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WO2011144021A1 - Hydrate de cefpiramide sodium, procédé de préparation et utilisations associées - Google Patents

Hydrate de cefpiramide sodium, procédé de préparation et utilisations associées Download PDF

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Publication number
WO2011144021A1
WO2011144021A1 PCT/CN2011/074207 CN2011074207W WO2011144021A1 WO 2011144021 A1 WO2011144021 A1 WO 2011144021A1 CN 2011074207 W CN2011074207 W CN 2011074207W WO 2011144021 A1 WO2011144021 A1 WO 2011144021A1
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low molecular
sodium
cefpiramide
hydrate
cefpiramide sodium
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Chinese (zh)
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刘力
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    • 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
    • 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

Definitions

  • the present invention relates to the field of medical technology, and in particular to providing an antibacterial drug, cefpiramide sodium hydrate, a preparation method and use thereof.
  • Cefpiramide sodium is a cephalosporin jointly developed by Sumitomo Pharmaceutical Co., Ltd. and Yamanouchi Pharmaceutical Co., Ltd., which is classified according to the principle of discovery date and antibacterial properties. The drug is between the third and fourth generations. In the meantime, some people call it 'three generations and a half' of cephalosporins. Cefpiramide sodium was first marketed in Japan in 1985 and subsequently marketed in other countries such as the United States. Its structure is characterized by a methyltetrazoliumthio group at the C3 position and a hydroxyphenyl group and a hydroxymethylpyridyl group at the C7 position, thereby greatly improving the antibacterial activity and pharmacokinetic characteristics of the original drug.
  • cefpiramide sodium Compared with other third-generation cephalosporins, the antibacterial spectrum of cefpiramide sodium has been further expanded. It is suitable for a variety of Gram and negative bacteria including Enterobacter, Pseudomonas aeruginosa and Haemophilus. Neisseria, Staphylococcus, and Streptococcus (except Enterococcus) have strong antibacterial activity. Cefpiramide sodium also showed good antibacterial activity against Gram-negative bacilli resistant to third-generation cephalosporins.
  • cefpiramide sodium improves the activity of the third and fourth generation cephalosporins against G + bacteria, Pseudomonas aeruginosa and anaerobic bacteria, and is in line with the research and development direction of cephalosporins.
  • Method A In the reaction vessel, add cefpiramide, add water, one of C 1 -C 6 low molecular alcohol, C 2 -C 8 low molecular ether, C 2 -C 6 low molecular nitrile or Several kinds, stir, add C 1 -C 12 low molecular amine at 10 °C, stir to dissolve, add sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium thiocyanate, sodium octanoate to the filtrate at 10 °C , sodium ethylhexanoate one water, C 1 -C 6 lower alcohol is, C 2 -C 8 ether of a low molecular weight, C 2 -C 6 of a low molecular weight nitrile, C 3 -C 8 ketones of low molecular weight, a solution of one or more of C 1 -C 6 low molecular halogenated hydrocarbons, stirred for 0.2 to 3 hours, adjusted to a pH of 6.0 to 8.0
  • the cefpiramide used in the reaction C 1 -C 12 low molecular amine: alkali (sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium thiocyanate, sodium octoate, sodium isooctanoate)
  • the molar ratio of one of them can generally be 1: 0.5-1.1: 0.5-1.1; cefpiramide (weight g) with water, C 1 -C 6 low molecular alcohol, C 2 -C 8 low molecular ether
  • the ratio of one or several (volume ml) of the C 2 -C 6 low molecular weight nitrile is generally: 1 (g): 1.5 to 50 (ml); water and organic solvent used in crystallization or recrystallization
  • the volume ratio is generally 1: 5 to 300.
  • the amount of activated carbon is from 0.01 to 3% by weight of the reactant.
  • the molar ratio of cefpirin:base one of sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium thiocyanate, sodium acetate, sodium octanoate, sodium isooctanoate
  • the molar ratio of cefpirin:base one of sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium thiocyanate, sodium acetate, sodium octanoate, sodium isooctanoate
  • the ratio of one or several (vol. ml) is generally: 1 (g): 1.5 to 50 (ml); the volume ratio of water to organic solvent used in crystallization or recrystallization is generally 1:20 to 300. .
  • the crystallizing or recrystallization solvent of cefpiramide sodium hydrate is selected from the group consisting of water, acetonitrile, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, butyl acetate, ethyl acetate, ethyl formate, diethyl ether, diisopropyl ether, tetrahydrofuran, One or more of dichloromethane, chloroform, etc.; cefpiramide sodium crystal or recrystallization solvent, preferably water, acetone, methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, diethyl ether, diisopropyl ether, chloroform One or several of them.
  • the cefpiramide sodium hydrate can be dissolved in water during the recrystallization process, and the activated carbon can be decolorized after dissolution (if the activated carbon is used for decolorization, the amount is generally 0.01-3% by weight of the decolorized solution) It is further crystallized by the solvent in the present invention.
  • the cefpiramide sodium aqueous solution can be added to the C 1 -C 6 low molecular alcohol, C 2 -C 8 low molecular ether, C 3 -C 8 low molecular ketone, C 2 -C 8 in the recrystallization process.
  • Preparation of sterile cefpiramide sodium hydrate is prepared aseptically in accordance with conventional procedures.
  • the cefpiramide sodium hydrate of the present invention may have different crystal forms.
  • the number of carbon atoms of the low molecular alcohol in the present invention is defined as C 1 -C 6 (ie, an alcohol having 1 to 6 carbon atoms) such as methanol, ethanol, isopropanol, etc.; the number of carbon atoms of the low molecular ether is defined as C 2 -C 8 (ie: an ether of 2-8 carbon atoms) such as diethyl ether, diisopropyl ether, dibutyl ether, tetrahydrofuran, etc.; the number of carbon atoms of the low molecular halogenated hydrocarbon is defined as C 1 -C 6 (ie: a halogenated hydrocarbon of 1 to 6 carbon atoms, including dichloromethane, dichloroethane, chloroform, etc.; the number of carbon atoms of the low molecular ester is defined as C 2 - C 8 (ie: an ester of 2-8 carbon atoms) ), including butyl a
  • the product of the present invention can be dried at different temperatures (e.g., 20-80 ° C), drying time (0.5 Hours to several days), or with other desiccants (including silica gel, phosphorus pentoxide, anhydrous calcium chloride, anhydrous sodium sulfate, etc.) under ambient conditions, or using atmospheric or decompression methods for the final
  • the product is dried. Its drying temperature is preferably 30-60 °C.
  • Powder X-ray diffraction is commonly used to characterize and/or identify polymorphs, for powder X-ray diffraction in characterization and / Or when identifying, use the modifier 'about' before reporting the peak.
  • This is a common practice in the field of solid state chemistry due to the inherent variations in peaks.
  • the typical accuracy of the 2 ⁇ x-axis value of the powder peak is ⁇ 0.2° 2 ⁇ Level, therefore, the powder X-diffraction peak appearing at 'about 8.0° 2 ⁇ means that when measured on most X-ray diffractometers, the peaks may be at 7.8° 2 ⁇ and 8.2° 2 ⁇ .
  • the change in peak intensity is the result of how each crystal is oriented in the sample container relative to the external X-ray source, and the orientation does not provide structural information about the crystal.
  • the invention provides different crystalline hydrates of cefpiramide sodium.
  • the invention provides crystalline hydrates of different crystalline forms and methods for their preparation.
  • the invention provides a pharmaceutical composition comprising any one or more of cefpiramide sodium crystalline hydrate prepared by the method of the invention, and one or more pharmaceutically acceptable excipients.
  • the invention further provides a process for the preparation of a pharmaceutical formulation comprising any one or more of cefpiramide sodium crystalline hydrate prepared by the process of the invention.
  • the present invention further provides cefpiramide sodium crystal hydrate and crystalline hydrates of different crystal forms, such as cefpiramide sodium 1 hydrate, 1.5
  • cefpiramide sodium 1 hydrate 1.5
  • Cefpiramide sodium crystal hydrate of the present invention Use: The cefpiramide sodium crystal hydrate of the present invention is used for preparing a solid preparation, an injection,
  • the injection includes lyophilized powder injection for injection, aseptic powder injection preparation, infusion preparation (including double chamber, large infusion, non-PVC solid-liquid double chamber, large infusion, non-PVC A large infusion solution made of a multi-layer co-extruded film), a tablet, a capsule, a granule, etc.; and can be used for preparing an anhydrate of cefpiramide sodium.
  • the preparation of the anhydrate can be obtained by the different crystallization methods of the crystalline hydrate of the present invention, and the preparation can be carried out at different temperatures (eg 60-100 ° C), drying time (hours to days), or with other desiccants (including silica gel, molecular sieves, phosphorus pentoxide, sodium hydroxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous Drying the final product under ambient conditions of sodium sulfate, anhydrous magnesium sulfate, etc., or by using atmospheric or reduced pressure, or by first distilling water with benzene, in combination with other drying as described herein. The method is obtained after drying.
  • desiccants including silica gel, molecular sieves, phosphorus pentoxide, sodium hydroxide, anhydrous sodium carbonate, anhydrous calcium chloride, anhydrous Drying the final product under ambient conditions of sodium sulfate, anhydrous magnesium sulfate, etc., or by using atmospheric
  • tablets including buccal tablets, sublingual tablets, oral patches, orally disintegrating tablets, vaginal tablets, etc.
  • capsules including rectal, vaginal capsules, etc.
  • granules which may contain pharmaceutically acceptable Fillers such as starch, modified starch, lactose, microcrystalline cellulose, cyclodextrin, sorbitol, mannitol, calcium phosphate, amino acids, etc.; pharmaceutically acceptable disintegrating agents such as starch, modified starch, microcrystalline fiber , sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, surfactant (sodium lauryl sulfate, etc.); pharmaceutically acceptable wetting agents and binders, such as gums Starch, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyvinylpyrrolidone, alginic acid and its salts; pharmaceutically acceptable lubricants and glidants such as
  • Suppository preparation of cefpiramide sodium crystal hydrate cefpiramide sodium crystal hydrate 1-50%, suppository base 50 ⁇ 99% composition, matrix can be ethanol, glycerin, petrolatum, glycerin gelatin, polyethylene glycol 200-8000 One or more of poloxamers, semi-synthetic hard fatty acid esters, carbomer series (931, 934, 940, 974, AA-1, 1342, etc.) and Tween 60-80.
  • the preparation method comprises the following steps: mixing the main drug with the substrate, heating, stirring, and melting in a water bath, stirring until evenly, and pouring into the mold of the suppository coated with the lubricant to slightly overflow the plug mold, and then flattening after cooling and starting the mold. Got it.
  • the crystal hydrate of the present invention is different from The deliquescent of the anhydrate prevents the air from being blocked during the treatment, and the crystallization hydrate has good slidability, thereby improving the operability of the preparation; and preparing the solid preparation It has good dissolution properties, making it easy to be absorbed into the blood circulation, improving bioavailability, and facilitating its rapid function. On the other hand, it is prevented from appearing in the case of aseptic dispensing, which is not easy to cause clogging due to moisture absorption, resulting in a difference in the amount of the load, resulting in insufficient dosage, resulting in product failure, or because of unqualified products.
  • cefpiramide sodium crystal hydrate which is prepared by:
  • Infusion preparations including double chamber, large infusion, non-PVC solid-liquid dual-chamber, large infusion, non-PVC
  • a large infusion solution made of a multi-layer co-extruded film is prepared in a conventional manner.
  • the preparation method of the lyophilized powder preparation is as follows: taking cefpiramide sodium crystal hydrate, adding pharmaceutically acceptable lyophilized support agent or auxiliary agent, stabilizer, water for injection, stirring to dissolve, if necessary, pharmacy can be used Acceptable acid and base to adjust pH For 6.0 ⁇ 8.0, add activated carbon 0.005 ⁇ 0.5% (W / V) for 15 ⁇ 45min, filter, hydration, sterile filtration, press 0.5 ⁇ 2g / Bottles are packed, freeze-dried, and tamponed to obtain finished products.
  • the regulator may be a pharmaceutically acceptable inorganic or organic acid, an inorganic base or an organic base, or a Lewis acid or a base in a broad sense, may contain one or more, and may be hydrochloric acid, propionic acid, acetic acid, and medicinal Salt, lactic acid and pharmaceutically acceptable salts, pharmaceutically acceptable salts of citric acid, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, phosphoric acid and pharmaceutically acceptable salts, tartaric acid and pharmaceutically acceptable salts thereof, borax, boric acid , succinic acid, caproic acid, adipic acid, fumaric acid, maleic acid, polyhydroxycarboxylic acid and pharmaceutically acceptable salts, such as glucuronic acid, gluconic acid, lactobionic acid, malic acid, threonic acid One or several of the others.
  • the pharmaceutically acceptable antioxidants and stabilizers thereof may be sulfurous acid and salts, bisulfite, pyrosulfite, dithionite, thiosulfate, organic sulfur compound thiourea, glutathione. , dimercaptopropanol, thioglycolic acid and salt, thiolactic acid and salt, thiodipropionic acid and salt, benzoic acid and pharmaceutically acceptable salts thereof (such as sodium benzoate), phenolic compounds such as gallic acid and salt, caffeic acid And salts, ferulic acid and salts, di-tert-butyl-p-phenol, 2 , 5-dihydroxybenzoic acid and salt, phenol or its derivatives, salicylic acid or its salt; ascorbic acid and salt, isoascorbic acid and salt, nicotinamide, tartaric acid, nitrate, phosphate, pharmaceutically acceptable salt, lemon Acid salt, EDTA And EDTA salts, such as EDTA
  • the ultrafilter may be a flat plate type, a coil type, a tube type, a hollow fiber type or a round box type, etc., preferably a roll type and a hollow fiber type ultrafilter, and the molecular weight of the interception is 50,000 to 300,000.
  • the filter removes the remaining heat source by using an ultrafiltration membrane with a molecular weight of 4,000 to 30,000, preferably an ultrafiltration membrane having a molecular weight of 6000 to 30,000.
  • cefpiramide sodium hydrate of the invention is suitable for preparing respiratory system, hepatobiliary system, facial features, human or animal caused by Gram-positive or negative bacteria-sensitive bacteria Use in the treatment or prevention of diseases such as urinary tract infections, abdominal infections, pelvic infections, sepsis, skin and soft tissue infections, bone and joint infections, endocarditis, meningitis, etc.
  • cefpiramide sodium hydrate is also used in the preparation of ⁇ - An antibacterial combination drug comprising one or more of a lactamase inhibitor, clavulanic acid or a pharmaceutically acceptable salt thereof, sulbactam or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, to further enhance the antibacterial activity thereof Effect, among which cefpiramide sodium hydrate and ⁇ - The weight ratio of lactamase inhibitor is 30:1 to 1:2.
  • the weight ratio of the composition of cefpiramide sodium hydrate to the ⁇ -lactamase inhibitor may vary depending on the ⁇ - The ratio of the lactamase inhibitor varies, and the weight ratio of the cefpiramide sodium hydrate to the ⁇ -lactamase inhibitor tazobactam or a pharmaceutically acceptable salt thereof is preferably 4:1 to 8:1.
  • the weight ratio of the general cefpiramide sodium hydrate to the ⁇ -lactamase inhibitor sulbactam or a pharmaceutically acceptable salt thereof is preferably 2:1 to 1:1; generally cefpiramide sodium hydrate and ⁇ -
  • the weight ratio of the composition of the lactamase inhibitor clavulanic acid or a pharmaceutically acceptable salt thereof is preferably 4:1 to 1:1.
  • the composition has a stronger antibacterial effect and is used in a medicament for treating or preventing a human or animal disease caused by a Gram-positive or a negative bacterial-sensitive bacterium.
  • the usual amount is 1 ⁇ 2g per day, divided into 1-2 intravenous injections or intravenous drip. In case of refractory or serious infection, it can be increased to 4g per day according to different symptoms, and divided into 2 to 3 intravenous infusions. child The usual amount is 30-80 mg per kilogram per day by weight, divided into 1 to 3 intravenous infusions. In the case of refractory or severe infection, it can be increased to 150 mg per kilogram per day according to different symptoms, and is divided into 1 to 3 intravenous infusions.
  • Intramuscular injection mild to moderate infection: daily dose 0.5-1 g, divided into 0.5-1% lidocaine injection for deep intramuscular injection.
  • oral administration changing the route of injection for absorption through the oral mucosa
  • adults 0.5 g to 4 g daily
  • rectal or vaginal (absorbed through the vaginal mucosa), 0.5 g to 4 g per day for adults.
  • the cefpiramide sodium containing crystal water obtained by the present invention is surprisingly that the cepporin sodium containing crystal water has a much lower wettability than the cefpiramide sodium containing crystal water, and the cefpiramide sodium containing crystal water. It is more stable than free of crystal water, easy to store and transport, and easy to make into preparations. Further, the deliquescent of the anhydrate causes the air to be prevented from blocking or the like during the treatment, and the hydrate has a good slidability, thereby improving the operability of the preparation. Crystalline solids have higher chemical stability and physical stability than amorphous forms and low crystallinity forms, and they may also exhibit improved hygroscopicity, bulk properties, and or flow properties.
  • characteristic, thermal analysis of hydrates of the invention (TG-DSC or TG-DTA)
  • the map has a corresponding endothermic peak under the weightless platform, and the thermal analysis map shows cefpiramide sodium crystal hydrate, such as cefpiramide sodium 0.5 hydrate, cefpiramide sodium 1 hydrate, cefpiramide sodium 1.5 Hydrate, cefpiramide sodium 2.5 hydrate, and the like.
  • cefpiramide sodium crystal hydrate of the present invention can be stably stored.
  • the ceppiramide sodium hydrate and anhydrate samples were subjected to a wettability test: cefpiramide sodium anhydrate and the hydrate of the present invention were about 5 g Placed in a dry and constant weight watch glass, precision weighed, 25 ° C, relative humidity 70 %, respectively, at 0h and 10h Sampling, calculating the percentage of wetting gain, the results show that the anhydrate-free wettability is much higher than the hydrate of the present invention, and the cefpiramide sodium crystal hydrate of the present invention can be stably stored.
  • Table 1 The results are shown in Table 1.
  • cefpiramide sodium crystallization hydrate and anhydrate sample were sealed in a vial for 6 months at 10 °C for accelerated stability test.
  • the content of cefpiramide sodium and the related substances were determined by HPLC: C8 (250mm ⁇ 4.6mm, 5 ⁇ m) in phosphate buffer solution (take potassium dihydrogen phosphate 4.1g with water 800ml to dissolve, adjust the pH with 1M sodium hydroxide solution to 7.5, diluted with water to 1000ml) - methanol (75: 25) as mobile phase; detection wavelength is 254nm, column temperature is room temperature, flow rate 1ml / min, measured and found
  • the content of cefpiramide sodium crystal hydrate is basically unchanged, and there is no significant increase in related substances, while the increase of cefpiramide sodium-free substance is higher than that of cefpiramide sodium crystal hydrate. .
  • the test results show that the cefpiramide sodium crystal hydrate of the present invention has good storage stability.
  • Figure 1 is a thermogram of cefpiramide sodium 1 hydrate.
  • Figure 2 is a thermogram of cefpiramide sodium 1.5 hydrate.
  • Figure 3 is a thermogram of cefpiramide sodium 2.5 hydrate.
  • Figure 4 is a thermogram of cefpiramide sodium 2 hydrate.
  • Figure 5 is a powder X-ray diffraction pattern of cefpiramide sodium 1 hydrate (Example 1).
  • Figure 6 is a powder X-ray diffraction pattern of cefpiramide sodium 2 hydrate (Example 7).
  • the term 'obtained' refers to a compound isolated at a valuable level of purity, including but not limited to greater than 90%. , 95%, 96%, 97%, 98%, and 99% purity levels.
  • the purity level can be determined by high performance liquid chromatography.
  • composition refers to a composition of a drug, which may contain at least one pharmaceutically acceptable carrier.
  • Thermal analysis test conditions Setaram Setsys 16 , sample volume of about 5mg, heating rate: 10K / min, N 2 flow rate: 50ml / min, temperature: room temperature ⁇ 400 ° C or so.
  • the thermal analysis (TG-DTA or TG-DSC) pattern of the hydrate of the present invention has a corresponding endothermic peak under the weightless platform, and the thermal analysis spectrum shows the crystallization of ceftizoxime sodium. Hydrates such as monohydrate, 1.5 hydrate, 2.5 hydrate, and the like.
  • the cefpiramide sodium 1 hydrate of the present invention may have corresponding characteristic values at positions including the following 2 ⁇ values (Fig. 5): about 4.8, 6.3, 6.8, 10.3, 11.8, 15.4, 19.6, 22.1, 25.1, 32.4.
  • the cefpiramide sodium 2 hydrate of the present invention may have corresponding characteristic values at positions including the following 2 ⁇ values (Fig. 6) of about 5.02, 10.95, 21.93. 39.85.
  • Example 1 Preparation of cefpiramide sodium 1 hydrate
  • 10 g of cefpiramide, 20 ml of water, and 30 ml of methanol were added, and the mixture was stirred, and 2.4 ml of triethylamine was added dropwise thereto with stirring at 5 ° C, and stirred for 30 minutes, and activated carbon was added thereto.
  • Example 2 Preparation of Cefpiramide Sodium 1 Hydrate 20 g of cefpiramide and 80 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous sodium carbonate solution was added dropwise thereto at 5 ° C to adjust the pH to about 6.8, and stirred.
  • Example 3 Preparation of Cefpiramide Sodium 1.5 Hydrate 20 g of cefpiramide and 80 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise thereto at 5 ° C to bring the pH to about 6.8, and stirred.
  • Example 4 Preparation of Cefpiramide Sodium 2.5 Hydrate 20 g of cefpiramide, 40 ml of water and 120 ml of methanol were added to the reaction flask, stirred, and a 25% solution of sodium isooctanoate in ethanol was added dropwise to the filtrate under stirring at 5 ° C to adjust the pH.
  • Example 5 Preparation of Cefpiramide Sodium 2.5 Hydrate 20 g of cefpiramide and 80 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise thereto at 5 ° C to adjust the pH to 7.2, and stirred 30 In minutes, add 0.1g of activated carbon, stir for 30 minutes, suction filtration, wash with water, suction filtration, add acetonitrile 600ml and isopropyl alcohol 550ml, place below -5 °C, make the solid charge analysis, suction filtration, chloroform wash 3 times, suction filtration, The obtained solid was dissolved in a small amount of water, and recrystallized from 350 ml of isopropyl alcohol, 200 ml of acetonitrile, and 20 ml of diethyl ether as a crystallization solvent, and left at -5 ° C for overnight, and the crystals were analyzed by
  • cefpiramide sodium hydrate was dried in a vacuum at about 80 ° C in the presence of phosphorus pentoxide for about 30 hours to obtain an anhydrate of cefpiramide sodium, and the water content thereof was determined to be within 1% by the Karl Fischer method.
  • Example 6 Preparation of Cefpiramide Sodium 0.5 Hydrate 10 g of cefpiramide and 50 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous solution of sodium carbonate was added dropwise thereto at 5 ° C to adjust the pH to 7.0, and stirred for 30 minutes.
  • Example 7 Preparation of Cefpiramide Sodium 2 Hydrate 10 g of cefpiramide and 32 ml of water were added to a reaction flask, and the mixture was stirred to form a suspension. A saturated aqueous solution of sodium hydrogencarbonate was added dropwise thereto at 5 ° C to bring the pH to 7.2, and stirred.
  • Example 8 Take cefpiramide sodium hydrate 100g, stir to dissolve, add mannitol 20g, EDTA disodium 0.05g, add about 500 ml of water for injection, stir to dissolve, adjust the pH to 6.5 ⁇ 7.5 with 1-5M citric acid and disodium hydrogen phosphate solution, add activated carbon 0.01 ⁇ Stir at 0.5% (w/v) for 15-30min, filter, filter with 0.22 micron microporous membrane, press 0.5g/bottle or 1g/ Bottles are packed, vacuum freeze-dried, and tamponed to obtain finished products.
  • Example 9 A sterile cefpiramide sodium hydrate 10 Kg (prepared according to the method of the present invention) was taken in an aseptic dispensing process. 0.5g / bottle or 0.75g / bottle or 1g / bottle or 2g / bottle is divided, stoppered, plugged, rolled aluminum cover finished product.
  • Example 10 Taking sterile cefpiramide sodium 1.5 hydrate 2Kg (Prepared according to the method of the present invention), according to the aseptic packaging process, according to the main drug 0.5g / bottle or 1g / bottle or 1.5g / bottle, the plug, the plug, and the rolled aluminum cover to obtain the finished product.
  • Cefpiramide sodium hydrate prepared according to the method of Example 1 or Example 2 or the method or example of Example 3 or Example 4 5 method or the preparation of the method 6
  • instant sorbitol microcrystalline cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate over 100 mesh sieve, mix, press into a large piece, and then press the sheet into 18 - 24 The mesh of the mesh, tableting.
  • Example 12 Preparation of cefpiramide sodium hydrate vaginal capsule of the present invention (main drug 125 mg / granule)
  • Cefpiramide sodium hydrate prepared according to Example 1 or Example 2 or Example 3 or Example 4 or Example 5
  • the method or the preparation method 6 is prepared by passing through a 100 mesh sieve, mixing, and filling the capsule.
  • Cefpiramide sodium hydrate (prepared according to the method of Example 1 or Example 2 or the method or example of Example 3 or Example 4 5 method or Example 6 preparation), glycerin, stearic acid polyoxyl (40 ), fat, poloxamer mixture, heated in a water bath, stirred, to be melted, stirred until evenly, quickly poured into the mold of the lubricant-coated suppository, to slightly overflow the plug mold, to be flat after cooling, the mold is obtained .
  • Cefpiramide sodium crystal hydrate prepared according to the method of Example 1 or Example 2 or Example 3 or Example 4 Method or Example 5 Method or Example 6 Preparation
  • Glycerin Polyethylene Glycol 1500, Polyethylene Glycol 4000, Poloxamer, EDTA
  • EDTA EDTA Mix the disodium, heat in a water bath, stir, melt, stir until it is evenly poured into the mold of the suppository that has been coated with the lubricant, until it is slightly spilled, and then flattened after cooling.
  • Example 15 Sterile cefpiramide sodium 1 hydrate and tazobactam sodium (8:1) 100 under GMP conditions According to the preparation procedure of powder injection, it is divided into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 16 Sterile cefpiramide sodium 0.5 hydrate and tazobactam sodium (4:1) under GMP conditions 100 g is operated according to the powder injection preparation process, and is divided into 50-200 bottles, which are stoppered, plugged, and rolled to obtain the finished product.
  • Example 17 100 g of sterile cefpiramide sodium 1.5 hydrate with sterile sulbactam sodium under GMP conditions 25g is fully mixed and processed according to the powder injection preparation process. It is divided into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 18 Sterile cefpiramide sodium 2.5 hydrate 100 under GMP conditions
  • the gram (prepared according to the method of the present invention) is thoroughly mixed with the sterile sulbactam sodium 50g, and is processed according to the powder injection preparation process, and is divided into 50-200 bottles, stoppered, plugged, and rolled to obtain the finished product.
  • Example 19 Sterile cefpiramide sodium 1 hydrate 100 under GMP conditions Gram (prepared according to the method of the present invention) is thoroughly mixed with sterile sulbactam sodium 100g, and is processed according to the powder injection preparation process, and is divided into 50-200 bottles, stoppered, plugged, rolled aluminum cover Get the finished product.
  • Example 20 100 g of sterile cefpiramide sodium 1 hydrate and sterile potassium clavulanate under GMP conditions 5g is fully mixed and fully mixed. According to the powder injection preparation process, it is divided into 50-200 bottles, stoppered, plugged, rolled aluminum cover to obtain the finished product.
  • Example 21 Sterile cefpiramide sodium 2.5 hydrate 100 under GMP conditions Glucose (prepared according to the method of the present invention) is thoroughly mixed with sterile sulbactam sodium 50g, and is processed according to the lyophilized powder injection preparation process, and is divided into 50-200 bottles, stoppered, freeze-dried, tamped, rolled Aluminum cap Get the finished product.
  • Example 22 Determination of Cefpiramide Sodium 1 Hydrate Minimum Inhibitory Concentration MIC, MIC 50 and MIC 90 using a two-fold dilution method as follows:
  • Example 23 Determination of cefpiramide sodium 1.5 hydrate minimum inhibitory concentration MIC, MIC 50 and MIC 90 using a two-fold dilution method as follows:
  • Example 24 Determination of cefpiramide sodium 2.5 hydrate minimum inhibitory concentration MIC, MIC 50 and MIC 90 using a two-fold dilution method as follows:
  • E. coli (6) Staphylococcus aureus (6) Cefpiramide sodium 1 hydrate (Example 1 method) : sulbactam sodium ( 2 : 1 ) 0.003 ⁇ 0.06 0.015 to 0.06 Cefpiramide sodium 2 hydrate (Example 7 method) : Tazobactam sodium (8: 1) 0.003 ⁇ 0.03 0.006 ⁇ 0.03

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Abstract

L'invention concerne de l'hydrate de cefpiramide sodium, son procédé de préparation et des utilisations associées. L'hydrate de cefpiramide sodium présente une meilleure stabilité au stockage, et peut être employé pour produire des médicaments à utiliser dans le traitement ou la prévention de maladies touchant l'homme et l'animal ou des infections du système respiratoire, du système hépatobiliaire, des organes des cinq sens et des voies urinaires, de la cavité abdominale, des infections pelviennes, l'ichorrhémie, les infections des tissus mous de la peau, les infections des os et des articulations, l'endocardite, la méningite et analogues, qui sont causées par des bactéries à gram positif ou à gram négatif.
PCT/CN2011/074207 2010-05-17 2011-05-17 Hydrate de cefpiramide sodium, procédé de préparation et utilisations associées Ceased WO2011144021A1 (fr)

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CN101838276B (zh) * 2010-05-17 2012-10-10 胡梨芳 头孢匹胺钠水合物及其制备方法和用途
CN102973570A (zh) * 2012-12-17 2013-03-20 苏州二叶制药有限公司 注射用头孢匹胺钠
CN103319505B (zh) * 2013-06-07 2016-01-20 华北制药河北华民药业有限责任公司 结晶生产头孢匹胺钠晶体的方法
CN104327099A (zh) * 2014-09-29 2015-02-04 联合康兴（北京）医药科技有限公司 头孢哌酮钠化合物实体及组合物和用途
CN109721618A (zh) * 2017-10-30 2019-05-07 刘力 头孢匹胺新化合物及其组合物和用途
CN107951842B (zh) * 2017-12-21 2020-03-27 广州白云山天心制药股份有限公司 一种微粉头孢匹胺的制备方法

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CN101037444A (zh) * 2007-04-18 2007-09-19 武汉同源药业有限公司 化合物头孢匹胺钠的合成方法
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CN1594324A (zh) * 2004-07-07 2005-03-16 广州白云山医药科技发展有限公司 头孢匹胺钠的制备方法
CN1965838A (zh) * 2005-11-17 2007-05-23 李海超 含头孢匹胺和β－内酰胺酶抑制剂的药物组合物
CN101037444A (zh) * 2007-04-18 2007-09-19 武汉同源药业有限公司 化合物头孢匹胺钠的合成方法
CN101838276A (zh) * 2010-05-17 2010-09-22 胡梨芳 头孢匹胺钠水合物及其制备方法和用途

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