CN102250123B - Cefodizime sodium hydrate and application thereof - Google Patents
Cefodizime sodium hydrate and application thereof Download PDFInfo
- Publication number
- CN102250123B CN102250123B CN201110124553.4A CN201110124553A CN102250123B CN 102250123 B CN102250123 B CN 102250123B CN 201110124553 A CN201110124553 A CN 201110124553A CN 102250123 B CN102250123 B CN 102250123B
- Authority
- CN
- China
- Prior art keywords
- cefodizime sodium
- cefodizime
- sodium
- hydrate
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
Abstract
The invention relates to cefodizime sodium hydrate as well as a preparation method and application thereof. The cefodizime sodium hydrate has better storage stability, and is suitable for being applied to the preparation of drugs for treating or preventing human or animal respiratory system diseases, hepatobiliary system diseases, diseases related to the five sense organs and urinary tract infection, abdominal cavity infection, pelvic cavity infection, septicemia, skin and soft tissue infections, bone and joint infections, adnexitis, intra-uterine infection, parametric connective tissue inflammation, meningitis, gonorrhea and other diseases caused by Gram-positive or negative bacteria sensitive bacteria.
Description
Technical field
The present invention relates to medical technical field, be specifically to provide antibacterials---Cefodizime sodium hydrate and its production and use.
Background technology
Cefodizime Sodium (Cefodizime sodium) is the third generation cephalosporin that injection for intravenous or intramuscular injection are used.Cefodizime Sodium has broad-spectrum antibacterial action, the gram-negative bacterias such as thunder Bai Shi pneumobacillus, Bacillus proteus, dysentery bacterium, Shigella, salmonella, Corynebacterium diphtheriae, hemophilus influenzae are had to stronger anti-microbial activity, gram positive organism is also had to good anti-microbial activity as Portugal bacterium, streptococcus pneumoniae, streptococcus, Neisseria gonorrheae (comprise and produce mould rope enzyme bacterial strain), the scorching diplococcus of neisseria meningitis.MSSA (MSSA) and staphylococcus epidermidis are had to certain anti-microbial effect, to Pseudomonas aeruginosa, acinetobacter calcoaceticus, citrobacter, methicillin-resistant staphylococcus aureus (MRSA) and enterococcal most of resistant strains.
Thiazole sulfur side chain on 3 of the cephem cores of Cefodizime Sodium makes it have good pharmaco-kinetic properties, long half time in human body, only need 1 administration concentration of can remaining valid every day, more stable to β-lactamase, the immunoregulation effect of tool uniqueness, in vitro tests shows, it can strengthen neutrophil leucocyte, phagocytic cell and lymphocytic activity, the patient that normal and phagocytic function is reduced is (as gerontal patient, multiple myeloma, renal failure person, all can strengthen its phagocytic function, and can improve CD
4lymphocyte number, makes CD
4/ CD
βlymphocyte is than recovering normal.To effective antibacterial therapy of immunologic hypofunction person infection and severe bacterial infections person, not only need the anti-microbial effect of medicine, need sound host defense mechanism to participate in, Cefodizime Sodium has broad-spectrum antimicrobial and immuno-potentiation concurrently simultaneously, infects particularly applicable to immunologic hypofunction person.
At present, disclosed document has only been reported Cefodizime Sodium (Cefodizime sodium) (C
20h
18n
6na
2o
7s
4, molecular weight: 628.63, No. CAS: 86329-79-5), up to the present, still there is no disclosed bibliographical information Cefodizime Sodium crystalline 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 antibacterial infection medicine Cefodizime sodium hydrate and its production and use, and its molecular formula is C
20h
18n
6na
2o
7s
4nH
2o, the numeral between n=0.5～2.7, comprises 0.5,0.6,0.7,0.75,0.8,1,1.25,1.5,2,2.25,2.5 etc.
The Cefodizime Sodium crystalline hydrate that the present invention obtains, surprisingly, it draws the moist Cefodizime Sodium far below containing non-crystallizable water, the Cefodizime Sodium that contains crystal water than containing crystal water more can be stable existence, be convenient to store and transport, be easy to make preparation.In addition, the deliquescence of anhydride makes will to completely cut off air in the time processing and prevents adhesion etc., and hydrate has good sliding, thereby improves the operability of preparation.
Surprisingly, distinctive, under the weightless platform of heat analysis (TG-DSC or the TG-DTA) collection of illustrative plates of hydrate of the present invention, there is corresponding endotherm(ic)peak, thermogram spectrum demonstrates Cefodizime sodium hydrate, as Cefodizime Sodium 0.5 hydrate, 0.6 hydrate, 0.75 hydrate, Cefodizime Sodium 1 hydrate, Cefodizime Sodium 1.5 hydrates, Cefodizime Sodium 2 hydrates Cefodizime Sodium 2.5 hydrates etc.
Cefodizime Sodium crystalline hydrate energy stable storage of the present invention.Cefodizime sodium hydrate and anhydride sample are drawn to moist test: get Cefodizime Sodium anhydride and the about 5g of hydrate of the present invention, be placed in the watch-glass of dry constant weight, precise weighing, 25 DEG C, relative humidity are 70%, respectively at test 0h and 10h sampling, calculate the percentage that draws wet weightening finish, result shows, anhydride draws moist all more much higher than hydrate of the present invention, and Cefodizime Sodium crystalline hydrate of the present invention better stable storage the results are shown in Table 1.Under RH75%, 10 DEG C of conditions, Cefodizime Sodium crystalline hydrate and anhydride sample are enclosed within to the stability test of carrying out in cillin bottle 6 months, with reference to the measuring method of 2010 editions Cefodizime Sodiums of Chinese Pharmacopoeia, the condition that Cefodizime Sodium HPLC method is measured: Cl8(5 μ m250 × 4.6mm), (get potassium primary phosphate 0.87g and disodium hydrogen phosphate,anhydrous 0.22g with phosphate buffered saline buffer, be dissolved in water and be diluted to 1000ml, shaking up)-acetonitrile (920:80) is for moving phase; Column temperature is room temperature, flow velocity 1ml/min, and detecting wavelength is that 262nm measures content, and detecting wavelength is that 231nm measures related substance, measures and finds that Cefodizime Sodium crystalline hydrate content is substantially constant, and the amplitude that related substance thing increases is starkly lower than anhydride.Test-results illustrates that Cefodizime sodium hydrate of the present invention has good storage stability.
Crystalline solid has chemical stability and the physical stability higher than amorphous form and low-crystallinity form, and they also can show as water absorbability, bulk properties and or the mobility of raising.
The discovery of the useful compound on new polymorphous medicine provides new chance once improving the action characteristic of medicament production, it has expanded formulation science man design example as having the pharmaceutical dosage form of medicine of target release profiles or other desired characteristic and the storehouse of the material that obtains, and this area needs Cefodizime Sodium crystalline hydrate or its polymorph.
Table 1. draws wet test result
Table 2. accelerated stability test result
The preparation of Cefodizime sodio-derivative---Cefodizime sodium hydrate comprises following method:
Method A., in reaction vessel, adds Cefodizime acid, 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 10 DEG C of following C that drip
1-C
12low molecular amine, stirring and dissolving, adds one or more and water, the C of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium Thiocyanate 99, Sodium octoate, Sodium isooctanoate at 10 DEG 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 solution, stir 0.2-3 hour, regulate pH to 6.0～7.5 with mineral acid or organic acid or its solution, above-mentioned solution is joined to 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 in, or 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, 20 DEG C of following placements, fully separate out solid, 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 or 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, C
2-C
8low molecule ester in one or more solvent recrystallization one or many, 20 DEG C of following placements, fully separate out crystallization, filter, washing, dry, obtain Cefodizime Sodium crystalline hydrate;
Wherein, the Cefodizime acid using in reaction: C
1-C
12low molecular amine: the mol ratio of alkali (one in sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium Thiocyanate 99, Sodium octoate, Sodium isooctanoate) is generally 1:0.5～1.1:1～1.1; Cefodizime acid (weight g) with 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): 1.5～50 (ml); The water using in crystallization or recrystallization and the volume ratio of organic solvent are generally 1:5～300.The consumption of gac is the 0.01-1% of institute's de-inking solution weight.
Or method B., in reaction vessel, adds Cefodizime acid, 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, below 10 DEG C, in filtrate, add one or more and water, the C of sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium Thiocyanate 99, Sodium octoate, Sodium isooctanoate
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 solution, stirring reaction 0.2-3 hour, regulates pH to 6.0～7.5 with mineral acid or organic acid or its solution, and above-mentioned solution is joined to 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 in, or 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, 20 DEG C of following placements, fully separate out solid, 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, C
2-C
8low molecule ester in one or more carry out one or many recrystallization for recrystallisation solvent, filter washing, the dry Cefodizime Sodium crystalline hydrate that to obtain.
Wherein, the Cefodizime acid using in reaction: the mol ratio of alkali (one in sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium-acetate, Sodium Thiocyanate 99, Sodium octoate, Sodium isooctanoate etc.) is generally 1:0.5～1.1:1～1.1; Cefodizime acid (weight g) with 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): 1.5～50 (ml); The water using in crystallization or recrystallization and the volume ratio of organic solvent are generally 1:10～300.Adding gac stirring decolouring can carry out in the various process of preparation, stirs bleaching time and is generally 10-45 minute, filters decarburization, washes.
The crystallization of Cefodizime sodium hydrate or recrystallization solvent are selected from one or more in water, acetonitrile, tetrahydrofuran (THF), methyl alcohol, ethanol, Virahol, acetone, N-BUTYL ACETATE, ethyl acetate, ethyl formate, ether, isopropyl ether, tetrahydrofuran (THF), methylene dichloride, chloroform etc.; Cefodizime Sodium crystallization crystallization or recrystallization solvent, preferably water, methyl alcohol, ethanol, Virahol, one or more in acetone, tetrahydrofuran (THF), ethyl acetate, ether, isopropyl ether, chloroform.In preparation method of the present invention, in recrystallization process, can first use water dissolution Cefodizime Sodium crystalline hydrate, after dissolving, can use activated carbon decolorizing (if use activated carbon decolorizing, its consumption is the 0.01-1% of institute's de-inking solution weight), then make its crystallization with the solvent in the present invention.In recrystallization process, Cefodizime acid sodium aqueous solution can be joined to 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 in, or add therein 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, let cool placement crystallization.The preparation of aseptic Cefodizime sodium hydrate is carried out aseptic technique preparation according to common process.Cefodizime sodium hydrate of the present invention can have different crystal formations.
The carbonatoms of the low mass molecule alcohol in the present invention is defined as C
1-C
6(that is: the alcohol of 1-6 carbon atom), as methyl alcohol, ethanol, Virahol etc.; The carbonatoms of low molecule ether is defined as C
2-C
8(that is: the ether of 2-8 carbon atom), as ether, isopropyl ether, butyl ether, tetrahydrofuran (THF) etc.; The carbonatoms of low molecule halohydrocarbon is defined as C
1-C
6(that is: the halohydrocarbon of 1-6 carbon atom), comprises methylene dichloride, ethylene dichloride, chloroform etc.; The carbonatoms of low molecule ester is defined as C
2-C
8(that is: the ester of 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, comprise pentane, normal hexane, hexanaphthene, sherwood oil etc.; The carbonatoms of low molecule aromatic hydrocarbon is defined as C
6-C
12(that is: the aromatic hydrocarbon of 6-12 carbon atom), comprises benzene, toluene etc.; C
1-C
6the carbonatoms of low molecular acid be defined as the organic acid of 1-6 carbon atom, comprise formic acid, acetic acid, propionic acid etc.; C
3-C
8low molecule ketone be defined as the ketone of 3-6 carbon atom, comprise acetone, butanone, hexone etc.; C
2-C
6low molecule nitrile (that is: the nitrile of 2-6 carbon atom), comprise acetonitrile, propionitrile 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, TERTIARY BUTYL AMINE, N-methylmorpholine, pyridine, picoline etc.; About any class description be " low molecule " compound amount of carbon atom marking method if in the application's text occur once, 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 drying mode of product of the present invention can be in differing temps (as 20-80 DEG C), time of drying (0.5 hour to a few days) or has 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 to be dried last product.Its drying temperature is preferably at 30-50 DEG C.
Powder X-ray diffraction can be used to characterize and/or differentiate polymorph conventionally, in the time characterizing and/or differentiate, before report peak value, uses modifier " approximately " for powder X-ray diffraction.In view of the intrinsic variation of peak value, this is the practice in solid state chemistry field.The common accuracy of the 2 θ x-axle values at powder collection of illustrative plates peak in ± 0.2 ° of 2 θ rank, therefore, so that " the powder X-ray diffraction peak that approximately 8.0 ° of 2 θ occurs means in the time measuring on most of x-ray diffractometers, and peak may be between 7.8 ° of 2 θ and 8.2 ° of 2 θ.The variation of peak intensity is the result how each crystal is orientated with respect to outside X-ray source in sampling receptacle, and orientation effect does not provide the structural information about crystal.
The present invention on the one hand, provides the different crystalline hydrate of Cefodizime Sodium.
The present invention on the other hand, provides the crystalline hydrate of different crystalline form and their preparation method.
The present invention provides a kind of medicinal compositions on the other hand, comprising any or multiple Cefodizime Sodium crystalline hydrate of being prepared by method of the present invention, and the acceptable vehicle of one or more pharmacy.
The present invention further provides the method for useful in preparing drug formulations, comprising any or multiple Cefodizime Sodium crystalline hydrate of being prepared by method of the present invention.
The present invention further provides the crystalline hydrate of Cefodizime Sodium crystalline hydrate and different crystal forms, as Cefodizime Sodium 1 hydrate, 1.5 hydrates, 2 hydrates, 2.5 hydrates etc., infecting for the preparation for the treatment of, comprise bacterium infection, Gram-positive and or the pharmaceutical composition that infects such as negative bacterium infection in purposes.
Cefodizime sodium hydrate purposes of the present invention: Cefodizime sodium hydrate of the present invention is for the preparation of 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 Cefodizime Sodium anhydride.The preparation of anhydride can be obtained through different drying meanss by Cefodizime sodium hydrate of the present invention, its preparation can be at differing temps (as 50-100 DEG C), 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.) envrionment conditions under, or and use the mode of normal pressure or decompression to be dried last product, also can be first by the method for benzene distillation band water, and obtain after dry in conjunction with other drying means described herein.
For the preparation of tablet (comprising buccal tablet, Sublingual tablet, mouth paster, orally disintegrating tablet, vaginal tablet etc.), capsule (comprising rectum, capsule for vagina etc.), 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, 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, as gelling starch, methylcellulose gum, Xylo-Mucine, ethyl cellulose, polyvinylpyrrolidone, Lalgine and salt thereof; Pharmaceutically acceptable lubricant and glidant, as stearic acid, Magnesium Stearate, Macrogol 4000-8000, talcum powder, micropowder silica gel, Stepanol MG etc.; Pharmaceutically acceptable sweeting agent and essence, as aspartame, Sodium Cyclamate, soluble saccharin, Sucralose, food flavour etc.
The suppository preparation of Cefodizime Sodium crystalline hydrate: Cefodizime Sodium crystalline hydrate 1～50%, suppository base 50～99% compositions, matrix can be one or more in ethanol, glycerine, Vaseline, glycogelatin, Macrogol 200～8000, poloxamer, semi-synthetic hard fatty acids fat, carbomer series (931,934,940,974, AA-1,1342 etc.), polysorbate60～80.Preparation method: main ingredient is mixed with matrix, heating in water bath, stir, wait to melt, be stirred in the mould of suppository that even, rapid impouring scribbled lubricant, to overflowing bolt mould a little, scabble after cold, molding and get final product.
The injection of Cefodizime 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.
Infusion preparation, 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, preparation according to a conventional method.
The preparation method of freeze-dried powder is: get Cefodizime sodium hydrate, can add pharmaceutically acceptable frozen-dried supporting agent or auxiliary shape agent, stablizer, water for injection, be stirred to dissolve, if desired, available pharmaceutically acceptable acid-alkali accommodation pH is 6.0～7.5, adds activated carbon 0.005～0.5%(W/V) stir 15～45min, filter, moisturizing, sterile filtration, by the packing of 0.5～2g/ bottle, lyophilize, tamponade, obtains finished product.
Its pharmaceutically acceptable pH adjusting agent can be pharmaceutically acceptable mineral acid or organic acid, mineral alkali or organic bases, also can be Lewis acid or the alkali of broad sense, 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, Citric Acid pharmaceutical salts, sodium carbonate, 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, as glucuronic acid, gluconic acid, lactobionic acid, oxysuccinic acid, threonic acid, one or several in glucoheptonic acid etc.
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, DHB 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 one or several in EDETATE SODIUM, EDTA tetra-sodium, N-bis-(2-hydroxyethyl) glycine etc.
Source and the degerming mode of reducing phlegm and internal heat can be to add the gac of 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 hyperfiltration process, that ultra-fine filter can be selected is flat, rolling, tubular type, tubular fibre formula or circle boxlike etc., preferably rolling and tubular fibre formula ultra-fine filter, it is that 50,000 to 300,000 filter membrane is removed after most of heat generation material and bacterium that relative molecular mass is held back in employing, adopt again the ultra-filtration membrane of holding back relative molecular mass 4000～30000 to remove residue thermal source, the preferably ultra-filtration membrane of relative molecular mass 6000～30000.
Cefodizime sodium hydrate of the present invention is applicable to: the application in the treatments of disease 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 preparation to the human or animal due to Gram-positive or negative bacteria sensitive organism, meningitis, gonorrhoea or the medicine of prevention.
The present invention further provides the composition of Cefodizime sodium hydrate and beta-lactamase inhibitor, Cefodizime sodium hydrate for the preparation of with the composition of beta-lactamase inhibitor, beta-lactamase inhibitor comprises the pharmaceutical salts of the pharmaceutical salts of Tazobactam Sodium or the pharmaceutical salts of Sulbactam or clavulanic acid, as sodium-tazobactam, Tazobactam Sodium sodium hydrate, sulbactam, Clavulanic Potassium etc.Cefodizime Sodium crystalline hydrate and enzyme inhibitors comprise that the part by weight of the pharmaceutical salts composition composition of the pharmaceutical salts of Tazobactam Sodium or the pharmaceutical salts of Sulbactam or clavulanic acid is 30:1～1:2.
Cefodizime sodium hydrate can be different with the ratio of different beta-lactamase inhibitors from the weight ratio of the composition of beta-lactamase inhibitor, preferred 4:1～the 8:1 of weight ratio of the composition of general Cefodizime sodium hydrate and beta-lactamase inhibitor Tazobactam Sodium or its pharmaceutical salts, preferred 2:1～the 1:1 of weight ratio of the composition of general Cefodizime sodium hydrate and beta-lactamase inhibitor Sulbactam or its pharmaceutical salts, said composition has stronger anti-microbial effect, for the treatment of human or animal's disease due to Gram-positive or negative bacteria sensitive organism or the application of the medicine of prevention.
Consumption usage: generally, for Cefodizime sodium hydrate (in anhydride), adult's consumption general every day of 1.0～2.0g, point 1-2 administration; Children's consumption general every day of 60～80mg/kg, can take the circumstances into consideration increase and decrease according to symptom.Intravenous injection: 0.5g or 1.0g solution is in 4ml water for injection, or 2.0g is dissolved in 10ml water for injection, injection in 3～5 minutes.Venoclysis: 0.5g, 1.0g or 2.0g are dissolved in 40ml water for injection, physiological saline or ringer's solution, infusion in 20～30 minutes.Intramuscular injection: 0.5g or 1.0g are dissolved in 4ml water for injection, or 2.0g is dissolved in 10ml water for injection, gluteus deep injection: for preventing pain, Cefodizime sodium hydrate can be dissolved in 1% lignocaine solution and inject.Or by orally administering (changing injecting pathway for absorbing by oral mucosa), adult 0.5g～2g every day; Or vagina administration (absorbing by vaginal mucosa) or rectal administration, adult 0.5g～2g every day.
Cefodizime sodium hydrate of the present invention comprises crystalline hydrate and noncrystalline hydrate, be applicable to: prepare antibacterial compound drug, these antibacterial compound drugs are made up of Cefodizime sodium hydrate and clavulanic acid or its pharmaceutical salts, Sulbactam or its pharmaceutical salts, Tazobactam Sodium or its pharmaceutical salts, wherein, the weight ratio of Cefodizime sodium hydrate and beta-lactamase inhibitor is 1:0.05～2, the preferred Clavulanic Potassium of clavulanic acid pharmaceutical salts, the preferred sulbactam of Sulbactam pharmaceutical salts, the preferred sodium-tazobactam of Tazobactam Sodium pharmaceutical salts.
The deliquescence that crystalline hydrate of the present invention is different from anhydride makes will to completely cut off air in the time processing and prevents adhesion etc., and crystalline hydrate has good sliding, thereby improves the operability of preparation; And make the solid preparation of preparation there is good dissolving out capability, and it is easily absorbed and enters blood circulation, improve bioavailability, and be conducive to bring into play fast its effect.From another aspect, it is prevented makes loading amount generation difference cause underdosage carrying out producing obstruction while being difficult for causing packing because of the moisture absorption when aseptic subpackaged, thereby bring the defective of product, or because underproof product is actual not undetected to forming by sampling observation, and then come into the market, in clinical treatment, patient's treatment is acted on behalf of to negative effect, or jeopardize patient's life because of underdosage.Or in the time of packing, cause whole production line to be forced to suspend because of the moisture absorption, seriously reduce the throughput of equipment, greatly increase the hidden danger of work time cost etc.In addition, prepare Cefodizime Sodium anhydride and need to consume more energy than the preparation of Cefodizime sodium hydrate.
This antibacterial compound drug also can be used for originally responsive poorly to Cefodizime sodium hydrate but merge the infectious diseases using due to Gram-positive or the negative bacteria that susceptibility strengthens after above-mentioned enzyme inhibitors, and above-mentioned composition is applicable to prepare the application in the treatments of disease 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, meningitis, gonorrhoea of the human or animal due to it or the medicine of prevention.
Brief description of the drawings
Fig. 1 is the thermogram spectrum of Cefodizime Sodium 1 hydrate.
Fig. 2 is the thermogram spectrum of Cefodizime Sodium 1.5 hydrates.
Fig. 3 is the thermogram spectrum of Cefodizime Sodium 2 hydrates.
Fig. 4 is the thermogram spectrum of Cefodizime Sodium 2.5 hydrates.
Fig. 5 is the powder X-ray diffractogram (embodiment 3) of Cefodizime Sodium 1.5 hydrate hydrates.
Fig. 6 is the powder X-ray diffractogram (embodiment 7) of Cefodizime Sodium 2.5 hydrates.
Embodiment
When having instruction in an embodiment and separately, in specification sheets and claims, all numerical value used should be understood to be in all examples and modify with term " about ", therefore, unless the contrary indication, in this specification sheets and appending claims, given numerical parameter is approximation, it can change according to the required character of looking for by present disclosure, at least, and 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.
Although setting numerical range and the parameter of the wide region of disclosure is approximation.But numerical value given in specific embodiment as far as possible accurately reported, any number comprises some error being certainly led to by the standard deviation of finding in their tests separately in essence.
Unless it is pointed out that explanation in addition clearly in literary composition, the singulative " ", " one " and " being somebody's turn to do " that use in this specification and the appended claims comprise the plural form that refers to thing, so, for example.If comprise the mixture of two or more compounds while mentioning the composition that contains " a kind of compound ", unless it should be noted that in addition explanation in addition clearly herein, term "or" generally includes "and/or".
As used herein, term " obtains " referring to that valuable purity level separates the compound obtaining, and described purity level includes but not limited to be greater than 90%, 95%, 96%, 97%, 98% and 99% purity level.Described purity level can be passed through high-performance liquid chromatogram determination.
Heat analysis method
Hot analytical test condition: the Setsys16 of Setaram company, sample size 5mg left and right, heat-up rate: 10K/min, N
2flow velocity: 50ml/min, temperature: DEG C left and right, room temperature～400.
Surprisingly, distinctive, under the weightless platform of heat analysis (TG-DTA or the TG-DSC) collection of illustrative plates of hydrate of the present invention, there is corresponding endotherm(ic)peak.
Powder X-ray diffraction approach
Utilize D/MX-III A X-ray diffractometer, voltage: 35kv, electric current: 30mA, sweep velocity: 10 °/min, step-length: 0.02 °/step; Copper target, monochromator: graphite monochromator; Wavelength wavelength
: 1.54, diffraction angle 2 θ, sweep limit 3-60 °, has measured the x-ray diffractogram of powder of Cefodizime Sodium crystalline hydrate, and all peak positions are in ± 0.2 ° of 2 θ.
In one embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, Cefodizime Sodium 1.5 hydrates of the present invention can have in the position that comprises following 2 θ values corresponding eigenwert (accompanying drawing 5): approximately 3.77,10.19,16.91,21.7.
In another embodiment, utilize powder X-ray diffractometry to measure, in diffraction angle 2 θ (3-60 °) useful range, Cefodizime Sodium 2.5 hydrates of the present invention can have in the position that comprises following 2 θ values corresponding eigenwert (accompanying drawing 6) approximately 4.47,6.16,9.97,11.95,16.26,19.88,21.91.
" pharmaceutical composition " used herein refers to the composition of medicine, and described pharmaceutical composition can contain at least one pharmaceutically acceptable carrier.
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 are described is for further illustrating the features and advantages of the present invention, instead of limiting to the claimed invention.
With specific embodiment, effect of the present invention is described below, but protection scope of the present invention is not limited by the following examples.
The preparation of embodiment 1 Cefodizime Sodium 1 hydrate adds Cefodizime acid 10g in reaction flask, water 30ml, stirring makes into suspension, at 5 DEG C, drip triethylamine 5ml, stir 30min, the ethanolic soln that drips 28% Sodium isooctanoate at 5 DEG C makes pH to 6.9 (after adding, with Glacial acetic acid adjusting pH to 6.9 left and right), stir, slowly drip acetone 50ml and acetonitrile 150ml,-5 DEG C of following placements, solid is fully separated out, suction filtration, a small amount of acetone is washed 3 times, suction filtration, gained solid just dissolves it with a small amount of water, add gac 0.15g, stir 30 minutes, suction filtration, washing, suction filtration, use again acetonitrile 200ml, acetone 200ml carries out recrystallization, 5 DEG C of following placements, crystallization is fully separated out, suction filtration, 30ml chloroform is washed, suction filtration, 45 DEG C of vacuum-drying 6h left and right, obtain off-white color crystallization 5.6g, HPLC: purity 99.3%, the retention time of its HPLC is consistent with the HPLC retention time of Cefodizime acid reference substance, fusing point: 195 DEG C of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), it is 3.13% that Ka Shi method is measured moisture, heat is analyzed: the weightless about 3.00%(Fig. 1 of platform), the result (theoretical value 2.79%) that this and sample contain 1 crystal water in limit of error, [α]
d=-59.3 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), infrared spectra: ν
kBr maxcm-
1ν
kBr maxcm-
13415 (wide), 2939,1763,1660,1593,1533,1387,1285,1180,1103,1044,895,691, ESI-MS:m/z:627, ultimate analysis theoretical value: C37.15%, H3.12%, N13.00%, S19.83%, Na7.11%, measured value: C37.07%, H3.23%, N12.85%, S19.72%, Na7.17%.
The preparation of embodiment 2 Cefodizime Sodium 1 hydrates adds Cefodizime acid 10g, water 30ml in reaction flask, stirs and makes into suspension, drips diethylamine 3.8ml at 5 DEG C, and stirring makes molten, adds gac 0.2
x, stir 30 minutes, suction filtration, washing, suction filtration, the ethanolic soln that drips 28% Sodium isooctanoate at 5 DEG C in filtrate makes pH to 6.9, stir, slowly be added in acetone 400ml, 0 DEG C of following placement, solid is fully separated out, suction filtration, a small amount of acetone is washed 3 times, suction filtration, gained solid just dissolves it with a small amount of water, carry out recrystallization with acetone 500ml again,-10 DEG C of following placements, crystallization is fully separated out, suction filtration, 30ml chloroform is washed, suction filtration, 45 DEG C of vacuum-drying 8h left and right, obtain off-white color crystallization 5.6g, fusing point: 196 DEG C of variable color (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), it is 2.7% that Ka Shi method is measured moisture, heat is analyzed: platform weightless approximately 2.73%, the result (theoretical value 2.79%) that this and sample contain 1 crystal water is in limit of error, [α]
d=-60.1 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), infrared spectra: ν
kBr maxcm
-13415 (wide), 2939,1763,1660,1593,1533,1387,1285,1180,1103,1044,895,691, ESI-MS:m/z:627, ultimate analysis theoretical value: C37.15%, H3.12%, N13.00%, S19.83%, Na7.11%, measured value: C37.10%, H3.18%, N13.07%, S19.76%, Na7.19%.
The preparation of embodiment 3 Cefodizime Sodium 1.5 hydrates adds Cefodizime acid 20g in reaction flask, water 50ml, stirring makes into suspension, the saturated aqueous solution that drips anhydrous sodium carbonate 3.8g at 5 DEG C makes pH to 7.0 (after adding, with Glacial acetic acid adjusting pH to 7.0 left and right), stir, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, in filtrate, slowly drip acetone 50ml, isopropyl ether 250ml, 4 DEG C of following placements, solid is fully separated out, suction filtration, acetone is washed 3 times, suction filtration, gained solid just dissolves it with a small amount of water, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, use isopropyl ether 100ml, acetone 420ml carries out recrystallization to it, 5 DEG C of following placements are spent the night, crystallization is fully separated out, suction filtration, 30ml chloroform is washed, suction filtration, 42 DEG C of left and right vacuum-drying 6h left and right, obtain off-white color crystallization 9.2g, HPLC: purity 99.5%, the retention time of its HPLC is consistent with the HPLC retention time of Cefodizime acid reference substance, fusing point: 192 DEG C of variable color (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), X powder diffraction: measure and have multiple obvious characteristic peaks within the scope of 3-60 °, it is 4.15% that Ka Shi method is measured moisture, heat is analyzed: the weightless about 3.93%(Fig. 2 of platform), the result (theoretical value 4.12%) that this and sample contain 1.5 crystal water is in limit of error, X powder diffraction: measure and have multiple obvious characteristic peaks (Fig. 5) within the scope of 3-60 °, specific optical rotation :-58.6 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), infrared spectra: ν
kBr maxcm
-13315 (wide), 3196,2940,1766,1658,1590,1533,1380,1284,1181,1107,1043,1110,969,935,896,808,690, ESI-MS:m/z:627, ultimate analysis theoretical value: C36.64%, H3.23%, N12.82%, S19.56%, Na7.01%, measured value: C36.56%, H3.31%, N12.88%, S19.67%, Na6.90%.
The preparation of embodiment 4 Cefodizime Sodium 1.5 hydrates adds Cefodizime acid 20g in reaction flask, water 5ml, methyl alcohol 200ml, stir, the ethyl acetate solution that drips 28% Sodium isooctanoate at 5 DEG C makes pH to 7.0, stir, slowly drip acetone 280ml, isopropyl ether 150ml,-5 DEG C of following placements, solid is fully separated out, suction filtration, acetone is washed 3 times, suction filtration, gained solid makes its dissolving with a small amount of water, add gac 0.3g, stir 30 minutes, suction filtration, filtrate adds acetone 300ml, acetonitrile 420ml, isopropyl ether 80ml is that recrystallisation solvent carries out recrystallization, 5 DEG C of following placements are spent the night, crystallization is fully separated out, suction filtration, 40ml chloroform is washed, suction filtration, 40 DEG C of vacuum-drying 4h left and right, obtain micro-yellow solid 10.6g, fusing point: 193 DEG C of decomposition (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), it is 4.46% that Ka Shi method is measured moisture, heat is analyzed: platform weightless approximately 4.41%, the result (theoretical value 4.12%) that this and sample contain 1.5 crystal water is in limit of error, [α]
d=-57.2 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), infrared spectra: ν
kBr maxcm
-13415 (wide), 2939,1763,1660,1593,1533,1387,1285,1180,1103,1044,895,691, ESI-MS:m/z:627, ultimate analysis theoretical value: C36.64%, H3.23%, N12.82%, S19.56%, Na7.01%, measured value: C36.48%, H3.33%, N12.76%, S19.48%, Na6.93%.
The preparation of embodiment 5 Cefodizime Sodium 2 hydrates adds Cefodizime acid 20g in reaction flask, water 5ml, methyl alcohol 100ml, stir, the aqueous isopropanol that drips 28% Sodium isooctanoate at 5 DEG C makes pH to 6.8, stir 60 minutes, slowly drip acetone 200ml and Virahol 200ml,-5 DEG C of following placements, solid is fully separated out, suction filtration, acetone is washed 3 times, suction filtration, gained solid makes its dissolving with a small amount of water, acetone 300ml, acetonitrile 100ml, isopropyl ether 60ml is that recrystallisation solvent carries out recrystallization, 4 DEG C of following placements are spent the night, crystallization is fully separated out, suction filtration, 10ml acetonitrile is washed, suction filtration, 38 DEG C of dry 22h left and right, obtain crystallization 12.6g, HPLC: purity 99.4%, the retention time of its HPLC is consistent with the HPLC retention time of Cefodizime acid reference substance, fusing point: 168 DEG C of variable colors (ELECTROTHERMAL MELTING POINT APPARATUS does not proofread and correct), specific optical rotation :-58.8 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), it is 5.66% that Ka Shi method is measured moisture, and heat is analyzed: the weightless about 5.80%(Fig. 3 of platform), the result (theoretical value 5.42%) that this and sample contain 2 crystal water is in limit of error, infrared spectra: ν
kBr maxcm
-13413 (wide), 2939,1763,1660,1593,1533,1387,1285,1180,1103,1044,895,691, ESI-MS:m/z:627, ultimate analysis theoretical value: C36.14%, H3.34%, N12.64%, S19.30%, Na6.92%, measured value: C36.02%, H3.46%, N12.49%, S19.17%, Na6.81%.By it, at 60 DEG C, under Vanadium Pentoxide in FLAKES, vacuum-drying 36h left and right, obtains Cefodizime Sodium anhydride.
The preparation of embodiment 6 Cefodizime Sodium 0.5 hydrates adds Cefodizime acid 20g in reaction flask, water 50ml, stirring makes into suspension, under 5 DEG C of stirrings, drip the saturated aqueous solution of sodium bicarbonate 5.8g, make to dissolve, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, filtrate slowly drips acetone 200ml, methylene dichloride 10ml, ether 200ml,-15 DEG C of following placements, solid is fully separated out, suction filtration, acetone is washed 3 times, suction filtration, gained solid just dissolves it with a small amount of water, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, filtrate adds acetone 300ml, methylene dichloride 10ml, ether 60ml is that recrystallisation solvent carries out recrystallization,-15 DEG C of following placements are spent the night, crystallization is fully separated out, suction filtration, 40ml chloroform is washed, suction filtration, 50 DEG C of dry vacuum 24h left and right, obtain crystallization 11.3g, fusing point: 196 DEG C of variable color (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), specific optical rotation: (get this product for-58.6 °, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), it is 1.57% that Ka Shi method is measured moisture, and heat is analyzed: platform weightlessness approximately 1.65%, and the result (theoretical value 1.41%) that this and sample contain 0.5 crystal water is in limit of error, infrared spectra: ν
kBr maxcm
-13413 (wide), 2939,1763,1660,1593,1533,1387,1285,1180,1103,1044,895,691, ESI-MS:m/z:627, ultimate analysis theoretical value: C37.67%, H3.00%, N13.18%, S20.11%, Na7.21%, measured value: C37.74%, H3.13%, N13.12%, S20.24%, Na7.28%.
The preparation of embodiment 7 Cefodizime Sodium 2.5 hydrates adds Cefodizime acid 10g in reaction flask, water 30ml, stirring makes into suspension, at 5 DEG C, drip sodium carbonate saturated aqueous solution and make pH to 7.2 left and right, stir, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, in filtrate, slowly drip acetone 200ml, Virahol 200ml, 15 DEG C of following placements, solid is fully separated out, suction filtration, isopropyl alcohol wash 3 times, suction filtration, gained solid just dissolves it with a small amount of water, add gac 0.3g, stir 30 minutes, suction filtration, washing, suction filtration, use Virahol 200ml, acetone 200ml carries out recrystallization to it, 10 DEG C of following placements are spent the night, crystallization is fully separated out, suction filtration, 30ml chloroform is washed, suction filtration, 40 DEG C of left and right, 0.09-0.2MPa left and right vacuum-drying 5h left and right, obtain off-white color crystallization 5.2g, fusing point: 185 DEG C of variable color (ELECTROTHERMAL MELTING POINT APPARATUS, do not proofread and correct), HPLC: purity 99.2%, the retention time of its HPLC is consistent with the HPLC retention time of Cefodizime acid reference substance, it is 6.88% that Ka Shi method is measured moisture, and heat is analyzed: the weightless about 7.02%(Fig. 4 of platform), the result (theoretical value 6.69%) that this and sample contain 2.5 crystal water is in limit of error, X powder diffraction: measure and have multiple obvious characteristic peaks (Fig. 6) within the scope of 3-60 °, specific optical rotation :-58.6 ° (get this product, accurately weighed, with water dissolution and quantitatively dilution make in every 1ml the approximately solution containing 10mg), infrared spectra: ν
kBr maxcm
-13332 (wide), 3192,2968,1767,1658,1589,1534,1379,1283,1234,1181,1107,1043,896,690, ESI-MS:m/z:627, ultimate analysis theoretical value: C35.66%, H3.44%, N12.47%, S19.04%, Na6.83%, measured value: C35.55%, H3.56%, N12.38%, S19.17%, Na6.71%.
Embodiment 8 gets Cefodizime sodium hydrate 100g, and stirring makes molten, with N.F,USP MANNITOL 20g, EDETATE SODIUM 0.05g, injects water 400～500ml left and right, and stirring makes molten, regulating pH with the citric acid about 1-5M and disodium phosphate soln is 6.0～7.5, add activated carbon 0.01～0.5%(W/V) stir 15-30min, filter, with 0.22 micron of filtering with microporous membrane, press 0.5g/ bottle or the packing of 1g/ bottle, vacuum lyophilization, tamponade, obtains finished product.
Embodiment 9 gets aseptic Cefodizime sodium hydrate 10Kg, presses 0.5g/ bottle or 0.75g/ bottle or 1g/ bottle or the packing of 2g/ bottle with aseptic subpackaged technique, jumps a queue, tamponade, rolls aluminium lid and obtains finished product.
Embodiment 10 gets aseptic Cefodizime Sodium 1 hydrate 2Kg, presses main ingredient 0.5g/ bottle or 1g/ bottle or the packing of 1.5g/ bottle with aseptic subpackaged technique, jumps a queue, tamponade, rolls aluminium lid and obtains finished product.
Embodiment 11 Cefodizime Sodium 1 hydrate sheets or capsule (50mg/ grain)
Prescription: Cefodizime Sodium 1 hydrate 50g
Lactose 145g
Sodium starch glycolate 5g
The aqueous ethanolic solution of 5%PVP30(50%) appropriate
Magnesium Stearate 2g
Cefodizime Sodium 1 hydrate, lactose, sodium starch glycolate are crossed to 100 mesh sieves, mix, with 50% the aqueous ethanolic solution of 5%PVP30 be tackiness agent softwood processed in right amount, cross 18-24 mesh sieve and granulate, dry, cross after the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix, compressing tablet or filling capsule.
Embodiment 12 Cefodizime Sodium 1.5 hydrate sheets (250mg/ sheet)
Prescription: Cefodizime Sodium 0.5 or 1.5 hydrate 250g
Sorbyl alcohol 185g
Low-substituted hydroxypropyl cellulose 45g
The aqueous ethanolic solution of 5%PVP K-30(50%) appropriate
Magnesium Stearate 4g
Cefodizime Sodium 0.5 or 1.5 hydrates, sorbyl alcohol, low-substituted hydroxypropyl cellulose are crossed to 100 mesh sieves, mix, with 50% the aqueous ethanolic solution of 5%PVP K30 be tackiness agent softwood processed in right amount, cross 18-24 mesh sieve and granulate, dry, cross after the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix, compressing tablet.
Embodiment 13 Cefodizime Sodium 2 hydrate sheets (250mg/ sheet)
Prescription: Cefodizime Sodium 2 hydrate 250g
N.F,USP MANNITOL 185g
Low-substituted hydroxypropyl cellulose 45g
The aqueous ethanolic solution of 5%PVP K-30(50%) appropriate
Magnesium Stearate 4g
Cefodizime Sodium 2 hydrates, N.F,USP MANNITOL, low-substituted hydroxypropyl cellulose are crossed to 100 mesh sieves, mix, with 50% the aqueous ethanolic solution of 5%PVP K30 be tackiness agent softwood processed in right amount, cross 18-24 mesh sieve and granulate, dry, cross after the whole grain of 14-20 mesh sieve, add Magnesium Stearate and mix, compressing tablet.
Embodiment 14 cefodizime sodium hydrate buccal tablets (250mg/ sheet)
Prescription: cefodizime sodium hydrate 250g
Sorbitol instant 185g
Microcrystalline Cellulose 20g
Low-substituted hydroxypropyl cellulose 45g
Magnesium Stearate 4g
Cefodizime sodium hydrate (standby by embodiment 1 or embodiment 2 methods preparations or embodiment 3 or embodiment 4 methods or embodiment 5 methods or embodiment 6 methods or embodiment 7 legal systems), sorbitol instant, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Magnesium Stearate are crossed to 100 mesh sieves, mix, be pressed into sheet, again this sheet is ground to the particle that is pressed into 18-24 mesh sieve, compressing tablet.
Embodiment 15: the preparation (main ingredient 125mg/ grain) of cefodizime sodium hydrate capsule for vagina of the present invention
Prescription: cefodizime sodium hydrate 125g
Cefodizime sodium hydrate (standby or embodiment 3 or embodiment 4 methods or embodiment 5 methods or embodiment 6 legal systems prepare standby by embodiment 1 or embodiment 2 legal systems) is crossed to 100 mesh sieves, mix filling capsule.
The suppository (125mg/ grain) of embodiment 16 Cefodizime Sodium crystalline hydrates
Prescription: Cefodizime Sodium crystalline hydrate 12.5g(100 grain feeds intake)
Polyoxyethylene stearate (40) fat 180g
Glycerine 5ml
Poloxamer 50g
Cefodizime Sodium crystalline hydrate (embodiment 1 legal system is standby), glycerine, polyoxyethylene stearate (40) fat, poloxamer 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 a little bolt mould, after cold, scabble molding and get final product.
The suppository (250mg/ grain) of embodiment 17 Cefodizime Sodium crystalline hydrates
Prescription: Cefodizime Sodium crystalline hydrate (embodiment 1 legal system is standby) 25g(100 grain feeds intake)
Macrogol 4000 140g
Polyethylene glycol 1500 80g
Glycerine 5ml
Poloxamer 50g
EDETATE SODIUM 1g
Cefodizime Sodium crystalline hydrate (standby or embodiment 3 or embodiment 4 methods or embodiment 5 methods or embodiment 6 legal systems prepare standby by embodiment 1 or embodiment 2 legal systems), glycerine, polyethylene glycol 1500, Macrogol 4000, poloxamer, EDETATE SODIUM 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 a little bolt mould, after cold, scabble molding and get final product.
Embodiment 18: under GMP condition, 100 grams of aseptic Cefodizime Sodium 1 hydrate and sodium-tazobactams (8:1) are pressed to preparation of injection procedure operation, be distributed into 50-200 bottle, jump a queue, tamponade, roll aluminium lid and obtain finished product.
Embodiment 19: under GMP condition, 100 grams of aseptic Cefodizime Sodium 2.5 hydrates and sodium-tazobactams (4:1) are pressed to preparation of injection procedure operation, be distributed into 50-200 bottle, jump a queue, tamponade, roll aluminium lid and obtain finished product.
Embodiment 20: under GMP condition, 100 grams, aseptic Cefodizime Sodium 1 hydrate is fully mixed with aseptic sulbactam 25g, by preparation of injection procedure operation, be distributed into 50-200 bottle, jump a queue, tamponade, roll aluminium lid and obtain finished product.
Embodiment 21: under GMP condition, 100 grams, aseptic Cefodizime Sodium 1.5 hydrate is fully mixed with aseptic sulbactam 50g, by preparation of injection procedure operation, will be distributed into 50-200 bottle, jump a queue, tamponade, roll aluminium lid and obtain finished product.
Embodiment 22: under GMP condition, 100 grams, aseptic Cefodizime Sodium 2 hydrate fully mixes with aseptic sulbactam 100g, by preparation of injection procedure operation, will be distributed into 50-200 bottle, jumps a queue, tamponade, rolls aluminium lid and obtains finished product.
Embodiment 23: under GMP condition, 100 grams, aseptic Cefodizime Sodium 1 hydrate is fully mixed to abundant mixing with aseptic Clavulanic Potassium 5g, by preparation of injection procedure operation, be distributed into 50-200 bottle, jump a queue, tamponade, roll aluminium lid and obtain finished product.
Embodiment 24: under GMP condition, 100 grams, aseptic Cefodizime Sodium 2 hydrate is fully mixed with aseptic sulbactam 50g, by lyophilized injectable powder preparation technology procedure operation, will be distributed into 50-200 bottle, jump a queue, lyophilize, tamponade, rolls aluminium lid and obtain finished product.
Embodiment 25: adopt doubling dilution to measure Cefodizime Sodium 1 hydrate minimum inhibitory concentration MIC, MIC
50and MIC
90as follows:
Table 3 Cefodizime Sodium 1 hydrate anti-microbial activity
Embodiment 26: adopt doubling dilution mensuration Cefodizime Sodium 1.5 hydrate minimum inhibitory concentration MIC, MIC50 and MIC90 as follows
Table 4 Cefodizime Sodium 1.5 hydrate anti-microbial activities
Embodiment 26: adopt doubling dilution to measure Cefodizime Sodium 2 hydrate minimum inhibitory concentration MIC, MIC
50and MIC
90as follows
Table 5 Cefodizime Sodium 2 hydrate anti-microbial activities
Table 6 Cefodizime Sodium 3 hydrate anti-microbial activities
The MIC(μ g.ml of table 7. Cefodizime Sodium crystalline hydrate to different bacterium
-1)
Above Cefodizime sodium hydrate is all standby according to specific embodiment legal system.
Be appreciated that from this professional angle, the variation of a lot of details is possible, and therefore this do not limit the scope of the invention and spirit, and the present invention is not limited to above-described embodiment.
Claims (8)
1. a Cefodizime sodium hydrate, is characterized in that: molecular formula is C
20h
18n
6na
2o
7s
4nH
2o, n=0.5,1,1.5,2,2.5.
2. Cefodizime sodium hydrate according to claim 1, is characterized in that: be Cefodizime Sodium 0.5 hydrate.
3. Cefodizime sodium hydrate according to claim 1, is characterized in that: be Cefodizime Sodium 1 hydrate.
4. Cefodizime sodium hydrate according to claim 1, is characterized in that: be Cefodizime Sodium 1.5 hydrates.
5. Cefodizime sodium hydrate according to claim 1, is characterized in that: be Cefodizime Sodium 2 hydrates.
6. Cefodizime sodium hydrate according to claim 1, is characterized in that: be Cefodizime Sodium 2.5 hydrates.
7. the purposes of Cefodizime sodium hydrate according to claim 1, it is characterized in that: for the preparation of solid preparation, injection, wherein injection is selected from injection freeze-dried powder, aseptic subpackaged powder injection, great transfusion preparation, solid preparation is selected from tablet, capsule, granule.
8. the purposes of Cefodizime sodium hydrate according to claim 1, is characterized in that: for the preparation of the application in the medicine of 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 negative bacteria sensitive organism, meningitic treatment or prevention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110124553.4A CN102250123B (en) | 2010-05-13 | 2011-05-13 | Cefodizime sodium hydrate and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010179594A CN101830915A (en) | 2010-05-13 | 2010-05-13 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
| CN201010179594.9 | 2010-05-13 | ||
| CN201110124553.4A CN102250123B (en) | 2010-05-13 | 2011-05-13 | Cefodizime sodium hydrate and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102250123A CN102250123A (en) | 2011-11-23 |
| CN102250123B true CN102250123B (en) | 2014-07-16 |
Family
ID=42715150
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010179594A Pending CN101830915A (en) | 2010-05-13 | 2010-05-13 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
| CN201110124553.4A Expired - Fee Related CN102250123B (en) | 2010-05-13 | 2011-05-13 | Cefodizime sodium hydrate and application thereof |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010179594A Pending CN101830915A (en) | 2010-05-13 | 2010-05-13 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN101830915A (en) |
| WO (1) | WO2011141004A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101830915A (en) * | 2010-05-13 | 2010-09-15 | 胡梨芳 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
| CN103110641A (en) * | 2013-02-04 | 2013-05-22 | 海南中元堂医药科技有限公司 | Pharmaceutical composition of injection cefodizime sodium and lidocaine hydrochloride injection |
| CN104327099A (en) * | 2014-09-29 | 2015-02-04 | 联合康兴（北京）医药科技有限公司 | Cefoperazone sodium compound entity, composition and application |
| CN110327284B (en) * | 2019-07-18 | 2022-11-22 | 石药集团中诺药业（石家庄）有限公司 | Cefodizime sodium for injection and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5126445A (en) * | 1989-04-07 | 1992-06-30 | Hoechst Aktiengesellschaft | Process for the preparation of cefodizime sodium |
| CN1565457A (en) * | 2003-06-21 | 2005-01-19 | 张哲峰 | Beta- lactamase suppressing antibacterial compound drugs |
| CN101239985A (en) * | 2008-03-12 | 2008-08-13 | 齐鲁安替制药有限公司 | Method for preparing cefodizime sodium |
| CN101723958A (en) * | 2008-10-22 | 2010-06-09 | 丽珠医药集团股份有限公司 | Cefodizime sodium medicament and preparation method thereof |
| CN101830915A (en) * | 2010-05-13 | 2010-09-15 | 胡梨芳 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3143537A1 (en) * | 1981-11-03 | 1983-05-11 | Hoechst Ag, 6230 Frankfurt | CRYSTALLINE SALTS FROM CEFODIZIM AND METHOD FOR THE PRODUCTION THEREOF |
-
2010
- 2010-05-13 CN CN201010179594A patent/CN101830915A/en active Pending
-
2011
- 2011-05-13 CN CN201110124553.4A patent/CN102250123B/en not_active Expired - Fee Related
- 2011-05-13 WO PCT/CN2011/074067 patent/WO2011141004A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5126445A (en) * | 1989-04-07 | 1992-06-30 | Hoechst Aktiengesellschaft | Process for the preparation of cefodizime sodium |
| CN1565457A (en) * | 2003-06-21 | 2005-01-19 | 张哲峰 | Beta- lactamase suppressing antibacterial compound drugs |
| CN101239985A (en) * | 2008-03-12 | 2008-08-13 | 齐鲁安替制药有限公司 | Method for preparing cefodizime sodium |
| CN101723958A (en) * | 2008-10-22 | 2010-06-09 | 丽珠医药集团股份有限公司 | Cefodizime sodium medicament and preparation method thereof |
| CN101830915A (en) * | 2010-05-13 | 2010-09-15 | 胡梨芳 | Cefodizime sodium hydrate, preparation method thereof and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| . |
| 卢娥辉，等.头孢地嗪钠合成路线图解.《中国医药工业杂志》.2009,第40卷(第3期),第235页4.1节. * |
| 第5页，实施例1和实施例2 |
| 说明书第11页及实施例19，21. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102250123A (en) | 2011-11-23 |
| WO2011141004A1 (en) | 2011-11-17 |
| CN101830915A (en) | 2010-09-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102180890B (en) | Cefathiamidine hydrate and preparation method and application thereof | |
| CN102180889A (en) | Ceftizoxime sodium crystalline hydrate and preparation method and application thereof | |
| CA2874815C (en) | Pharmaceutical compositions comprising rifaximin and amino acids, preparation method and use thereof. | |
| CN104327099A (en) | Cefoperazone sodium compound entity, composition and application | |
| CN102250123B (en) | Cefodizime sodium hydrate and application thereof | |
| CN101838276B (en) | Cefpiramide sodium hydrate and preparation method and application thereof | |
| CN101830916B (en) | Cefbuperazone sodium hydrate, preparation method thereof and application thereof | |
| AU2020281120A1 (en) | Tebipenem pivoxil crystalline forms, compositions including the same, methods of manufacture, and methods of use | |
| CN101633683A (en) | Antihepatitis medicament, preparation method thereof and use thereof | |
| CN104628796A (en) | Gastrodin medicine, and composition and use thereof | |
| US7527808B2 (en) | Amorphous cefditoren pivoxil composition and process for producing the same | |
| CN104072519A (en) | Cefuroxime sodium compound entity and application thereof | |
| CN102212074A (en) | Cefonicid sodium hydrate and preparation method and application thereof | |
| CN101838277A (en) | Cefotetan disodium hydrate and preparation method and application thereof | |
| CN110393720B (en) | New indication of pharmaceutical preparation of troxofen ceftriaxone sodium for treating infection of patients with low immune function | |
| CN104402908B (en) | Cefoxitin sodium compound entity and combinations thereof and purposes | |
| CN102746183A (en) | Tigecycline crystalline hydrate, preparation method thereof and uses thereof | |
| CN101418015B (en) | Ceftriaxone phosphorylation derivates | |
| CN112778363B (en) | Nitroimidazole derivative and preparation method and application thereof | |
| CN102911226B (en) | Erythromycin octadecanoate compounds thing entity and uses thereof | |
| CN110041347A (en) | Brizolina noval chemical compound and combinations thereof and purposes | |
| CN102311451A (en) | Ticarcillin disodium hydrate and preparation method as well as application thereof | |
| CN111499658B (en) | Cefoperazone compound medicinal preparation and new indication for treating endometritis and other gynecological genital tract infection | |
| CN112778369B (en) | Triazole derivative and preparation method and application thereof | |
| CN102079717A (en) | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140716 Termination date: 20190513 |