CN105078999A - Anti-infective medicine of cefamandole nafate composition - Google Patents
Anti-infective medicine of cefamandole nafate composition Download PDFInfo
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- CN105078999A CN105078999A CN201510545329.0A CN201510545329A CN105078999A CN 105078999 A CN105078999 A CN 105078999A CN 201510545329 A CN201510545329 A CN 201510545329A CN 105078999 A CN105078999 A CN 105078999A
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- cefamandole nafate
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- mandokef
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Abstract
The invention discloses an anti-infective medicine of a cefamandole nafate composition, and belongs to the technical field of medicine. The composition comprises components including cefamandole nafate and sodium chloride; the cefamandole nafate is crystals; an X-ray powder diffraction pattern obtained through Cu-K alpha ray measurement is shown as figure 1. The novel crystal form of the cefamandole nafate provided by the invention is different from the crystal form structure in the prior art. Through experimental verification, users pleasantly and surprisedly find that the purity of a novel crystal form compound is high; the flowability is good; the stability is good; the polymer content is low; hygroscopicity is avoided; the clinical application is safe and reliable. Powder injections prepared from the novel crystal form compound have the advantages that the stability is good; the stability after the matching with solvents is good; the insoluble particulate content is extremely low; the powder injections are very suitable for clinical application.
Description
Technical field
The invention belongs to medical art, relate to a kind of anti-infectives Mandokef composition of sodium.
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 anti-infectives Mandokef composition of sodium.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of anti-infectives Mandokef composition of sodium, consisting of of described compositions: cefamandole nafate 1 weight portion, sodium chloride 0.04-0.08 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, sodium chloride 0.05-0.07 weight portion.
Preferably, consisting of of described compositions: cefamandole nafate 1 weight portion, sodium chloride 0.06 weight portion.
Preferably, the dosage form of described compositions is injection, and the preparation method of this injection comprises the following steps:
(1) take Mandokef sodium crystal and sodium chloride 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:
Get cefamandole nafate crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the water of cefamandole nafate weight 8 times, acetone, N-methylacetamide, water, acetone, N-methylacetamide volume ratio are 4:1:0.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is cefamandole nafate weight 10 times of methanol, isobutanol, ether, the volume ratio of methanol, isobutanol, ether is 2:3:4; After being added dropwise to complete, be cooled to 0 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described 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 99.9%, 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
Get cefamandole nafate crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the water of cefamandole nafate weight 8 times, acetone, N-methylacetamide, water, acetone, N-methylacetamide volume ratio are 4:1:0.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is cefamandole nafate weight 10 times of methanol, isobutanol, ether, the volume ratio of methanol, isobutanol, ether is 2:3:4; After being added dropwise to complete, be cooled to 0 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described Mandokef sodium crystal.
As shown in Figure 1, its purity of high-performance liquid chromatogram determination is 99.9% 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, sodium chloride 0.04 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and sodium chloride 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, sodium chloride 0.05 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and sodium chloride 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, sodium chloride 0.06 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and sodium chloride 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, sodium chloride 0.07 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and sodium chloride 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, sodium chloride 0.08 weight portion.
Preparation method is:
(1) take Mandokef sodium crystal and sodium chloride 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. an anti-infectives Mandokef composition of sodium, is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, sodium chloride 0.04-0.08 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. anti-infectives Mandokef composition of sodium according to claim 1, is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, sodium chloride 0.05-0.07 weight portion.
3. anti-infectives Mandokef composition of sodium according to claim 2, is characterized in that, consisting of of described compositions: cefamandole nafate 1 weight portion, sodium chloride 0.06 weight portion.
4. anti-infectives Mandokef composition of sodium according to claim 1, 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 sodium chloride in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
5. anti-infectives Mandokef composition of sodium according to claim 1, is characterized in that, the crystal preparation method of described cefamandole nafate is:
Get cefamandole nafate crude drug, the volume adding 30 DEG C is that in the mixed solvent A of the water of cefamandole nafate weight 8 times, acetone, N-methylacetamide, water, acetone, N-methylacetamide volume ratio are 4:1:0.5, obtain solution; Then in the horizontal direction of the liquid level of gained solution, the stationary magnetic field that magnetic field intensity is 1.5T is applied, and under the condition of this stationary magnetic field, in solution, dripping the mixed solvent B that volume is cefamandole nafate weight 10 times of methanol, isobutanol, ether, the volume ratio of methanol, isobutanol, ether is 2:3:4; After being added dropwise to complete, be cooled to 0 DEG C, leave standstill 3 hours, filter, washing, vacuum drying, obtains described Mandokef sodium crystal.
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| CN201510545329.0A CN105078999A (en) | 2015-08-31 | 2015-08-31 | Anti-infective medicine of cefamandole nafate composition |
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| CN201510545329.0A CN105078999A (en) | 2015-08-31 | 2015-08-31 | Anti-infective medicine of cefamandole nafate composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2015
- 2015-08-31 CN CN201510545329.0A patent/CN105078999A/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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