CN103142617A - Cefuroxime lysine medicinal composition - Google Patents
Cefuroxime lysine medicinal composition Download PDFInfo
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Abstract
The invention relates to cefuroxime lysine, and particularly relates to a cefuroxime lysine medicinal composition. The cefuroxime lysine medicinal composition comprises cefuroxime lysine and sodium chloride serving as active ingredients in a weight ratio of 10: (0.1-2), and at least one of mannitol, sorbitol, sodium bisulfite and sodium metabisulfite can be added to the active ingredients. The cefuroxime lysine medicinal composition has the advantages of low impurity content, good stability and high flowability and is very suitable for clinical application.
Description
Technical field
The present invention relates to cefuroxime lysine, specifically, relate to a kind of Pharmaceutical composition of cefuroxime lysine.
Background technology
Cefuroxime lysine is arranged, molecular formula: C
16H
16N
4O
8SC
6H
14N
2O
2Chemical name: L-2,6-diaminocaproic acid (6R, 7R)-7-[2-furyl (methoxyimino) acetylamino]-3-carbamyl oxygen methyl-8-oxo-5-thia-1-azabicyclic [4.2.0] oct-2-ene-2-formates chemical structural formula as shown in the formula (I):
Cefuroxime lysine is the salt that cefuroxime acid and Lysine binding form, at water intermediate ion generation cefuroxime.Cefuroxime is a kind of bactericidal cephalosporin antibiotics, can resist most beta-lactamase, and effective to multiple Gram-positive and gram negative bacteria.Cefuroxime Sodium is a kind of semi-synthetic second generation cephalosporin, has broad-spectrum antibacterial action preferably, its mechanism of action be by with bacterial cell membrane on penicillin-binding protein (PBPs) combination, suppress cell division and growth, make at last bacterolysis and death.The infection at the positions such as respiratory tract, urinary system, skin and soft tissue, bone and joint, muliebria of clinical practice due to the gram-negative bacteria of sensitivity etc.
Patent ZL2006100545935 discloses a kind of synthetic method of Cefuroxime Sodium.the method is that 7-amino-cephalosporanic acid (7-ACA) is obtained 3-deacetylation 7 amino-Cephalosporanic acid (7-DACA) with the alkali liquor selective hydrolysis, with [cis]-2-[2-furyl]-the 2-[methoxyimino] the chloroacetic chloride condensation obtains 3-deammoniation formoxyl cefuroxime acid (DCCF), methylol with 3 of N-Chlorosulfonyl isocyanate (CSI) transformation 3-deammoniation formoxyl cefuroxime acids (DCCF) obtains cefuroxime acid, react rear directly the processing with Sodium isooctanoate. and obtained the Cefuroxime Sodium crude product, the Cefuroxime Sodium crude product is by the refining Cefuroxime Sodium finished product that obtains of dilution crystallization method.The method is strict not to process regulation, and purity and the activity of medicine are lower.
Patent ZL200910017764.0 discloses a kind of synthetic method of cefuroxime sodium compound, namely adopt triphosgene and triphenylphosphinc oxide as catalyst, use 7-amino-cephalosporanic acid and (Z)-methoxy imino furan ammonium acetate reactant salt, add successively the reaction of chlorosulfonic acid isocyanate and Sodium isooctanoate. to obtain target product.The purity of the Cefuroxime Sodium of the method preparation by this invention is still lower.
patent application 201010101490.6 discloses a kind of preparation method of cefuroxime acid, be specially: take 7-amino-cephalosporanic acid (7-ACA) as raw material, carry out the N-acylation reaction with the furan chloroacetic chloride at 7, then at low temperatures, with sodium hydrate aqueous solution, 3 acetyl group are hydrolyzed post crystallizations, filter, drying obtains the nor-acylamino-cefuroxime of intermediate 3-(DCC), quantitatively join in tetrahydrofuran solvent, drip N-Chlorosulfonyl isocyanate and carry out nucleophilic addition generation chlorosulfonylation cefuroxime acid, add again the purified water hydrolysis to make the cefuroxime acid reactant liquor.After adding the sodium bicarbonate salify, with dichloromethane, ethyl acetate and oxolane tri compound extractant, remove side reaction product lactone and other non-saponifiable matter impurity in reactant liquor, after layering, water adds the hydrochloric acid acidify, then adds tri compound extractant extraction and tell cefuroxime acid, removes water-solubility impurity, organic facies makes cefuroxime acid through distillation post crystallization, filtration, drying, but its purity does not still reach 99%.
About cefuroxime lysine, the report of more existing documents and patent, patent ZL201010191440.1 for example, a kind of cefuroxime lysine crystal compound and preparation method thereof, disclose a kind of cefuroxime lysine crystal compound and preparation method thereof, the crystal formation of described compound is crystal form II I.Preparation method is: lysine hydrochloride and alkali are joined be continuously stirring to the reaction solution clarification in solvent; And then add cefuroxime acid, and be continuously stirring to reaction solution clarification under-5 ℃～40 ℃, then add dissolved agent crystallization body, growing the grain 0.5～3 hour, more after filtration, obtain product after washing, drying.
Given this, the present invention proposes Pharmaceutical composition and the preparation of the cefuroxime lysine that a kind of purity is high, preparation technology simple, stability is high.
Summary of the invention
Goal of the invention of the present invention has been to propose a kind of Pharmaceutical composition of cefuroxime lysine, in this Pharmaceutical composition, the effective ingredient composition of medicine is cefuroxime lysine and sodium chloride, can also add the other drug adjuvant with the performance of further this Pharmaceutical composition of raising.
In order to realize purpose of the present invention, the technical scheme of employing is:
The present invention relates to a kind of Pharmaceutical composition of cefuroxime lysine, contain cefuroxime lysine, sodium chloride in described Pharmaceutical composition, wherein, cefuroxime lysine: the weight ratio of sodium chloride is 10:0.1～2, preferred 10:0.5～1.
The first optimal technical scheme of the present invention is: also contain adjuvant in described compositions, described adjuvant is selected from excipient, stabilizing agent, antioxidant or at least one of the preservatives, the addition of adjuvant is 0.1～100%, preferred 0.5～50% of cefuroxime lysine weight.
The second optimal technical scheme of the present invention is: described adjuvant is selected from least a in mannitol, sorbitol, sodium sulfite, sodium pyrosulfite.
The 3rd optimal technical scheme of the present invention is: described cefuroxime lysine is crystalline compounds, and the X-ray powder diffraction pattern that described crystalline compounds use Cu-K alpha ray measures as shown in Figure 1.
The 4th optimal technical scheme of the present invention is:, it is characterized in that, described cefuroxime lysine crystal master particle diameter is 300～750 μ m, the dispersion of distribution is 200～1000 μ m; Preferred main particle diameter is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.
The 5th optimal technical scheme of the present invention is: the preparation method of described cefuroxime lysine crystal is:
(1) cefuroxime lysine solid is joined in the distilled water of 25～45 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 25～30KHz, output are under the sound field of 30～40W in frequency, add the dehydrated alcohol of 0～5 ℃ and the mixed solution of ethyl acetate, the limit edged stirs;
(3) mixed solvent adds recession falling tone field, and standing growing the grain is 1～5 hour under 5～15 ℃ of conditions;
(4) filter, the filter cake washing with alcohol, vacuum drying 3～6 hours obtains cefuroxime lysine crystal.
(5) 5. according to cefuroxime lysine preparations claimed in claim 4, it is characterized in that, the volume ratio of described dehydrated alcohol and ethyl acetate is 1:0.1～0.2.
The 6th optimal technical scheme of the present invention is: the speed that described dehydrated alcohol and ethyl acetate mixture add is v=M/30～M/12, and wherein M is the volume of cefuroxime lysine solid aqueous solution, and unit is milliliter, and the unit of speed v is ml/min.
The 7th optimal technical scheme of the present invention is:, the volume that adds dehydrated alcohol and ethyl acetate in step (2) is 2～4 times of cefuroxime lysine solid aqueous solution volume.
The 8th optimal technical scheme of the present invention is: the mixing speed in step (2) is 60～150 rev/mins.
The 9th optimal technical scheme of the present invention is: the preparation of described Pharmaceutical composition is selected from the injectable powder of lyophilized injectable powder, aqueous injection or direct packaging, is preferably the injectable powder of direct packaging.
The below makes further explanation content of the present invention:
Sodium chloride is a kind of basis in tissue, to guaranteeing normal physiology, biochemical activity and function in body, plays an important role.Na+ and Cl-effect in vivo connects each other together with elements such as K+, and is intricate.Its topmost effect is the electrolyte balance of controlling in cell, tissue fluid and blood, with the normal circulation of maintenance body fluid and the acid-base balance in control volume.Na+ and K+, Ca2+, Mg2+ also help to keep the suitable stress level of N﹠M; NaCl and KCl work to proper viscosity or the denseness of regulating blood; Beginning in stomach to digest the acid of some food and the digestant compound in other gastric juice, pancreatic juice and bile, is also to be formed by the sodium salt in blood and potassium salt.In addition, the Na+ of debita spissitudo, K+ and Cl-also play an important role for the physiological process of retina light reflex.
Cefuroxime is a kind of bactericidal cephalosporin antibiotics, can resist most beta-lactamase, and effective to multiple Gram-positive and gram negative bacteria.Not clear and definite or caused by sensitive bacterial and be fit to treat with it when infecting yet on the antibacterial that infects.In addition, it can prevent the postoperative infection of many operations effectively.
Lysine is one of essential amino acid, can promote the human development, strengthen immunologic function, and be improved the effect of central nervous tissue function.Lysine is alkaline essential amino acids, and it improves the interior absorption to grain protein of body to regulating the internal metabolism balance, improves human diet nutrition, and enhancing development all plays an important role.Because it can not be synthetic by human body oneself, must be by absorbing in food, so lysine has the title of aminoacid " first must ", it and child and teen-age growth promoter have substantial connection.
The present invention proposes a kind of Pharmaceutical composition of cefuroxime lysine, its active component is cefuroxime lysine and sodium chloride, add a small amount of sodium chloride in cefuroxime lysine, not only can reduce cefuroxime lysine hygroscopicity, improve the stability of cefuroxime lysine preparations, also can accelerate cefuroxime lysine and be absorbed the speed that enters blood, thereby improve curative effect.The present invention adopts by cefuroxime lysine is carried out recrystallization, thereby improved the purity of cefuroxime lysine, guaranteed the drug safety of its Pharmaceutical composition, detect through high performance liquid chromatography, its purity 99.95%, and therefore no solvent residue is a kind of very safe crystal, is highly suitable for preparing various pharmaceutical combination preparations.Confirm through stability study, the crystal of the cefuroxime lysine of the present invention's preparation and Pharmaceutical composition all possess good stability.
Cefuroxime lysine crystal of the present invention, the X-ray powder diffraction pattern that use Cu-K alpha ray measures as shown in Figure 1, decomposition temperature is 172～176 ℃, it is 300～750 μ m that its crystal size is measured as main particle diameter through sem observation and particle size analyzer, and the dispersion of distribution is 200～1000 μ m; Preferred main particle diameter is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.The particle diameter of the crystal that the present invention prepares is even, crystal structure of the present invention is described in order.
Its preparation method is:
(1) cefuroxime lysine solid is joined in the distilled water of 25～45 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 25～30KHz, output are under the sound field of 30～40W in frequency, add the dehydrated alcohol of 0～5 ℃ and the mixed solution of ethyl acetate, the limit edged stirs, and mixing speed is 60～150 rev/mins; The volume ratio of dehydrated alcohol and ethyl acetate is 1:0.1～0.2, the volume of dehydrated alcohol and ethyl acetate is 2～4 times of cefuroxime lysine solid aqueous solution volume, the speed that adds is v=M/30～M/12, wherein M is the volume of cefuroxime lysine solid aqueous solution, unit is milliliter, and the unit of speed v is ml/min;
(3) mixed solvent adds recession falling tone field, and standing growing the grain is 1～5 hour under 5～15 ℃ of conditions;
(4) filter, the filter cake washing with alcohol, vacuum drying 3～6 hours obtains cefuroxime lysine crystal.
The preparation of Pharmaceutical composition of the present invention is selected from the injectable powder of lyophilized injectable powder, aqueous injection or direct packaging, is preferably the injectable powder of direct packaging, and its preparation method can be selected the conventional method preparation in this area.
Description of drawings:
Fig. 1 is the X-ray powder diffraction pattern of the cefuroxime lysine crystal of embodiment 1 preparation.
The specific embodiment of the present invention only limits to further explain and explanation the present invention, not to Composition of contents restriction of the present invention.
The specific embodiment
Embodiment 1
(1) cefuroxime lysine solid is joined in 100ml, the distilled water of 25 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 25KHz, output are under the sound field of 30W in frequency, add the dehydrated alcohol of 0 ℃ and the mixed solution of ethyl acetate, the limit edged stirs, and mixing speed is 600 rev/mins; The volume ratio of dehydrated alcohol and ethyl acetate is 1:0.2, and the volume of dehydrated alcohol and ethyl acetate is 200ml, and the speed that adds is the v=3.33 ml/min;
(3) mixed solvent adds recession falling tone field, and standing growing the grain is 5 hours under 5 ℃ of conditions;
(4) filter, the filter cake washing with alcohol, vacuum drying 3 hours obtains cefuroxime lysine crystal.
The X-ray powder diffraction pattern that the cefuroxime lysine crystal for preparing measures by the Cu-K alpha ray as shown in Figure 1; Being measured as main particle diameter through sem observation and particle size analyzer is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.Detect through high performance liquid chromatography, its purity is 99.96%; Decomposition temperature is 172～176 ℃.
Embodiment 2
(1) cefuroxime lysine solid is joined in 600ml, the distilled water of 30 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 30KHz, output are under the sound field of 40W in frequency, add the dehydrated alcohol of 1 ℃ and the mixed solution of ethyl acetate, the limit edged stirs, and mixing speed is 150 rev/mins; The volume ratio of dehydrated alcohol and ethyl acetate is 1:0.1, and the volume of dehydrated alcohol and ethyl acetate is 2400ml, and the speed that adds is 5 ml/min;
(3) mixed solvent adds recession falling tone field, and standing growing the grain is 5 hours under 15 ℃ of conditions;
(4) filter, the filter cake washing with alcohol, vacuum drying 6 hours obtains cefuroxime lysine crystal.
The X-ray powder diffraction pattern that the cefuroxime lysine crystal for preparing measures by the Cu-K alpha ray as shown in Figure 1; Being measured as main particle diameter through sem observation and particle size analyzer is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.Detect through high performance liquid chromatography, its purity is 99.96%; Decomposition temperature is 172～176 ℃.
Embodiment 3
(1) cefuroxime lysine solid is joined in 300ml, the distilled water of 45 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 30KHz, output are under the sound field of 30W in frequency, add the dehydrated alcohol of 1 ℃ and the mixed solution of ethyl acetate, the limit edged stirs, and mixing speed is 120 rev/mins; The volume ratio of dehydrated alcohol and ethyl acetate is 1:0.2, and the volume of dehydrated alcohol and ethyl acetate is 900ml, and the speed that adds is 2 ml/min;
(5) mixed solvent adds recession falling tone field, and standing growing the grain is 5 hours under 8 ℃ of conditions;
(6) filter, the filter cake washing with alcohol, vacuum drying 6 hours obtains cefuroxime lysine crystal.
The X-ray powder diffraction pattern that the cefuroxime lysine crystal for preparing measures by the Cu-K alpha ray as shown in Figure 1; Being measured as main particle diameter through sem observation and particle size analyzer is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.Detect through high performance liquid chromatography, its purity is 99.96%; Decomposition temperature is 172～176 ℃.
Embodiment 4
(1) cefuroxime lysine solid is joined in 480ml, the distilled water of 40 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 25KHz, output are under the sound field of 30W in frequency, add the dehydrated alcohol of 5 ℃ and the mixed solution of ethyl acetate, the limit edged stirs, and mixing speed is 90 rev/mins; The volume ratio of dehydrated alcohol and ethyl acetate is 1:0.1, the volume 1840ml of dehydrated alcohol and ethyl acetate, and the speed that adds is 2 ml/min;
(7) mixed solvent adds recession falling tone field, and standing growing the grain is 5 hours under 5 ℃ of conditions;
(8) filter, the filter cake washing with alcohol, vacuum drying 6 hours obtains cefuroxime lysine crystal.
The X-ray powder diffraction pattern that the cefuroxime lysine crystal for preparing measures by the Cu-K alpha ray as shown in Figure 1; Being measured as main particle diameter through sem observation and particle size analyzer is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.Detect through high performance liquid chromatography, its purity is 99.96%; Decomposition temperature is 172～176 ℃.
Embodiment 5:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 1mg.
Preparation is the injectable powder of direct packaging, and the cefuroxime lysine crystal that embodiment 1～4 is prepared fully mixes with sodium chloride, fills nitrogen, tamponade after being mixed, rolls lid, entirely examines the qualified composite preparation of cefuroxime lysine of getting final product to get.
Embodiment 6:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.5mg.
Preparation is the injectable powder of direct packaging, and the cefuroxime lysine crystal that embodiment 1～4 is prepared fully mixes with sodium chloride, fills nitrogen, tamponade after being mixed, rolls lid, entirely examines the qualified composite preparation of cefuroxime lysine of getting final product to get.
Embodiment 7:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.1mg, mannitol 10mg.
Preparation is lyophilized injectable powder, take cefuroxime lysine crystal, sodium chloride and mannitol that embodiment 1～4 prepares, first add the water for injection of dosing total amount 80% in Agitation Tank, add successively cefuroxime lysine crystal, sodium chloride and the mannitol of recipe quantity, be stirred to dissolve into clear and bright solution; The supplementary injection water is to full dose, mix homogeneously, between sodium hydroxide solution regulator solution pH value to 6～7, add 0.1% medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, after the intermediate detection is qualified, filter fill, half tamponade through 0.22 μ m secondary terminals degerming, lyophilization gets final product to get the composite preparation of cefuroxime lysine.
Embodiment 8:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.5mg, sorbitol 4mg.
Preparation is lyophilized injectable powder, take cefuroxime lysine crystal, sodium chloride and sorbitol that embodiment 1～4 prepares, first add the water for injection of dosing total amount 80% in Agitation Tank, add successively cefuroxime lysine crystal, sodium chloride and the mannitol of recipe quantity, be stirred to dissolve into clear and bright solution; The supplementary injection water is to full dose, mix homogeneously, between sodium hydroxide solution regulator solution pH value to 6～7, add 0.1% medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, after the intermediate detection is qualified, filter fill, half tamponade through 0.22 μ m secondary terminals degerming, lyophilization gets final product to get the composite preparation of cefuroxime lysine.
Embodiment 9:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.2mg, sodium sulfite 0.05mg.
Preparation is the injectable powder of direct packaging, cefuroxime lysine crystal, sodium chloride, sodium sulfite that embodiment 1～4 is prepared fully mix, and fill nitrogen, tamponade after being mixed, roll lid, entirely examine the qualified composite preparation of cefuroxime lysine of getting final product to get.
Embodiment 10:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 1mg, mannitol 5mg, sodium pyrosulfite 0.01mg.
Preparation is lyophilized injectable powder, take cefuroxime lysine crystal, sodium chloride and mannitol that embodiment 1～4 prepares, first add the water for injection of dosing total amount 80% in Agitation Tank, add successively cefuroxime lysine crystal, sodium chloride and the mannitol of recipe quantity, be stirred to dissolve into clear and bright solution; The supplementary injection water is to full dose, mix homogeneously, between sodium hydroxide solution regulator solution pH value to 6～7, add 0.1% medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, after the intermediate detection is qualified, filter fill, half tamponade through 0.22 μ m secondary terminals degerming, lyophilization gets final product to get the composite preparation of cefuroxime lysine.
Embodiment 11:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.1mg, mannitol 10mg, sodium sulfite 0.05mg.
Preparation is lyophilized injectable powder, take cefuroxime lysine crystal, sodium chloride, mannitol, sodium sulfite that embodiment 1～4 prepares, first add the water for injection of dosing total amount 80% in Agitation Tank, add successively cefuroxime lysine crystal, sodium chloride and the mannitol of recipe quantity, be stirred to dissolve into clear and bright solution; The supplementary injection water is to full dose, mix homogeneously, between sodium hydroxide solution regulator solution pH value to 6～7, add 0.1% medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, after the intermediate detection is qualified, filter fill, half tamponade through 0.22 μ m secondary terminals degerming, lyophilization gets final product to get the composite preparation of cefuroxime lysine.
Embodiment 12:
A kind of Pharmaceutical composition of cefuroxime lysine, its formula is: cefuroxime lysine 10mg, sodium chloride 0.1mg, mannitol 3mg, sodium pyrosulfite 0.01mg.
Preparation is lyophilized injectable powder, take cefuroxime lysine crystal, sodium chloride, mannitol, sodium pyrosulfite that embodiment 1～4 prepares, first add the water for injection of dosing total amount 80% in Agitation Tank, add successively cefuroxime lysine crystal, sodium chloride and the mannitol of recipe quantity, be stirred to dissolve into clear and bright solution; The supplementary injection water is to full dose, mix homogeneously, between sodium hydroxide solution regulator solution pH value to 6～7, add 0.1% medicinal carbon stirring and adsorbing, through taking off charcoal and 0.22 μ m aseptic filtration for the first time, after the intermediate detection is qualified, filter fill, half tamponade through 0.22 μ m secondary terminals degerming, lyophilization gets final product to get the composite preparation of cefuroxime lysine.
Experimental example 1
This experimental example detects the mobility of the cefuroxime lysine crystal of the embodiment of the present invention 1, adopt the fixed funnel method, funnel is placed in suitable height on graph paper, make cefuroxime lysine crystal under the bell mouth Free-flow, until the cone top that forms contacts with bell mouth, measure hypotenuse and the horizontal angle (θ angle of repose) of cefuroxime lysine accumulation horizon.Table 1: cefuroxime lysine crystal mobility experiment
| Batch | 1 | 2 | 3 | 4 | 5 | Meansigma methods |
| θ（°） | 35 | 35 | 34 | 34 | 34 | 34.4 |
From the interpretation of table 1, the mobility of the cefuroxime lysine crystal that the embodiment of the present invention 1 prepares is fine, and the cefuroxime lysine crystal of the embodiment of the present invention 2～4 is also detected, and has obtained similar experimental result.
Experimental example 2
This experimental example detects the mobility of the cefuroxime lysine preparations that the embodiment of the present invention 5 prepares, and detection method is with experimental example 1.
Table 2: cefuroxime lysine preparations mobility experiment
| Batch | 1 | 2 | 3 | 4 | 5 | Meansigma methods |
| θ（°） | 31 | 30 | 30 | 31 | 30 | 30.4 |
Interpretation from table 2, the mobility of the cefuroxime lysine preparations that the embodiment of the present invention 5 prepares is fine, the mobility that is better than cefuroxime lysine crystal, cefuroxime lysine of the present invention is also detected through the injectable powder of direct packaging, obtained similar experimental result.
Embodiment 3: influence factor's experiment
Three batches 101,102,103 of the cefuroxime lysine that the embodiment of the present invention 1 is prepared, aseptic subpackaged, fill nitrogen, be prepared into injectable powder, simulation listing packing is carried out stability test;
The cefuroxime lysine crystal that simultaneously embodiment of the present invention 1 is prepared is prepared into injectable powder according to formula and the method for embodiment 5, and three batches 501,502,503, simulation listing packing is carried out stability test;
1. hot test
With the aseptic powder injection of cefuroxime lysine and the aseptic powder injection of compositions, put in the sealing clean container, placed 10 days at 40 ℃ of temperature, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.
2. high humidity experiment
With the aseptic powder injection of cefuroxime lysine and the aseptic powder injection of compositions, put in the sealing clean container, in 25 ± 2 ℃ of temperature, placed 10 days under the condition of relative humidity 90 ± 5%, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.
3. strong illumination test
With the aseptic powder injection of cefuroxime lysine and the aseptic powder injection of compositions, put in the sealing clean container, be to place 10 days under the condition of 4500lx in illumination, in the 5th day and sampling in the 10th day, detect result and comparison in 0 day by stable high spot reviews project.
Result of the test is as shown in table 3.
Table 3: influence factor's result of the test
Result shows: the preparation of preparation of the present invention, under the condition of simulation listing packing, to place 10 days under illumination, hot conditions, and indices is without significant change.More a step improves for composite preparation of the present invention, its stability.
Experimental example 8: accelerate experiment
Three batches 201,202,203 of the cefuroxime lysine that the embodiment of the present invention 2 is prepared, aseptic subpackaged, fill nitrogen, be prepared into injectable powder, simulation listing packing is carried out stability test;
The cefuroxime lysine crystal that simultaneously embodiment of the present invention 2 is prepared is prepared into injectable powder according to formula and the method for embodiment 5, three batches 501,502,503, simulation listing packing, carry out stability test: in 40 ℃ ± 2 ℃, placed 6 months under the condition of 75% ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Experimental result is as shown in table 4.
Table 4: accelerated test result
By the accelerated test result as can be known, preparation of the present invention was investigated through accelerated test in 6 months, and related substance and content slightly change, and significant change does not occur all the other indices.The stability that confirms cefuroxime lysine compound of the present invention and composite preparation thereof is good, and the solution colour of cefuroxime lysine composite preparation is more stable.
Experimental example 9: long term test
Three batches 301,302,303 of the cefuroxime lysine that the embodiment of the present invention 3 is prepared, aseptic subpackaged, fill nitrogen, be prepared into injectable powder, simulation listing packing, carry out following stability test:
The cefuroxime lysine crystal that simultaneously embodiment of the present invention 3 is prepared is prepared into injectable powder according to formula and the method for embodiment 5, and three batches 501,502,503, simulation listing packing is carried out stability test;
Put in the sealing clean container, at 30 ℃ ± 2 ℃, placed 24 months under 60% ± 5%RH spare, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each stable high spot reviews project is tested.Result of the test is as shown in table 5:
Table 5: long-term test results
By long-term test results as can be known, cefuroxime lysine compound of the present invention and composite preparation thereof were investigated through long term test in 24 months, and significant change does not all occur indices.The stability that confirms cefuroxime lysine compound of the present invention and composite preparation thereof is good, and the solution colour of cefuroxime lysine composite preparation is more stable.
Experimental example 10: compare with the accelerated test of Cefuroxime Sodium (zinacef)
Three batches 401,402,403 of the cefuroxime lysine that the embodiment of the present invention 4 is prepared, aseptic subpackaged, fill nitrogen, be prepared into injectable powder, simulation listing packing, carry out following stability test: in 40 ℃ ± 2 ℃, placed 6 months under the condition of 75% ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stable high spot reviews project is tested.Simultaneously, adopt commercially available zinacef (manufacturer: GlaxoSmithKline PLC pharmacy (Suzhou) company limited, lot number: H022, the packing: Aluminum Bottle) powder pin (batch D01, D02, D03) is tested under the same conditions, and experimental result is as shown in table 6,7.
Table 6: limit requirement
Table 7: comparative test result
Experimental example 11: compare with the long-term experiment of Cefuroxime Sodium (zinacef)
Three batches 501,502,503 of the cefuroxime lysine that the embodiment of the present invention 5 is prepared, aseptic subpackaged, fill nitrogen, be prepared into injectable powder, simulation listing packing, carry out following stability test: in 25 ℃ ± 2 ℃, placed 12 months under the condition of 60% ± 10%RH, at duration of test respectively at 3,6,9,12 samplings at the end of month once, each stable high spot reviews project is tested.Simultaneously, adopt commercially available zinacef (manufacturer: GlaxoSmithKline PLC pharmacy (Suzhou) company limited, lot number: H022, the packing: Aluminum Bottle) the powder pin is tested under the same conditions, and experimental result is as shown in table 8.
Table 8: cefuroxime lysine long-term test results:
The experimental result confirmation, the stability of the cefuroxime lysine for preparing of the present invention is much higher than Cefuroxime Sodium, and solution colour is better than Cefuroxime Sodium.
Claims (10)
1. the Pharmaceutical composition of a cefuroxime lysine, is characterized in that, the effective ingredient of described Pharmaceutical composition is cefuroxime lysine, sodium chloride, and wherein, cefuroxime lysine: the weight ratio of sodium chloride is 10:0.1～2, preferred 10:0.5～1.
2. the Pharmaceutical composition of cefuroxime lysine according to claim 1, it is characterized in that, also contain adjuvant in described compositions, described adjuvant is selected from excipient, stabilizing agent, antioxidant or at least one of the preservatives, the addition of adjuvant is 0.1～100%, preferred 0.5～50% of cefuroxime lysine weight.
3. the Pharmaceutical composition of cefuroxime lysine according to claim 2, is characterized in that, described adjuvant is selected from least a in mannitol, sorbitol, sodium sulfite, sodium pyrosulfite.
4. the Pharmaceutical composition of cefuroxime lysine according to claim 1, is characterized in that, described cefuroxime lysine is crystalline compounds, and the X-ray powder diffraction pattern that described crystalline compounds use Cu-K alpha ray measures as shown in Figure 1.
5. the Pharmaceutical composition of cefuroxime lysine according to claim 4, is characterized in that, described cefuroxime lysine crystal master particle diameter is 300～750 μ m, and the dispersion of distribution is 200～1000 μ m; Preferred main particle diameter is 350～600 μ m, and the dispersion of distribution is 250～800 μ m.
6. the Pharmaceutical composition of cefuroxime lysine according to claim 4, is characterized in that, the preparation method of described cefuroxime lysine crystal is:
(1) cefuroxime lysine solid is joined in the distilled water of 25～45 ℃ the saturated solution of preparation cefuroxime lysine solid;
(2) be that 25～30KHz, output are under the sound field of 30～40W in frequency, add the dehydrated alcohol of 0～5 ℃ and the mixed solution of ethyl acetate, the limit edged stirs;
(3) mixed solvent adds recession falling tone field, and standing growing the grain is 1～5 hour under 5～15 ℃ of conditions;
(4) filter, the filter cake washing with alcohol, vacuum drying 3～6 hours obtains cefuroxime lysine crystal.
(5) 5. according to cefuroxime lysine preparations claimed in claim 4, it is characterized in that, the volume ratio of described dehydrated alcohol and ethyl acetate is 1:0.1～0.2.
7. the Pharmaceutical composition of cefuroxime lysine according to claim 4, it is characterized in that, the speed that described dehydrated alcohol and ethyl acetate mixture add is v=M/30～M/12, wherein M is the volume of cefuroxime lysine solid aqueous solution, unit is milliliter, and the unit of speed v is ml/min.
8. the Pharmaceutical composition of cefuroxime lysine according to claim 4, is characterized in that, the volume that adds dehydrated alcohol and ethyl acetate in step (2) is 2～4 times of cefuroxime lysine solid aqueous solution volume.
9. the Pharmaceutical composition of cefuroxime lysine according to claim 4, is characterized in that, the mixing speed in step (2) is 60～150 rev/mins.
10. the Pharmaceutical composition of cefuroxime lysine according to claim 1, is characterized in that, the preparation of described Pharmaceutical composition is selected from the injectable powder of lyophilized injectable powder, aqueous injection or direct packaging, is preferably the injectable powder of direct packaging.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104771370A (en) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | Parecoxib sodium freeze-dried powder injection and preparation method thereof |
| CN105232468A (en) * | 2015-11-03 | 2016-01-13 | 浙江永宁药业股份有限公司 | Flomoxef sodium powder injection and preparation method thereof |
| CN114191375A (en) * | 2021-12-20 | 2022-03-18 | 广东金城金素制药有限公司 | Cefuroxime sodium for injection and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721379A (en) * | 2009-11-19 | 2010-06-09 | 海南美兰史克制药有限公司 | cefuroxime sodium suspension powder injection |
| CN101830914A (en) * | 2010-06-04 | 2010-09-15 | 杨铁耀 | Cefuroxime lysine crystal compound and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721379A (en) * | 2009-11-19 | 2010-06-09 | 海南美兰史克制药有限公司 | cefuroxime sodium suspension powder injection |
| CN101830914A (en) * | 2010-06-04 | 2010-09-15 | 杨铁耀 | Cefuroxime lysine crystal compound and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104771370A (en) * | 2014-01-14 | 2015-07-15 | 南京圣和药业股份有限公司 | Parecoxib sodium freeze-dried powder injection and preparation method thereof |
| CN105232468A (en) * | 2015-11-03 | 2016-01-13 | 浙江永宁药业股份有限公司 | Flomoxef sodium powder injection and preparation method thereof |
| CN114191375A (en) * | 2021-12-20 | 2022-03-18 | 广东金城金素制药有限公司 | Cefuroxime sodium for injection and preparation method thereof |
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