CN105055419A - Cefamandole nafate composition for the treatment of infectious diseases - Google Patents
Cefamandole nafate composition for the treatment of infectious diseases Download PDFInfo
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- CN105055419A CN105055419A CN201510471730.4A CN201510471730A CN105055419A CN 105055419 A CN105055419 A CN 105055419A CN 201510471730 A CN201510471730 A CN 201510471730A CN 105055419 A CN105055419 A CN 105055419A
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- cefamandole nafate
- sodium
- mandokef
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Abstract
The present invention discloses a cefamandole nafate composition for the treatment of infectious diseases and belongs to the technical field of medicine. The composition comprises cefamandole nafate and anhydrous sodium carbonate; the cefamandole nafate is a novel crystalline form compound; and an X-ray powder diffraction pattern obtained by Cu-K alpha radiation measurement is shown as a figure 1. The cefamandole nafate novel crystalline form provided by the invention differs from the crystal structure in the prior art; experiment verification is pleasantly surprised to find that the novelcrystalline compound has high purity, good liquidity, good stability, low polymer content and no hygroscopicity, and is safe and reliable for clinical applications; powder prepared from the novel crystalline form compound has good stability, good compatibility stability with the solvent and very low content of insoluble particles, and is very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Mandokef composition of sodium for the treatment of infectious disease.
Background technology
Cefamandole nafate is all effective a kind of broad-spectrum antibiotic of kind disease caused gram negative bacteria and gram positive bacteria, extensive at clinical middle Application comparison, but containing unstable beta-lactam nucleus in the structure of cefamandole nafate, easy generation hydrolysis and rearrangement reaction, cause structural damage and lose antibacterial activity, some catabolite may produce anaphylaxis, and therefore the stability of this kind of antibiotic in transfusion should cause extensive attention.Meanwhile, because its basic structure is the same with antibiotic in the many semisynthetic beta-lactam gone on the market, also can forms high molecular polymer, also can cause type Ⅰ hypersensitivity reaction in Clinical practice, very harmful to patient.Meanwhile, cefamandole nafate very easily draws wet, has very adverse influence to its stability.Prior art improves its stability from aspects such as raising content, reduction impurity mostly.
Research proves, the anaphylactogen causing beta-lactam antibiotic type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in cefamandole nafate crude drug, improve stability, make it can ensure the lower effective way being the reaction of reduction anaphylactic shock and occurring of the content of its high molecular polymer existed in long term storage.Therefore, be necessary to provide the Cefamandole nafate compounds that a kind of high molecular polymer content is low, performance is more superior.
The present invention, through large quantifier elimination, obtains a kind of crystal compound being different from prior art, passes through verification experimental verification, surprisingly find that this crystal compound purity is high, good fluidity, good stability, polymer content is low, not easily draw wet, clinical practice is safe and reliable, utilizes the injectable powder that this crystal compound is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Mandokef composition of sodium for the treatment of infectious disease.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine Mandokef composition of sodium for infectious disease, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.001-0.003 weight portion; Described cefamandole nafate is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
Preferably, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.0015-0.0025 weight portion.
Preferably, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.002 weight portion.
Preferably, the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
The preparation method of the Mandokef sodium crystal in the present composition comprises the following steps:
(1) ground by cefamandole nafate crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of cefamandole nafate weight, and 130 revs/min are stirred 10 minutes;
Add the methanol that volume is 4 times of cefamandole nafate weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, under 150 revs/min of stirring conditions, the volume of dropping 0 DEG C is 8 times of ethanol, the chloroform mixed solution of cefamandole nafate weight, and the volume ratio of ethanol, chloroform is at the uniform velocity dropwise in 3:1,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 80 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Mandokef sodium crystal.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Cefamandole nafate is Beta-lactam medicine, the easy open loop of its monoamides ring, form impurity and easily self-polymerization occur after open loop, form high molecular polymer, thus reduction medicament contg, cause drug titers to reduce, the sterilization of cefamandole nafate and fungistatic effect are reduced, and high polymer can cause endogenous anaphylaxis.The good stability of the Cefamandole nafate compounds that the present invention prepares, not easily open loop is decomposed, its polymer content trace.
Cefamandole nafate has and draws moist, can cause the change of the physicochemical properties such as the decline of caking, mobility, deliquescence, crystal formation change, thus affect the interior qualities such as product stability, effectiveness, safety after moisture absorption.And according to the literature, many antibiotic are stablized in the dry state, but will decompose after making moist.Therefore, hygroscopicity has very important impact for the stability of cefamandole nafate.Therefore, if can reduce the hygroscopicity of cefamandole nafate, then the stability for cefamandole nafate has very important meaning.Meanwhile, bibulous medicine needs strictly to control the relative humidity between subpackage in formulation manufacturing processes, is no more than critical relative humidity, thus ensures product quality and stability.If not easily moisture absorption, then the production of convenient preparation, ensures stability simultaneously.
A kind of germ killing drugs Cefamandole nafate compounds of the present invention, the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.By to its hygroscopic research, the discovery that inventor is pleasantly surprised, its hygroscopicity of compound of the present invention is significantly less than existing crystalline compounds.Thus illustrate that cefamandole nafate crystalline compounds of the present invention is more stable, and more adapt to the preparation of preparation.
The purity of cefamandole nafate crystalline compounds of the present invention can reach 99.8%, and its structure is confirmed through proton nmr spectra.The preparation method of cefamandole nafate crystalline compounds of the present invention is simple, and purity is high, and yield is high, most suitable large-scale industrial production.
The injectable powder that cefamandole nafate crystalline compounds of the present invention is obtained, good stability, good with solvent compatibility rear stability, particulate matter content is extremely low, is very suitable for clinical practice.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the Mandokef sodium crystal of the embodiment of the present invention 1 preparation uses the measurement of Cu-K alpha ray to obtain.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Mandokef sodium crystal
(1) ground by cefamandole nafate crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of cefamandole nafate weight, and 130 revs/min are stirred 10 minutes;
Add the methanol that volume is 4 times of cefamandole nafate weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, under 150 revs/min of stirring conditions, the volume of dropping 0 DEG C is the mixed solution of cefamandole nafate weight 8 times of ethanol, chloroform, and the volume ratio of ethanol, chloroform is at the uniform velocity dropwise in 3:1,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 80 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Mandokef sodium crystal.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.8% to the X-ray powder diffraction pattern that the Mandokef sodium crystal prepared uses the measurement of Cu-K alpha ray to obtain.
embodiment 2:the preparation of Mandokef composition of sodium
Consist of: Mandokef sodium crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.001 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 3:the preparation of Mandokef composition of sodium
Consist of: Mandokef sodium crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.0015 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 4:the preparation of Mandokef composition of sodium
Consist of: Mandokef sodium crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.002 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 5:the preparation of Mandokef composition of sodium
Consist of: Mandokef sodium crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.0025 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
embodiment 6:the preparation of Mandokef composition of sodium
Consist of: Mandokef sodium crystal 1 weight portion prepared by the present invention, natrium carbonicum calcinatum 0.003 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
experimental example 1:accelerated test
Example 1 and commercially available Mandokef sodium raw materials, simulation listing packaging, put in sealing clean container, place 6 months under temperature 40 DEG C ± 2 DEG C, relative humidity 70% ± 5% condition, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.The results are shown in Table shown in 1.
Table 1 Acceleration study result
experimental example 2:wettability test
1 instrument
PL203 electronic balance, LRH-250-S constant temperature and humidity incubator, HH-400SD testing chamber for medicine stability;
2 methods
Get the glass desicator (for ensureing that saline solution is saturated, excessive salt should be had bottom exsiccator to exist) that bottom fills salt supersaturated solution, the built-in weighing botle of exsiccator, places 48h to constant humidity in calorstat.Sample thief is about 2g, puts in weighing botle, accurately weighed, bottle cap is opened, puts into exsiccator top, put in 25 DEG C of constant temperature and humidity incubators or 20 DEG C of stability test casees by different temperatures requirement and preserve, operation repetitive 3 parts, weighs respectively at different time, calculates the hydroscopicity of different time.
Computing formula: hydroscopicity=(medicated powder weight after moisture absorption-moisture absorption prodrug grain weight amount)/moisture absorption prodrug grain weight amount × 100%.Result is as table 2:
Table 2 hygroscopicity test results
According to above-mentioned experiment, the hygroscopicity of cefamandole nafate crystalline compounds prepared by the present invention is low, good stability.
experimental example 3:mobility is tested
The mobility of this experimental example to the cefamandole nafate crystalline compounds of the embodiment of the present invention 1 detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, cefamandole nafate crystalline compounds is freely flowed down from bell mouth, until the cone top formed contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of cefamandole nafate crystalline compounds accumulation horizon.Experimental result is as shown in table 3.
Table 3: mobility experimental result
From the interpretation of table 3, the mobility of the cefamandole nafate crystalline compounds that the embodiment of the present invention 1 prepares is fine.
Claims (5)
1. treat a medicine Mandokef composition of sodium for infectious disease, it is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.001-0.003 weight portion; Described cefamandole nafate is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
2. the medicine Mandokef composition of sodium for the treatment of infectious disease according to claim 1, is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.0015-0.0025 weight portion.
3. the medicine Mandokef composition of sodium for the treatment of infectious disease according to claim 2, is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, natrium carbonicum calcinatum 0.002 weight portion.
4., according to the medicine Mandokef composition of sodium of the arbitrary described treatment infectious disease of claim 1-3, it is characterized in that: the dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take Mandokef sodium crystal and natrium carbonicum calcinatum in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
5. the medicine Mandokef composition of sodium for the treatment of infectious disease according to claim 1, is characterized in that, the crystal preparation method of described cefamandole nafate is:
(1) ground by cefamandole nafate crude product, cross 60 mesh sieves, then joining volume is in the deionized water of 6 times of cefamandole nafate weight, and 130 revs/min are stirred 10 minutes;
Add the methanol that volume is 4 times of cefamandole nafate weight under (2) 90 revs/min of stirrings, be warming up to 30 DEG C simultaneously;
(3) after solution adds, leave standstill 3 hours, the volume dripping 0 DEG C under 150 revs/min of conditions stirred is 8 times of ethanol of cefamandole nafate weight, the mixed solution of chloroform, and the volume ratio of ethanol, chloroform is at the uniform velocity dropwise in 3:1,2h;
(4) be cooled to-5 DEG C after being added dropwise to complete, continue to stir 2h under the stir speed (S.S.) of 80 revs/min, leave standstill 1h crystallize out, filter, washing, vacuum drying obtains Mandokef sodium crystal.
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CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN101829118A (en) * | 2010-06-12 | 2010-09-15 | 山东罗欣药业股份有限公司 | Cefamandole nafate composition powder injection |
CN103044453A (en) * | 2013-01-22 | 2013-04-17 | 湖北济生医药有限公司 | Cefamandole nafate compound and pharmaceutical composition thereof |
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CN101829118A (en) * | 2010-06-12 | 2010-09-15 | 山东罗欣药业股份有限公司 | Cefamandole nafate composition powder injection |
CN103044453A (en) * | 2013-01-22 | 2013-04-17 | 湖北济生医药有限公司 | Cefamandole nafate compound and pharmaceutical composition thereof |
Cited By (1)
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CN105566351A (en) * | 2016-02-18 | 2016-05-11 | 海南灵康制药有限公司 | New crystal form cefamandole nafate compound prepared by adopting particle process crystal product molecular assembling and morphology optimizing technology and preparation |
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Application publication date: 20151118 |