(19) T ZZ ¥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
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• 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
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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,
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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, or a suppository for intravaginal or rectal administration. [0020] In one embodiment according to the third aspect, the invention provides a process for preparing a hydrate of erythromycin salts according to the present invention, comprising:
20 Method A: in a reaction container, using one of chloroform, C 3-C6 ketone, C2-C6 ester, water and C1-C5 alcohol or a mixture thereof as solvent, adding erythromycin, stirring, adding lactobionic acid or thiocyanic acid, then adding one or more of C3-C6 ketone, chloroform, C1-C5 alcohol, C2-C6 ether, C2-C6 ester and benzene after complete reaction, cooling, filtering, washing the resultant solid with one or more organic solvents of C1-C5 alcohol, C3-C6 ketone, C2-C6 ether and chloroform, filtering under a reduced pressure, and drying to obtain the hydrate of eryth- 25 romycin lactobionate or thiocyanate salts; or
Method B: adding a lactobionic acid or thiocyanic acid solution in a desired molar ratio into a reaction container containing erythromycin and one or more of water, 1C-C5 alcohol and C3-C6 ketone as the solvent(s), stirring, reacting at a temperature between -10°C and 30°C for 0.5-24h, decoloring with activated carbon or filtering with an 30 ultrafilter membrane after complete reaction, cooling to a temperature between -70°C and -30°C, and drying under vacuum to obtain the hydrates of erythromycin lactobionate or thiocyanate salt; or
Method C: adding a lactobionic acid or thiocyanic acid or a solution thereof in a desired molar ratio into a reaction container containing erythromycin and water, stirring, reacting at a temperature between -5°C and 20°C for 0.5-24h, 35 decoloring with activated carbon or filtering with an ultrafilter membrane after complete reaction, and spray drying to obtain the hydrate of erythromycin lactobionate or thiocyanate salt.
[0021] In one embodiment according to the fourth aspect, the invention provides use of a hydrate of erythromycin salts according to the present invention in the manufacture of a medicament, wherein the medicament is useful in the treatment 40 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, erysipelas, folliculitis, furuncle and wound infections), acute otitis, mycoplasmal pneu- monia, urethritis and cervicitis caused by chlamydia trachomatis and E. legionella infections, mycobacterium avium 45 infections and helicobacter pylori infections. [0022] In one embodiment according to the fourth aspect, the invention provides use of a hydrate of erythromycin salt according to the present invention for the preparation or purification of erythromycin, for the preparation of erythromycin oxime and further for the synthesis of intermediates of roxithromycin, clarithromycin, azithromycin, dirithromycin, bridged erythromycin, cethromycin and other macrolides, and medicaments thereof. 50 [0023] The inventors of the present invention have found by studying that the hydrates of erythromycin salts according to the present invention have surprising technical effects. Specifically, the hydrates of erythromycin salts according to the present invention have hygroscopicity (moisture absorption) generally lower than that of the corresponding anhydrous and usually are stable. For example, unlike erythromycin that is sparingly soluble in water and erythromycin lactobionate anhydrous that is more hygroscopic, erythromycin lactobionate having crystal water and the like is soluble in water, has 55 a good stability during storage at room temperature, convenient for preparing a freely soluble and absorptive formulation, and convenient for storage and transportation. In addition, the anhydrous can be moisturized so that it must be treated under the isolation of air to avoid adhering, while the hydrates have a good flow property which improves the processing of formulation and facilitates preparation of a pharmaceutical formulation.
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[0024] The hydrates of erythromycin salts according to the present invention can be stably stored. A sample of the above hydrates was sealed in a vial, and an accelerated stability test was conducted at 30°C and changes of the content and related substances were measured by a HPLC method (C18 reverse phase column, 0.01M KH2PO4-acetonitrile (60:40) as the mobile phase, detective wavelength: 215nm, column temperature: 35°C, flow rate: 1.0ml/min) (upon 5 different hydrates of erythromycin salts, such as crystalline hydrates of erythromycin thiocyanate, the pH of the mobile
phase can be adjusted and KH2PO4 can be changed into NaH2PO4, the detective wavelength can be changed into 210nm, and the column temperature can be set at 35-55°C, such as 50°C for analysis and measurement). Surprisingly, the content and the related substances of the hydrates of organic acid salts of erythromycin according to the present invention show no significant change. According to China Pharmacopeia CP2005, a 5g sample of the hydrate of eryth- 10 romycin salts was tested in a hygroscopic test at 25°C and a relative humidity of 75%, and it was surprisingly found that the hydrates of the erythromycin salts of the present invention had a relatively small proportion of weight gain caused by moisture absorption. As compared to the anhydrous of erythromycin salt, the hydrates of erythromycin salts according to the present invention have a lower hygroscopicity, i.e., has a better stability of hygroscopicity, which facilitates the package and storage thereof, or is a more advantageously stable form for storage relative to the anhydrous. The results 15 are shown in the following tables.
Table 1: Results of the accelerated stability test for erythromycin lactobionate hexahydrate Sampling time (Month) Form Assay (%)
20 0 off-white powder 99.7 1 off-white powder 99.6 2 off-white powder 100.2 3 off-white powder 99.8 6 off-white powder 99.6 25
Table 2: Results of the accelerated stability test for erythromycin lactobionate pentahydrate Sampling time (Month) Form Assay (%) 30 0 off-white powder 99.9 1 off-white powder 100.2 2 off-white powder 99.8 3 off-white powder 100.1 35 6 off-white powder 99.9
Table 3: Results of the accelerated stability test for erythromycin lactobionate trihydrate
40 Sampling time (Month) Form Assay (%) 0 off-white powder 99.9 1 off-white powder 100.2 2 off-white powder 99.8 3 off-white powder 100.1 45 6 off-white powder 99.9
Table 4: Results of the accelerated stability test for erythromycin thiocyanate trihydrate 50 Sampling time (Month) Form Assay (%) 0 off-white powder 99.8 1 off-white powder 99.9 2 off-white powder 100.6 55 3 off-white powder 100.3 6 off-white powder 100.1
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Table 5: Results of the accelerated stability test for erythromycin thiocyanate dihydrate Sampling time (Month) Form Assay (%)
5 0 off-white powder 99.9 1 off-white powder 99.9 2 off-white powder 100.4 3 off-white powder 100.2 6 off-white powder 99.8 10
Table 6: Results of the accelerated stability test for erythromycin thiocyanate hemitri(1.5)hydrate Sampling time (Month) Form Assay (%) 15 0 off-white powder 99.9 1 off-white powder 100.3 2 off-white powder 100.5 3 off-white powder 100.1 20 6 off-white powder 100.2
Table 7: Results of the hygroscopic test for the lactobionic acid salts of erythromycin (RH 75%, 25°C)
25 Sampling time (48h) Hygroscopic weight gain %, relative to 0h Erythromycin lactobionate undecahydrate 0.04% Erythromycin lactobionate hexahydrate 7.31% Erythromycin lactobionate pentahydrate 8.93% Erythromycin lactobionate tetrahydrate 10.12% 30 Erythromycin lactobionate trihydrate 12.07% Erythromycin lactobionate anhydrous 17.86%
35 Table 8: Results of the hygroscopic test of the thiocyanic acid salts of erythromycin (RH 75%, 25°C) Sampling time (48h) Hygroscopic weight gain %, relative to 0h Erythromycin thiocyanate trihydrate 0.02% Erythromycin thiocyanate dihydrate 2.03% 40 Erythromycin thiocyanate hemitri(1.5)hydrate 3.12% Erythromycin thiocyanate anhydrous 6.75%
[0025] The hydrates of erythromycin salts are dissolved in water or ethanol aqueous solution, then NaHCO 3 or Na 2CO3 45 or ammonia or other basic solution is added, the obtained precipitate is filtered, washed with water, and recrystallized with one or more of water or methanol, ethanol or acetone. The resultant crystal is consistent with erythromycin in terms of specific rotation, MS and the like data or spectra. [0026] The hydrates of erythromycin salts according to the present invention can be used for the preparation or purification of erythromycin, for the preparation of erythromycin oxime, for the further synthesis of intermediates of 50 macrolides such as roxithromycin, clarithromycin, azithromycin, dirithromycin, bridged erythromycin, cethromycin, and of medicaments thereof. [0027] The tablets, capsules, powders, pulvis, premix, soluble powder, granules for the preparation of dosage forms for enteral administration can comprise pharmaceutically acceptable a filler, such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acids; pharmaceutically acceptable 55 disintegrating agent, such as starch, modified starch, microcrystalline cellulose, sodium carboxymethyl starch, cross- linked polyvinylpyrrolidinone, low-substituted hydroxypropyl cellulose, surfactants; pharmaceutically acceptable wetting agent and adhesive, such as pregelatinized starch, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinylpyrrolidinone, alginic acid and salts thereof; pharmaceutically acceptable lubricant and flow aid, such as stearic
6 EP 2 301 945 B1
acid, magnesium stearate, polyethylene glycol 4,000-6,000, talc powder, micronized silica gel, magnesium laurylsulfate; pharmaceutically acceptable sweeteners and flavoring agents, such as aspartame, sodium cyclamate, saccharin sodium, sucrose, and edible flavor. [0028] The hydrates of the present invention are different from erythromycin that is sparingly soluble in water, so that 5 the dissolution rate of solid dosage form thereof is significantly influenced by the formulation process. The hydrates of erythromycin salts of organic acids or inorganic acids are freely soluble in water, so that the solid dosage forms thereof have good dissolubility, can be readily absorbed and enter blood circulation, have an improved bioavailability and facilitate the rapid onset of their antibacterial effects. [0029] The premix of the hydrate of erythromycin salts according to the present invention can be obtained by mixing 10 hydrate with animal-acceptable drugs or feeds (including corn feeds), feed additives (including amino acids, vitamins, flavoring essences), binding agents. The pulvis or soluble powder of the hydrate of erythromycin salts according to the present invention can be prepared by convention process and equipment with other pharmaceutically acceptable fillers, disintegrating agents, wetting agents and binding agents. [0030] The suppository and gel according to the present invention are different from erythromycin suppository or 15 ointment. Since erythromycin is sparingly soluble in water, an oil soluble excipient is usually added, which may easily cause contamination that can hardly be cleaned. However, the hydrates of erythromycin salts are more soluble in water, so that the suppository and gel thereof have a good release property, can be readily absorbed and enter into blood circulation, thereby having an improved bioavailability, facilitating the rapid onset of the antibacterial effects. Since no oil soluble excipient is needed, a contamination is normally not caused and can be readily cleaned. 20 [0031] The suppository of the hydrates of erythromycin salts: consist of a hydrate of erythromycin salts 5-50%, and suppository base 50-95%, in which the base may be ethanol, glycerol, glycerol gelatine, polyethylene glycol 200-8,000, poloxamer, semi-synthetic fatty acid esters, Carbomer (931, 934, 940, 974, AA-1, 1342, etc.), and Tween 60-80. Prep- aration method: mixing the active ingredient with the base, heating in a water bath, stirring, melting, stirring uniformly, rapidly pouring into a suppository mould coated with a lubricant until slightly overflowing the suppository mould, cooling 25 and smoothing, and removing the mould to obtain the suppository. [0032] Methods for preparing the gel of hydrates of erythromycin salts: uniformly mixing a hydrate of erythromycin salts (charging in an amount based on erythromycin) with 50-95% of bases, in which the base can be ethanol, glycerol, triethanolamine, glycerol gelatine, polyethylene glycol 200-8,000, poloxamer, polyvinylpyrrolidinone, semi-synthetic fatty acid ester, water-soluble monoglyceride, Carbomer (931, 934, 940, 974, AA-1, 1342, etc.), and Tween 60-80. The gel 30 may comprise a pharmaceutically acceptable preservative and stabilizing agent. When formulating, Carbomer can be dispersed in water, then glycerol and polyethylene glycol 200-8,000 are added, heated, stirred and mixed, a prescribed amount of a hydrate of erythromycin lactobionate is added, stirred, a pharmaceutically acceptable inorganic or organic base is added to adjust the pH to about 5.0-7.0, and then water is added to the full volume. The mixture is stirred uniformly and filled to obtain the gel. 35 [0033] Methods for preparing the lyophilized powder injection: a hydrate of organic acid salts of erythromycin (in an amount based on erythromycin) and optional pharmaceutically acceptable lyophilizing supporter or excipient are dis- solved in water for injection, a pharmaceutically acceptable acid/base is added to reach a pH of 5.0-7.5, if necessary, 0.005-0.5% (W/V) of activated carbon is added and stirred for 15-45min, filtered, and the filtrate is supplemented with water, filtrated under aseptic condition, filled in 25-250mg/bottle (based on the active ingredient), lyophilized, and plugged 40 to obtain the product. [0034] Methods for preparing a small volume injection of the hydrates of lactobionic acid or thiocyanic acid salts of erythromycin: a hydrate of lactobionicacid or thiocyanic acid salts of erythromycin is mixed with water for injection and pharmaceutically acceptable additives such as pharmaceutically acceptable pH regulating agent, pharmaceutically ac- ceptable antioxidant, inert gases, then filtered, and the filtrate is sterilized to obtain the small volume injection having a 45 pH of 5.0-7.5. [0035] The pharmaceutically acceptable pH regulating agent can be a pharmaceutically acceptable inorganic or organic acid, inorganic or organic base, as well as a general Lewis acid or base, and may be one or more selected from a group consisting of hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetic acid salts, such as sodium acetate, lactic acid and pharmaceutically acceptable lactates, pharmaceutically acceptable citrates, sodium carbonate, sodium 50 hydrogen carbonate, sodium hydroxide, potassium hydroxide, phosphates, tartaric acid and pharmaceutically acceptable salts thereof, sodium borate, boric acid, succinic acid, caproic acid, adipic acid, fumaric acid, maleic acid, trihydroxyami- omethane, diethanolamine, ethanolamine, isopropanolamine, diisopropanolamine, 2-amino-2-(hydroxymethyl) 1,3-pro- pan-1,3-diol-amine, hexane-1,2-diamine, N-methyl glucamine, diisopropylamine and salts thereof, polyhydroxy carbox- ylic acid and salts thereof, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid, glucoheptonic 55 acid, amino acids and salts of amino acids. [0036] The pharmaceutically acceptable antioxidant and stabilizer may be one or more of sulfinic acid, sulfites, hydro- sulfites, pyrosulfites, hyposulfites, thiosulfate, organosulfur compound such as thiourea, glutathione, dimercaptopropa- nol, thioglycollic acid and salts thereof, thiolactic acid and salts thereof, thiodipropionic acid and salts thereof, phenol
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compounds such as gallic acid and salts thereof, caffeic acid, caffeates, ferulic acid, ferulates, di-tert-butl-p-phenol, 2,5- dihydroxybenzoic acid, 2,5-dihydroxybenzoate, phenol and derivatives, salicylic acid and salts thereof; amino acids and salts thereof; ascorbic acid and ascorbates, isoascorbic acid and isoascorbates, nicotinamide, tartaric acid, nitrates, phosphates, pharmaceutically acceptable acetates, citrates, EDTA and EDTA salts such as disodium EDTA, tetrasodium 5 EDTA, N-di(2-hydroxyethyl)glycine. [0037] The pharmaceutically acceptable isotonic regulating agent may be one or more of glucose, fructose, xylitol, sorbitol, mannitol, invertose, maltose, dextran, sodium chloride, potassium chloride, sodium lactate. [0038] The method for removing pyrogens and bacteria can comprise: adding 0.005-3% of activated carbon to remove pyrogens, using micropore filter to remove bacteria and using an autoclaves sterilizer, as well as using ultrafilter to 10 remove bacteria and pyrogens. By ultrafiltration, the used ultrafilter can be in form of plate, roll, tube, hollow fiber or round box, preferably in form of roll and hollow fiber. After most of heat generation substances and bacteria are removed by using a filtration membrane having a relative molecular weight cut-off of 50,000-300,000, then the residual pyrogens are removed by using an ultrafilter membrane having a relative molecular weight cut-off of 4,000-60,000, preferably an ultrafilter membrane having a relative molecular weight cut-off of 6,000-30,000. 15 [0039] The hydrates of erythromycin lactate can be used for preparing erythromycin base or other organic acid salts of erythromycin or hydrates thereof in high quality; the hydrate of erythromycin thiocyanate can be used for preparing erythromycin base or erythromycin oxime or erythromycin A oxime or salts thereof. The erythromycin oxime or salts thereof can be further used for synthesizing intermediates and medicaments of macrolides such as roxithromycin, clarithromycin, azithromycin, dirithromycin, bridged erythromycin, cethromycin. For example, the hydrate of erythromycin 20 thiocyanate, hydroxyamine or hydroxyamine hydrochloride, sodium hydroxide or ammonium hydrogen carbonate or other Lewis bases or aqueous solution thereof, methanol or isopropanol are added to a reaction bottle, reaction with stirring at about 20-60°C for 6-72h, cooled down to 20°C or below, filtered, the filter cake is added to isopropanol or acetone and adjusted with ammonia or sodium carbonate or NaOH solution to reach a pH of 9.5-12, stirred, cooled to precipitate a precipitate, which is filter out to obtain erythromycin oxime. 25 [0040] The antibacterial activities of the hydrates of erythromycin salts are determined by culturing clinically obtained bacteria and measuring in accordance with pharmacological test methods (the tube double dilution method), and the results are shown in the following tables 9, 10, 11 and 12.
Table 9: Antibacterial activity of erythromycin lactobionate hexahydrate MIC (mg/L) 30 Bacteria for infection Strains MIC MIC (mg/L) MIC50 MIC90 Staphylococcus aureus 26 0.06-128 0.12 128 Staphylococcus epidermidis 21 0.12-128 16 128 Pneumococcus 18 0.03-0.5 0.06 1 35 Streptococcus viridan 23 0.03-128 0.06 0.5 Streptococcus hemolyticus 16 0.03-32 0.06 32 Neisseria gonorrhoeae 16 0.06-2 0.25 1 Bacillus influenzae 17 0.12-8 4 8 Escherichia coli 21 0.5-128 4 128 40 Bacillus fragilis 15 0.5-64 4 16 Shigella 25 0.12-128 128 128 Propionibacterium 18 0.03-16 0.06 0.12 Anaerobe 16 0.06-64 2 16 45
Table 10: Antibacterial activity of erythromycin lactobionate pentahydrate MIC (mg/L)
Bacteria for infection Strains MIC MIC (mg/L) MIC50 MIC90 50 Staphylococcus aureus 26 0.06-128 0.12 128 Staphylococcus epidermidis 21 0.12-128 16 128 Pneumococcus 18 0.03-0.5 0.06 1 Streptococcus viridan 23 0.03-128 0.06 0.5
55 Streptococcus hemolyticus 16 0.03-32 0.06 32 Neisseria gonorrhoeae 16 0.06-2 0.25 1 Bacillus influenzae 17 0.12-8 4 8
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(continued)
Bacteria for infection Strains MIC MIC (mg/L) MIC50 MIC90 Escherichia coli 21 0.5-128 4 128 5 Bacillus fragilis 15 0.5-64 4 16 Shigella 25 0.12-128 128 128 Propionibacterium 18 0.03-16 0.06 0.12
10 Table 11: Antibacterial activity of erythromycin lactobionate trihydrate MIC (mg/L)
Bacteria for infection Strains MIC MIC (mg/L) MIC50 MIC90 Staphylococcus aureus 26 0.06-128 0.12 128
15 Staphylococcus epidermidis 21 0.6-128 16 128 Pneumococcus 18 0.03-0.5 0.06 1 Streptococcus viridan 23 0.03-128 0.06 0.5 Streptococcus hemolyticus 16 0.03-32 0.06 32 Neisseria gonorrhoeae 16 0.06-2 0.25 1 20 Bacillus influenzae 17 0.12-8 4 8 Escherichia coli 21 0.5-128 4 128 Bacillus fragilis 15 0.5-64 4 16 Shigella 25 0.12-128 128 128 Propionibacterium 18 0.03-16 0.06 0.12 25
Table 12: Antibacterial activity of erythromycin thiocyanate dihydrate MIC (mg/L)
Bacteria for infection Strains MIC MIC (mg/L) MIC50 MIC90 30 Staphylococcus aureus 26 0.03-128 0.12 128 Staphylococcus epidermidis 21 0.6-128 16 128 Pneumococcus 18 0.03-0.5 0.06 1 Streptococcus viridan 23 0.03-128 0.06 0.5 35 Streptococcus hemolyticus 16 0.03-32 0.06 32 Neisseria gonorrhoeae 16 0.06-2 0.25 1 Bacillus influenzae 17 0.12-8 4 8 Escherichia coli 21 0.5-128 4 128
40 Bacillus fragilis 15 0.5-64 4 16 Shigella 25 0.12-128 128 128 Propionibacterium 18 0.03-16 0.06 0.12 Anaerobe 16 0.06-64 2 16
45 Clinical applications of the hydrates of erythromycin salts according to the present invention
[0041] The hydrates of salts of the macrolide derivative erythromycin of the present invention, as antibacterial drugs, have a broad spectrum of antibacterial activities, and are useful in medicaments 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 50 infection is selected from the group consisting of A. infections of nasopharynx: tonsillitis, pharyngitis, sinusitis; B. infect ions of lower respiratory duct: acute bronchitis, acute onset of chronic bronchitis, and pneumonia; C. infections of skin and soft tissues: impetigo, erysipelas, folliculitis, furuncle and wound infections; D. acute otitis, mycoplasmal pneumonia, urethritis and cervicitis caused by chlamydia trachomatis; and E. legionella infections, mycobacterium avium infections, helicobacter pylori infections. 55 [0042] In general, for an animal or a human with a body weight of 10-70 kg, intramuscular injection: 25-500mg (based on erythromycin); intravenous administration: mixing 25-500mg (based on erythromycin) of the injection of the present invention in 50-500ml of 0.9% NaCl solution for transfusion or 5% glucose solution, intravenous injection, 1-2 times per
9 EP 2 301 945 B1
day. [0043] Dose and usage for oral administration (based on erythromycin): for an animal or a human with a body weight of 10-70 kg, in general, 50-500 mg/day, once per 6-8h. [0044] Dose and usage for suppository (based on erythromycin): in general, 50-500 mg/day. 5 BRIEF DESCRIPTION OF THE DRAWINGS
[0045]
10 Fig.1 is a thermogram of erythromycin lactobionate undecahydrate.
Fig.2 is a thermogram of erythromycin lactobionate hexahydrate.
Fig.3 is a thermogram of erythromycin lactobionate pentahydrate. 15 Fig.4 is a thermogram of erythromycin lactobionate trihydrate.
Fig.5 is a thermogram of erythromycin thiocyanate trihydrate.
20 Fig.6 is a thermogram of erythromycin thiocyanate dihydrate.
Fig.7 is a thermogram of erythromycin thiocyanate hemitri(1.5)hydrate.
CONCRETE MODES FOR CARRYING OUR THE INVENTION 25 [0046] The following examples are provided to further illustrate the present invention, but are not intended to limit the present invention to these examples in any way.
Example 1: Preparation of erythromycin lactobionate undecahydrate 30 [0047] In a three-necked flask, 50ml of acetone and 8g erythromycin were added, stirred, lactobionic acid or an aqueous solution thereof was added, and stirred at 5-35°C. After complete reaction, anhydrous acetone was added slowly, and the mixture was cooled to about -30-5°C. After a solid was precipitated and filtered out, the solid was washed with anhydrous acetone, and filtered under a reduced pressure to obtain an off-white crystal powder, which was very freely 35 soluble in water. HPLC: the main peak of the sample shows a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 56.79% (56.88%); melting point: 95.1-116.3°C (not corrected), water content by Karl Fischer method was 15.53% (the theoretical value: 15.36%), TG: weight loss at platform before 200°C was about 15.56% (see Fig.1), MS(ESI) m/z: 1092, 734, 358. Element analysis: found: C 45.73, H 8.54, N 1.15; theoretical values: C 45.61, H 8.67, N 1.09. 40 Example 2: Preparation of erythromycin lactobionate hexahydrate
[0048] In a three-necked flask, 50ml of acetone and 10g erythromycin were added, equimolar lactobionic acid or a solution thereof in acetone-water was added at 10-40°C with stirring, and reaction was performed for 0.2-4 h. After 45 complete reaction, anhydrous acetone in 1-8 times was added slowly. The mixture was cooled to a temperature of -45°C to -10°C, filtered, the resultant solid was washed with acetone, filtered under a reduced pressure and dried at about 80°C to obtain an off-white powder, which was very freely soluble in water. HPLC: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 61.91 % (the theoretical value: 62.08%); melting point: 132.6-137.7°C (not corrected); water content (by Karl Fischer method): 9.16%, 50 TG: weight loss at platform before 200°C was about 9.09% (the theoretical value: 9.01 %) (see Fig.2), MS(ESI, FAB) m/z: 1092, 1091, 734, 733, 358, 357; Element analysis: found: C 49.11, H 8.55, N 1.21; calculated: C 49.03, H 8.48, N 1.17. The obtained sample was dissolved in water, added with a saturated Na2CO3 solution to produce a precipitate, the precipitate was filtered out, washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in terms of specific optical rotation and MS data. 55 Example 3: Preparation of erythromycin lactobionate trihydrate
[0049] Lactobionic acid and erythromycin 10g in a molar ratio (1: 1) were added into a reaction bottle, added with
10 EP 2 301 945 B1
water, stirred and dissolved while maintaining the temperature at 5-40°C. After complete reaction, 1ml of the resultant mixture was filled in each of 20ml bottles, and cooled to -50°C for 0.5-6h. The condenser temperature was cooled to -55°C, vacuumized, and then the temperature was elevated increasingly by a shelf to about -16°C. The mixture was kept for about 28h at about -16°C, and the temperature was further elevated to about 30°C and kept for about 10h to 5 obtain an off-white powder having a yield of 99%. The obtained sample was very freely soluble in water. HPLC: the main peak of the sample had a retention time in consistent with that of erythromycin control; melting point: 137.2-138.7°C (not corrected); water content by Karl Fischer method was 4.67% (the theoretical value: 4.72%), TG-DTA: weight loss before 200°C was about 4.39%, which was in the error range of the sample containing 3 crystal water (see Fig.4), MS(ESI, FAB) m/z: 1092, 1091, 734, 733, 358, 357. The obtained sample was dissolved in water, added with a sodium carbonate 10 solution to generate a precipitate, the precipitate was washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in terms of specific optical rotation and MS data. Element analysis: found: C 51.21 %, H 8.43%, N 1.17%; calculated: C 51.34%, H 8.35%, N 1.22%.
Example 4: Preparation of erythromycin lactobionate pentahydrate 15 [0050] In a three-necked flask, 50ml of anhydrous acetone and 12g erythromycin were added, dissolved, then added with equimolar lactobionic acid aqueous solution to erythromycin, and continuously stirred at 10-60°C. After complete reaction, 60-400ml of anhydrous acetone was added slowly. The mixture was cooled to a temperature between -45°C and -10°C. After filtration, the resultant solid was washed with acetone or chloroform, filtered under a reduced pressure 20 and dried under vacuum at 80°C for about 4-10h to obtain an off-white crystal powder, which was very freely soluble in water. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 61.78% (the theoretical value: 62.08%); melting point: 142.2-145.9°C (not corrected), water content by Karl Fischer method was 7.68% (the theoretical value: 7.62%), TG-DTA: weight loss before 200°C was about 7.62%, which was in the error range of the sample with 5 crystal water (see Fig.3), MS(ESI, FAB) m/z: 25 1092, 1091, 734, 733, 358, 357; Element analysis: found: C 49.66, H 8.57, N 1.12; calculated: C 49.78, H 8.44, N 1.18. The obtained sample was added to a sodium carbonate solution to generate a precipitate, the precipitate was washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in terms of specific optical rotation and MS data.
30 Example 5: Preparation of erythromycin lactobionate hemihepta(3.5)hydrate
[0051] In a three-necked flask, 12g erythromycin was added and added with acetone to make it dissolved, then added with equimolar lactobionic acid aqueous solution to erythromycin, and continuously stirred at 0-30°C. After complete reaction, 60-400ml of anhydrous acetone was added slowly. The mixture was cooled to a temperature between -45°C 35 and -10°C. After filtration, the resultant solid was washed with acetone or chloroform, filtered under a reduced pressure and dried under vacuum at 100°C for about 4h to obtain an off-white crystal powder, which was very freely soluble in water. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 63.07% (the theoretical value: 63.53%); melting point: 159.0-161.2°C (not corrected), water content measured by Karl Fischer method was 5.62% (the theoretical value: 5.46%), TG-DTA: weight 40 loss before 200°C was about 5.36%, which was in the error range of the sample with 3.5 crystal water, MS(ESI, FAB) m/z: 1092, 1091, 734, 733, 358, 357; Element analysis: found: C 50.82, H 8.52, N 1.13; calculated: C 50.94, H 8.38, N 1.21. The obtained sample was added to a sodium bicarbonate solution to generate a precipitate, the precipitate was washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in term of MS data. 45 Example 6: Preparation of erythromycin thiocyanate trihydrate
[0052] In a three-necked flask, 50ml of water and 10g erythromycin were added and stirred, then added with equimolar 2M lactic acid aqueous solution to erythromycin, and stirred at 5-40°C. After complete reaction, the mixture was filtered, 50 10% sodium thiocyanate solution in a molar ratio to erythromycin of 1:1-1.2 was added dropwise, cooled to a temperature between -15°C and 10°C, the resultant solid was washed with water, filtered under a reduced pressure and dried at room temperature for 48h to obtain an off-white crystal powder. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 86.61 % (the theoretical value: 86.65%); melting point: 161.9-165.1°C (not corrected), water content measured by Karl Fischer method 55 was 6.42% (the theoretical value: 6.38%), thermogram TG-DTA: weight loss before 140°C was about 6.39%, which was in the error range of the sample with 3 crystal water (see Fig.5), MS(ESI, FAB) m/z:793, 792, 734, 733, 59, 58. Element analysis: found: C 53.95, H 8.88, N 3.39, S 3.70; calculated: C 53.88, H 8.81, N 3.31, S 3.79.
11 EP 2 301 945 B1
Example 7: Preparation of erythromycin thiocyanate dihydrate
[0053] In a three-necked flask, 12g of erythromycin was dissolved in butyl acetate or acetone, added with 2M acetic acid aqueous solution and 10% sodium thiocyanate solution (in a molar ratio to erythromycin of 1: 1: 1-1.2), and stirred 5 continuously at 15-60°C. After complete reaction, the mixture was added with water, cooled to a temperature between -25°C and 10°C, filtered, the resultant solid was washed with water, filtered under a reduced pressure, and dried at 60°C for about 4h to obtain an off-white crystal powder. HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 88.46% (the theoretical value: 88.54%); melting point: 165.8-169.8°C (not corrected), water content by Karl Fischer method was 4.62% (the theoretical 10 value: 4.35%), TG-DTG: weight loss before 140°C was about 4.51 %, which was in the error range of the sample having 2 crystal water (see Fig.6), MS(ESI, FAB) m/z:793, 792, 734, 733, 59, 58. Element analysis: found: C 54.93, H 8.87, N 3.29, S 3.76; calculated: C 55.05, H 8.75, N 3.38, S 3.87. The obtained sample having 2 crystal water was added to a sodium carbonate solution to generate a precipitate, the precipitate was washed with water, recrystallized from water- ethanol, and the product was consistent with raw material erythromycin in terms of specific optical rotation and MS data. 15 Example 8: Preparation of erythromycin thiocyanate hemitri(1.5)hydrate
[0054] In a three-necked flask, 0.02 mol of erythromycin and 20ml of water was added, suspended, and added with 2M acetic acid aqueous solution at 0-30°C with stirring to make the suspension to be clear. The mixture was filtered, 20 and the filtrate was slowly added dropwise with a solution of 2M sodium thiocyanate or ammonium thiocyanate (in a molar ratio to erythromycin of 1-1.2) with stirring, cooled to a temperature between -10°C and 10°C, filtered, the resultant solid was washed with water, and filtered under a reduced pressure. The resultant solid was dissolved in methanol, added with 60ml of water, cooled to a temperature between -15°C and 10°C until complete crystallization and precipitation, and dried under vacuum at 60°C for about 3h to obtain an off-white crystal powder. HPLC analysis: the main peak of 25 the sample had a retention time in consistent with that of erythromycin control, in which the content of erythromycin was 89.66% (the theoretical value: 89.51 %); melting point: 162.4-165.7°C (not corrected), water content by Karl Fischer method was 3.47% (the theoretical value: 3.30%), TG-DTA: weight loss before 125°C was about 3.45%, which was in the error range of the sample with 1.5 crystal water (see Fig.7), MS(ESI, FAB) m/z:793, 792, 734, 733, 59, 58. IR(KBr) (cm-1) 3400-3600(b, s), 978(s), 2879(s), 2046(s), 1681 (s), 1467(s), 1380(s), 1175(s), 1095(s); Element analysis: found: 30 C 55.58, H 8.82, N 3.35, S 3.84; calculated: C 55.66, H 8.73, N 3.42, S 3.91.
Example 9: Preparation of erythromycin lactobionate hexahydrate
[0055] 20% Lactobionic acid solution was added dropwise to a reaction container containing erythromycin and water 35 in a molar ratio, the mixture was stirred, and the temperature was controlled between -2°C and 10°C. The reaction was performed for 0.5-4h with the pH controlled at 6.4-7, decolored with activated carbon or filtered by an ultrafilter membrane, spray dried with an inlet temperature of 103-115°C, an outlet temperature of 78-88°C and a spray pressure of 1.1-1.3 kg/cm2 to obtain erythromycin lactobionate hexahydrate.
40 Example 10: Preparation of erythromycin lactobionate hemihepta(3.5)hydrate
[0056] 20% Lactobionic acid solution was added dropwise to a reaction container containing 20kg of erythromycin, 100L of water, and 10L of acetone in a molar ratio. The mixture was stirred with the temperature controlled at 0-10°C, reacted for 1-8h with the pH controlled at 6.4-7, decolored with activated carbon or filtered by an ultrafilter membrane, 45 spray dried with an inlet temperature of 108-120°C, an outlet temperature of 80-90°C and a spray pressure of 1.2-1.5 kg/cm2 to obtain erythromycin lactobionate pentahydrate; melting point: 139.6-143.7°C (not corrected), HPLC analysis: the main peak of the sample had a retention time in consistent with that of erythromycin control; potency: 626 u/mg, pH=7.0, water content by Karl Fischer method was 7.72% (the theoretical value: 7.62%), TG-DTA spectrum: weight loss before 198°C was about 7.856%, which was in the error range of the sample with 5 crystal water (see Fig.3), MS(ESI, 50 FAB) m/z: 1092, 1091, 734, 733, 358, 357; the sample was dried at about 100°C for about 4h to obtain erythromycin lactobionate hemihepta(3.5)hydrate. The obtained sample was dissolved in water, added with a saturated sodium car- bonate solution to generate a precipitate, the precipitate was washed with water, recrystallized from water-ethanol, and the product was consistent with raw material erythromycin in term of MS data.
55 Example 11: Preparation of lyophilized powders of erythromycin lactobionate hydrate
[0057] 20 Kg of an erythromycin lactobionate hydrate (based on erythromycin) was added with 0-5 Kg of xylitol and 700-1000L of fresh water for injection, and the mixture was stirred and dissolved. The pH value was measured, and if
12 EP 2 301 945 B1
the pH was 5.0-7.0, no regulation was needed, if the pH was outside this range, 1 M NaH 2PO4 and 1 M Na 2HPO4 were added to reach a pH of 5.0-7.0. The mixture was added with activated carbon 0.01-0.5% (W/V), stirred for 15-45 min, filtered, supplemented with water to reach 800-1200L, filtered with 0.22 mm micropore filtration membrane or an ultrafilter membrane with a relative molecular weight cut-off of 1,000-8,000, and filled in 62.5 mg/bottle or 125 mg/bottle (based 5 on erythromycin), lyophilized, plugged to obtain the product.
Example 12: Preparation of injections of erythromycin lactobionate hydrate
[0058] An aseptic erythromycin lactobionate hydrate or erythromycin citrate hydrate or erythromycin phosphate hydrate 10 25 Kg (based on erythromycin) was weighed, and filled in 125 mg/bottle or 250 mg/bottle or 500 mg/bottle (based on erythromycin) by an aseptic filing process. The bottle was plugged and covered with an aluminum cap to obtain product.
Example 13: Preparation of erythromycin thiocyanate hydrate tablets
15 [0059] Tablets of erythromycin thiocyanate dihydrate or erythromycin lactobionate trihydrate (250 mg/tablet, based on erythromycin) [0060] Formula:
Erythromycin thiocyanate dihydrate or erythromycin lactobionate trihydrate 250g (based on erythromycin) 20 Microcrystalline cellulose 200g Sodium carboxymethyl starch 20g Aspartame 2g Polyvinylpyrrolidinone 5% q.s. Magnesium stearate 2g 25
[0061] Erythromycin thiocyanate dihydrate or erythromycin lactobionate trihydrate, microcrystalline cellulose, sodium carboxymethyl starch, and aspartame were passed through a 100 mesh sieve, processed with 5% polyvinylpyrrolidinone to obtain a soft material, and the material was passed through a 18-24 mesh sieve to form granules. The granules were 30 dried, passed through a 14-20 mesh sieve, finished, added with micronized silica gel and magnesium stearate, mixed and tabletted.
Example14: Preparation of erythromycin lactobionate trihydrate capsule
35 [0062] Formula:
Erythromycin lactobionate trihydrate 125g (based on erythromycin) Microcrystalline cellulose 100g Lactose 20g 40 Gelatinized starch, 10% q.s. Magnesium stearate 2g
[0063] Erythromycin lactobionate trihydrate, microcrystalline cellulose, and lactose were passed through a 100 mesh 45 sieve, processed with 10% gelatinized starch to form a soft material, and the material was passed through a 18-24 mesh sieve to form granules. The granules were dried, passed through a 14-20 mesh sieve, finished, added with magnesium stearate, mixed and filled in capsules (125 mg/capsule, based on erythromycin).
Example 15: Preparation of erythromycin salt hydrate granules 50 [0064] Granules of erythromycin lactobionate hydrate or erythromyin lactate hydrate or erythromycin nicotinate hydrate or erythromycin citrate hydrate or erythromycin thiocyanate hydrate (125 mg/packet, based on erythromycin) and the like are prepared as follows. [0065] Formula: 55 A hydrate of organic acid salts of erythromycin 125g (based on erythromycin) Mannitol 100g
13 EP 2 301 945 B1
(continued) Lactose 20g Sodium cyclamate 2g 5 Solid edible flavor 1g Polyvinylpyrrolidinone, 5% q.s.
[0066] The hydrate of organic acid salt of erythromycin, mannitol, lactose, sodium cyclamate, and solid edible flavor were passed through a 100 mesh sieve, and processed with 5% polyvinylpyrrolidinone to form a soft material. The 10 material was passed through a 18-24 mesh sieve, dried at a temperature of below 60°C, passed through a 14-20 mesh sieve, finished, and filled.
Example 16: Preparation of erythromycin salt hydrate suppository
15 [0067] A suppository of erythromycin lactobionate hydrate of erythromycin lactate hydrate or erythromycin nicotinate hydrate or erythromycin citrate hydrate or erythromycin thiocyanate hydrate and the like is prepared as follows. [0068] Formula:
Hydrate of organic acid salts of erythromycin 25g (based on erythromycin, for 100 suppositories) 20 Polyethylene glycol 4000 80g Propylene glycol 60ml Poloxamer 80g Water 100ml
25 [0069] Glycerol, polyethylene glycol 4000, poloxamer, and propylene glycol were mixed. The mixture was heated in a water bath, stirred to be melt, added with the hydrate of organic acid salts of erythromycin, stirred uniformly, poured rapidly into a suppository mould previously coated with a lubricant until slightly overflowing, smoothed after cooling, and the mould was remove to obtain the product. 30 Example 17: Preparation of erythromycin lactobionate hydrate gel
[0070]
35 Formula: erythromycin lactobionate hydrate 25g (based on erythromycin) Polyethylene glycol 6000 50g Polyethylene glycol 400 10g Glycerol 5ml Carbomer 934 8g 40 Carbomer 1342 2g Water 400-500ml
[0071] Carbomer 1342 and Carbomer 934 were dispersed into water separately, added with glycerol, polyethylene 45 glycol 6,000 and polyethylene glycol 400, stirred and mixed, added with erythromycin lactobionate hydrate, heated, stirred uniformly, added with Na2HPO4 and NaH2PO4 solution to adjust the pH to about 5.0-7.0, and filled to obtain the product (250 mg/dose, based on erythromycin).
Example 18: Preparation of erythromycin A oxime thiocyanate and erythromycin oxime 50 [0072] 20ml anhydrous methanol and 9g hydroxyamine hydrochloride were added to a 250ml three-necked flask at room temperature. The mixture was slowly added portionwise with 7.8g ammonium bicarbonate with stirring, added with 20g erythromycin A thiocyanate hydrate (based on the anhydrous), keeping the temperature at 40-80°C and the pH at 6-7, reacted for 10-40h, cooled to -10-10°C, filtered, the resultant filter cake with 40-60ml ice-water twice, dried in an 55 oven to obtain 16g of product, mp: 160°C (decomposition). 15g isopropanol and 8g erythromycin A oxime thiocyanate were added into a 100ml three-necked flask at room temperature. The mixture was stirred with the temperature kept at 40-70°C, added dropwise with ammonia to keep the pH at 9.5-12, stirred for 30-90min, added with 50ml water, cooled
14 EP 2 301 945 B1
to 0-15°C, stirred for 0.5-1 h, filtered, and dried to obtain 6.2g of product with a yield of 83%, erythromycin A (E) oxime content of 92%, and melting point: 154-157°C.
Example 19: Thermogravimetry of the erythromycin salt hydrates of the present invention 5
[0073] Method and conditions: Setsys 16 from Setaram Company, temperature increasing rate: 10K/min, N 2 flow rate: 50ml/min, room temperature to about 400°C, and the sample amount of about 5mg.
Example 20: Measurement of water content of the erythromycin salt hydrates of the present invention 10 [0074] Measurement method: water content was measured by the Karl Fischer’s method according to China Phar- macopoeia 2005 Edition (CP2005).
15 Claims
1. A hydrate of erythromycin salt, which is erythromycin lactobionate undecahydrate.
2. A hydrate of erythromycin salt, which is erythromycin lactobionate hexahydrate. 20 3. A hydrate of erythromycin salt, which is erythromycin lactobionate pentahydrate.
4. A hydrate of erythromycin salt, which is erythromycin lactobionate hemihepta(3.5)hydrate.
25 5. A hydrate of erythromycin salt, which is erythromycin lactobionate trihydrate.
6. A hydrate of erythromycin salt, which is erythromycin thiocyanate trihydrate.
7. A hydrate of erythromycin salt, which is erythromycin thiocyanate dihydrate. 30 8. A hydrate of erythromycin salt, which is erythromycin thiocyanate hemitri(1.5)hydrate.
9. A pharmaceutical composition, comprising a hydrate of erythromycin salt according to any one of claims 1 to 8 and at least one pharmaceutically acceptable excipient. 35 10. A process for preparing a hydrate of erythromycin salt according to any one of claims 1 to 8, comprising:
Method A: in a reaction container, using one of chloroform, C 3-C6 ketone, C 2-C6 ester, water and C 1-C5 alcohol and a mixture thereof as solvents, adding erythromycin, stirring, adding lactobionic acid or thiocyanic acid, 40 adding one or more of C3-C6 ketone, chloroform, C1-C5 alcohol, C2-C6 ether, C2-C6 ester and benzene after complete reaction, cooling, filtering, washing the resultant solid with one or more organic solvents of 1C-C5 alcohol, C3-C6 ketone, C2-C6 ether and chloroform, filtering under a reduced pressure, and drying to obtain the hydrate of erythromycin lactobionate or thiocyanate salt; or Method B: adding a lactobionic acid or thiocyanic acid solution in a desired molar ratio into a reaction container 45 containing erythromycin and one or more of water, C1-C5 alcohol and C3-C6 ketone as the solvents, stirring, reacting at a temperature between -10°C and 30°C for 0.5-24h, decoloring with activated carbon or filtering with an ultrafilter membrane after complete reaction, cooling to a temperature between -70°C and -30°C, and drying under vacuum to obtain the hydrate of erythromycin lactobionate or thiocyanate salt; or Method C: adding a lactobionic acid or thiocyanic acid or a solution thereof in a desired molar ration into a 50 reaction container containing erythromycin and water, stirring, reacting at a temperature between -5°C and 20°C for0.5-24h, decoloring with activatedcarbon or filteringwith an ultrafilter membraneafter completereaction, and spray drying to obtain the hydrate of erythromycin lactobionate or thiocyanate salt.
11. Use of a hydrate of erythromycin salt according to any one of claims 1 to 8 in the manufacture of a medicament for 55 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: A. infections of nasopharynx: tonsillitis, pharyngitis, sinustitis; B. infections of lower respiratory duct: acute bronchitis, acute onset of chronic bronchitis, and pneumonia; C. infections of skin and soft tissues: impetigo, erysipelas, folliculitis, furnucle and wound infections; D.
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acute otitis, mycoplasmal pneumonia, urethritis and cervicitis caused by chlamydia trachomatis; and E. legionella infections, mycobacterium avium infections, helicobacter pylori infections.
12. Use of a hydrate of erythromycin salt according to claim 11, wherein the medicament is formulated to form a 5 lyophilized powder injection, a sterilized-filled powder injection, a small volume injection, a dosage form for enteral administration, an ointment and gel for percutaneous administration, or a suppository for intravaginal or rectal administration.
13. Use of a hydrate of erythromycin salt according to any one of claims 1 to 8 for the preparation or purification of 10 erythromycin, for the preparation of erythromycin oxime, for the further synthesis of intermediates of roxithromycin, clarithromycin, azithromycin, dirithromycin, bridged erythromycin, cethromycin and other macrolides, and medica- ments thereof.
15 Patentansprüche
1. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycin-lactobionat-undecahydrat handelt.
2. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycin-lactobionat-hexahydrat handelt. 20 3. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycin-lactobionat-pentahydrat handelt.
4. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycin-lactobionat-hemihepta(3,5)hydrat handelt.
25 5. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycin-lactobionat-trihydrat handelt.
6. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycinthiocyanat-trihydrat handelt.
7. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycinthiocyanat-dihydrat handelt. 30 8. Hydrat eines Erythromycinsalzes, bei dem es sich um Erythromycinthiocyanat-hemitri(1,5)hydrat handelt.
9. Pharmazeutische Zusammensetzung, umfassend ein Hydrat eines Erythromycinsalzes nach einem der Ansprüche 1 bis 8 und mindestens ein pharmazeutisch verträgliches Exzipiens. 35 10. Verfahren zur Herstellung eines Hydrats eines Erythromycinsalzes nach einem der Ansprüche 1 bis 8, umfassend:
Methode A: Zugeben von Erythromycin unter Verwendung von einem der Bestandteile Chloroform, C 3-C6-Ke- tone, C2-C6-Ester, Wasser und C1-C5-Alkohole und Gemische davon als Lösungsmittel in einen Reaktionsbe- 40 hälter, Rühren, Zugeben von Lactobionsäure oder Thiocyansäure, Zugeben von einem oder mehreren der
Bestandteile C3-C6-Ketone, Chloroform, C 1-C5-Alkohole, C2-C6-Ether, C2-C6-Ester und Benzol nach beendeter Umsetzung, Kühlen, Filtrieren, Waschen des erhaltenen Feststoffes mit einem oder mehreren der organischen
Lösungsmittel C1-5-Alkohole, C3-C6-Ketone, C2-C6-Ether und Chloroform, Filtrieren unter vermindertem Druck und Trocknen, wodurch man das Hydrat eines Erythromycin-lactobionat- oder -thiocyanatsalzes erhält; oder 45 Methode B: Zugeben einer Lösung von Lactobionsäure oderThiocyansäure in einem erwünschten Molverhältnis in einen Reaktionsbehälter mit einem Gehalt an Erythromycin und einem oder mehreren der Bestandteile
Wasser, C1-5-Alkohole und C3-C6-Ketone als Lösungsmittel, Rühren, Umsetzen bei einer Temperatur von -10 °C bis 30 C für 0,5-24 Stunden, Entfärben mit Aktivkohle oder Filtrieren mit einer Ultrafiltrationsmembran nach vollständiger Umsetzung, Abkühlen auf eine Temperatur von -70°C bis -30 °C und Trocknen unter Vakuum, 50 wodurch man das Hydrat eines Erythromycin-lactobionat- oder -thiocyanatsalzes erhält; oder Methode C: Zugeben von Lactobionsäure oder Thiocyansäure oder einer Lösung davon in einem erwünschten Molverhältnis in einen Reaktionsbehälter, der Erythromycin und Wasser enthält, Rühren, Umsetzen bei einer Temperatur von -5 °C bis 20 °C für 0,5-24 Stunden, Entfärben mit Aktivkohle oder Filtrieren mit einer Ultrafilt- rationsmembran nach vollständiger Umsetzung und Sprühtrocknen, wodurch man das Hydrat eines Erythro- 55 mycin-lactobionat- oder -thiocyanatsalzes erhält.
11. Verwendung eines Hydrats eines Erythromycinsalzes nach einem der Ansprüche 1 bis 8 zur Herstellung eines Arzneimittels zur Behandlung einer Infektion bei einem Menschen oder einem Tier, die durch Bakterien, Mykoplas-
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men oder Chlamydien hervorgerufen worden ist und die auf Erythromycin anspricht, wobei die Infektion aus der Gruppe ausgewählt ist, die besteht aus A: Nasopharynx-Infektionen: Tonsillitis, Pharyngitis, Sinusitis; B: Infektionen des unteren Atmungstrakts: akute Bronchitis, akutes Einsetzen von chronischer Bronchitis und Pneumonie; C: Infektionen von Haut und Bindegewebe: Impetigo, Erysipele, Follikulitis, Furunkel und Wundinfektionen; D: akute 5 Otitis, Mykoplasma-Pneumonie, Urethritis und Zervizitis, die durch Chlamydia trachomatis verursacht worden sind; und E: Legionelleninfektionen, Mycobacterum avium-Infektionen und Helicobacter pylori-Infektionen.
12. Verwendung eines Hydrats eines Erythromycinsalzes nach Anspruch 11, wobei das Arzneimittel unter Bildung eines lyophilisierten Pulvers für Injektionszwecke, eines sterilisierten-gefüllten Pulvers für Injektionszwecke, einer klein- 10 volumigen Injektionsflüssigkeit, einer Dosierungsform für die enterale Verabreichung, einer Salbe oder eines Gels für die perkutane Verabreichung oder eines Suppositoriums für die intravaginale oder rektale Verabreichung zube- reitet ist.
13. Verwendung eines Hydrats eines Erythromycinsalzes nach einem der Ansprüche 1 bis 8 zur Herstellung oder 15 Reinigung von Erythromycin, zur Herstellung von Erythromycin-oxim, zur weiteren Synthese von Zwischenprodukten von Roxithromycin, Clarithromycin, Azithromycin, Dirithromycin, verbrücktem Erytrhomycin, Cethromycin und an- deren Macroliden und Arzneimitteln davon.
20 Revendications
1. Hydrate de sel d’érythromycine, qui est l’undécahydrate de lactobionate d’érythromycine.
2. Hydrate de sel d’érythromycine, qui est l’hexahydrate de lactobionate d’érythromycine. 25 3. Hydrate de sel d’érythromycine, qui est le pentahydrate de lactobionate d’érythromycine.
4. Hydrate de sel d’érythromycine, qui est l’hémihepta(3,5)hydrate de lactobionate d’érythromycine.
30 5. Hydrate de sel d’érythromycine, qui est le trihydrate de lactobionate d’érythromycine.
6. Hydrate de sel d’érythromycine, qui est le trihydrate de thiocyanate d’érythromycine.
7. Hydrate de sel d’érythromycine, qui est le dihydrate de thiocyanate d’érythromycine. 35 8. Hydrate de sel d’érythromycine, qui est l’hémitri(1,5)hydrate de thiocyanate d’érythromycine.
9. Composition pharmaceutique, comprenant un hydrate de sel d’érythromycine suivant l’une quelconque des reven- dications 1 à 8 et au moins un excipient pharmaceutiquement acceptable. 40 10. Procédé pour préparer un hydrate de sel d’érythromycine suivant l’une quelconque des revendications 1 à 8, comprenant :
Procédé A : dans un récipient de réaction, utilisation de l’un du chloroforme, d’une cétone en 3C à C6, d’un 45 ester en C2 à C6, de l’eau, d’un alcool en C1 à C5 et d’un de leurs mélanges comme solvants, l’addition d’érythromycine, une agitation, l’addition d’acide lactobionique ou d’acide thiocyanique, l’addition d’un ou plu-
sieurs d’une cétone en C3 à C6, de chloroforme, d’un alcool en C1 à C5, d’un éther en C2 à C6, d’un ester en C6 à C6 et du benzène après achèvement de la réaction, un refroidissement, une filtration, un lavage de la substance solide résultante avec un ou plusieurs solvants organiques consistant en un alcool en C 1 à C5, une 50 cétone en C3 à C6, un éther en C2 à C6 et le chloroforme, une filtration sous pression réduite et un séchage pour obtenir l’hydrate de sel lactobionate ou thiocyanate d’érythromycine ; ou Procédé B : l’introduction d’une solution d’acide lactobionique ou d’acide thiocyanique en un rapport molaire désiré dans un récipient de réaction contenant de l’érythromycine et un ou plusieurs de l’eau, d’un alcool en
C1 à C 5 et d’une cétone en C 3 à C6 comme solvants, une agitation, une réaction à une température entre -10°C 55 et 30°C pendant 0,5 à 24 heures, une décoloration avec du charbon actif ou une filtration avec une membrane d’ultrafiltration après achèvement de la réaction, un refroidissement à une température entre -70°C et -30°C et un séchage sous vide pour obtenir l’hydrate de sel lactobionate ou thiocyanate d’érythromycine ; ou Procédé C : l’introduction d’un acide lactobionique ou acide thiocyanique ou d’une solution de cet acide en un
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rapport molaire désiré dans un récipient de réaction contenant de l’érythromycine et de l’eau, une agitation, une réaction à une température entre -5°C et 20°C pendant 0,5 à 24 heures, une décoloration avec du charbon actif ou une filtration avec une membrane d’ultrafiltration après achèvement de la réaction et un séchage par atomisation pour obtenir l’hydrate de sel lactobionate ou thiocyanate d’érythromycine. 5 11. Utilisation d’un hydrate de sel d’érythromycine suivant l’une quelconque des revendications 1 à 8, dans la production d’un médicament pour le traitement chez un être humain ou un animal d’une infection provoquée par une bactérie, un mycoplasme ou une Chlamydia, qui est sensible à l’érythromycine, dans laquelle l’infection est choisie dans le groupe consistant en : A. des infections du rhinopharynx : amygdalite, pharyngite, sinusite ; B. des infections du 10 tractus respiratoire inférieur : bronchite aiguë, déclenchement aigu de la bronchite chronique et pneumonie ; C. des infections de la peau et des tissus mous : impétigo, érysipèle, folliculite, furoncle et infections de plaies ; D. l’otite aiguë, la pneumonie à mycoplasmes, l’urétrite et la cervicite provoqués par Chlamydia trachomatis ; et E. des infections par E. legionella, des infections par Mycobacterium avium, des infections par Helicobacter pylori.
15 12. Utilisation d’un hydrate de sel d’érythromycine suivant la revendication 11, dans laquelle le médicament est formulé pour former une poudre lyophilisée injectable, une poudre injectable stérilisée au remplissage, une formulation injectable à bas volume, une forme posologique pour administration entérale, une pommade et un gel pour l’admi- nistration percutanée, ou un ovule pour l’administration intravaginale ou suppositoire pour l’administration rectale.
20 13. Utilisation d’un hydrate de sel d’érythromycine suivant l’une quelconque des revendications 1 à 8, pour la préparation ou la purification de l’érythromycine, pour la préparation d’une oxime d’érythromycine, pour la synthèse supplémen- taire d’intermédiaires de roxithromycine, de clarithromycine, d’azithromycine, de dirithromycine, d’érythromycine pontée, de céthromycine et d’autres macrolides, et de médicaments en contenant.
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REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description
• EP 1302205 A [0003] • US 4340582 A [0003] • US 3764595 A [0003]
Non-patent literature cited in the description
• DUTTA, S. K. ;GHOSH, A. K. ;SOUMYA, S. D. • China Pharmacopoeia. 2005 [0074] Preparation of water-soluble salts of erythromycin and study of some of their properties.INDIAN DRUGS, 1980, 354-356 [0003]
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