WO2011144021A1 - Cefpiramide sodium hydrate, preparation method and uses thereof - Google Patents

Abstract

A cefpiramide sodium hydrate, preparation method and uses thereof are disclosed. The cefpiramide sodium hydrate has better storage stability, and is applicable to produce medicaments for treating or preventing human or animals diseases of respiratory system infection, hepatobiliary system infection, five sense organs and urinary tract infections, abdominal cavity infection, pelvic infection, ichorrhemia, skin soft tissue infection, bones and joints infection, endocarditis, cephalomeningitis and the like, which are caused by Gram-positive or negative bacteria.

Description

Cefpiramide sodium hydrate, preparation method and use thereof Technical Field

 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.

Background Art

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. 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. The antibacterial activity and clinical efficacy of cefpiramide sodium can be seen that the efficacy of cefpiramide sodium is comparable to that of ceftazidime and cefotaxime, and its advantage is that the spectrum of antibacterial activity in vitro is broader, covering Gram-positive and Gram-negative bacteria. (including Pseudomonas aeruginosa). Therefore, 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.

At present, the published literature only reports Cefpiramide sodium (C ₂₅ H ₂₃ N ₈ NaO ₇ S ₂ , molecular weight: 634.62, CAS No.: 74849-93-7), so far, there is no The published literature reports the cefpiramide sodium crystalline hydrate of the present invention, its preparation method and use.

Technical Problem

The invention relates to an antibacterial infection drug cefpiramide sodium hydrate, a preparation method thereof and a use thereof, wherein the molecular formula is C ₂₅ H ₂₃ N ₈ NaO ₇ S ₂ · nH ₂ O , n=0.5 ～3, Includes 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, etc.

Technical Solution

 Preparation of Cefpiramide Sodium Derivative-Cefpiramide Sodium Crystalline Hydrate comprises the following methods:

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 with a mineral acid or an organic acid or a solution thereof, and added to the solution 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 low molecular ester, C ₂ - C ₆ low molecular nitrile, C One or more of ₁ - C ₆ low molecular halogenated hydrocarbons, or a C ₁ -C ₆ low molecular alcohol, a C ₂ -C ₈ low molecular ether, a C ₃ -C ₈ low molecular ketone , C ₂ -C ₈ esters of low molecular weight, C ₂ -C ₆ of a low molecular weight nitrile, C ₁ -C ₆ of One or more molecules of a halogenated hydrocarbon, below 10 ℃ placed sufficiently precipitate the solid, filtered off with suction, with C ₁ -C ₆ lower alcohol, and C ₂ -C ₈ ether of a low molecular weight, C ₃ -C ₈ is a low molecular weight ketones, C ₂ -C ₈ esters of low molecular weight, C ₂ -C ₆ of a low molecular weight nitrile, C ₁ -C ₆ halogenated hydrocarbons of low molecular weight of one or more washing 1-3 times, Filtration, the obtained solid with water and C ₁ -C ₆ low molecular alcohol, C ₂ -C ₈ low molecular ether, C ₃ -C ₈ low molecular ketone, C ₂ -C ₆ low molecular nitrile, C ₁ -C ₆ is a low molecular weight halogenated hydrocarbons, one or more solvents for recrystallization C ₂ -C ₈ esters of low molecular weight in one or more times below 10 ℃ placed sufficiently precipitate crystal was filtered, washed, and dried to give cephalosporin Sodium citrate crystal hydrate;

Among them, 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.

Or method B. Adding cefpiramide to a reaction vessel, adding water, a C ₁ -C ₆ low molecular alcohol, a C ₂ -C ₈ low molecular ether, or a C ₂ -C ₆ low molecular nitrile Or several, stirring, adding 10% sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium thiocyanate, sodium acetate, sodium octanoate, sodium isooctanoate to water, C ₁ -C ₆ at 10 ° C a solution of one or more of a low molecular alcohol, a C ₂ -C ₈ low molecular ether, a C ₃ -C ₈ low molecular ketone, stirred for 0.2-3 hours, using a mineral acid or an organic acid or a solution thereof pH was adjusted to 6.0 to 8.0, the above solution was added to the lower alcohol of C1-C6, C ₂ -C ₈ ether of a low molecular weight, C ₃ -C ₈ low molecular weight ketones, C ₂ -C ₈ esters of low molecular weight, One or more of C ₂ -C ₆ low molecular nitriles, C ₁ -C ₆ low molecular halogenated hydrocarbons, or C ₁ -C ₆ low molecular alcohols, C ₂ -C ₈ low molecules One or more of ether, C ₃ -C ₈ low molecular ketone, C ₂ -C ₈ low molecular ester, C ₂ -C ₆ low molecular nitrile, C ₁ -C ₆ low molecular halogenated hydrocarbon , below 10 ℃ placed sufficiently precipitate the solid, filtered, washed with C ₁ -C ₆ of low molecular Alcohols, C ₂ -C ₈ ether of a low molecular weight, C ₃ -C ₈ low molecular weight ketones, C ₂ -C ₆ of a low molecular weight nitrile, C ₁ -C ₆ halogenated hydrocarbons of low molecular weight of one or more Washing 1-3 times, filtering, the obtained solid is water with 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 low molecular weight One or more of the ester, a C ₂ -C ₆ low molecular nitrile, and a C ₁ -C ₆ low molecular halogenated hydrocarbon are recrystallized one or more times by a crystallization solvent, filtered, washed, dried, and dried to obtain a cephalosporin Sodium citrate crystalline hydrate.

Wherein, the molar ratio of cefpirin:base (one of sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium thiocyanate, sodium acetate, sodium octanoate, sodium isooctanoate) used in the reaction is generally 1 : 0.5-1.1 : 0.5-1.1 ; cefpiramide (g) and water, C ₁ -C ₆ low molecular alcohol, C ₂ -C ₈ low molecular ether, C ₂ -C ₆ low molecular nitrile 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. In the preparation method of the present invention, 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. One or more of a low molecular ester, a C ₂ -C ₆ low molecular nitrile, a C ₁ -C ₆ low molecular halogenated hydrocarbon, or a 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 low molecular ester, C ₂ -C ₆ low molecular nitrile, C ₁ -C ₆ low molecular halogenated hydrocarbon One or several of them are placed in a cold place to crystallize. 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 acetate, ethyl acetate, ethyl formate, etc.; the number of carbon atoms of a low molecular linear or branched alkane or a cycloalkane is defined as C ₅ - C ₁₀ , including pentane, n-hexane, cyclohexane, Petroleum ethers, etc.; the number of carbon atoms of a low molecular aromatic hydrocarbon is defined as C ₆ -C ₁₂ (ie, an aromatic hydrocarbon of 6-12 carbon atoms), including benzene, toluene, etc.; C ₁ -C ₆ low molecular acid carbon It is defined as the number of atoms from 1 to 6 carbon atoms and an organic acid, including formic acid, acetic acid, propionic acid; low molecular weight ketone is defined as C ₃ -C ₈ ketones of 3-8 carbon atoms, include acetone, methyl ethyl ketone, Cyclohexanone and the like; C ₂ -C ₆ nitriles low molecular weight (i.e.: nitrile 2-6 carbon atoms), include acetonitrile, propionitrile and the like; low molecular weight amines defined C ₁ -C ₁₂ from 1 to 12 carbon atoms, Organic amines, including dimethylamine, diethylamine, triethylamine, cyclohexylamine, dicyclohexylamine, ethanolamine, etc.; any method for labeling the number of carbon atoms described as a 'low molecular' compound is only Once in the text of the application, any other unlabeled compound of the class described as 'low molecule' has the same number of carbon atoms as the number already indicated herein.

 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 2θ x-axis value of the powder peak is ±0.2° 2θ Level, therefore, the powder X-diffraction peak appearing at 'about 8.0° 2θ means that when measured on most X-ray diffractometers, the peaks may be at 7.8° 2θ and 8.2° 2θ. Between. 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.

 In one aspect, the invention provides different crystalline hydrates of cefpiramide sodium.

 In another aspect, the invention provides crystalline hydrates of different crystalline forms and methods for their preparation.

In another aspect, 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 The use of hydrates, hydrates, 2.5 hydrates, and the like, in the preparation of pharmaceutical compositions for the treatment of infections, including bacterial infections, Gram-positive and or Gram-negative infections.

 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.

For the preparation of 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 stearic acid, stearic acid Magnesium, polyethylene glycol 4000 - 8000, talc, micronized silica gel, magnesium lauryl sulfate, etc.; pharmaceutically acceptable sweeteners and flavors such as aspartame, cyclamate, sodium saccharin, sucralose, food flavors, and the like.

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. It has not been sampled to form an actual missed test, and then flows into the market, causing a negative effect on the patient's therapeutic agent in clinical treatment, or jeopardizing the patient's life due to insufficient dose. Or in the case of dispensing, the entire production line is forced to suspend due to moisture absorption, which seriously reduces the production capacity of the equipment and greatly increases the hidden troubles such as working hours.

 An injection of 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.

 Preparation of aseptically dispensed powdered needles: Dispensing using sterile raw materials according to normal practice.

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.

 Its pharmaceutically acceptable pH 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 disodium, EDTA tetrasodium, N-di (2 One or more of -hydroxyethyl)glycine and the like. The above antioxidant or stabilizer may also be added to the sterile powder needle or large infusion solution.

 De-heating and sterilization methods can be added to the amount of liquid From 0.005 to 3% of activated carbon to heat source, microporous membrane sterilization and hot pressing sterilization, ultrafiltration can also be used to remove bacteria and heat sources. In the ultrafiltration method, 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. After removing most of the heat-generating substances and bacteria, 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.

The 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.

 The use of cefpiramide sodium hydrate is also used in the preparation of β- 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 β - The weight ratio of lactamase inhibitor is 30:1 to 1:2.

 The weight ratio of the composition of cefpiramide sodium hydrate to the β-lactamase inhibitor may vary depending on the β- The ratio of the lactamase inhibitor varies, and the weight ratio of the cefpiramide sodium hydrate to the β-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 β-lactamase inhibitor sulbactam or a pharmaceutically acceptable salt thereof is preferably 2:1 to 1:1; generally cefpiramide sodium hydrate and β- 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.

 Consumption usage: under normal circumstances, for

 Cefpiramide sodium hydrate (based on anhydrous matter),

Usage and dosage Adults, 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. Or by oral administration (changing the route of injection for absorption through the oral mucosa), adults 0.5 g to 4 g daily; or rectal, or vaginal (absorbed through the vaginal mucosa), 0.5 g to 4 g per day for adults.

Advantageous Effects

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.

The discovery of new polymorphic pharmaceutically useful compounds provides new opportunities to enhance the action characteristics of pharmaceutical products, and it expands the formulation of pharmaceutical agents that formulate drugs such as drugs with target release profiles or other desirable properties. A library of materials that requires cefpiramide sodium crystalline hydrate or a polymorph thereof.

 Surprisingly, 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.

The 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. The results are shown in Table 1. At RH75%, The 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, 5μm) 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.

 Table 1. Results of the wettigation test

 Sampling time (10 hours)  % weight gain compared to 0 hours  Cefpiramide sodium 0.5 hydrate  5.33  Cefpiramide sodium 1 hydrate  4.02  Cefpiramide sodium 1.5 hydrate  2.68  Cefpiramide sodium 2 hydrate  0.84  Cefpiramide sodium 2.5 hydrate  0.43  Cefpiramide sodium anhydrate  8.07

 Table 2. Acceleration Stability Test Results

 Sampling time (June)  Multiples of related substances compared with 0 months  Cefpiramide sodium 0.5 hydrate  0.49  Cefpiramide sodium 1 hydrate  0.37  Cefpiramide sodium 1.5 hydrate  0.43  Cefpiramide sodium 2.5 hydrate  0.55  Cefpiramide sodium anhydrate  0.68

Description of Drawings

 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).

Best Mode

Mode for Invention

All numerical values used in the specification and claims are to be understood as being modified by the term 'about' in all instances, unless otherwise indicated, unless otherwise indicated. The numerical parameters set forth in the appended claims are approximations, which may vary depending on the nature of the properties sought in the present disclosure, and are not intended to limit the scope of the scope of the claims. Numerical parameters should be interpreted in consideration of the number of significant digits and the conventional rounding method.

Although a wide range of numerical ranges and parameters for setting the disclosure are approximate. However, the numerical values given in the specific examples are reported as accurately as possible, and any numerical value inherently contains certain errors necessarily resulting from the standard deviation found in their respective tests.

It is to be understood that the singular forms "a", "the" and "the" are used in the <RTI ID=0.0> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; If a composition containing 'a compound' is mentioned, it includes a mixture of two or more compounds, and it should be noted that the term 'or' generally includes 'and unless explicitly stated otherwise herein. / or '.

 As used herein, 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.

Pharmaceutical composition, 'pharmaceutical composition' as used herein refers to a composition of a drug, which may contain at least one pharmaceutically acceptable carrier.

In order to further understand the present invention, the preferred embodiments of the present invention are described in the accompanying drawings.

 The effects of the present invention are described below by way of specific examples, but the scope of the present invention is not limited by the following examples.

 Thermal analysis method

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. Surprisingly, characteristically, 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.

 Powder X-ray diffraction

 Using D/MX-III A X-ray diffractometer, voltage: 35kv, current: 30mA, scanning speed: 10o/min, step size: 0.02 o / step; copper target, monochromator: graphite monochromator; wavelength wavelength (Å): 1.54, diffraction angle 2θ, scanning range 3-60o A powder X-ray diffraction pattern of cefpiramide sodium crystal hydrate was measured, and all peak positions were within ±0.2o 2θ.

 In one embodiment, measured by powder X-ray diffraction at a diffraction angle of 2θ (3-60°) Within the measurement range, the cefpiramide sodium 1 hydrate of the present invention may have corresponding characteristic values at positions including the following 2θ values (Fig. 5): about 4.8, 6.3, 6.8, 10.3, 11.8, 15.4, 19.6, 22.1, 25.1, 32.4.

 In another embodiment, measured by powder X-ray diffraction at a diffraction angle of 2θ (3-60°) Within the measurement range, the cefpiramide sodium 2 hydrate of the present invention may have corresponding characteristic values at positions including the following 2θ values (Fig. 6) of about 5.02, 10.95, 21.93. 39.85.

 Specific embodiment

Example 1 Preparation of cefpiramide sodium 1 hydrate In a reaction flask, 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. g, stirring for 30 minutes, suction filtration, washing with water, suction filtration, adding 25% sodium isooctanoate (2.8 g) in ethanol solution at 5 ° C, stirring, adding acetone 250 ml and ethanol 350 ml, placed below 0 ° C, so that The solid was charged and analyzed, suction filtered, and washed with a small amount of chloroform three times. After suction filtration, the obtained solid was dissolved in a small amount of water, and recrystallized with acetone 330 ml, ethanol 100 ml, and isopropanol 300 ml, and placed at -6 ° C to make a solid. The mixture was filtered, filtered, and washed with a small amount of chloroform three times. After suction filtration, the obtained solid was vacuum dried at 52 ° C for about 6 h to obtain white crystals of 5.1 g; HPLC: purity: 99.3%, HPLC retention time and cefoperamide reference substance HPLC retention time is consistent; melting point: 172 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), Karlsberg method for moisture 2.72%, thermal analysis: platform weight loss of about 3.21% (Figure 1), which contains 1 crystal with the sample Water results (theoretical value 2.76%) Within the error range, the infrared spectrum: ν ^KBr _max cm ^-1 3402 (width), 3264, 3068, 2815, 1766, 1663, 1638, 1515, 1389, 1350, 1241, 1175, 1104, 1061, 791, 699, ESI -MS: m/z: 633; Elemental analysis: C 46.01%, H 3.86%, N 17.17%, S 9.83%, Na 3.52%; Found: C 46.12%, H 3.99%, N 17.05%, S 9.74%, Na 3.43%.

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. 30 minutes, add activated carbon 0.5g, stir for 30 minutes, suction filtration, water washing, suction filtration, add acetone 450ml and acetonitrile 450ml, placed below 0 °C, the solid is fully analyzed, suction filtration, acetone washing 3 times, suction filtration, the resulting solid It was dissolved in a small amount of water, and recrystallized with 450 ml of acetone, 400 ml of acetonitrile and 70 ml of chloroform. The mixture was allowed to stand at -10 ° C or less overnight, and the crystals were analyzed by suction, filtered, washed with a small amount of acetone three times, suction filtered, vacuum dried at 52 ° C for 6 h. Left and right, white crystals 13.4g, HPLC: purity 98.7%, the retention time of HPLC is consistent with the HPLC retention time of cefpiramide reference substance; melting point: 175 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), Cartesian The method measures moisture of 2.87%, thermal analysis: platform weight loss is about 2.96%, which is within the error range of the sample containing one crystal water (theoretical value 2.76%), infrared spectrum: ν ^KBr _max cm ^-1 3402 (width) 326 4, 3068, 2815, 1766, 1663, 1638, 1515, 1389, 1350, 1241, 1175, 1104, 1061, 791, 699, ESI-MS: m/z: 633; Elemental analysis: C 46.01%, H 3.86%, N 17.17%, S 9.83%, Na3.52%; Found: C 46.07%, H 3.97%, N 17.07%, S 9.94%, Na 3.45%.

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. 30 minutes, add activated carbon 0.3g, stir for 30 minutes, suction filtration, water washing, suction filtration, add acetone 650ml and ethanol 650ml, placed below 0 °C, the solid is fully analyzed, suction filtration, ethanol washing 3 times, suction filtration, the resulting The solid was dissolved in a small amount of water, and recrystallized from 300 ml of ethanol, 300 ml of acetonitrile and 80 ml of isopropyl ether as a crystallization solvent, and left at -10 ° C overnight to allow the crystal to be fully analyzed, suction filtered, vacuum dried at 45 ° C 0.06-0.09 MPa. About 10h, white crystals were obtained 10.6g; HPLC: purity: 99.0%, the retention time of HPLC was consistent with the HPLC retention time of cefpiramide reference substance; melting point: 170°C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), card The moisture content was 2.81%, thermal analysis: platform weight loss was about 3.92% (Fig. 2), which is within the error range of the sample containing 1.5 crystal water (theoretical value 2.98%), infrared spectrum: ν ^KBr _max cm ^{- 1} 3400 (width), 3264, 3068, 2815, 1766, 1663, 1638, 1515, 1389, 1350, 1241, 1175, 1104, 1061, 791, 699, ESI-MS: m/z: 633; theoretical value of elemental analysis: C 45.38%, H 3.96%, N 16.94%, S 9.69%, Na 3.47%; Found: C 45.26%, H 4.12%, N 16.85%, S 9.57%, Na 3.38%.

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. To 7.2, stir for 30 minutes, add 0.5g of activated carbon, stir for 30 minutes, suction filtration, wash with water, suction filtration, add 450ml of acetone and 450ml of isopropanol, place below -5 °C, make the solid charge analysis, suction filtration, chloroform wash 3 After suction filtration, the obtained solid was dissolved in a small amount of water, and recrystallized from 350 ml of acetone, 300 ml of isopropyl alcohol and 20 ml of tetrahydrofuran as a crystallization solvent, and allowed to stand overnight at 0 ° C to analyze the crystals, suction filtration, and a small amount of chloroform. 3 times, suction filtration, the solid was dried at 40 ° C for about 20 h to obtain 12.8 g of white crystals; HPLC: purity 99.1%, the retention time of HPLC was consistent with the HPLC retention time of cefpiramide reference substance; melting point: 164 ° C Color change (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), the moisture content was 6.75% by Karl Fischer, thermal analysis: platform weight loss was about 6.37% (Fig. 3) , which is the result of the sample containing 2.5 crystal water (theoretical value 6.63%). error Inner circle, IR spectrum: ν ^KBr _max cm ^-1 3397 (broad), 3264,3068,2815,1766,1663,1638,1515,1389,1350,1241,1175,1104,1061,791,699, ESI-MS : m/z: 633 ; Theoretical analysis of elemental analysis: C 44.18%, H 4.15%, N 16.49%, S 9.44%, Na 3.38%; Found: C 44.29%, H 4.24%, N 16.37%, S 9.56 %, Na 3.47%.

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 suction, and filtered at about 40 ° C for about 20 hours. Obtained white crystals 10.6 g, HPLC: purity 99.2%, the retention time of HPLC was consistent with the HPLC retention time of cefpiramide reference substance; melting point: 164 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), Karl Fischer method Water is 6.89%, thermal analysis: platform weight loss is about 6.72%, which is within the error range of the sample containing 2.5 crystal water (theoretical value 6.63%), infrared spectrum: ν ^KBr _max cm ^-1 3398 (width), 3264 , 3068 , 2815, 1766, 1663, 1638, 1515, 1389, 1350, 1241, 1175, 1104, 1061, 791, 699, ESI-MS: m/z: 633; elemental analysis: C 44.18%, H 4.15%, N 16.49%, S 9.44%, Na3.38%; Found: C 44.29%, H 4.24%, N 16.37%, S 9.56%, Na 3.47%. The 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. Add 0.2g of activated carbon, stir for 30 minutes, suction filtration, wash with water, suction filtration, add 250ml of acetonitrile and 250ml of ethanol, place at -10°C, solidify and analyze the mixture, suction filtration, chloroform wash 3 times, suction filtration, use the obtained solid A small amount of water is allowed to dissolve, and it is recrystallized with 300 ml of ethanol, 200 ml of acetonitrile and 20 ml of isopropyl ether as a crystallization solvent, and left at -10 ° C for overnight, and the crystals are charged and analyzed, suction-filtered, and vacuum dried at about 52 ° C for about 30 hours. White crystal 11.8 g, HPLC: purity 98.7%, its HPLC retention time is consistent with the HPLC retention time of cefpiramide reference; melting point: 175 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected), Karl Fischer method for determining moisture 1.61%, thermal analysis: platform weight loss is about 1.53%, which is within the error range of the sample containing 0.5 crystal water (theoretical value 1.4%), infrared spectrum: ν ^KBr _max cm ^-1 3400 (width), 3264, 3068 , 2815, 1766, 1663, 1638, 1515, 1389, 1350, 1241, 1175, 1104, 1061, 791, 699, ESI-MS: m/z: 633; theoretical value of elemental analysis: C 46.65%, H 3.76%, N 17.41%, S 9.96%, Na 3.57%; Found: C 46.57%, H 3.88%, N 17.31%, S 9.83%, Na 3.69%.

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. In minutes, add 0.1g of activated carbon, stir for 20 minutes, suction filtration, wash with water, suction filtration, add chloroform 30ml, acetone 400ml, isopropyl alcohol 420ml, place below 5 °C, make the solid charge analysis, suction filtration, chloroform wash 3 times, pump Filtration, the obtained solid was dissolved in a small amount of water, and recrystallized from 400 ml of acetone and 320 ml of isopropanol as a crystallization solvent, and left at 5 ° C or less overnight to allow the crystal to be fully analyzed, and suction filtered at about 36 ° C, 0.07-0.09 MPa. Vacuum drying for about 12 h, 7.8 g of white crystals were obtained, HPLC: purity: 99.2%, the retention time of HPLC was consistent with the HPLC retention time of cefpiramide reference substance; melting point: 166 ° C discoloration (ELECTROTHERMAL MELTING POINT APPARATUS, uncorrected) The Karl Fischer method measures moisture at 5.58%, and thermal analysis: platform weight loss is about 5.61% (Fig. 4) . This is in the range of error with the sample containing 2 crystal water (theoretical value 5.37%). Infrared spectrum: ν ^KBr _max Cm ^-1 3396 (width), 3264, 3068, 2815, 1767, 1663, 1638, 1516, 1388, 1351, 1241, 1175, 1104, 1061, 791, 699, ESI-MS: m/z: 633; theoretical value of elemental analysis: C 44.71%, H 4.20%, N 16.68%, S 9.55%, Na 3.42%; Found: C 44.83%, H 4.29%, N 16.56%, S 9.45%, Na 3.55%.

 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.

 Example 11 Cefpiramide Sodium Hydrate Oral Tablets (250 mg/tablet)

 Prescription: Cefpiramide Sodium Hydrate 250g

 Instant Sorbitol 185g

 Microcrystalline cellulose 20g

 Low substituted hydroxypropyl cellulose 45g

 Magnesium stearate 4g

 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)

 Prescription: Cefpiramide sodium hydrate 125g

 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.

 Example 13 Cefpiramide sodium crystal hydrate suppository (125mg/granule)

 Prescription: Cefpiramide sodium crystal hydrate 12.5g (100 tablets)

 Stearic acid polyoxyl (40) fat 180g

 Glycerin 5ml

 Polosham 50g

 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 .

 Example 14 Cefpiramide sodium crystal hydrate suppository (250mg/granule)

 Prescription: Cefpiramide sodium crystal hydrate 25g (100 capsules)

 Polyethylene glycol 4000 140g

 Polyethylene glycol 1500 80g

 Glycerin 5ml

 Polosham 50g

 EDTA disodium 1g

 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 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:

 Table 3 Cefpiramide sodium 1 hydrate Antibacterial activity

 Infected bacteria  Strain  MIC ( mg/L ) MIC MIC ₅₀ MIC ₉₀  Staphylococcus aureus  15  0.06-4  1  2  Pneumococcal  11  0.012-0.25  0.06  0.12  Pseudomonas  13  0.5-64  2  16  E.coli  15  0.06-32  4  16  Proteus mirabilis  13  0.06-32  2  8  Serratia  11  0.12-128  8  32

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:

 Table 4 Cefpiramide sodium 1.5 hydrate Antibacterial activity

 Infected bacteria  Strain  MIC ( mg/L ) MIC MIC ₅₀ MIC ₉₀  Staphylococcus aureus  15  0.06-4  1  2  Pneumococcal  11  0.012-0.25  0.06  0.12  Pseudomonas  13  0.5-64  2  16  E.coli  15  0.06-32  4  16  Proteus mirabilis  13  0.06-32  2  8  Serratia  11  0.06-128  8  32

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:

 Table 5 Cefpiramide sodium 2.5 hydrate Antibacterial activity

 Infected bacteria  Strain  MIC ( mg/L ) MIC MIC ₅₀ MIC ₉₀  Staphylococcus aureus  15  0.06-4  1  2  Pneumococcal  11  0.012-0.25  0.06  0.12  Pseudomonas  13  0.5-64  2  16  E.coli  15  0.06-32  4  16  Proteus mirabilis  13  0.06-32  2  8

Table 6. MIC (μg.ml ^-1 ) of cefpiramide sodium crystal hydrate for different bacteria

 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

It is to be understood that many variations of the details are possible from the point of view of the present invention, which is not intended to limit the scope and spirit of the invention, and the invention is not limited to the embodiments described above.

Industrial Applicability

Sequence List Text

Claims (10)

A cefpiramide sodium hydrate characterized by a molecular formula of C25H23N8NaO7S2•nH2O, n=0. 5 to 3. The cefpiramide sodium hydrate according to claim 1, which is cefpiramide sodium 0.5 hydrate. The cefpiramide sodium hydrate according to claim 1, which is cefpiramide sodium monohydrate. The cefpiramide sodium hydrate according to claim 1, which is cefpiramide sodium 1.5 hydrate. The cefpiramide sodium hydrate according to claim 1, which is cefpiramide sodium 1.5 hydrate. The cefpiramide sodium hydrate according to claim 1, which is cefpiramide sodium 2.5 hydrate. The cefpiramide sodium hydrate according to claim 1, wherein the preparation method comprises the following steps: Method A. In the reaction vessel, add cefpiramide, add water, C1-C6 low molecular alcohol, C2-C8 low molecular ether, One or more of C2-C6 low molecular weight nitriles, stirred, add C1-C12 low molecular amine at 10 ° C, stir to dissolve, Adding sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium octanoate, sodium isooctanoate to water, C1-C6 low molecular alcohol, C2-C8 low molecular ether, C2 in the filtrate at 10 °C -C6 low molecular nitrile, C3-C8 low molecular ketone, a solution of one or more of C1-C6 low molecular halogenated hydrocarbons, stirred, adjusted to a pH of 6.0 to 8.0 with a mineral acid or an organic acid or a solution thereof, and added to the C1-C6 low molecular alcohol, a low molecular ether of C2-C8, a low molecular ketone of C3-C8, a low molecular ester of C2-C8, a low molecular nitrile of C2-C6, One or more of C1-C6 low molecular halogenated hydrocarbons, or C1-C6 low molecular alcohol, C2-C8 low molecular ether, C3-C8 low molecular ketone, C2-C8 low molecular ester, One or more of C2-C6 low molecular nitrile and C1-C6 low molecular halogenated hydrocarbon, placed at 10 ° C or lower, the solid is fully analyzed, filtered, and C1-C6 low molecular alcohol, a low molecular ether of C2-C8, a low molecular ketone of C3-C8, a low molecular nitrile of C2-C6, One or more of the C1-C6 low molecular halogenated hydrocarbons are washed 1-3 times, filtered, and the obtained solid is mixed with water with a C1-C6 low molecular alcohol, a C2-C8 low molecular ether, and a C3-C8 low molecular weight. ketone, a low molecular ester of C2-C8, a low molecular weight nitrile of C2-C8, One or more of the C1-C6 low molecular halogenated hydrocarbons are recrystallized one or more times, placed at 10 ° C or lower, the crystals are fully analyzed, filtered, washed, and dried to obtain cefpiramide sodium hydrate; Or method B. In the reaction vessel, add cefpiramide, add water, C1-C6 low molecular alcohol, C2-C8 low molecular ether, One or more of C2-C6 low molecular weight nitriles, stirred, and added to the filtrate at 10 ° C with sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, sodium acetate, sodium octanoate, sodium isooctanoate and water , C1-C6 low molecular alcohol, Low molecular ether of C2-C8, a solution of one or more of the low molecular ketones of C3-C8, stirred, adjusted to a pH of 6.0 to 8.0 with a mineral acid or an organic acid or a solution thereof, and added to the C1-C6 low molecular alcohol, a low molecular ether of C2-C8, a low molecular ketone of C3-C8, a low molecular ester of C2-C8, a low molecular nitrile of C2-C6, One or more of C1-C6 low molecular halogenated hydrocarbons, or C1-C6 low molecular alcohol, C2-C8 low molecular ether, C3-C6 low molecular ketone, C2-C8 low molecular ester, One or more of C2-C6 low molecular nitrile, C1-C6 low molecular halogenated hydrocarbon, placed below 10 ° C, the solid is fully analyzed, filtered, using C1-C6 low molecular alcohol, a low molecular ether of C2-C8, a low molecular ketone of C3-C6, a low molecular nitrile of C2-C6, One or more of the C1-C6 low molecular halogenated hydrocarbons are washed 1-3 times, filtered, and the obtained solid is mixed with water with a C1-C6 low molecular alcohol, a C2-C8 low molecular ether, a C3-C8 low molecular weight. ketone, a low molecular ester of C2-C8, a low molecular weight nitrile of C2-C6, One or more of the C1-C6 low molecular halogenated hydrocarbons are recrystallized one or more times by a crystallization solvent, filtered, washed, dried, and dried to obtain cefpiramide sodium hydrate. The cefpiramide sodium hydrate according to claim 1, which is used for preparing an injection, a solid preparation, and a suppository; and the injection comprises a lyophilized powder preparation for injection, and a sterile powder injection needle. Formulations, large infusion preparations; the solid preparations include tablets, capsules, granules. The cefpiramide sodium hydrate according to claim 1, which is used for preparing a respiratory system, hepatobiliary system, facial features, urinary tract infections of human or animals caused by Gram-positive or negative bacteria-sensitive bacteria, Application in the treatment or prevention of abdominal infection, pelvic infection, sepsis, skin and soft tissue infection, bone and joint infection diseases. The cefpiramide sodium hydrate according to claim 1, which is used for preparing a composition containing the hydrate, comprising preparing a β-lactamase inhibitor clavulanic acid or a pharmaceutically acceptable salt thereof, Shuba An antibacterial combination drug comprising one or more of tamoxifen or a pharmaceutically acceptable salt thereof, tazobactam or a pharmaceutically acceptable salt thereof, wherein the weight ratio of cefpiramide sodium hydrate to β-lactamase inhibitor is 30 :1~1:2.

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