WO2021228008A1 - 头孢呋辛镁化合物、组合物、制备方法及用途 - Google Patents

头孢呋辛镁化合物、组合物、制备方法及用途 Download PDF

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WO2021228008A1
WO2021228008A1 PCT/CN2021/092554 CN2021092554W WO2021228008A1 WO 2021228008 A1 WO2021228008 A1 WO 2021228008A1 CN 2021092554 W CN2021092554 W CN 2021092554W WO 2021228008 A1 WO2021228008 A1 WO 2021228008A1
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cefuroxime
magnesium compound
magnesium
compound
suspension
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PCT/CN2021/092554
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English (en)
French (fr)
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刘翠哲
刘金霞
宋鸿儒
魏晓芬
金鹏
白红红
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承德医学院
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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
    • C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
    • C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
    • 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 invention relates to the technical field of medicine, in particular to a preparation method and application of a cefuroxime magnesium compound, a composition, an antibacterial composition, and a cefuroxime magnesium compound.
  • Cefuroxime is a second-generation cephalosporin with a broad-spectrum antibacterial effect and a wide range of applications. It can be used for respiratory infections, ear, nose, throat infections, urinary tract infections, skin and soft tissue infections, bone and bone infections caused by sensitive bacteria. Joint infections, gonorrhea, other infections including sepsis and meninges.
  • cefuroxime sodium is usually administered intravenously or intramuscularly. However, the stability of cefuroxime sodium still needs to be improved.
  • the main technical problem solved by the present invention is to provide a cefuroxime magnesium compound, a composition, an antibacterial composition, and a preparation method and application of the cefuroxime magnesium compound, which can improve the stability of the cefuroxime salt.
  • a technical solution adopted by the present invention is to provide a cefuroxime magnesium compound, the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • another technical solution adopted by the present invention is to provide a method for preparing a cefuroxime magnesium compound, including: providing a cefuroxime-containing compound, providing a magnesium compound; making the cefuroxime-containing magnesium compound The compound chemically reacts with the magnesium compound; the product of the cefuroxime magnesium compound obtained by the chemical reaction is obtained.
  • said providing a cefuroxime-containing compound includes: providing a cefuroxime acid suspension; wherein, providing a cefuroxime acid suspension includes: sieving cefuroxime acid to obtain powdered cefuroxime acid ; The powdered cefuroxime acid is added to water and suspended to obtain the cefuroxime acid suspension.
  • said providing a magnesium compound includes: providing a magnesium compound suspension; wherein, said providing a magnesium compound suspension includes: pulverizing the magnesium compound into a fine powder and sieving to obtain a powdered magnesium compound; The powdered magnesium compound is added to water and suspended to obtain the magnesium compound suspension.
  • the chemical reaction between the cefuroxime-containing compound and the magnesium compound includes: chemically reacting the cefuroxime-containing compound and the magnesium compound in water at a predetermined temperature range; Wherein, the predetermined temperature range is 15-30°C.
  • the obtaining the product of the cefuroxime magnesium compound obtained by the chemical reaction includes: drying the filtrate obtained from the chemical reaction to obtain the cefuroxime magnesium compound; wherein the method of drying is heating and evaporation, spray drying Or freeze-dried.
  • the molar ratio of cefuroxime to magnesium element is 2:1; wherein, the magnesium compound includes magnesium hydroxide, magnesium bicarbonate, and magnesium acetate.
  • another technical solution adopted by the present invention is to provide a composition comprising a cefuroxime magnesium compound, and the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • an antibacterial composition comprising an antibacterial effective dose of cefuroxime magnesium compound and a pharmaceutically acceptable carrier, wherein the The molecular formula of cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2.
  • another technical solution adopted by the present invention is to provide a use of the above-mentioned cefuroxime magnesium compound in the preparation of antibacterial drugs.
  • another technical solution adopted by the present invention is to provide a use of the above-mentioned cefuroxime magnesium compound in the preparation of anti-hypomagnesemia drugs.
  • the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • the beneficial effect of the present invention is: different from the prior art, the preparation method of the present invention chemically reacts the cefuroxime-containing reactant with the magnesium compound to obtain the cefuroxime magnesium compound obtained by the reaction.
  • the preparation method The operation is simple and it is easy to realize large-scale industrial production; the cefuroxime magnesium compound can be used as an antibacterial cefuroxime drug, and compared with cefuroxime sodium, it can improve the stability of the cefuroxime drug.
  • Fig. 1 is a schematic flow chart of an embodiment of the preparation method of the cefuroxime magnesium compound of the present invention.
  • the present invention provides a cefuroxime magnesium compound, the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • the molecular weight of the cefuroxime magnesium compound is 870.
  • the cefuroxime magnesium compound is the magnesium salt of cefuroxime.
  • Fig. 1 is a schematic flow chart of an embodiment of the preparation method of the cefuroxime magnesium compound of the present invention, and the method includes:
  • Step S101 providing a compound containing cefuroxime, and providing a magnesium compound.
  • Step S102 chemically react the cefuroxime-containing compound with the magnesium compound.
  • Step S103 Obtain the product of the cefuroxime magnesium compound obtained by the chemical reaction.
  • the cefuroxime-containing compound includes, but is not limited to: cefuroxime acid.
  • Magnesium compounds include, but are not limited to: magnesium hydroxide, magnesium bicarbonate, magnesium acetate, and the like.
  • the molar ratio of cefuroxime to magnesium is 2:1.
  • the preparation method of the embodiment of the present invention chemically reacts the cefuroxime-containing reactant with the magnesium compound to obtain the cefuroxime magnesium compound obtained by the reaction.
  • the preparation method has simple operation and is easy to realize large-scale industrial production.
  • step S102 may include: causing a chemical reaction between the cefuroxime-containing compound and the magnesium compound in water at a predetermined temperature range;
  • the predetermined temperature range is 15-30°C; for example: 15°C, 20°C, 25°C, 30°C, and so on.
  • the solid cefuroxime-containing reactant and the solid magnesium compound can be put into the reaction vessel, and then water is added to cause a chemical reaction within a predetermined temperature range.
  • the solid cefuroxime-containing reactant and the solid magnesium compound are separately added to water in advance.
  • the specific instructions are as follows:
  • step S101 a compound containing cefuroxime is provided, which may specifically include:
  • a cefuroxime acid suspension is provided; specifically, the cefuroxime acid is sieved to obtain powdered cefuroxime acid; the powdered cefuroxime acid is added to water and suspended to obtain a cefuroxime acid suspension.
  • providing a magnesium compound includes: providing a magnesium compound suspension; specifically, pulverizing the magnesium compound into a fine powder and sieving to obtain a powdered magnesium compound; adding the powdered magnesium compound to water and suspending , To obtain a magnesium compound suspension.
  • step S103 obtaining the product of the cefuroxime magnesium compound obtained by the chemical reaction may specifically include: drying the filtrate obtained by the chemical reaction to obtain the cefuroxime magnesium compound.
  • the way of drying is heating and evaporation, spray drying or freeze drying.
  • the heating and evaporating to dryness in this embodiment refers to heating and evaporating the water in the filtrate obtained by the chemical reaction to obtain a cefuroxime magnesium compound with a water content of 2.0% or less (by weight).
  • the spray drying in this embodiment uses spray drying equipment to disperse the filtrate obtained from the chemical reaction into particles, and contact the particles with hot air to instantly remove their moisture, and obtain cephalosporins with a water content of 2.0% or less (by weight).
  • Magnesium furosemide compound is a product currently on the market, for example, a product sold under the trade name QZR-5 by the Linzhou Dryer Factory Company of Xishan City, Jiangsu province.
  • the freeze-drying in this embodiment uses freeze-drying equipment to freeze the filtrate obtained from the chemical reaction to below 0°C, and heat it under a high vacuum to directly sublime the water from the solid state into water vapor, remove the water, and obtain a water content of 2.0% The following (by weight) cefuroxime magnesium compound.
  • the freeze-drying equipment is a product currently on the market, such as a product sold by Beijing Sihuan Scientific Instrument Factory Co., Ltd. under the trade name LGJ-22D.
  • the method for determining the water content in the cefuroxime magnesium compound in this embodiment is the drying method.
  • the crude cefuroxime magnesium compound obtained by drying can also be purified to obtain a purified cefuroxime magnesium compound.
  • cefuroxime magnesium compound obtained after the preliminary purification is further purified, for example, by recrystallization, octadecylsilane reverse phase column, and preparative liquid chromatography to achieve a cefuroxime magnesium compound content of more than 90% (By weight), even more than 95% (by weight).
  • the recrystallization purification is carried out in ethanol-water (1:9-9:1) solvent at 25°C.
  • Octadecylsilane reversed phase column is a commonly used reversed phase chromatography column, also called C18 column; because it is a long-chain alkyl bonded phase, it has a higher carbon content and better hydrophobicity It has stronger adaptability to various types of biological macromolecules, so it is the most widely used in biochemical analysis.
  • ODS column purification is performed using an ODS column sold by YMC under the trade name GEL C18AAG12S50 under the condition of 5%-50% acetonitrile-methanol-water as the eluent.
  • the instrument used for preparative liquid chromatography purification is a preparative liquid phase sold by Shimadzu under the trade name CTO-10A, the preparative column is discoveryC18, and the liquid phase conditions are acetonitrile-methanol-water (volume ratio is 5:50: 45).
  • a preparation process of cefuroxime sodium is as follows: dissolve cefuroxime acid in aqueous acetone, add activated carbon to decolorize and sterilize after it is completely dissolved, wash the carbon residue with acetone, combine the filtrate, and slowly add sodium isooctanoate/acetone dropwise Liquid, the feeding time is 1h, continue to stir, cool to about 5°C in an ice bath, and filter out the crystals. It was washed with acetone to pH 6.0 and dried under vacuum at 40°C to obtain cefuroxime sodium with a yield of 91.1% and a content of >86.0%.
  • the preparation method of the cefuroxime magnesium compound in the embodiment of the present invention is simple to operate, does not use organic solvents, does not generate toxic and harmful substances, and the finished product has high purity, which is convenient for industrial production.
  • Mg 2+ One magnesium ion (Mg 2+ ) reacts with two carboxyl groups on cefuroxime to produce cefuroxime magnesium, the molecular formula is Mg(C 16 H 15 N 4 O 8 ) 2 , and the molecular weight is 870.
  • the structure of the prepared cefuroxime magnesium compound is analyzed by ultraviolet absorption spectroscopy.
  • the UV absorption spectra of the reference substance and the cefuroxime magnesium compound at 200-400nm were measured by the reference substance comparison method.
  • the cefuroxime acid, cefuroxime sodium, and cefuroxime magnesium compound are automatically scanned by the instrument for ultraviolet absorption spectra at 200-400 nm.
  • cefuroxime acid and cefuroxime sodium are reference substances; the equipment used for ultraviolet absorption spectroscopy analysis is Agilent 8453.
  • cefuroxime magnesium Dissolve 2mg cefuroxime acid, 2mg cefuroxime sodium and 2mg cefuroxime magnesium compound (abbreviated as cefuroxime magnesium) prepared by the present invention in 10ml methanol respectively, and then the instrument automatically scans the ultraviolet absorption spectrum at 200-400nm, The maximum absorption wavelength was measured, and the results are shown in Table 1.
  • the present invention also provides a composition comprising a cefuroxime magnesium compound, the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • the present invention also provides an antibacterial composition, the antibacterial composition comprising an effective dose of cefuroxime magnesium compound and a pharmaceutically acceptable carrier, wherein the molecular formula of the cefuroxime magnesium compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • the present invention also provides a use of the above-mentioned cefuroxime magnesium compound in the preparation of antibacterial drugs.
  • the present invention also provides an anti-hypomagnesemia composition.
  • the anti-hypomagnesemia composition comprises an effective dose of a cefuroxime magnesium compound and a pharmaceutically acceptable carrier, wherein the cefuroxime magnesium
  • the molecular formula of the compound is: Mg(C 16 H 15 N 4 O 8 S) 2 .
  • the present invention also provides a use of the above-mentioned cefuroxime magnesium compound in the preparation of anti-hypomagnesemia drugs.
  • the preparation method of cefuroxime magnesium compound includes the following steps:
  • the preparation method of cefuroxime magnesium compound includes the following steps:
  • step D Drying: drying the filtrate obtained in step C to obtain a cefuroxime magnesium compound.
  • the preparation method of cefuroxime magnesium compound includes the following steps:
  • step D Drying: drying the filtrate obtained in step C to obtain a cefuroxime magnesium compound.
  • This example compares the stability of the prepared cefuroxime magnesium compound and cefuroxime sodium and the comparison of in vitro antibacterial tests, which are specifically described as follows: (1) the stability of cefuroxime sodium and cefuroxime magnesium compound Sexual comparison:
  • Preparation of liquid culture medium accurately weigh 2g beef extract, 3g yeast, 5g sodium chloride, and 700ml distilled water, adjust the pH of the liquid culture medium to about 7.0, autoclave in a steam sterilizer for 30 minutes, and adjust the temperature to Take it out after sterilization at 120°C and put them into 6 conical flasks.
  • the volume of the liquid culture medium in each conical flask is 100ml, which is sealed and ready for use.
  • Preparation of drug solution accurately weigh cefuroxime sodium and cefuroxime magnesium compound according to the number of equimolar ⁇ -lactam rings, add distilled water to make the volume to 10ml, and dilute to make cefuroxime sodium and cefuroxime magnesium compound solution The concentrations were 32 ⁇ g/ml and 31.36 ⁇ g/ml, respectively, filtered with a 0.22 ⁇ m filter membrane, and then the filtrate was taken for later use.
  • the preparation of the bacterial solution Take the second-generation bacteria of Escherichia coli (Gram-negative bacteria) and Staphylococcus albicans (Gram-positive bacteria) from the nutrient agar slant respectively, and inoculate them into two In the conical flask of liquid culture medium, gently shake the conical flask, place it in a gas bath constant temperature shaker, adjust the temperature to 37°C, culture for 24-48h, observe that the liquid becomes turbid, that is, the bacteria resurrection is successful.
  • Escherichia coli Gram-negative bacteria
  • Staphylococcus albicans Gram-positive bacteria
  • Turbidimetric experiment Before the experiment, autoclave the required experimental supplies at 120°C for 30 minutes, and sterilize the laboratory with a UV lamp for 30 minutes. Under aseptic operating conditions, 32 test tubes were taken and divided into four groups, and liquid medium was added to each test tube to dilute the cefuroxime sodium and cefuroxime magnesium compound solution in multiples. Add 50 ⁇ l of Staphylococcus albicans solution to 16 of them, add 50 ⁇ l of Escherichia coli solution to the remaining 16 and place them in a constant temperature incubator for 18-24 hours to observe the turbidity.
  • the cefuroxime sodium and cefuroxime magnesium compounds have a certain inhibitory effect on the two drug-resistant bacteria. With the increase of drug concentration, the antibacterial effect is more obvious.
  • the inhibitory effect of cefuroxime magnesium compound on Staphylococcus albicans is 31.2 ⁇ g/ml, 7.84 ⁇ g/ml
  • the antibacterial effect is stronger than that of the same molar number of ⁇ -lactam rings corresponding to the concentration of cefuroxime sodium at 32 ⁇ g/ml, 8 ⁇ g/ml, and 4 ⁇ g/ml; in terms of its inhibitory effect on Escherichia coli , Cefuroxime magnesium compound at the concentration of 15.6 ⁇ g/ml, 1.95 ⁇ g/ml, 0.98 ⁇ g/ml, the antibacterial effect
  • the rats were adaptively reared for one week, their body temperature was monitored every morning and evening for 3 days.
  • the rats with body temperature fluctuation less than 0.5°C were selected into the experiment and randomly divided into 6 groups: blank group, model group, cefuroxime sodium low-dose group, cefuroxime sodium high-dose group, cefuroxime magnesium low-dose group, cefuroxime
  • the octylmagnesium high-dose group has 10 rats in each group.
  • the rat is anesthetized, open the mouth of the rat to fully expose the throat, and slowly insert the tracheal tube with a syringe into the trachea through the mouth, push in 0.6ml of bacterial liquid, and push the same volume of normal saline in the blank group.
  • the rat was erected, and the rat was kept upright for about 20s to ensure that the inoculated bacteria liquid entered the lungs due to gravity.
  • Tail vein injection dosage: 50mg/kg for low-dose group, 100mg/kg for high-dose group (dose are equivalent to cefuroxime), twice a day for three consecutive days, blank group and model group Give an equal volume of saline.
  • the lungs were fixed with 10% formaldehyde solution, routinely embedded in paraffin, sectioned, and stained with hematoxylin-eosin (HE). The pathological changes of liver tissues were observed under light microscope.
  • the administration group and the model group began to experience shortness of breath, reduced food intake, and poor response to the surrounding environment.
  • the animals had a significant decrease in eating and mobility, and their hair was straight and curled in the corner of the cage.
  • the cefuroxime sodium (low and high-dose) group had faster breathing than the cefuroxime magnesium (low and high-dose) group, and the food intake was significantly less than that of the cefuroxime magnesium group.
  • the appetite and activity of the animals in the administration group increased.
  • the rats in the cefuroxime sodium group were still breathing faster than the cefuroxime magnesium group. feel.
  • the appetite, activity level, body weight, and body temperature of rats in the blank group did not change significantly compared with those before vaccination.
  • the number of white blood cells in the model group increased significantly (P ⁇ 0.01); compared with the model group, the number of white blood cells in each administration group decreased significantly (P ⁇ 0.01), indicating that cefuroxime sodium and magnesium are both Murine pneumonia has a therapeutic effect, and compared with the low-dose cefuroxime sodium group, the number of white blood cells in the low-dose cefuroxime magnesium group decreased more significantly (P ⁇ 0.05).
  • the blank group there was a significant difference in the high-dose cefuroxime sodium group (P ⁇ 0.01), and there was no significant difference in the high-dose cefuroxime magnesium group.
  • the percentage of lymphocytes in the model group decreased significantly (P ⁇ 0.01); compared with the model group, the number of lymphocytes in each administration group increased significantly (P ⁇ 0.01, P ⁇ 0.05). It shows that both cefuroxime sodium and magnesium have therapeutic effects on pneumonia in rats, and compared with the low-dose cefuroxime sodium group, the percentage of lymphocytes in the low-dose cefuroxime magnesium group increased significantly (P ⁇ 0.05).
  • magnesium is an essential element that participates in the normal life activities and metabolic processes of organisms. Magnesium affects various biological functions of cells, affects potassium ion and calcium ion transport, regulates signal transmission, participates in energy metabolism, protein and nucleic acid synthesis; activates and inhibits catalytic enzymes, and regulates cell cycle, cell proliferation and cell differentiation; magnesium It is also involved in maintaining the stability of the genome, and is also related to the body's oxidative stress and tumorigenesis.
  • the cefuroxime magnesium compound can combine magnesium and cefuroxime, which can reduce the mortality of critically ill patients, is beneficial to some inflammations, and can have a synergistic effect.
  • the cefuroxime magnesium compound can be used as an antibacterial cefuroxime drug. Compared with cefuroxime sodium, it can improve the stability of the cefuroxime drug; its preparation method is simple to operate, can simplify the production process, and is convenient for industrialization. Large-scale production; the preparation method can avoid the use of organic solvents, and no toxic and harmful substances are generated; the purity of the prepared finished product can reach more than 95%; at the same time, it provides a choice for patients who are clinically unsuitable for sodium.

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Abstract

本发明公开了一种头孢呋辛镁化合物、组合物、制备方法及用途，该制备方法包括：提供含头孢呋辛的化合物，提供镁化合物；使所述含头孢呋辛的化合物与所述镁化合物发生化学反应；获得化学反应得到的头孢呋辛镁化合物的产物。通过这种方式，本发明能够为实现大规模的工业化生产提供技术支持，且能够提高头孢呋辛盐的稳定性。

Description

头孢呋辛镁化合物、组合物、制备方法及用途 技术领域
本发明涉及医药技术领域，尤其涉及一种头孢呋辛镁化合物、组合物、抗菌组合物、头孢呋辛镁化合物的制备方法及用途。
背景技术
头孢呋辛为第二代头孢菌素，具有广谱抗菌作用，适应范围广，可用于敏感菌所致的呼吸道感染、耳、鼻、喉科感染、泌尿道感染、皮肤和软组织感染、骨和关节感染、淋病、包括败血症及脑膜等其他感染。
临床上常使用的注射剂为头孢呋辛钠。头孢呋辛钠通常经静注或肌注给药。但是，头孢呋辛钠的稳定性依然有待提高。
发明内容
本发明主要解决的技术问题是提供一种头孢呋辛镁化合物、组合物、抗菌组合物、头孢呋辛镁化合物的制备方法及用途，能够提高头孢呋辛盐的稳定性。
为解决上述技术问题，本发明采用的一个技术方案是：提供一种头孢呋辛镁化合物，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
为解决上述技术问题，本发明采用的另一个技术方案是：提供一种头孢呋辛镁化合物的制备方法，包括：提供含头孢呋辛的化合物，提供镁化合物；使所述含头孢呋辛的化合物与所述镁化合物发生化学反应；获得化学反应得到的头孢呋辛镁化合物的产物。
其中，所述提供含头孢呋辛的化合物，包括：提供头孢呋辛酸混悬液；其中，所述提供头孢呋辛酸混悬液，包括：将头孢呋辛酸过筛，得到粉末状的头孢呋辛酸；将所述粉末状的头孢呋辛酸加入水中混悬，得到所述头孢呋辛酸混悬液。
其中，所述提供镁化合物，包括：提供镁化合物混悬液；其中，所述提供镁化合物混悬液，包括：将镁化合物粉碎成细粉并过筛，得到粉末状的镁化合物；将所述粉末状的镁化合物加入水中混悬，得到所述镁化合物混悬液。
其中，所述使所述含头孢呋辛的化合物与所述镁化合物发生化学反应，包括：使所述含头孢呋辛的化合物与所述镁化合物在水中、在预定温度范围下发生化学反应；其中，所述预定温度范围是15-30℃。
其中，所述获得化学反应得到的头孢呋辛镁化合物的产物，包括：将化学反应得到的滤液进行干燥，得到所述头孢呋辛镁化合物；其中，进行干燥的方式是加热蒸干、喷雾干燥或冷冻干燥。
其中，头孢呋辛与镁元素的摩尔比为2:1；其中，所述镁化合物包括氢氧化镁、碳酸氢镁以及乙酸镁。
为解决上述技术问题，本发明采用的另一个技术方案是：提供一种组合物，所述组合物包括头孢呋辛镁化合物，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
为解决上述技术问题，本发明采用的另一个技术方案是：提供一种抗菌组合物，所述抗菌组合物包括抗菌有效剂量的头孢呋辛镁化合物以及医药上可接受的载体，其中，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S)2。
为解决上述技术问题，本发明采用的另一个技术方案是：提供一种如上所述的头孢呋辛镁化合物在抗菌的药物的制备中的用途。
为解决上述技术问题，本发明采用的另一个技术方案是：提供一种如上所述的头孢呋辛镁化合物在抗低镁血症的药物的制备中的用途。
为解决上述技术问题，本发明采用的另一个技术方案是：所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
本发明的有益效果是：区别于现有技术的情况，本发明的制备方法通过使含头孢呋辛的反应物与镁化合物发生化学反应，进而获得反应得到的头孢呋辛镁化合物，该制备方法操作简单，容易实现大规模的工业化生产；头孢呋辛镁化合物可以作为抗菌的头孢呋辛药物，相比头孢呋辛钠，能够提高头孢呋辛药物的稳定性。
附图说明
图1是本发明头孢呋辛镁化合物的制备方法一实施例的流程示意图。
具体实施方式
本发明提供一种头孢呋辛镁化合物，该头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。头孢呋辛镁化合物的分子量是870。头孢呋辛镁化合物是头孢呋辛的镁盐。
参见图1，图1是本发明头孢呋辛镁化合物的制备方法一实施例的流程示意图，该方法包括：
步骤S101：提供含头孢呋辛的化合物，提供镁化合物。
步骤S102：使含头孢呋辛的化合物与镁化合物发生化学反应。
步骤S103：获得化学反应得到的头孢呋辛镁化合物的产物。
含头孢呋辛的化合物包括但不限于：头孢呋辛酸。
镁化合物包括但不限于：氢氧化镁、碳酸氢镁、乙酸镁，等等。
其中，头孢呋辛与镁元素的摩尔比是2:1。
本发明实施例的制备方法通过使含头孢呋辛的反应物与镁化合物发生化学反应，进而获得反应得到的头孢呋辛镁化合物。该制备方法操作简单，容易实现大规模的工业化生产。
在一实施例中，为了不产生有毒有害的物质，不使用有机溶剂而是使用普通的水作为含头孢呋辛的反应物与镁化合物发生化学反应的溶剂，并且水的成本也低廉。
具体地，步骤S102可以包括：使含头孢呋辛的化合物与镁化合物在水中、在预定温度范围下发生化学反应；
其中，预定温度范围是15-30℃；例如：15℃、20℃、25℃、30℃，等等。
在实际应用中，可以将固体的含头孢呋辛的反应物与固体的镁化合物放入反应容器后，再加入水，在预定温度范围下发生化学反应。在一实际应用中，为了加快反应速度，预先分别将固体的含头孢呋辛的反应物与固体的镁化合物加入水中，具体说明如下：
其中，步骤S101中，提供含头孢呋辛的化合物，具体可以包括：
提供头孢呋辛酸混悬液；具体地，将头孢呋辛酸过筛，得到粉末状的头孢呋辛酸；将粉末状的头孢呋辛酸加入水中混悬，得到头孢呋辛酸混悬液。
其中，步骤S101中，提供镁化合物，包括：提供镁化合物混悬液；具体地，将镁化合物粉碎成细粉并过筛，得到粉末状的镁化合物；将粉末状的镁化合物加入水中混悬，得到镁化合物混悬液。
在一实施例中，步骤S103中，获得化学反应得到的头孢呋辛镁化合物的产物，具体可以包括：将化学反应得到的滤液进行干燥，得到头孢呋辛镁化合物。
其中，进行干燥的方式是加热蒸干、喷雾干燥或冷冻干燥。
本实施例中的加热蒸干是指将化学反应得到的滤液中的水分加热蒸发除去，得到水含量为2.0％以下(以重量计)的头孢呋辛镁化合物。
本实施例中的喷雾干燥是采用喷雾干燥设备将化学反应得到的滤液分散成微粒，并且让微粒与热空气接触，在瞬间除去其水分，得到水含量为2.0％以下(以重量计)的头孢呋辛镁化合物。其中，喷雾干燥设备是目前市场上销售的产品，例如由江苏锡山市林州干燥机厂公司以商品名QZR-5型销售的产品。
本实施例中的冷冻干燥是采用冷冻干燥设备将化学反应得到的滤液冷冻至0℃以下，并在高真空下通过加热使水分直接从固态升华为水汽，除去其水分，得到水含量为2.0％以下(以重量计)的头孢呋辛镁化合物。其中，冷冻干燥设备是目前市场上销售的产品，例如由北京四环科学仪器厂有限公司以商品名LGJ-22D型销售的产品。
其中，本实施例头孢呋辛镁化合物中水含量测定方法是烘干法。
在一应用中，干燥之后，还可以将干燥得到的头孢呋辛镁化合物粗提物进行纯化，得到纯化后的头孢呋辛镁化合物。
进一步，将初步纯化后得到的头孢呋辛镁化合物进一步纯化，例如采用重结晶、十八烷基硅烷反相柱、制备液相色谱法进行纯化，以达到头孢呋辛镁化合物含量为90％以上(以重量计)，甚至达到95％以上(以重量计)。
其中，重结晶纯化是在乙醇-水(1：9～9:1)溶剂中在25℃条件下进行的。
十八烷基硅烷反相柱(ODS，octadecylsilane)是一种常用的反相色谱柱，也叫C18柱；由于它是长链烷基键合相，有较高的碳含量和更好的疏水性，对各种类型的生物大分子有更强的适应能力，因此在生物化学分析工作中应用最为广泛。其中，使用ODS柱纯化是在使用由YMC公司以商品名GEL C18AAG12S50销售的ODS柱在5％-50％乙腈-甲醇-水作为洗脱液条件下进行的。
其中，使用制备液相色谱法纯化所用仪器为岛津公司以商品名CTO-10A销售的制备液相，制备色谱柱为discoveryC18，液相条件为乙腈-甲醇-水(体积 比是5：50：45)。
头孢呋辛镁化合物含量是根据高效液相色谱法测定的，所用仪器为Agilent 1260，色谱柱为ODS C18，液相条件为醋酸钠缓冲液(pH为3.4)：乙腈为流动相＝10：1，流速为1mL/min，检测波长273nm，进样量为20μL；柱温为25℃。
头孢呋辛钠的一制备工艺为：将头孢呋辛酸溶于含水丙酮中，待完全溶解后加活性炭脱色除菌，用丙酮洗炭渣，合并滤洗液，缓缓滴加异辛酸钠/丙酮液，加料时间1h，继续搅拌，冰浴冷却至5℃左右，滤出晶体。用丙酮洗涤至pH6.0，40℃以下真空干燥，得头孢呋辛钠，收率91.1％，含量>86.0％。与上述头孢呋辛钠的制备工艺相比，本发明实施例头孢呋辛镁化合物的制备方法操作简单，不使用有机溶剂，无有毒有害物质生成，产成品纯度高，便于工业化生产。
一个镁离子(Mg 2+)与两个头孢呋辛上的羧基发生反应，生成头孢呋辛镁，分子式为Mg(C 16H 15N 4O 8) 2，分子量为870。
下面采用紫外吸收光谱对制备得到的头孢呋辛镁化合物进行结构分析。采用对照品比较法测定对照品和头孢呋辛镁化合物在200-400nm下的紫外吸收光谱。具体地，将头孢呋辛酸、头孢呋辛钠以及头孢呋辛镁化合物在200-400nm下仪器自动扫描紫外吸收光谱。其中，头孢呋辛酸、头孢呋辛钠均是对照品；紫外吸收光谱分析使用的设备是Agilent 8453。
将2mg头孢呋辛酸、2mg头孢呋辛钠以及2mg本发明制备的头孢呋辛镁化合物(简写为头孢呋辛镁)分别溶于10ml甲醇中，然后在200-400nm下仪器自动扫描紫外吸收光谱，测定最大吸收波长，其结果列于表1中。
表1头孢呋辛酸、头孢呋辛钠以及头孢呋辛镁的最大吸收波长
Figure PCTCN2021092554-appb-000001
从表1可以看出，头孢呋辛酸、头孢呋辛钠与头孢呋辛镁化合物的紫外最大吸收波长(λmax)相同，它们都在274nm处有最大吸收；这些紫外吸收光谱结果表明，镁离子的结合对头孢呋辛的离域共振结构影响不大。
本发明还提供一种组合物，该组合物包括头孢呋辛镁化合物，头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
本发明还提供一种抗菌组合物，该抗菌组合物包括抗菌有效剂量的头孢呋辛镁化合物以及医药上可接受的载体，其中，头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
本发明还提供一种如上所述的头孢呋辛镁化合物在抗菌的药物的制备中的用途。
本发明还提供一种抗低镁血症组合物，该抗低镁血症组合物包括抗低镁血症有效剂量的头孢呋辛镁化合物以及医药上可接受的载体，其中，头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
本发明还提供一种如上所述的头孢呋辛镁化合物在抗低镁血症的药物的制备中的用途。
下面以具体的实施例来说明本发明头孢呋辛镁化合物的制备方法。
实施例1：
头孢呋辛镁化合物的制备方法，包括以下步骤：
(A)制备头孢呋辛酸混悬液：将0.02摩尔头孢呋辛酸过筛，将粉末状的头孢呋辛酸加入80ml纯化水中混悬，得到头孢呋辛酸混悬液；
(B)制备镁化合物混悬液：将0.01摩尔碳酸氢镁粉碎成细粉，过筛，将粉末状的镁化合物加入50ml纯化水中，混悬，得到镁化合物混悬液；
(C)反应：将步骤B得到的镁化合物混悬液按照一定比例加入步骤A得到的头孢呋辛酸混悬液中，在温度25℃下搅拌，再加入活性炭搅拌脱色，过滤，得到滤液；
(D)干燥：将步骤C得到的滤液冷冻干燥，得到头孢呋辛镁化合物。
实施例2：
头孢呋辛镁化合物的制备方法，包括以下步骤：
(A)制备头孢呋辛酸混悬液：将0.02摩尔头孢呋辛酸过筛，将粉末状的头孢呋辛酸加入50ml纯化水中，得到头孢呋辛酸混悬液；
(B)制备镁化合物混悬液：将0.01摩尔乙酸镁粉碎成细粉，过筛，将粉末状的镁化合物加入20ml纯化水中混悬，得到镁化合物混悬液；
(C)反应：将步骤B得到的镁化合物混悬液按照一定比例加入步骤A 得到的头孢呋辛酸混悬液中，在温度30℃下搅拌，再加入活性炭搅拌脱色，过滤，得到滤液；
(D)干燥：将步骤C得到的滤液进行干燥，得到头孢呋辛镁化合物。
实施例3：
头孢呋辛镁化合物的制备方法，包括以下步骤：
(A)制备头孢呋辛酸混悬液：将0.02摩尔头孢呋辛酸过筛，将粉末状的头孢呋辛酸加入200ml纯化水中，得到头孢呋辛酸混悬液；
(B)制备镁化合物混悬液：将0.01摩尔氢氧化镁粉碎成细粉，过筛，将粉末状的镁化合物加入80ml纯化水中混悬，得到镁化合物混悬液；
(C)反应：将步骤B得到的镁化合物混悬液按照一定比例加入步骤A得到的头孢呋辛酸混悬液中，在温度15℃下搅拌，再加入活性炭搅拌脱色，过滤，得到滤液；
(D)干燥：将步骤C得到的滤液进行干燥，得到头孢呋辛镁化合物。
本实施例对制备得到的头孢呋辛镁化合物与头孢呋辛钠进行稳定性的比较以及体外抑菌等试验的比较，具体说明如下：(一)头孢呋辛钠与头孢呋辛镁化合物的稳定性比较：
进行加速试验，比较头孢呋辛钠与头孢呋辛镁化合物的稳定性。准确称取头孢呋辛钠和头孢呋辛镁化合物约0.1g共12份，分别均匀平铺于12个50mL表面皿底部，将表面皿置于恒温恒湿箱内进行恒温恒湿加速实验。实验条件为：温度为60℃，湿度75％，分别于5天、10天取样，每次取3份测定含量，取平均值，其结果列于表3中。
表3头孢呋辛钠与头孢呋辛镁的稳定性结果
Figure PCTCN2021092554-appb-000002
由表3可见，头孢呋辛镁在加速试验条件下，含量变化比头孢呋辛钠变化更小，稳定性更好。
(二)头孢呋辛钠与头孢呋辛镁化合物体外抑菌试验的比较：
根据徐淑云编写的《药理实验方法学》(第三版)，第63章中抗菌药物 实验法，进行体外抑菌实验。
液体培养基的制备：精密称定牛肉膏2g、酵母3g、氯化钠5g、蒸馏水700ml混合，调节液体培养基的pH值为7.0左右，在蒸汽灭菌锅里高压灭菌30min，温度调至120℃，灭菌完毕后取出，分别放入6个锥形瓶中，每一个锥形瓶中液体培养基的体积为100ml，密封好，备用。
药液的制备：按照等摩尔的β-内酰胺环数精密称取头孢呋辛钠和头孢呋辛镁化合物，加蒸馏水定容至10ml，稀释后使头孢呋辛钠和头孢呋辛镁化合物溶液浓度分别为32μg/ml、31.36μg/ml，采用0.22μm滤膜过滤，取续滤液，备用。
菌液的制备：将大肠埃希菌(革兰阴性菌)、白葡萄球菌(革兰阳性菌)第二代细菌从营养琼脂斜面上分别挑取一接种环的量，接种到2个带有液体培养基的锥形瓶中，轻轻摇晃锥形瓶后，放置在气浴恒温振荡器中，温度调节至37℃，培养24-48h后，观察液体变浑浊，即细菌复活成功。
比浊法实验：实验前，将所需实验用品120℃下高压灭菌30分钟，用紫外灯消毒实验室30min。在无菌操作条件下，取32支试管，分为四组，每支试管加入液体培养基，倍比稀释头孢呋辛钠和头孢呋辛镁化合物溶液。其中16支加入50μl白葡萄球菌液，其余16支加入50μl大肠杆菌液，再次放入恒温培养箱中培养18-24h，观察浊度。
抑菌效果评价：通过紫外分光光度计测量OD600值，3次重复实验均有抑菌效果，视为抑菌作用有效，结果见表4、表5。
表4头孢呋辛钠及头孢呋辛镁对白葡萄球菌的抑菌效果
Figure PCTCN2021092554-appb-000003
表5头孢呋辛钠及头孢呋辛镁化合物对大肠杆菌的抑菌效果
Figure PCTCN2021092554-appb-000004
Figure PCTCN2021092554-appb-000005
根据测量OD600值，确定头孢呋辛钠和头孢呋辛镁化合物对2种耐药性细菌均有一定的抑制作用，随着药物浓度的升高，抑菌效果越明显。通过对比相同摩尔的β-内酰胺环数的头孢呋辛钠和头孢呋辛镁化合物的OD值，在对白葡萄球菌的抑制作用上，头孢呋辛镁化合物在31.2μg/ml、7.84μg/ml、3.92μg/ml浓度时，抑菌效果分别强于相同摩尔的β-内酰胺环数对应头孢呋辛钠在32μg/ml、8μg/ml、4μg/ml浓度；在对大肠杆菌的抑制作用上，头孢呋辛镁化合物在15.6μg/ml、1.95μg/ml、0.98μg/ml浓度时，抑菌效果分别强于相同摩尔的β-内酰胺环数对应头孢呋辛钠在16μg/ml、2μg/ml、1μg/ml浓度，综合考虑，头孢呋辛镁盐对白葡萄球菌和大肠杆菌的抑制作用较强，强于头孢呋辛钠。
(四)头孢呋辛镁化合物体内抗菌实验的疗效：
1、方法：
将真空冻干保存的肺炎链球菌标准株用液体培养基溶解后，加入到含有10％小牛血清的营养肉汤中，7.5％二氧化碳，37℃培养24h。将复苏后的细菌传代至血琼脂平板培养基上，7.5％二氧化碳，37℃培养24h。使用前，在无菌超净台上用取菌环将细菌挑出，用无菌生理盐水稀释至适当浓度并检测600nm吸光度(A600nm)值为2.489。
大鼠适应性饲养一周后，每天早晚监测体温，连续监测3d。选择体温浮动小于0.5℃的大鼠纳入实验，随机分为6组：空白组、模型组、头孢呋辛钠低剂量组、头孢呋辛钠高剂量组、头孢呋辛镁低剂量组、头孢呋辛镁高剂量组，每组10只。大鼠麻醉后，撑开大鼠口腔，充分暴露咽喉部，用连接注射器的气管导管经口缓慢插入气管，推入0.6ml菌液，空白组推入相同体积的生理盐水。接种后立即竖立大鼠，使大鼠保持直立位约20s，以保证接种菌液因重力作用而入肺。
尾静脉注射给药，给药剂量：低剂量组为50mg/kg，高剂量组为100mg/kg (剂量为均相当于头孢呋辛)，一日两次，连续三天，空白组和模型组给予等体积生理盐水。
2、观察内容及检测指标：
观察大鼠生理病理状况是否主动摄食摄水；是否呆滞、竖毛、嗜睡；鼻腔及眼眶有无分泌物；有无气促，有无喘鸣音；尿色、量及粪便变化等。
末次给药12h后，腹腔注射4％水合氯醛10mg/kg麻醉，腹主动脉取血1.5mL于加有EDTA抗凝真空采血管中，混匀，血液分析仪测定全血WBC计数及分类。
取双肺用10％甲醛溶液固定，常规石蜡包埋，切片，苏木素-伊红(HE)染色，于光镜下观察肝组织病理学变化。
采用SPSS 19.0统计软件处理实验数据，计量数据以x±s表示。组间均数比较采用单因素方差分析，以P＜0.05表示有统计学意义。
3、结果：
3.1、一般状态：
动物接种后第1天,给药组和模型组开始出现呼吸急促、进食减少、对周围环境反应差。第2天动物进食、活动度明显下降，毛发直竖，卷曲于饲养笼角落。头孢呋辛钠(低、高剂量)组均较头孢呋辛镁(低、高剂量)组呼吸急促，且进食量明显少于头孢呋辛镁组。第3天，给药组动物食欲、活动度上升，头孢呋辛钠组大鼠较头孢呋辛镁组呼吸依旧急促，模型组大鼠可闻及明显呼吸喘鸣声，体重减轻,出现明显骨感。空白组大鼠食欲、活动度、体质量、体温较接种前无明显变化。
3.2、血常规，结果见表6：
3.2.1、对白细胞数的影响：
与空白组比较，模型组大鼠白细胞数显著上升(P＜0.01)；与模型组比较，各给药组大鼠白细胞数显著降低(P＜0.01)，说明头孢呋辛钠、镁均对大鼠肺炎有治疗作用，并且与头孢呋辛钠低剂量组比较，头孢呋辛镁低剂量组的白细胞数降低更为显著(P＜0.05)。与空白组比较，头孢呋辛钠高剂量组差异显著(P＜0.01)，头孢呋辛镁高剂量组无明显差异。
3.2.2、对中性粒细胞百分比的影响：
与对照组比较，模型组大鼠中性粒细胞百分比显著上升(P＜0.01)；与模 型组比较，各给药组大鼠中性粒细胞数显著降低(P＜0.01，P＜0.05)，说明头孢呋辛钠、镁均对大鼠肺炎有治疗作用，并且与头孢呋辛钠低剂量组比较，头孢呋辛镁低剂量组的中性粒细胞百分比降低更为显著(P＜0.05)。与空白组比较，头孢呋辛钠高剂量组差异显著(P＜0.01)，头孢呋辛镁高剂量组无明显差异。
3.2.3、对淋巴细胞百分比的影响：
与对照组比较，模型组大鼠淋巴细胞百分比显著下降(P＜0.01)；与模型组比较，各给药组大鼠淋巴细胞数显著升高(P＜0.01，P＜0.05)。说明头孢呋辛钠、镁均对大鼠肺炎有治疗作用，并且与头孢呋辛钠低剂量组比较，头孢呋辛镁低剂量组的淋巴细胞百分比升高更为显著(P＜0.05)。
表6头孢呋辛呋辛镁体内药效实验结果
Figure PCTCN2021092554-appb-000006
注：与模型组比较， *p＜0.05， **p＜0.01；与空白组比较， #p＜0.05， ##p＜0.01；与头孢呋辛钠低剂量组比较， △P＜0.05， △△P＜0.01
另外，镁是一种参与生物体正常生命活动及新陈代谢过程的必不可少的元素。镁影响细胞的多种生物功能，影响钾离子和钙离子转运，调控信号传递，参与能量代谢、蛋白质和核酸合成；催化酶的激活和抑制及对细胞周期、细胞增殖及细胞分化的调控；镁还参与维持基因组的稳定性，并且还与机体氧化应激和肿瘤发生有关。
本申请实施例中，头孢呋辛镁化合物能够使镁与头孢呋辛合用，可以降低危重患者的死亡率，并对一些炎症有益处，可以起到协同增效的作用。
综上所述，头孢呋辛镁化合物可以作为抗菌的头孢呋辛药物，相比头孢呋辛钠，能够提高头孢呋辛药物的稳定性；其制备方法操作简单，能够简化 生产工艺，便于工业化大规模生产；制备方法能够不使用有机溶剂，无有毒有害物质生成；制备得到的成品纯度高，可达到95％以上；同时为临床上不适合钠盐的患者提供一种选择。

Claims (8)

  1. 一种头孢呋辛镁化合物，其特征在于，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
  2. 一种头孢呋辛镁化合物的制备方法，其特征在于，包括：
    提供含头孢呋辛的化合物，提供镁化合物；
    使所述含头孢呋辛的化合物与所述镁化合物发生化学反应；
    获得化学反应得到的头孢呋辛镁化合物的产物。
  3. 根据权利要求2所述的方法，其特征在于，所述提供含头孢呋辛的化合物，包括：
    提供头孢呋辛酸混悬液；
    其中，所述提供头孢呋辛酸混悬液，包括：
    将头孢呋辛酸过筛，得到粉末状的头孢呋辛酸；
    将所述粉末状的头孢呋辛酸加入水中混悬，得到所述头孢呋辛酸混悬液；
    其中，所述提供镁化合物，包括：
    提供镁化合物混悬液；
    其中，所述提供镁化合物混悬液，包括：
    将镁化合物粉碎成细粉并过筛，得到粉末状的镁化合物；
    将所述粉末状的镁化合物加入水中混悬，得到所述镁化合物混悬液。
  4. 根据权利要求2所述的方法，其特征在于，所述使所述含头孢呋辛的化合物与所述镁化合物发生化学反应，包括：
    使所述含头孢呋辛的化合物与所述镁化合物在水中、在预定温度范围下发生化学反应；
    其中，所述预定温度范围是15-30℃；
    其中，所述获得化学反应得到的头孢呋辛镁化合物的产物，包括：
    将化学反应得到的滤液进行干燥，得到所述头孢呋辛镁化合物；
    其中，进行干燥的方式是加热蒸干、喷雾干燥或冷冻干燥。
  5. 根据权利要求2所述的方法，其特征在于，头孢呋辛与镁元素的摩尔比为2:1；
    其中，所述镁化合物包括氢氧化镁、碳酸氢镁以及乙酸镁。
  6. 一种组合物，其特征在于，所述组合物包括头孢呋辛镁化合物，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
  7. 一种抗菌组合物，其特征在于，所述抗菌组合物包括抗菌有效剂量的头孢呋辛镁化合物以及医药上可接受的载体，其中，所述头孢呋辛镁化合物的分子式是：Mg(C 16H 15N 4O 8S) 2。
  8. 一种如权利要求1所述的头孢呋辛镁化合物在抗菌的药物的制备中的用途。
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