiotic, its pharmacologically acceptable salt or its hydrate, it can be administered orally in an amount of 319213 49 200800233, such as 0.01 to 50 mg/kg. At the same time, the total amount of the rim-like substance in the preparation of the present invention is, for example, a strip at 25 C and a relative humidity of 60%. After storage for 3 months, it is preferably 3% or less, and more preferably 1.5% or less. · = and in order to improve the stability of the preparation of the present invention, it is preferably blister pack (PTP; press thrGUgh Paekage) or bottled (for example, polyacetal bottles, glass bottles, aluminum cans). The macrolide antibiotic coating preparation of the present invention may also contain an antibacterial agent other than antibiotics in the d d ring. The main component of the coating material may be a polyvinyl alcohol or a polyvinyl alcohol copolymer, but may contain other coating components. Further, the present invention provides a method for inhibiting the formation of the same substance of the macrolide antibiotic. , which is a macrocyclic lactone antibiotic of the following partial structural formula (in the formula, the pro-form: or the protective group of a hydroxyl group), its '7K glutathione salt or a hydrate of these or The solid form containing these is coated with a begular alcohol or a poly(ethyl alcohol) copolymer. The macro ring contains the salt of the y = 8 M ^ Shanggu § noon salt, and their hydrate 'coating agent , ^ method of covering, etc. are as described above.

50 319213 200800233 ' Further, the present invention is characterized in that the above-mentioned partially-constituted cyclic lactone antibiotic, a pharmaceutically acceptable salt thereof or a solid substance having a substantial amount of these are contained in a polyvinyl alcohol. f 抡 合物 / compound or covering agent «, the salt allowed by the ring of the ring or the hydrate of their hydrates is determined by the city's i ^. steroids antibiotics, /, clothing The permissible salts, their hydrates, hephax, etc. are as described above. <Reagents and coatings. The following description will be made more particularly by the description of the examples, but the scope of the present invention is not limited to these examples. [Examples] Example 1 I- _ interesting copolymer coating agent affects the core of the main drug stability peak) Ning Shi of the coating agent according to the manufacturing flow chart shown in Figure 1, can be shown in the following table i A coated preparation (formulation 1). [Table 1] ~~^-~~---_ ~5W1 granule internal crystal) 1 OO.Omg _ D_mannitol-__〇38.4mg Hydroxypropyl cellulose 4.6mg 15.0mg granules outside --- ----------- 'V ^4' carboxymethyl starch sodium magnesium stearate ______ο_ 4.0mg bare bond 162.0mg coating copolymer 18 .Omg coating meter 18 .Omg total 180.0ms Coating ratio (weight 1%) (for bare ingot) 11.1% 319213 51 200800233 Further, the above-mentioned bare ingot coated with a polyvinyl alcohol copolymer is obtained through the following steps (1) to (7). . (1) A lozenge of Φ 8 mm and 0 9 mm two-stage R was produced by a rotary tableting machine using wet granulation by a stirring granulator. (2) The polyvinyl alcohol copolymer having a polymerization degree of 500 is gradually stirred and added to the purified water to prepare an aqueous solution of a polyvinyl alcohol copolymer of 8 to 10% by weight. When it is necessary to mix titanium oxide, it can be prepared by stirring and dispersing in TK ROBOMICS (Special Machine Chemical Industry) to prepare a polyethylene l-alcohol copolymer aqueous solution containing titanium oxide. (3) A tablet of 1 to 1.5 kg was charged into a ventilated coater Highcoater HCT-48 with a two-fluid nozzle. (4) After heating for a certain period of time at a supply air temperature of 60 ° C, a supply air volume of 2.5 m 3 /min, and an exhaust air volume of 4.5 m 3 /min, the product temperature is maintained at 40 t: or more. (5) 8 to 10% by weight of polyethylene, with a spray gun diameter of 0.8, a spray air volume of 65 to 70 L/min, and a pump rotation of 20 rpm, as the tablet temperature is maintained above 40 °C. After the aqueous solution of the alcohol copolymer is sprayed in the range of 5 to 10 g/min ►, the polyvinyl alcohol copolymer can be coated on the tablet. (6) After the predetermined amount of the polyvinyl alcohol copolymer is coated, talc, magnesium stearate or both thereof are spread on the surface of the tablet, and the tablet is discharged from the ventilating coater Highcoater HCT-48. (7) The prepared ingot is dried by a shed dryer (air supply temperature: 65 ° C, drying time: 90 minutes). (2) Evaluation of the stability of the macrolide-based coating preparation. The stability of the ester-based coating formulation (Formulation 1) was compared with the uncovered bare ingot of 52 319213 200800233. The evaluation method is as follows. The coating agent and the bare ingot were taken for 3 months under the conditions of i-injection, 6〇% relative humidity, no packaging, and shading. After 5 months, after 1 month, 2 months, and 3 months, the residual amount of the compound (dish) and the amount of the rim-like substance were measured by liquid chromatography. In addition, the cover of the naked syllabus uses the same manufacturing lot number (1 called macrolide lactone-based antibiotic (compound (BI))., liquid layer dragon method, slant wave 谛, _ ♦ (1), coating agent and bare After each of the ingots is separately wrapped in the drug wrap and quickly pulverized, the whole amount is poured into a 1 mL flask of the flask. (2) Adding a liquid chromatography to an acetonitrile/water mixture (7:3) 7 〇mL.Wu is used by Idle Liquid Chromatography (hereinafter, the same). (3) Vibrate for 10 minutes. (4) Add liquid chromatography to acetonitrile/water mixture (7: 3) to make It is exactly 100 mL. • (5) A membrane filter with a pore size of 45·45 " m (Kurab. Company's 'chromatodisk non-aqueous 13N) liquid (4) After that, 2 mL of the initial filtrate was removed, and the remaining filtrate was used as a sample solution. Ujfe Standard Solution 'Accurately weigh approximately 1 mg of the compound (ffi) for the use of the drug as a standard substance. The same batch number used in the coating agent and the bare ingot. This compound (Π) is dissolved in 70% acetonitrile and made precise to the condition of iq mL 〇 chromatography> 3192 13 53 200800233 - The area of the spike produced by the main drug and the rim material is determined by the automatic calculation method. Detector: UV spectrophotometer (measurement wavelength range: 195 to 400 nm, extraction wavelength · 21 〇 nm) L-column ODS, 5 // m, 4·6χ250 mm (chemical substance evaluation research institute) Column temperature: a certain temperature near 40 移动 mobile phase Α: 0.005 mol/L of potassium hydride buffer of ρΗ8·0/ Acetonitrile (3/2) • mixed liquid mobile phase B: acetonitrile / ρ Η 8 · 0 〇 〇 12mol / L potassium dihydrogen phosphate buffer (3 / 1) mixture. · . . Gradient program: [Table 2]

=mount: UmL/min (maintaining time of the main component at the time of setting is about % > main input amount: 10//L sample cooler temperature: 25 injection needle cleaning solution: acetonitrile surface spear measurement range: 65 after sample injection Minutes 319213 54 200800233 • <System Suitability~=Appropriate = For the standard solution, the same liquid 211: The retention time of the component is about - minutes. (%) ^ ^ ^ # t * (%) ^ ^ Μ α τ ^ * ; . · Parental mass (%) = (Ai / ZA) xi (8) Total mass (%) = (ΣΑί / ΣΑ) χ 1 (Κ)

Ai : peak area of each rim material Σ Ah sum of peak areas of each rim material Σ A • sum of areas outside the system peak = chromatogram of the coating agent after 1 month of storage as shown in Fig. 2 Shown. At the same time [not in Table 3].

Lead 6 is the peak of the compound (melon) from the main drug. Humans other than Peak 6 319213 55 200800233 . Peaks are peaks from rim-like substances, especially peaks 1 and 2 are major by-products that increase due to storage. / Figure 3 shows the change in the ratio (%) of the total amount of the edge-like substance in the coating agent and the bare ingot to the main drug. In Fig. 3, a ruthenium mark indicates a bare ingot, and a fingerprint indicates a coated ingot coated with a polyvinyl alcohol copolymer. It can be confirmed from Fig. 3 that the coated material of the present invention has almost no change in the quality of the edge material even after three months, whereas the main drug in the uncovered bare ingot is rapidly performed - . After 3 months, the mass of the rim was about 9%. Thus, the stability of the coated preparation of the present invention can be verified. Example 2 Effect of the coating dose on the stability of the main drug In the method for producing the macrolide-based coating preparation of Example 1, the ratio of the total amount of the coating agent to the coating preparation was in the range of 5 to 15% by weight. , and various variable amounts of coated preparations were produced. One of these coated preparations was taken and stored for one week under conditions of 4 ° C, 75% relative humidity, no packaging, and shading. Next, the ratio (%) of the total amount of the rim-like substance to the main drug was calculated in the same manner as in Example 1. The results are shown in Figure 4. As can be seen from Fig. 4, when the coating amount of the polyvinyl alcohol copolymer as a coating agent is in the range of about 7.5 to 15% (w/w), the macrolide-based coating preparation of the present invention is particularly stable. Example 3, the formulation of the polyvinyl alcohol copolymer coating agent of titanium dioxide affecting the stability of the main drug. According to the manufacturing flow chart shown in Fig. 5, it is as shown in Table 4 56 319213 200800233

Bare ingot meter

Hard fat € magnesium • Composition of coated preparations (formulation 9 〇立二卜 曰二曲 钊 2, 3 and 5). The coating conditions were the same as in Example 4 except that a coating agent containing titanium oxide (1% by weight) was used. [Table 4]

Hydroxypropyl fiber ft f Crystalline cellulose stearin 7.8% 7.0% Covering amount of coated proportion of copolymer (°/〇) 7#^ξ^ 4.6mg 6.9mg 9.2mg 8.0mg 12.0mg 16.0mg 5.0mg 7.5mg lO .Omg 4.0mg 6.0mg 8,0mg 160.0mg 240.Qmg 320,0mg 18.0mg 18.0mg 22.5mg 2.5 mg Trace micro: amount 2Q.0mg 20.Qmg 25.0mg 18Q.0mg 260,Qmg 345.Omg J2J% sJ% The stability of ITT% 7.5% and the top-loading _ s intended coating formulation (Formulation 2) was compared with the uncovered bare ingot. The evaluation method is as follows. The ingot and the bare ingot were each taken in an ingot, and stored for 1 month under conditions of 2 rc, 6 〇% relative humidity, no packaging, and shading. After 0.5 months and one month later, the residue of the compound (melon) as a main drug and the amount of the rim-like substance were measured by liquid chromatography. Further, the coating agent and the bare ingot were used in the same manner as the macrolide lactone-based antibiotic (compound ()). No. in Fig. 6 is the total amount of the edge material in the coating agent and the bare ingot. 57 319213 200800233 . The change in the ratio (%) of the main drug. In Fig. 6, the sputum mark indicates a bare ingot and a printed ingot which is coated with a polyvinyl alcohol copolymer in which titanium dioxide is formulated. It can be ascertained from Fig. 6 that the coated preparation of the present invention has almost no change in the quality of the rim-like substance after one month, and the main drug in the uncovered uncovered defect is rapidly decomposed, and in 1 After a month, the mass of the rim is about 4%. Thus, the stability of the coated preparation of the present invention can be indicated. Example 4 Discussion of the influence of the polyvinyl alcohol copolymer coating agent on the stability of the main drug _ According to the manufacturing flow chart shown in Fig. 7, a coating preparation (formulation 4) having the composition shown in Table 5 was obtained. [Table 5] Formulation 4 Intragranular compound (DI) (Form 1 crystal) 100. Omg D-mannitol 3 8.4 mg Hydroxypropyl cellulose 4.6 mg Extracellular carboxymethyl starch sodium 15. Omg Magnesium stearate 4. Omg bare ingots 162.0 mg coating agent polyvinyl alcohol 15.5 mg talc micro coating amount 15.5 mg total 177.5 mg coating ratio (%) (for bare bonds) 9.6% The above obtained macrolide-based coating preparation (formulation 4) The stability is compared to uncovered bare ingots. The evaluation method is as follows. 58 319213 200800233 • One tablet of each of the coating agent and the bare ingot is stored for 3 months under the conditions of 25〇c, 60% relative humidity, no packaging, and shading. After 5 months, 1 month, 2 months, and 3 months later, the amount of the compound (m) remaining as a main drug and the amount of the rim-like substance were measured by liquid chromatography. Further, the coating agent and the bare ingot are used in the same manner as the macrocyclic vinegar-based antibiotic (compound (ΠΓ)). Port 1 shows the change in the ratio (%) of the total amount of the edge-like substance in the coating agent and the bare ingot to the main drug. In Fig. 8, the stencil indicates that the bare ingot and the stencil indicate that the coated ingot is coated with the polyvinyl alcohol copolymer. In the coated preparation of the present invention after 3 months from the eighth figure, the rim-like substance was hardly formed and stabilized. Since it is directly stored in the state of bare ingots, it is rapidly generated to produce a rim-like substance, and after storage for 3 months, the ratio (%) of the total primordial substance to the main drug is about 9%. (w/w). [Industrial Applicability] In the present invention, a coated preparation of a macrocyclic vinegar-based antibiotic coated with a polyethylene material or a copolymer thereof can be used for the itch/therapy of a human mammal. In the fish, the pain in the pupa is caused by a wide range of dry infections caused by bacteria, scorpion scorpion Ji Pusun, and from the sputum. [Simple description of the drawing] The manufacturing flow chart shown by the brother 1 is shown. The coated preparation of the vinegar-based antibiotic of the macrocyclic ring of the shellfish & Example 1 was coated and stored for one month. Fig. 2 shows the liquid chromatogram of the agent of Example 1. The macrolide antibiotic is shown in Fig. 3 for the total amount of rim-like material under the conditions of 319213 59 200800233 C, 60 / 〇 relative humidity of the first embodiment, τ Α Α of the helmet The ratio of the main music (w/w〇//.) in the coated preparations after 2 months, 2 months, and 2 months, 2 months, and 3 months later, was set. Figure 4 shows the ratio (W/W%) of the amount of coating of the bare ingot relative to the polyvinyl alcohol copolymer. ': It is stored in the same week as the rim-like substance at 4 〇Τ, 75% relative s The total amount of the post-medical drug (w/w%^^10) Fig. 5 is a flow chart showing the production of the coated sample of the macrocyclic-based antibiotic of Example 2. Let FIG. 6 show the use of the macrolide of Example 2. The antibiotics were evaluated by the female sex of only u. In the figure, the sputum marks the bare ingot and the punch indicates the tablet made of the polyvinyl alcohol copolymer formulated with titanium oxide. It is expressed at 25 C, 60. ° / Relative humidity, no packaging conditions, the total amount (w/w%) of the main drug in the coating agent relative to the coating agent after 5 months and 1 month. The figure shows the manufacturing flowchart of the coating preparation of the macrolide-type antibiotic of Example 3. The figure 8 shows the evaluation result of the stability of the coating of the macrolide-type antibiotic by the Example 3. The mark indicates that the bare ingot and the sputum mark indicate the coated ingot which is broken with polyvinyl alcohol, and the vertical axis indicates that under the condition of 25 〇, 6〇% relative humidity, and no packaging, The total amount of the main drug (w/w〇/0) of the rim-like substance relative to the coating agent after 0.5 months, 1 month, 2 months, and 3 months later. 60 319213

Claims (2)

200800233 _ X. Patent application scope: 1. A coated preparation of macrolide antibiotics, characterized by comprising a macrolide antibiotic of the group represented by the following structural formula (I), which is pharmaceutically Permissible salts or their hydrates: r < R2a H3C, human (wherein R2a represents a hydrogen atom or a protecting group of a hydroxyl group), and is coated with a coating agent containing a polyvinyl alcohol or a polyvinyl alcohol copolymer. 2. The coating agent for a macrolide antibiotic according to the first aspect of the patent application, wherein the macrolide antibiotic comprises a macrolide lactone having a base represented by the following structural formula (1) Antibiotics, their pharmaceutically acceptable salts or their hydrates: R23' h3c, .CH, , N human ν α) (wherein R 2a represents a hydrogen atom or a protecting group for a hydroxyl group) 61 319213 200800233 ^ 3:. H ^ g ^ ^ I ^ ^ £ € ^ S| ^ ^ ± ^ ^ ^ ^ ^ ^ 八中 'The macrolide lactone antibiotic sun 14 to 16 members of the ring system macrolide antibiotics. 4. The macrocyclic ring of the third aspect of the patent application (4) is a coated preparation of antibiotics, wherein 'the macrocyclic antibiotics in the macrocyclic ring are compounds represented by the general formula (II), their permissible salts or their Hydrate: In the formula, A represents a group selected from the following: a) -OH, b) C^R (wherein 'rp represents a protecting group of a thiol group), '(3) a heteroaryl C>R (wherein , Rl 傣 denotes (1) aryl, (7) substituted aryl or substituted heteroaryl), phantom 〇 ^ 1 (m has the meaning of pre-production), ' R2 represents (1) hydrogen atom, (2) _ a gas atom, (3) any s famous atom, a sulfur atom, and a ruthenium in a nitrogen atom to three hetero atoms, which may be M2 or more in the group consisting of a self-priming, an aryl group, a substituted aryl group, and a heteroaryl group. Substituent substituted Ci_Ci2t square 319213 62 200800233 0) Any & containing 选自 to 3 _ atoms selected from oxygen, sulfur and nitrogen atoms may be selected from halogen, aryl, substituted aryl, heteroaryl a base group, or (5) optionally containing from an oxygen atom, a sulfur atom and a gas t2, to 3 hetero atoms, which may be selected from a halogen, an aryl group, a heteroaryl group or a substituted heteroaryl group. a C2-C12 alkynyl group substituted by one or more substituents, f> 〇R (wherein ana 2 has the same g, _S(〇)nRn (wherein n A ] X. "I" and R have the same as before The sound of the sample is), Ο·(9)NHRU (in the formula, R11-like j)-NHS(0)2Rii (in the formula, „present, 铋μ我) In the heart of the formula, R4 is the same, meaning the same meaning ), and R y 刀 independently of the table *Rn 'Rn has the same meaning as described above), and 1) capture R3 - (wherein R3 represents an amine protecting group) 丨 B system means: a) wind atom , b) heavy hydrogen, c) halogen atom, d) -OH - R2 (wherein R1 has the same meaning as described above), f > R2 (in the formula, disgusting 2 "g") g) - 〇Rp (form Medium, = two: sample _ /, some people say the same meaning); 319213 63 200800233 But 疋, when B is halogen, -〇H or ·〇κρ, a means or _r2 or A and B are combined The carbon atoms together represent a) C- 0 b) C(OR2)2 (R2 has the same meaning as described above), c) C(SR2)2 (R2 has the same meaning as described above), d) C[»0 -(CH2)m]2 (m is 2 or 3), e) C[_S-(CH2)m]2 (m has the same meaning as described above), · fyC^CHR11^1! has the same meaning as described above), Gf OR (R has the same meaning as described above), or h) C = NO-Ar^-M-Ar2 [eight, -ArL means R31, R31 alone The ground indicates a) the divalent group formed by the hydrogen atom in the 攸R (r1 has the meaning of the above), b) optionally contains the Q to the hetero atom selected from the oxygen atom, the sulfur atom, and the nitrogen atom. An ei_Cl 2 alkyl group substituted with one or more substituents selected from a halogen, an aryl group, a substituted aryl group, a heteroaryl group, or a heteroaryl group, and an aryl group selected from the group consisting of (tetra) and aryl groups a substituted aryl group, a hydrazine in (4), a substituent substituted by two or more alkenyl groups, or an aero atom, a sulfur atom, and a substituent: aryl: = halogen, aryl, substituted aryl, heteroaryl or 319213 64 200800233 c2_c] 2 extended block bases in the base; l to 3, -N 2 N- and -C (0 in 〇K) Up to 3 are bonded or a) arbitrarily containing a selected one selected from the group consisting of an oxygen atom, a hetero atom, and a Ci-Ci2 exo group selected from the group - an atom and transported from -C==N-, ;? rvm Cb aa λ C) optionally containing 0 to 3 ^ heteroatoms selected from the group consisting of a sulfur atom of a sulfonium 7 atom and a nitrogen atom, and a G wire selected from the group consisting of -〇N_, _n=n Y n main 3, and G in the like (9). 3(d) d) substituting an extended aryl group, e) a substituted heteroaryl group or f) a substituted heterocyclic alkyl group; 3)-Ar2 represents a) aryl, b) substituted aryl, c) heteroaryl, or d) substituted heteroaryl]; OCsNHHR'R11 has the same meaning as described above), j) C = NNHC (0) Rn (Rn has the meaning of the above ^, blowing = 丽 HC (0) NHRn (Rn has the same meaning as described above) C = NNHS (0) 2R11 (R11 has the same meaning as described above), m) C = NNHR3 (R3 has the same meaning as described above), 319213 65 200800233 Ρ · CHRll (Rl1 has the same meaning as described above); X and Y's one-seven main & t squares are not gas atoms, the other is a) hydrogen Atom, b) heavy hydrogen, c) -OH vd) -ORp (Rp has the same meaning as described above, e-W is independently represented) (1) hydrogen atom, tetra-, aryl, substituted aryl, heteroaryl a group substituted with one or more substituents of a substituted or substituted heteroaryl group, or 1 12^ ΜΕ ^ R 1 together with a nitrogen atom to be bonded, represents a quinone in a human ancient oxygen atom, a sulfur atom, and a nitrogen atom. to? The factory has selected '嗲 atoms to _ (four) rings; or MY series and junctions ^ Q • Atomic representation a) C = 0 or b) C = NQ (where Ω is expressed as (1) R (R has the same as above (2) Amine protecting group, (3) c(〇)R (R 1 has the same meaning as described above), (4) -OR6 (R6 independently represents 319213 66 200800233 - (a) hydrogen atom , (b) -CH2〇(CH2)2〇CH3 v (c) -CH2〇(CH2〇)nC^ ϋ W iC ^ m ^ t AO (d) can be a square group, a substituted aryl group, a heteroaryl group Ci_Ci2 alkyl substituted with 1 or more substituents in the substituted and substituted heteroaryl groups, (e) C3-C12 cycloalkyl, .alkyl, - . . . . {(〇)-(:3_(:12-cycloalkyl, 10 (hK:(0)-R1 (R1 has the same meaning as described above) or Rb and Re each independently represents a Cr-Cu alkyl group, an aryl group Or substituted aryl); or (5)0 C(R )(R )·〇#叱 has the same meaning as described above; however, R is not a c(0)-crCl2 alkyl group, c(〇)-c3- C12 cycloalkyl or =(〇)-R 'R and R8 together with a bonded carbon atom form a _C3_C^ cycloalkyl group, or a (1) hydrogen atom or (2) a Ci_Ci2 alkyl group) ; blood L system indicates a) -CH3 b) -CH2CH3, c) -CH(0H)CH3 > d) may be one or two of the aryl, substituted aryl, heteroaryl or substituted heteroaryl groups C _C6 alkyl, e) substituted by more than one substituent may be a C 2 -C 6 olefin substituted with one or more substituents selected from an aryl group, a substituted aryl group, a heteroaryl group or a substituted heteroaryl group a group, or f) may be a C2_C6 block group substituted with 1 319213 67 200800233 • or 2 or more substituents; the Z series represents a a hydrogen atom, b) a fluorenyl group, or c) a halogen atom; R2a represents a hydrogen atom or a protecting group of a hydroxyl group}. 5. If the application of the macrolide lactone antibiotics in the fourth paragraph of the patent application is completed, 1] 'the '5 hai giant sulphate antibiotics are the following or their pharmaceutical contents • Xu Zhiyan or their Hydrate (1) (1R, 2R53R56R, 8R, 9R510R516S, 18R) represented by the following formula (III) - 忖-[9-(354,6-trideoxy-3-didecylamino--- 0-mu-hexa-n-glycosyloxy)-3-ethyl-2-keto-25658510,16518-hexamethylene- 5,7-two prison base-13-[(Ε)·[6-( ° ϋ - - base) 吼. Alkyl iodide] _4,1U5_trioxabicyclo[8,5,4]a ninth -17 meryl acetamide 68 319213 200800233 . (2) Telithromycin represented by the following formula (W) (3) GW773546 represented by the following formula (V) 0 (V) (4) TEA-0777 69 319213 200800233 represented by the following formula (VI) (5) CP-544372 represented by the following formula (W) (6) JNJ-17069546 70 319213 200800233 represented by the following formula (Μ) • (7) erythromycin represented by the following formula (Κ) (8) (1115211, 3 feet, 6 feet 58 feet, 9 feet, 10 feet, 168518 feet) -] ^ [9 垂 (3,4,6·three deoxy- 3-^- fluorenyl---/ 3 _D-木-己旅 南南糖-oxy)-3-ethyl-2-hydroxy 2,6,8,10,16,18-hexamethylene-5,7-dione-13-[made )-[6-(2-Amino 11 to 17-hex-6-yl)pyridin-3-yl]nonyloxyimino]-4,11,1 5 -dioxabicyclo[8,554] 19-19-17-yl]acetamide. 6. The coated preparation of the macrolide antibiotic according to the fifth aspect of the patent application, wherein the macrolide antibiotic is 71 319213 200800233 of the following formula (Π): (1 ft, 2 ft, 3 reverse, 6! 1, 8 feet, 9 艮 1 〇艮 16 hearts 18 and) - redundant _ [9-(3,4,6-trideoxy-3-dimethylamino--?-D- P-hexylpyranosyloxy)-3-ethyl-2-hydroxy-2,658,10,16,18-hexamethylene-5,7-mono-yl-13-[(Ε)-[6- (σΛ 嗤-1-yl)pyridin-3-yl]methoxyimino]-4, indole, 15-trioxabicyclo[8,5,4]yen-17_17Ε'-yl]ethylamine Pharmaceutically acceptable salts or hydrates thereof 7. The coated preparation of the macrolide antibiotic according to claim 1, wherein the macrolide antibiotic has a selected from the group consisting of 26»= 14.3, Η·5, 15.1 in the powder X-ray diffraction pattern. At least one of 18, 8, 20, 5, 2, 2, 24, 9, 25, 6, 29, 0, 34.1, 37.7, 3 8.1, 38··9, and 40·4 (unit: degree) The peak is (1R, 2R53R, 6R, 8R, 9R, 10R, 16S5 18R)_N-[9_(354,6_trideoxy-3·didecylamino-D-wood-hexamethylene glycol)氧基oxy)_3_ethyl_2_hydroxy-2,6,8,10,16,18-hexamethylene-5,7--fluorenyl-13-[(E)-[6-(. Specific 嗤-1 -yl) corpse ratio _3-yl] oxime imine 72 319213 200800233 base] 4,11·,15-trioxabicyclo[8,5,4]Asian-19-17E- Type 1 crystal of acetaminophen. 8. A coated preparation of a macrolide antibiotic according to the seventh aspect of the patent application, wherein the type 1 is an anhydrate crystal. 9. A coated preparation of a macrolide-based antibiotic according to the first aspect of the patent application, wherein the coated preparation is a solid preparation. I〇·^ Patent Application No. 9 and the coating of vinegar-based antibiotics in the ring 4' wherein the solid preparation is a tablet or granule. 1 · The coating of the macrolide antibiotic of the first item of the scope of the patent application range of the above-mentioned patents, wherein the coating agent contains an average degree of polymerization of 1,300 or less, and at least one polymerizable ethylenic monomer. A polyvinyl alcohol copolymer obtained by copolymerizing a body at a weight ratio of 6 ♦ 4 to 9 · 1. = Declaring the coating of the macrolide antibiotic of the eleventh item of the patent dry circumference q ', medium' The average degree of polymerization of the polyvinyl alcohol is 900 or less. 1 Declaring the coating agent of the macrolide antibiotic of the 12th article of the patent circumference, wherein the average degree of polymerization of the xylo-xanol-alcohol is 200-000. Μ·If you apply for a patent court, Hungarian ^^4, the 11th mate of the macrolide lactone antibiotic coating 15: From this, the polyvinyl alcohol is part of the I-polyvinyl alcohol. Agent, 』 利 耗 围 围 围 11 11 11 11 11 11 11 11 11 11 11 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该 该Aromatic B is a large group of aromatic hydrocarbons, and a mixture of heterocyclics and their salts. 16 Coating 319213 73 200800233 & In one or more polymerizable ethylenic monomers, at least one of ^ ^ It ii il ^ ^ M , , ^ ^ ^ ^ ^ ^ ^ ^ ^ g | II ° 17.^ In tlf /, the unsaturated tannic acid or a salt thereof is selected from the group consisting of acrylic acid, methacrylic acid, crotonic acid, fumaric acid, maleic acid, itaconic acid and the like thereof. The ester of unsaturated decanoic acid is selected from the group consisting of methyl methyl methacrylate, methyl acrylate, ethyl methacrylate, ethyl acrylate, /butyl methacrylate, butyl acrylate, methacrylic acid Butyl ester, acrylonitrile, chlorhexidine methacrylate, cyclohexyl acrylate, 2-ethylhexyl methacrylate, propylene 2_ethylhexyl vinegar, methacrylic acid=ethyl ester, hydroxyethyl acrylate, ester of polyethylene glycol and methacrylic acid, polyethylene glycol and acrylic acid, and glycerin group of polypropylene glycol and acrylic acid The invention relates to the coating of the macrolide antibiotic of claim 15 in the patent scope, wherein the unsaturated carboxylic acid or a salt thereof and the ester neck of the unsaturated carboxylic acid are compounds represented by the general formula (X) or Its salt H2c= CCR^-COO^ (x ) (wherein R R represents a hydrogen atom or a methyl group, r 2 represents a hydrogen atom and an alkyl group of 4 carbon atoms). ^ 19 ·= Patent Application No. A coating preparation of the macrolide antibiotic of the group 6 or more, wherein the unsaturated carboxylic acid or a salt thereof is acrylic acid or a salt thereof, and the ester of the carboxylic acid is methyl methacrylate. 319213 74 200800233 The ratio is 3 ·· 7 to 〇 · 5 : 9 · 5. 2·=Declaration of the weight of the saponified polyvinyl alcohol, methyl methacrylate and acrylic acid in the coating of the macrolide lactone in the 21st patent of the patent Ratio, from 60 to 90: 7 to 38: 〇·5 to 12. The coated preparation of the macrolide-based antibiotic of the first aspect of the invention, wherein the content of the coating agent is 2% by weight or more based on the bare or bare particles. 24. The coating of the macrolide antibiotic of the first application of the patent scope is called "sword", wherein the coated preparation of the macrolide antibiotic is 25. Under the condition of 60% relative humidity, the total amount of the rim-like substance after 3 months of storage is 3% or less. 25. The coated preparation of the macrolide antibiotic according to the first aspect of the patent application, wherein the macrolide antibiotic is (1r, 2R, 3R, 6R, 8R59R, 10R, 16S, 18R)-N- [9-(3,456-trideoxy-3-didecylamino-D-wood-hexylpyranosyloxy)·3-ethyl-2-hydroxy-2,6,8510,16,18- Six 75 319213 200800233 , methyl-557-dione based _13-[(E)-[6 ten ratio. Sitting -1- base).唆-3-yl]methoxyimino group; H., ll, 15-triazabicyclo[8,5,4]yenthylene vl7E-yl]acetamide type 1 crystal, coating agent Polyethylene with or without titanium dioxide. Alcohol or polyvinyl alcohol copolymer, after storage at 25 ° C, 60% relative humidity for 3 months, the total amount of the rim of the genus is less than 1.5%. 26. The coated preparation of the macrolide lactone antibiotic according to the first item of claim 1, wherein the macrolide antibiotic is (1R, 2R, 3R, 6R, 8R, 9R, I0R516S518R)-N-[9 -(354,6-trideoxy-teledecylamino-n 10 wood-hexa-glucosyloxy)-3 -ethyl-2-yl 2,6,8,1 〇, 16 , 18-hexamethylene _5,7·dione 13-[(E)-[6 ϋ ϋ 小 ) ) ) , , , , , , , , , , , , , , , , Η Η Η Η Η Η Η , , , , The total amount of the rim-like substance after 3 months of storage of the type 1 crystal of trioxacyclo[8,5,4]yen-17_17Ε-yl]acetamide at 25t: and relative humidity of 60% For the following. 27. A coating of a macrolide antibiotic according to claim 26 of the patent application, which is packaged in a blister pack (PTP; press thr〇ugh package) or bottled. A method for inhibiting the formation of a primordial substance of the macrolide antibiotic, which is characterized in that a macrolide antibiotic having a base represented by the following structural formula is used, a pharmaceutically acceptable salt thereof or Their hydrates or solids containing them, coated with polyvinyl alcohol or polyvinyl alcohol copolymer 319213 76 200800233 R2aH3C\ CH3 (wherein, the ruler 2& represents a protective group of a hydrogen atom or a hydroxyl group). : 29. A method for stabilizing a macrocyclic antibiotic, a pharmaceutically acceptable salt thereof, or a hydrate of 10 of the macrocyclic ring, characterized in that the macrocyclic ring having the base represented by the following moiety and the structural formula is: A lactone-based antibiotic, a pharmaceutically acceptable salt thereof or a hydrate of a scorpion or a solid containing a zither, coated with a coating agent containing a polyvinyl alcohol or a polyvinyl alcohol copolymer R2aH3C\ /H3 (wherein R2a• represents a protecting group of a halogen atom or a hydroxyl group). 77 319213