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Hydrates of Erythromycin Salts, the Preparation And (19) TZZ ¥Z__T (11) EP 2 301 945 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07H 17/08 (2006.01) A61K 31/7048 (2006.01) 15.10.2014 Bulletin 2014/42 A61P 31/00 (2006.01) (21) Application number: 09793794.0 (86) International application number: PCT/CN2009/000787 (22) Date of filing: 10.07.2009 (87) International publication number: WO 2010/003319 (14.01.2010 Gazette 2010/02) (54) HYDRATES OF ERYTHROMYCIN SALTS, THE PREPARATION AND THE USE THEREOF HYDRATE AUS ERYTHROMYCINSALZEN SOWIE IHRE HERSTELLUNG UND VERWENDUNG HYDRATES DE SELS D’ÉRYTHROMYCINE, LA PRÉPARATION ET L’UTILISATION DE CEUX-CI (84) Designated Contracting States: • DATABASE REGISTRY [Online] CHEMICAL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR ABSTRACTS SERVICE, COLUMBUS, OHIO, US; HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL 16 November 1984 (1984-11-16), XP002662315, PT RO SE SI SK SM TR retrieved from stn accession no. 14444-93-0 Database accession no. 14444-93-0 (30) Priority: 10.07.2008 CN 200810048383 • DATABASE REGISTRY [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; (43) Date of publication of application: 16 November 1984 (1984-11-16), XP002662316, 30.03.2011 Bulletin 2011/13 retrieved from stn accession no. 14550-96-0 Database accession no. 14550-96-0 (73) Proprietor: Liu, Li • DATABASE REGISTRY [Online] CHEMICAL Guangdong 528500 (CN) ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 16 November 1984 (1984-11-16), XP002662317, (72) Inventor: Liu, Li retrieved from stn accession no. 14638-05-2 Guangdong 528500 (CN) Database accession no. 14638-05-2 • DATABASE REGISTRY [Online] CHEMICAL (74) Representative: Held, Stephan et al ABSTRACTS SERVICE, COLUMBUS, OHIO, US; Meissner, Bolte & Partner GbR 16 November 1984 (1984-11-16), XP002662318, Widenmayerstraße 47 retrieved from stn accession no. 65945-12-2 80538 München (DE) Database accession no. 65945-12-2 • DATABASE REGISTRY [Online] CHEMICAL (56) References cited: ABSTRACTS SERVICE, COLUMBUS, OHIO, US; EP-A1- 1 302 205 CN-A- 1 030 422 10 September 1993 (1993-09-10), XP002662319, CN-A- 1 232 037 CN-A- 1 625 560 retrieved from stn accession no. 149908-23-6 US-A- 3 764 595 US-A- 4 340 582 Database accession no. 149908-23-6 • DATABASE REGISTRY [Online] 16 November 1984 (1984-11-16), XP002662320, retrieved from stn accession no. 65945-11-1 Database accession no. 65945-11-1 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 301 945 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 301 945 B1 • DUTTA S K ET AL: "PREPARATION OF WATER- SOLUBLE SALTS OF ERYTHROMYCIN AND STUDY OF SOME OF THEIR PROPERTIES", INDIAN DRUGS, INDIAN DRUG MANUFACTURERS’ ASSOCIATION, IN, vol. 17, no. 11, 1 August 1980 (1980-08-01), pages 354-356, XP001083744, ISSN: 0019-462X 2 EP 2 301 945 B1 Description TECHNICAL FIELD 5 [0001] The present invention relates to the technical field of medicine, and specifically to the hydrates of salts of erythromycin, a macrolide derivative, preparation and use thereof. BACKGROUND 10 [0002] Only erythromycin lactobionate [C37H67NO13·C12H22O12, CAS No.: 3847-29-8], erythromycin thiocyanate C37H67NO13·HCNS, (CAS No.: 7704-67-8) and the like, and uses thereof have been reported in the prior art, but so far there is no published references that disclose a hydrate of salts of macrolide derivative erythromycin and preparation thereof, though the structures of erythromycin salts, like erythromycin-oxalate-dihydrate (CAS No. 14444-93-0), eryth- romycin monohydroiodide-monohydrate (CAS No. 14550-96-0), erythromycin ethanedioate-dihydrate (CAS No. 15 14638-05-2), erythromycin ethanedioate-hydrate (CAS No. 65945-12-2), erythromycin with N-acetyl-L-cysteine 2 hy- droxybenzoate-dihydrate (CAS No. 149908-23-6) and erythromycin hydroiodine-hydrate (CAS No. 65945-11-1) are known from the chemical abstracts service. [0003] Salts of other macrolides, like clarithromycin, in the citrate-salt form have been reported in EP1302205 as well. Nevertheless, erythromycin is also known in some salt forms, e. g. erythromycin citrate and maleate (Dutta, s. K., Ghosh, 20 A. K., Soumya, S. D., Preparation of water-soluble salts of erythromycin and study of some of their properties, INDIAN DRUGS, p. 354 - 356, 1980) or as erythromycin aspartate (US3764595). Further, the use of the erythromycin base dihydrate in a tablet core is known from US4340582. CONTENTS OF THE INVENTION 25 [0004] In the first aspect, the present invention relates to hydrates of erythromycin salts, which are erythromycin lactobionate undecahydrate, erythromycin lactobionate hexahydrate, erythromycin lactobionate pentahydrate, erythro- mycin lactobionate hemihepta(3.5)hydrate, erythromycin lactobionate trihydrate, erythromycin thiocyanate trihydrate, erythromycin thiocyanate dihydrate and erythromycin thiocyanate hemitri(1.5)hydrate. 30 [0005] In the second aspect, the present invention relates to a pharmaceutical composition, comprising a hydrate of erythromycin salts according to the present invention and at least one pharmaceutically acceptable excipient. [0006] In the third aspect, the present invention relates to a process for preparing a hydrate of erythromycin salts according to the present invention. [0007] In the fourth aspect, the present invention relates to use of a hydrate of erythromycin salts according to the 35 present invention in the manufacturing of a medicament for the treatment of an infection in a human or an animal caused by bacteria, mycoplasma or chlamydia which is sensitive to erythromycin, wherein the infection is selected from the group consisting of infections of nasopharynx (tonsillitis, pharyngitis, sinusitis, infections of the lower respiratory duct (acute bronchitis, acute onset of chronic bronchitis and pneumonia), infections of skin and soft tissues (impetigo, ery- sipelas, folliculitis, furuncle and wound infections), acute otitis, mycoplasmal pneumonia, urethritis and cervicitis caused 40 by chlamydia trachomatis and E. legionella infections, mycobacterium avium infections and helicobacter pylori infections. [0008] In one embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin lactobionate undecahydrate. [0009] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin lactobionate hexahydrate. 45 [0010] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin lactobionate pentahydrate. [0011] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin lactobionate hemihepta(3.5)hydrate. [0012] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, 50 which is erythromycin lactobionate trihydrate. [0013] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin thiocyanate trihydrate. [0014] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin thiocyanate dihydrate. 55 [0015] In another embodiment according to the first aspect, the invention provides a hydrate of erythromycin salts, which is erythromycin thiocyanate hemitri(1.5)hydrate. [0016] The hydrates of erythromycin salts according to the present invention can be in different crystal forms, but in any cases, characteristically, when the hydrates of the present invention are dihydrated at an elevated temperature, 3 EP 2 301 945 B1 their thermograms (TG-DTA/DSC) show apparent endothermic peaks, and their hygroscopicity is generally lower than that of the anhydrous. Some of the hydrates can be stably stored and have advantages of convenient for preparation or production of a solid formulation and aseptic filling of a formulation. [0017] The results of water content as measured by Karl Fischer’s method are consistent with those by the thermo- 5 gravimetry. The thermogravimetric results demonstrate the following hydrates: crystalline 3-, 4-, 5-, 6-, undecahydrate of erythromycin lactobionate (C 38H69NO13·C12H22O123H2O, C38H69NO13·C12H22O12·4H2O (not according to the inven- tion), C38H69NO13·C12H22O12·5H2O, C38H69NO13·C12H22O12·6H2O, C38H69NO13·C12H22O12·11H2O) as well as crys- talline hydrates of erythromycin thiocyanate (1.5-, 2-, 2.5- (not according to the invention), 3-hydrate), and erythromycin phosphate hydrate including (C38H69NO13·H3PO4·2.5H2O (not according to the invention). 10 [0018] In one embodiment according to the second aspect, the invention provides a pharmaceutical composition, comprising a hydrate of erythromycin salts according to the present invention, and at least one pharmaceutically ac- ceptable excipient. [0019] The pharmaceutical composition or medicament comprising a hydrate of erythromycin salts according to the present invention may be formulated to form a lyophilized powder injection, sterilized-filled powder injection, a small 15 volume injection, a dosage form for enteral administration, an ointment and gel for percutaneous administration,
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