CN102212074A - Cefonicid sodium hydrate and preparation method and application thereof - Google Patents
Cefonicid sodium hydrate and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a cefonicid sodium hydrate and a preparation method and application thereof. The cefonicid sodium hydrate has better storage stability and is applicable to preparation of the medicaments for treating or preventing such diseases caused by gram positive or negative sensitive bacteria as respiratory system infection, hepatobiliary system infection, five sense infection, urinary tract infection, abdominal infection, pelvic infection, sepsis, skin soft tissue infection, bone and joint infections, annexitis, intrauterine infection, parametritis, meningitis, gonorrhea and the like of human or animals.
Description
Technical field
The present invention relates to medical technical field, specifically provide antibacterials---cefonicid sodium hydrate and its production and use.
Background technology
Cefonicid sodium (Cefonicid sodium) is the second generation cephalosporin that injection for intravenous or intramuscular injection are used.The anti-microbial effect of cefonicid sodium is compared with first generation cephalosporin, the anti-gram negative bacillus effect of wide spectrum is arranged, compare with Cefamandole, then better Chinese People's Anti-Japanese Military and Political College enterobacteria, the white pneumobacillus of Cray, Proteus mirabilis, citric acid bacillus, enterobacter effect, but then inferior slightly the positive Bacillus proteus of anti-indoles etc.Cefonicid sodium all has good action to bloodthirsty hemophilus influenza and Nai Shi gonococcus.But cefonicid sodium is to streptococcus faecium, the drug-fast streptococcus aureus of penicillin and staphylococcus epidermidis bacterial strain, false single armful of resistance such as Pseudomonas, serratia and bacillus aceticus.
At present, disclosed document has only been reported cefonicid sodium (C
18H
16N
6Na
2O
8S
3, molecular weight: 586.53, CAS number: 61270-78-8), up to the present, still do not have disclosed bibliographical information cefonicid sodium hydrate of the present invention and its production and use both at home and abroad.
Summary of the invention
Involved in the present invention is antibiotic infection medicine cefonicid sodium hydrate and its production and use, and its molecular formula is C
18H
16N
6Na
2O
8S
3NH
2O, the numeral between n=0.48～2.25 comprises 0.5,0.75,1,1.25,1.5,2 etc.
The cefonicid sodium hydrate that the present invention obtains, surprisingly, it draws moist far below the cefonicid sodium anhydride, and existence that more can be stable than cefonicid sodium anhydride is convenient to store and transportation, is easy to make preparation.In addition, the deliquescence of anhydride makes wants secluding air to prevent adhesion etc. when handling, and hydrate has good sliding, thereby improves the operability of preparation.
Surprisingly, distinctive, have corresponding endotherm(ic)peak under the weightless platform of the heat analysis of hydrate of the present invention (TG-DSC or TG-DTA) collection of illustrative plates, the thermogram spectrum demonstrates the cefonicid sodium hydrate, as cefonicid sodium 1 hydrate, cefonicid sodium 2 hydrates etc.Cefonicid sodium hydrate of the present invention, hydrate can have different crystalline forms, also can be amorphous.
Cefonicid sodium hydrate of the present invention can stable storage.Cefonicid sodium hydrate and anhydride sample are drawn moist test: get cefonicid sodium anhydride and the about 5g of hydrate of the present invention, place the watch-glass of dry constant weight, precision is weighed, 25 ℃, relative humidity are 70%, respectively at test 0h and 10h sampling, calculate the percentage that draws wet weightening finish, the result shows, anhydride draws moist all more much higher than hydrate of the present invention, and cefonicid sodium hydrate of the present invention stable storage better the results are shown in Table 1.Under RH75%, 25 ℃ of conditions, the cefonicid sodium hydrate sample of the embodiment of the invention is enclosed within the stability test of carrying out in the cillin bottle 6 months, (regulating pH to 7.0 with ammonia solution)-methyl alcohol (84: 16) is moving phase to the condition that cefonicid sodium HPLC method is measured: Cl8 (150mm * 4.6mm, 5 μ m) with the 0.02mol/L ammonium dihydrogen phosphate; The detection wavelength is 272nm, and column temperature is a room temperature, flow velocity 1ml/min, and mensuration is found cefonicid sodium 0.5 hydrate, cefonicid sodium 1 hydrate content is constant substantially and the related substance thing does not have obvious increase.Test-results illustrates that cefonicid sodium hydrate of the present invention has good storage stability.
The preparation of cefonicid sodio-derivative---cefonicid sodium hydrate comprises following method:
Method A. adds cefonicid acid in reaction vessel, add water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in one or more, stir, 10 ℃ drip C down
1-C
12Low molecular amine, stirring and dissolving adds gac, stirs 10-45 minute, filters, and adds one or more and water, the C of yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate under 10 ℃ in filtrate
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone in one or more solution, stirred 0.2-3 hour, regulate pH to 6.0～7.0 with mineral acid or organic acid or its solution, add C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
8Low molecule ester, C
1-C
6Low molecule halohydrocarbon in one or more, place below 10 ℃, solid is fully separated out, suction filtration, a small amount of C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
6Low molecule nitrile, C
1-C
6Low molecule halohydrocarbon in one or more wash 1-3 time, filter gained solid water and C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
6Low molecule nitrile, C
1-C
6Low molecule halohydrocarbon in one or more solvent recrystallization one or many, place below 10 ℃, crystallization is fully separated out, filter, drying, the cefonicid sodium hydrate;
Wherein, employed cefonicid acid: C in the reaction
1-C
12Low molecular amine: the mol ratio of alkali (yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate) generally can be 1: 1-2.2: 1-2.2 is (if generally can be 1 by equivalence ratio: 1-11: 1-11); Cefonicid acid (weight g) and water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in the ratio of one or more (volume ml) for being generally: 1 (g): 3～30 (ml); The water that uses in crystallization or the recrystallization is generally 1: 10～300 with the volume of organic solvent ratio.The consumption of gac is the 0.01-1% of institute's de-inking solution weight.
Perhaps method B. adds cefonicid acid in reaction vessel, adds water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in one or more, stir, under 10 ℃, in filtrate, add one or more and water, the C of yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone in one or more solution, stirring reaction 0.2-3 hour, regulate pH to 6.0～7.0 with mineral acid or organic acid or its solution, add C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
8Low molecule ester, C
1-C
6Low molecule halohydrocarbon in one or more, place below 10 ℃, solid is fully separated out, filter a small amount of C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
6Low molecule nitrile, C
1-C
6Low molecule halohydrocarbon in one or more wash 1-3 time, filter gained solid water and C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
1-C
6Low molecule halohydrocarbon in one or more carry out the one or many recrystallization for recrystallisation solvent, filter dry cefonicid sodium hydrate.
Wherein, employed cefonicid acid in the reaction: the mol ratio of alkali (in yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, the Sodium isooctanoate etc. a kind of) generally can be 1: 1-2.2: 1-2.2 is (if generally can be 1 by equivalence ratio: 1-1.1: 1-1.1); Cefonicid acid (weight g) and water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in the ratio of one or more (volume ml) for being generally: 1 (g): 3～50 (ml); The water that uses in crystallization or the recrystallization is generally 1: 10～300 with the volume of organic solvent ratio.
The crystallization of cefonicid sodium hydrate or recrystallization solvent are selected from one or more in water and acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, N-BUTYL ACETATE, ethyl acetate, ethyl formate, ether, isopropyl ether, tetrahydrofuran (THF), methylene dichloride, chloroform etc.; Cefonicid sodium crystallization crystallization or recrystallization solvent, preferably water and methyl alcohol, ethanol, Virahol, one or more in tetrahydrofuran (THF), ethyl acetate, ether, isopropyl ether, the chloroform.In preparation method of the present invention, in recrystallization process, can use water dissolution cefonicid sodium hydrate earlier, can use activated carbon decolorizing (if use activated carbon decolorizing, its consumption is the 0.01-1% of institute's de-inking solution weight) after the dissolving, make its crystallization with the solvent among the present invention again.Cefonicid sodium hydrate of the present invention can have different crystal formation or amorphous.
The lower alcohol among the present invention or the carbonatoms of low mass molecule alcohol are defined as C
1-C
6(that is: the alcohol of 1-6 carbon atom) is as methyl alcohol, ethanol, Virahol, butanols etc.; C
2-C
6The carbonatoms of rudimentary nitrile be defined as C
2-C
6, as acetonitrile, propionitrile etc.; C
2-C
8Rudimentary ether or the carbonatoms of the low molecule ether ether that is defined as 2-8 carbon atom, as ether, isopropyl ether, butyl ether etc.; The carbonatoms of lower halogenated hydrocarbon is defined as C
1-C
6(being 1-6 carbon atom) comprises methylene dichloride, ethylene dichloride, chloroform etc.; The carbonatoms of lower member ester is defined as C
2-C
8(being 2-8 carbon atom) comprises N-BUTYL ACETATE, ethyl acetate, ethyl formate etc.; The carbonatoms of low molecule straight or branched alkane or naphthenic hydrocarbon is defined as C
5-C
10(being 5-10 carbon atom) comprises pentane, normal hexane, hexanaphthene, sherwood oil etc.; The carbonatoms of low molecule aromatic hydrocarbon is defined as C
6-C
12(being 6-12 carbon atom) comprises benzene, toluene etc.; C
3-C
8Low molecule ketone be defined as the ketone of 3-8 carbon atom, comprise acetone, butanone, hexone etc.; C
1-C
6The carbonatoms of low molecular acid be defined as the organic acid of 1-6 carbon atom, comprise formic acid, acetate, propionic acid etc.; C
1-C
12Low molecular amine be defined as the organic amine of 1-12 carbon atom, comprise dimethylamine, diethylamine, triethylamine, hexahydroaniline, dicyclohexyl amine, dicyclohexyl amine, special octylame, pentanoic, Diisopropylamine, N-tertiary butyl hexahydroaniline etc.; The marking method of amount of carbon atom that about any class description is " low molecule " compound is as long as occur once in the application's text, and the carbonatoms of the similar compound of other any unmarked being described as " low molecule " is consistent with the quantity of having indicated herein.
The preparation of aseptic raw material of the present invention can be carried out according to the usual manner or the method for cephalosporins medicine preparation.
The drying mode of product of the present invention can be in differing temps (as 20-80 ℃), time of drying (0.5 hour to a few days) or with under the envrionment conditions of other siccative (comprising silica gel, Vanadium Pentoxide in FLAKES, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate etc.) or use the mode of normal pressure or decompression that last product is carried out drying.Its drying temperature is preferably at 30-45 ℃.
Cefonicid sodium hydrate purposes of the present invention: cefonicid sodium hydrate of the present invention is used to prepare solid preparation, injection, wherein injection comprises injection freeze-dried powder, aseptic subpackaged powder injection, infusion preparation (comprising the instant-matching type infusion solutions that two chambers instant-matching type infusion solutions, the two chambers of non-PVC solid-liquid instant-matching type infusion solutions, non-PVC multi-layer co-extruded film are made), tablet, capsule, granule etc.; And can be used for preparing the cefonicid sodium anhydride.The preparation of anhydride can be obtained through different drying meanss by cefonicid sodium hydrate of the present invention, its preparation can be at differing temps (as 60-100 ℃), time of drying (a few hours are to a few days), or (comprise silica gel with other siccative, molecular sieve, Vanadium Pentoxide in FLAKES, sodium hydroxide, anhydrous sodium carbonate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous magnesium sulfate etc.) under the envrionment conditions, or and use the mode of normal pressure or decompression that last product is carried out drying, also can be earlier by the method for benzene distillation band water, and in conjunction with obtaining after other drying means drying of describing herein.
Be used to prepare tablet (comprising buccal tablet, Sublingual tablet, mouth paster, orally disintegrating tablet, vaginal tablet etc.), capsule, granule, wherein can contain pharmaceutically acceptable weighting agent, as starch, modified starch, lactose, Microcrystalline Cellulose, cyclodextrin, sorbyl alcohol, N.F,USP MANNITOL, calcium phosphate, amino acid etc.; Pharmaceutically acceptable disintegrating agent is as starch, modified starch, Microcrystalline Cellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, tensio-active agent (sodium lauryl sulphate etc.); Pharmaceutically acceptable wetting agent and tackiness agent are as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant are as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence are as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
The deliquescence that cefonicid sodium hydrate of the present invention is different from anhydride makes wants secluding air to prevent adhesion etc. when handling, and the cefonicid sodium hydrate has good sliding, thereby improves the operability of preparation; And the solid preparation that makes preparation has good dissolving out capability, makes it be absorbed easily and enters blood circulation, improves bioavailability, and helps bringing into play fast its effect.From another aspect, making it prevent produces obstruction and makes loading amount generation difference cause underdosage when carrying out being difficult for when aseptic subpackaged to cause packing because of the moisture absorption, thereby bring the defective of product, or because underproof product is not inspected by random samples the actual omission of formation, and then come into the market, in clinical treatment,, perhaps jeopardize patient's life because of underdosage to patient's the negative effect of treatment agency.Perhaps when packing, cause whole production line to be forced to suspend because of the moisture absorption, seriously reduce the throughput of equipment, increase the hidden danger of work time cost etc. greatly.In addition, preparation cefonicid sodium anhydride need consume more energy than the preparation of cefonicid sodium hydrate.
The injection of cefonicid sodium hydrate, its preparation method is:
The preparation of aseptic subpackaged powder pin: use aseptic raw material to carry out packing according to common convention.
The great transfusion preparation of cefonicid sodium hydrate comprises the instant-matching type infusion solutions that two chambers instant-matching type infusion solutions, the two chambers of non-PVC solid-liquid instant-matching type infusion solutions, non-PVC multi-layer co-extruded film are made, and all can prepare according to ordinary method.
The preparation method of freeze-dried powder is: get the cefonicid sodium hydrate, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, stablizer, water for injection, stirring makes dissolving, and (the cefonicid sodium hydrate also can only add the injection water, stirring makes dissolving), if need, available pharmaceutically acceptable acid-alkali accommodation pH is 6.0～7.5, add activated carbon 0.005～0.5% (W/V) and stir 15～45min, filter moisturizing, sterile filtration, by the packing of 0.5～2g/ bottle, lyophilize, tamponade gets finished product.
Its pharmaceutically acceptable pH regulator agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be generalized Lewis acid or alkali, can contain one or several, can be hydrochloric acid, phosphoric acid, propionic acid, acetic acid and acetate, as sodium-acetate etc., lactic acid and lactic acid pharmaceutical salts, the Citric Acid pharmaceutical salts, yellow soda ash, sodium bicarbonate, saleratus, sodium hydroxide, potassium hydroxide, phosphoric acid salt, tartrate and pharmaceutical salts thereof, borax, boric acid, Succinic Acid, caproic acid, hexanodioic acid, FUMARIC ACID TECH GRADE, maleic acid, multi-hydroxy carboxy acid and pharmaceutical salts are as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, in the glucoheptonic acid etc. one or several.
Its pharmaceutically acceptable oxidation inhibitor and stablizer can be sulfurous acid, sulphite, hydrosulphite, pyrosulfite, hyposulfite, thiosulphate, organosulfur compound thiocarbamide, gsh, dimercaprol dimercaptopropanol, Thiovanic acid and salt, thiolactic acid and salt, thio-2 acid and salt, phenol compound, as gallic acid and salt, coffic acid, caffeiate, forulic acid, ferulate, di-t-butyl Pyrogentisinic Acid, 2,5-resorcylic acid, 2,5-resorcylic acid salt, phenol or derivatives thereof, Whitfield's ointment or its salt; Xitix and ascorbate salt, saccharosonic acid and erythorbate, niacinamide, tartrate, nitrate, phosphoric acid salt, acetic acid pharmaceutical salts, Citrate trianion, EDTA and edta salt, as in EDTA disodium, EDTA four sodium, N-two (2-hydroxyethyl) glycine etc. one or several.
Source and the degerming mode of reducing phlegm and internal heat can be the gac that adds dosing amount 0.005～3% source of reducing phlegm and internal heat, and millipore filtration degerming and pressure sterilizing also can adopt heat sterilization, the source of reducing phlegm and internal heat.In the hyperfiltration process, that ultra-fine filter can be selected for use is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc., preferred rolling and tubular fibre formula ultra-fine filter, it is after 50,000 to 300,000 filter membrane is removed most of heat generation material and bacterium that relative molecular mass is held back in employing, adopt the ultra-filtration membrane of holding back relative molecular mass 4000～30000 to remove the residue thermal source, the ultra-filtration membrane of preferred relative molecular mass 6000～30000 again.
The suppository preparation method of cefonicid sodium hydrate: suppository is by cefonicid sodium hydrate (weight ratio is generally 1-40%), all the other are made up of suppository base, matrix can be ethanol, glycerine, glycogelatin, Macrogol 200-8000, poloxamer, Vaseline, semi-synthetic hard fatty acids fat (comprises polyoxyethylene stearate (40) fat, propylene glycol stearate, glycerin fatty acid ester etc.), carbomer series (931,934,940,974 etc.), polysorbate60-80 grade a kind of or several, and can contain pharmaceutically acceptable other additives in the suppository, as stablizer and absorption enhancer etc.The preparation method: main ingredient is mixed with matrix, heating in water bath, stir, wait to melt, be stirred in the suppository mould that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly.
The cefonicid sodium hydrate prepares the preparation of administrations such as Sublingual tablet, vagina administration or suppository, make this medicine not by intravenously administrable or avoid GI destruction and directly from mucosal absorption, change comparatively dull at present mode of administration, make this medicine can be used for the prevention and the treatment of disease better.
Cefonicid sodium hydrate of the present invention is applicable to: preparation is to the application in the medicine of treatment of diseases such as the other inflammation of connective tissue in respiratory system, liver and gall, face, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, adnexitis, intra-uterine infection, uterus of the human or animal due to Gram-positive or the negative bacteria sensitive organism, meningitis, gonorrhoea or prevention.
The consumption usage: generally speaking, for cefonicid sodium hydrate (in anhydride), the common dosage of being grown up is per 24 hours 1g, can supply intramuscular injection, intravenous injection and intravenous drip usefulness, and children's amount of reducing by half is above to be used.Also available in some cases 2g is grown up.Specific as follows: the renal function normal patient general slight to grade and moderate infection adult dosage every day be 1g, per 24 hours are once; In severe infections or life-threatening infection, but every day 2g, per 24 hours are once.Uncomplicated urinary tract infections: every day 0.5g, per 24 hours are once.Surgical prophylaxis infects: preceding 1 hour single dose administration 1g performs the operation.During intramuscular injection,, the cefonicid sodium hydrate fully can be dissolved in the 1% Xylotox solution for preventing pain.Need reach 2g as dosage, then should divide two position injections.The intravenous injection time should be greater than 3-5 minute.Intravenous drip: the cefonicid sodium hydrate is dissolved in following any solution more than the 50ml: 0.9% sodium chloride injection, 5% glucose injection, 5% glucose injection and 0.9% sodium chloride injection, 10% glucose injection, Lactated Ringer'S Solution.Perhaps by orally administering (changing injecting pathway absorbs for the through port transmucosal), adult 0.5g～2g every day; Or vagina administration (absorbing) by vaginal mucosa, adult 0.5g～2g every day.
Document had once been reported cefonicid sodium antimicrobial compound (ZL200310109808.5), same cefonicid sodium hydrate of the present invention is used to prepare the composition with beta-lactamase inhibitor, beta-lactamase inhibitor comprises Tazobactam Sodium or its pharmaceutical salts or Sulbactam or its pharmaceutical salts or clavulanic acid or its pharmaceutical salts etc., as sodium-tazobactam, the Tazobactam Sodium sodium hydrate, sulbactam, Clavulanic Potassium etc.Cefonicid sodium hydrate and enzyme inhibitors comprise that the part by weight of Tazobactam Sodium or its pharmaceutical salts or Sulbactam or its pharmaceutical salts or clavulanic acid or its pharmaceutical salts composition composition is 32: 1～1: 1.The weight ratio of cefonicid sodium hydrate and the composition of beta-lactamase inhibitor can be different with the ratio of different beta-lactamase inhibitors, preferred 4: 1～8: 1 of the weight ratio of the composition of general cefonicid sodium hydrate and beta-lactamase inhibitor Tazobactam Sodium or its pharmaceutical salts, preferred 2: 1～1: 1 of the weight ratio of the composition of general cefonicid sodium hydrate and beta-lactamase inhibitor Sulbactam or its pharmaceutical salts, said composition has stronger anti-microbial effect, is used for the application to the medicine of human or animal's treatment of diseases due to Gram-positive or the negative bacteria sensitive organism or prevention.Above-mentioned composition is applicable to the application in the medicine of treatment of diseases such as the human or animal of preparation due to it the other inflammation of connective tissue in respiratory system, liver and gall, face, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, adnexitis, intra-uterine infection, uterus, meningitis, gonorrhoea or prevention.
Description of drawings
Fig. 1 is the thermogram spectrum of cefonicid sodium 1 hydrate.
Fig. 2 is the thermogram spectrum of cefonicid sodium 2 hydrates.
Embodiment
When in an embodiment and in addition indication being arranged, used all numerical value should be understood to be in all examples and modify with term " about " in specification sheets and claims, therefore, unless opposite indication is arranged, given numerical parameter is an approximation in this specification sheets and the appending claims, it can change according to the required character of looking for by present disclosure, at least, and be not the application that is intended to limit doctrine of equivalents claim scope, each numerical parameter should consider that the number of significant figure and the routine method of rounding up explain.
Though setting the numerical range and the parameter of the wide region of disclosure is approximation.But numerical value given in specific embodiment is reported that as far as possible accurately any number comprises some in essence by the error of finding that standard deviation certainly led in their tests separately.
In order further to understand the present invention, below in conjunction with embodiment the preferred embodiment of the invention is described, but should be appreciated that these describe just to further specifying the features and advantages of the present invention, rather than to the restriction of claim of the present invention.
Below with specific embodiment effect of the present invention is described, but protection scope of the present invention is not limited by the following examples.
Heat analysis method
Hot analytical test condition: the Setsys of Setaram company 16, about sample size 5mg, heat-up rate: 10K/min, N2 flow velocity: 50ml/min, temperature: about room temperature～400 ℃.
Surprisingly, distinctive, have corresponding endotherm(ic)peak under the weightless platform of the heat analysis of hydrate of the present invention (TG-DTA or TG-DSC) collection of illustrative plates.
The powder X-ray diffraction approach
Utilize the D/MX-IIIA X-ray diffractometer, voltage: 35kv, electric current: 30mA, sweep velocity: 10 °/min, step-length: 0.02 °/step; The copper target, monochromator: graphite monochromator; Wavelength wavelength (A): 1.54, diffraction angle 2 θ, have measured the x-ray diffractogram of powder of cefonicid sodium hydrate by sweep limit 3-60 °.
Cefonicid sodium 1 hydrate can have amorphous powder and crystalline powder two big class solids.
In an embodiment (implementing 2), utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, cefonicid sodium 1 hydrate of the present invention can have corresponding eigenwert in the position that comprises following 2 θ values: about 4.11,4.71,14.52,21.7,24.55,25.49,53.6,54.57,58.29.
Draw wet test
Cefonicid sodium hydrate of the present invention is stable storage more.Cefonicid sodium hydrate and anhydride sample are drawn moist test: get cefonicid sodium anhydride and the about 5g of hydrate of the present invention, place the watch-glass of dry constant weight, precision is weighed, 25 ℃, relative humidity are 70%, respectively at test 0h and 10h sampling, calculate the percentage that draws wet weightening finish, the result shows, anhydride draws moist all more much higher than hydrate of the present invention, and cefonicid sodium crystalline hydrate of the present invention stable storage better the results are shown in Table 1.
Table 1. draws the wet test result
Embodiment
The preparation of embodiment 1 cefonicid sodium 1 hydrate adds cefonicid acid 10g in reaction flask, water 20ml, stirring makes into suspension, drip triethylamine 4ml down at 5 ℃, stirring and dissolving, add gac 0.1g, stirred 30 minutes, suction filtration, washing, suction filtration, stirring the aqueous isopropanol that drips 20% Sodium isooctanoate under following 5 ℃ in filtrate makes pH to 6.5 (behind the base excess, regulate pH to 6.5 with Glacial acetic acid), stirred 40 minutes, slowly drip acetone 50ml and ethanol 150ml, place below 5 ℃, solid is fully separated out, suction filtration, small amount of ethanol is washed 3 times, suction filtration, the gained solid makes its dissolving with less water, uses ethanol 200ml again, acetone 200ml, chloroform 5ml carries out recrystallization, places below-5 ℃, solid is fully separated out, suction filtration, 10ml * 2 chloroforms are washed 2 times, suction filtration, about 40 ℃ of following vacuum-drying 3.5h of 20mmHg, get off-white color solid 5.8g, fusing point: 166 ℃ of variable colors (ELECTROTHERMAL MELTING POINT APPARATUS proofreaies and correct), HPLC: purity 99.1%, the retention time of its HPLC is consistent with the HPLC retention time of cefonicid reference substance; [α]
D=-40.2 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 2.92% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 2.89% (Fig. 1) of platform, this and sample contain result's (theoretical value 2.98%) of 1 crystal water in limit of error, infrared spectra: v
KBr MaxCm
-13389 (wide), 3062,3011,2953,1762,1677,1603,1542,1394,1235,1189,1104,1047,819,760,699, ESI-MS:m/z:585; Proton nmr spectra
1H-NMR (600MHz, D
2O) δ 7.20 (m, 5H), δ 5.39 (d, 1H), δ 5.26-5.34 (dd, 2H), δ 5.06 (s, 1H), δ 4.82 (d, 1H), δ 4.21 (d, 1H), δ 3.89 (d, 1H), δ 3.44 (d, 1H) δ 3.13 (d, 1H); Ultimate analysis theoretical value: C35.76%, H 3.00%, and N 13.90%, and S 15.91%, Na7.61%; Measured value: C 35.84%, H 3.05%, and N 13.96%, S15.85%, Na7.89%.
The preparation of embodiment 2 cefonicid sodiums 1 hydrate adds cefonicid acid 20g in reaction flask, water 40ml, stirring makes into suspension, stir, make pH to 6.6 at 5 ℃ of saturated aqueous solutions that drip anhydrous sodium carbonate down, add gac 0.1g, stirred 30 minutes, suction filtration adds acetonitrile 400ml and Virahol 250ml in the filtrate, place below-10 ℃, solid is fully separated out, and suction filtration, ethanol are washed 3 times, suction filtration, the gained solid makes it intact molten with less water, uses Virahol 300ml, acetonitrile 420ml, isopropyl ether 80ml is that recrystallisation solvent carries out recrystallization, places below-15 ℃ and spends the night, solid is fully separated out, suction filtration about 40 ℃ of following vacuum-drying 4h of 20mmHg, gets off-white color solid 10.6g, fusing point: 165 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: purity 99.0%, the retention time of its HPLC is consistent with the HPLC retention time of cefonicid reference substance; [α]
D=-40.8 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 2.8% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 2.94% (theoretical value 2.98%) of platform, infrared spectra: v
KBr MaxCm
-13384 (wide), 3062,3011,2954,1762,1677,1603,1522,1396,1361,1234,1188,1103,1046,1103,1046,984,819,759,698, ESI-MS:m/z:585; Ultimate analysis theoretical value: C 35.76%, H 3.00%, and N 13.90%, S15.91%, Na7.61%; Measured value: C 35.69%, H 3.09%, and N 13.82%, and S 15.80%, Na7.72%.
The preparation of embodiment 3 cefonicid sodiums 1 hydrate adds cefonicid acid 20g in reaction flask, water 5ml, methyl alcohol 200ml, stir, 5 ℃ of ethanolic solns that drip 28% Sodium isooctanoate down make pH to 6.6 (behind the base excess, regulate pH to 6.6 with Glacial acetic acid), stirred 30 minutes, slowly drip acetone 50ml and ethanol 150ml, place below 5 ℃, solid is fully separated out, suction filtration, ethanol is washed 3 times, suction filtration, and the gained solid makes its dissolving with less water, use ethanol 300ml, acetonitrile 420ml, isopropyl ether 80ml is that recrystallisation solvent carries out recrystallization, place below-10 ℃ and spend the night, crystallization is fully separated out, suction filtration, 10ml * 3 chloroforms are washed 3 times, suction filtration about 40 ℃ of following vacuum-drying 4h of 20mmHg, gets off-white color crystallization 12.1g, fusing point: 166 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: purity 98.8%, the retention time of its HPLC is consistent with the HPLC retention time of cefonicid reference substance; [α]
D=-39.5 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 3.49% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 3.07%, and this and sample contain result's (theoretical value 2.98%) of 1 crystal water in limit of error, infrared spectra: v
KBr MaxCm
-13396 (wide), 3062,301,2,2953,2897,176,1,1676,1603,1523,1394,1361,1290,1235,1189,1104,1047,1011,985,819,760,699, ESI-MS:m/z:585; Ultimate analysis theoretical value: C 35.76%, H 3.00%, and N 13.90%, S15.91%, Na7.61%; Measured value: C 35.69%, H 3.09%, and N 13.82%, and S 15.80%, Na7.72%.
The preparation of embodiment 4 cefonicid sodiums 0.5 hydrate adds cefonicid acid 20g in reaction flask, water 5ml, methyl alcohol 200ml, stir, the ethanolic soln that drips 28% Sodium isooctanoate under 5 ℃ in filtrate makes pH to 6.5 (after adding, regulate about pH to 6.5 with Glacial acetic acid), stirred 40 minutes, slowly drip acetone 150ml and Virahol 150ml, place below-5 ℃, solid is fully separated out, suction filtration, ethanol is washed 3 times, suction filtration, and the gained solid makes its firm dissolving with less water, add ethanol 300ml, acetonitrile 420ml, ether 80ml is that recrystallisation solvent carries out recrystallization, place below 5 ℃ and spend the night, crystallization is fully separated out, suction filtration, the 10ml chloroform is washed, suction filtration about 40 ℃ of following vacuum-drying 24h of 10mmHg, gets off-white color solid 11.8g, fusing point: 166 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: purity 98.7%, the retention time of its HPLC is consistent with the HPLC retention time of cefonicid reference substance; [α]
D=-40.2 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 1.65% that the Ka Shi method is measured moisture, and heat is analyzed: platform is weightless about 1.72%, and this and sample contain result's (theoretical value 1.51%) of 0.5 crystal water in limit of error, infrared spectra: v
KBr MaxCm
-13384,3062,3011,2953,1762,1677,1603,1542,1394,1235,1189,1104,1047,819,699, ESI-MS:m/z:585; Ultimate analysis theoretical value: C36.30%, H 2.88%, and N 14.11%, and S 16.15%, Na7.72%; Measured value: C36.23%, H 2.98%, and N 14.02%, and S 16.26%, Na7.61%.
The preparation of embodiment 5 cefonicid sodiums 2 hydrates adds cefonicid acid 20g in reaction flask, water 5ml, methyl alcohol 200ml, stir, the ethanolic soln that drips 28% Sodium isooctanoate under 5 ℃ in filtrate makes pH to 6.6, stirred 60 minutes, slowly drip acetone 50ml, ethanol 150ml, place down for-20 ℃, solid is fully separated out, and suction filtration, acetone are washed 3 times, suction filtration, the gained solid makes its dissolving with less water, uses ethanol 100ml, acetonitrile 400ml, isopropyl ether 100ml is that recrystallisation solvent carries out recrystallization, places below 5 ℃ and spends the night, crystallization is fully separated out, suction filtration, the 10ml acetonitrile is washed, suction filtration, about 35 ℃ of dry 22h, get off-white color solid 12.9g, fusing point: 160 ℃ of variable colors (ELECTROTHERMAL MELTING POINTAPPARATUS proofreaies and correct), HPLC: purity 99.2%, the retention time of its HPLC is consistent with the HPLC retention time of cefonicid reference substance; [α]
D=-41.3 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 6.03% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 5.78% (Fig. 2) of platform, this and sample contain result's (theoretical value 5.79%) of 2 crystal water in limit of error, infrared spectra: v
KBr MaxCm
-13389 (wide), 3062,3011,2953,1762,1677,1603,1542,1394,1235,1189,1104,1047,819,699, ESI-MS:m/z:585; Ultimate analysis theoretical value: C 34.73%, H 3.24%, and N 13.50%, S16.45%, Na7.39%; Measured value: C 34.61%, H 3.35%, and N 13.43%, and S 16.37%, Na7.46%.
The preparation of embodiment 6 cefonicid sodiums 1 hydrate adds cefonicid acid 20g in reaction flask, water 60ml, stirring makes into suspension, stir, make pH to 6.9 at 5 ℃ of saturated aqueous solutions that drip anhydrous sodium carbonate down, add gac 0.1g, stirred 30 minutes, press filtration is again with 0.22 μ m millipore filtration sterile filtration, about ℃ freezing 4～6h of filtrate-60～-40, heat up then between-20～-10 ℃ about lyophilize 20h, be warming up to about 30～43 ℃ of vacuum-drying 4h, get off-white color solid 20.2g, fusing point: 164 ℃ of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), [α]
D=-40.3 ° (get this product, the accurate title, decide, and makes the solution that contains 10mg among every 1ml approximately with dissolve with methanol and quantitative dilution); It is 2.86% that the Ka Shi method is measured moisture, and heat is analyzed: weightless about 2.69% (theoretical value 2.98%) of platform, infrared spectra: v
KBr MaxCm
-13384 (wide), 3062,3011,2954,1762,1677,1603,1522,1396,1361,1234,1188,1103,1046,1103,1046,984,819,759,698, ESI-MS:m/z:585;
Embodiment 7 gets cefonicid sodium hydrate 100g (pressing the preparation of embodiment 1 or embodiment 2 methods), and stirring makes molten, with N.F,USP MANNITOL 20g, EDTA disodium 0.05g adds about injection water 400～500ml, and stirring makes molten, regulating pH with citric acid about 1-5M and disodium phosphate soln is 6.5～7.5, add activated carbon 0.01～0.5% (W/V) and stir 15-30min, filter, with 0.22 micron filtering with microporous membrane, press 0.5g/ bottle or the packing of 1g/ bottle, vacuum lyophilization, tamponade gets finished product.
Embodiment 8 gets aseptic cefonicid sodium hydrate 10Kg (press embodiment 1 or embodiment 2 methods preparation), presses 0.5g/ bottle or 0.75g/ bottle or 1g/ bottle or the packing of 2g/ bottle with aseptic subpackaged technology, jumps a queue, tamponade, rolls aluminium lid and gets finished product.
Embodiment 9 gets aseptic cefonicid sodium 1 hydrate 2Kg, presses main ingredient 0.5g/ bottle or 1g/ bottle or the packing of 1.5g/ bottle with aseptic subpackaged technology, jumps a queue, tamponade, rolls aluminium lid and gets finished product.
Prescription:
Cefonicid sodium 1 hydrate (by embodiment 1 or the preparation of embodiment 2 methods), Microcrystalline Cellulose, sodium starch glycolate are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution with 5%PVP 30 is tackiness agent system softwood in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet or can capsule.
Embodiment 11 cefonicid sodium hydrate buccal tablets (250mg/ sheet)
Prescription:
Cefonicid sodium hydrate (by embodiment 1 or the preparation of embodiment 2 methods or embodiment 3 or embodiment 4 methods or embodiment 5 methods or the preparation of embodiment 6 methods), sorbitol instant, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Magnesium Stearate are crossed 100 mesh sieves, mixing, be pressed into sheet, again this sheet is ground the particle that is pressed into the 18-24 mesh sieve, compressing tablet.
Embodiment 12 cefonicid sodiums, 1 hydrate sheets (250mg/ sheet)
Prescription:
Cefonicid sodium 1 hydrate (by embodiment 1 or the preparation of embodiment 2 methods), N.F,USP MANNITOL, low-substituted hydroxypropyl cellulose are crossed 100 mesh sieves, mixing, 50% aqueous ethanolic solution with 5%PVP K30 is tackiness agent system softwood in right amount, crossing the 18-24 mesh sieve granulates, dry, after crossing the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix compressing tablet.
Embodiment 13: the preparation of cefonicid sodium hydrate capsule for vagina of the present invention (main ingredient 125mg/ grain)
Prescription: cefonicid sodium hydrate 125g
With cefonicid sodium 0.5 hydrate or cefonicid sodium 1 hydrate or cefonicid sodium 2 hydrates (preparing) mistake 100 mesh sieves by embodiment 1 or the preparation of embodiment 2 methods or embodiment 3 or embodiment 4 methods or embodiment 5 methods or embodiment 6 legal systems, mixing, the can capsule.
The suppository of embodiment 14 cefonicid sodium hydrates (250mg/ grain)
Prescription:
Cefonicid sodium hydrate (pressing preparation of embodiment 1 or embodiment 2 methods or embodiment 3 or the preparation of embodiment 4 methods), glycerine, polyethylene glycol 1500, Macrogol 4000, poloxamer, EDTA disodium are mixed, heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing the bolt mould a little, treat to scabble after cold, molding promptly.
Embodiment 15: under the GMP condition, aseptic cefonicid sodium 1 hydrate (pressing the preparation of embodiment 1 or embodiment 2 methods) and sodium-tazobactam (8: 1) 100 grams are pressed the preparation of injection procedure operation, be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 16: under the GMP condition, aseptic cefonicid sodium 2 hydrates (pressing the preparation of embodiment 1 or embodiment 2 methods) and sodium-tazobactam (4: 1) 100 grams are pressed the preparation of injection procedure operation, be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 17: under the GMP condition, with aseptic cefonicid sodium 1 hydrate 100 grams (pressing the preparation of embodiment 1 or embodiment 2 methods) and aseptic sulbactam 25g thorough mixing, press the preparation of injection procedure operation, be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 18: under the GMP condition, with aseptic cefonicid sodium 0.5 hydrate 100 grams and aseptic sulbactam 50g thorough mixing, press the preparation of injection procedure operation, will be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 19: under the GMP condition, aseptic cefonicid sodium 1 hydrate 100 grams (pressing the preparation of embodiment 1 or embodiment 2 methods) and aseptic sulbactam 100g thorough mixing are pressed the preparation of injection procedure operation, will be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 20: under the GMP condition, with aseptic cefonicid sodium 1 hydrate 100 grams (pressing the preparation of embodiment 1 or embodiment 2 methods) and aseptic Clavulanic Potassium 5g thorough mixing thorough mixing, press the preparation of injection procedure operation, be distributed into the 50-200 bottle, jump a queue, tamponade, roll aluminium lid and get finished product.
Embodiment 21: under the GMP condition, with aseptic cefonicid sodium 1 hydrate 100 grams (pressing the preparation of embodiment 1 or embodiment 2 methods) and aseptic sulbactam 50g thorough mixing, press lyophilized injectable powder preparation technology procedure operation, to be distributed into the 50-200 bottle, jump a queue, lyophilize, tamponade is rolled aluminium lid and is got finished product.
Be appreciated that from this professional angle the variation of a lot of details is possible, therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to the foregoing description.
Claims (9)
1. cefonicid sodium hydrate, it is characterized in that: molecular formula is C
18H
16N
6Na
2O
8S
3NH
2O, n=0.48～2.25.
2. cefonicid sodium hydrate according to claim 1 is characterized in that: be cefonicid sodium 0.5 hydrate.
3. cefonicid sodium hydrate according to claim 1 is characterized in that: be cefonicid sodium 1 hydrate.
4. cefonicid sodium hydrate according to claim 1 is characterized in that: be cefonicid sodium 2 hydrates.
5. cefonicid sodium hydrate according to claim 1, it is characterized in that: its preparation method comprises:
Method A. adds cefonicid acid in reaction vessel, add water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in one or more, stir, 10 ℃ drip C down
1-C
12Low molecular amine, stirring and dissolving adds gac and stirred 10-45 minute, filters, and adds one or more and water, the C of yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate under 10 ℃ in filtrate
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile, C
3-C
8Low molecule ketone, C
1-C
6Low molecule halohydrocarbon in one or more solution, stirring reaction 0.2-3 hour, regulate pH to 6.0～7.0 with mineral acid or organic acid or its solution, add C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
8Low molecule ester in one or more, place below 10 ℃, solid is fully separated out, suction filtration is used C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
6Low molecule nitrile, C
1-C
6Low molecule halohydrocarbon in one or more wash 1-3 time, filter gained solid water and C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
1-C
6Low molecule halohydrocarbon in one or more solvent recrystallization one or many, place below 10 ℃, solid is fully separated out, filter, drying, the cefonicid sodium hydrate;
Perhaps method B. adds cefonicid acid in reaction vessel, adds water, C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
2-C
6Low molecule nitrile in one or more, stir, under 10 ℃, in filtrate, add one or more and water, the C of yellow soda ash, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium octoate, Sodium isooctanoate
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone in one or more solution, stirring reaction 0.2-3 hour, regulate pH to 6.0～7.0 with mineral acid or organic acid or its solution, add C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
8Low molecule ester, C
1-C
6Low molecule halohydrocarbon in one or more, place below 10 ℃, solid is fully separated out, filter, use C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
2-C
6Low molecule nitrile, C
1-C
6Low molecule halohydrocarbon in one or more wash 1-3 time, filter gained solid water and C
1-C
6Low mass molecule alcohol, C
2-C
8Low molecule ether, C
3-C
8Low molecule ketone, C
1-C
6Low molecule halohydrocarbon in one or more carry out the one or many recrystallization for solvent, filter, drying, the cefonicid sodium hydrate.
6. cefonicid sodium hydrate according to claim 1, it is characterized in that: be used to prepare solid preparation, injection, wherein injection comprises injection freeze-dried powder, aseptic subpackaged powder injection, great transfusion preparation, solid preparation comprises tablet, capsule, granule.
7. cefonicid sodium hydrate according to claim 1 is characterized in that: be used to prepare the cefonicid sodium anhydride.
8. cefonicid sodium hydrate according to claim 1 is characterized in that: be used for preparing the application of the medicine of treatment of diseases such as the other inflammation of connective tissue in respiratory system, liver and gall, face, urinary tract infections, abdominal cavity infection, pelvic infection, septicemia, skin soft-tissue infection, bone and the infection of joint, adnexitis, intra-uterine infection, uterus to the human or animal due to Gram-positive or the negative bacteria sensitive organism, meningitis, gonorrhoea or prevention.
9. cefonicid sodium hydrate according to claim 1, it is characterized in that: be used for preparing antibacterial compound drug with one or more compositions of beta-lactamase inhibitor clavulanic acid or its pharmaceutical salts, Sulbactam or its pharmaceutical salts, Tazobactam Sodium or its pharmaceutical salts, wherein, the weight ratio of cefonicid sodium hydrate and beta-lactamase inhibitor is 32: 1～1: 2.
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| CN109232610B (en) * | 2018-09-04 | 2020-06-30 | 华北制药河北华民药业有限责任公司 | Refining method of cefonicid dibenzylethylenediamine salt |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156771A2 (en) * | 1984-03-29 | 1985-10-02 | Biochemie Gesellschaft M.B.H. | Cephalosporins |
| US5625058A (en) * | 1993-07-16 | 1997-04-29 | Farmabios S.R.1. | Process for the preparation of cephalosporins |
| CN101085781A (en) * | 2007-06-01 | 2007-12-12 | 深圳信立泰药业股份有限公司 | Method for preparing cefonicid or its medicinal salt and intermediate |
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2010
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0156771A2 (en) * | 1984-03-29 | 1985-10-02 | Biochemie Gesellschaft M.B.H. | Cephalosporins |
| US5625058A (en) * | 1993-07-16 | 1997-04-29 | Farmabios S.R.1. | Process for the preparation of cephalosporins |
| CN101085781A (en) * | 2007-06-01 | 2007-12-12 | 深圳信立泰药业股份有限公司 | Method for preparing cefonicid or its medicinal salt and intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106366096A (en) * | 2016-08-24 | 2017-02-01 | 南昌立健药业有限公司 | Cefonicid sodium compound for injection, preparation method, and medicine composition thereof |
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