CN102942577B - Cefoxitin sodium compound-containing pharmaceutical composition - Google Patents
Cefoxitin sodium compound-containing pharmaceutical composition Download PDFInfo
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- CN102942577B CN102942577B CN201210514291.7A CN201210514291A CN102942577B CN 102942577 B CN102942577 B CN 102942577B CN 201210514291 A CN201210514291 A CN 201210514291A CN 102942577 B CN102942577 B CN 102942577B
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- cefoxitin sodium
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Abstract
The invention relates to a pefoxitin sodium compound-containing pharmaceutical composition. The pefoxitin sodium compound is crystal and has X-ray diffraction pattern shown by figure 1. A preparation method of the pharmaceutical composition comprises the steps of: 1) adding mixed solvent of n-butyl alcohol and tetrahydrofuran with 55-85 DEG C into pefoxitin sodium crude product, and stirring for dissolving to obtain the n-butyl alcohol and tetrahydrofuran solution of the pefoxitin sodium; 2) dripping diethyl ether into the n-butyl alcohol and tetrahydrofuran solution of the pefoxitin sodium obtained in the step 1) under the ultrasonic field until the crystal is separated out; and 3) closing the ultrasonic field, cooling, standing still, filtering, washing a filter cake by ethanol, and drying to obtain the pefoxitin sodium compound crystal. The pefoxitin sodium compound crystal has better stability and basically does not absorb moisture.
Description
Technical field
The invention belongs to medical compounds field, be specifically related to a kind of pharmaceutical composition containing Cefoxitin sodium compound.
Background technology
Cefoxitin sodium is cephamycin-type microbiotic, system is the cephamycin C (Cephamycin C) produced by streptomycete Streptomyces Iactamdurans, through a semi-synthetic obtained class new antibiotic, its parent nucleus is similar to cynnematin, and anti-microbial property is also similar, be also put into traditionally in second generation cephalosporin class.Cefoxitin is by combining with one or more penicillin-binding protein (PBPs), and the cell wall of the mitotically active cell of anti-bacteria synthesizes, thus plays anti-microbial effect.Cefoxitin sodium all has stronger anti-microbial effect to hemophilus influenzae, klebsiella bacillus, Escherichia coli, morganella morganii, Mirabilis jalapa mycetozoan, providencia rettgeri and gonococcal sensitive strain in gram-negative bacteria.
Due to cefoxitin sodium instant effect, dosage is little, side effect is little, is particularly useful for Obstetric and Gynecologic Department prevention cesarean section postoperative infection when participating in the cintest.The factor of cesarean section postoperative infection is intricate and consequence is serious, along with domestic and international cesarean section constantly rises, Cesarean esction infects and more and more causes most attention, for many years, prevention cesarean section postoperative infection suppresses to take the above microbiotic of postoperative use bigeminy until the method for taking out stitches, but there will be the abuse of antibiotics that postoperative administration causes, and drug containing in the milk of assisting in, be unfavorable for the problems such as mother and baby feeds.And due to cefoxitin sodium drug level peak 30-60min after medication, onset is very fast, just in Cesarean operation process, the method of the disposable application cefoxitin sodium of average of operation periods can be adopted, both solved the problems referred to above, also alleviate curative activity and patient needle shouting pain hardship, and patient recovered good, Be very effective, highly advocates.
But the shortcoming, particularly its look level and content of raw material of cefoxitin sodium medicine existence and stability difference are always comparatively large, and have stronger water absorbability, affect drug quality.
For improving its stability, " cefoxitin sodium stability improvement " [Wei Qingjie. cefoxitin sodium stability improvement [J]. Hebei chemical industry, 2011(34): 14-15] by screening raw material of cefoxitin sodium medicine crystallization processes, regulate the pH value of cefoxitin sodium, add stablizer, change remaining oxygen and different crystalline states, its stability is improved, and yield is about 95%.
" improvement of cefoxitin sodium crystallization processes " [Wei Qingjie, Huifen LI. cefoxitin sodium crystallization processes improves [J]. Chemical Industry in Guangzhou, 2011(39): 102-103] by the screening to salt forming agent and organic solvent, the crystallization processes of cefoxitin sodium is optimized, obtain the cefoxitin sodium product that crystal formation is good, quality is high, cost is low, yield is greater than 95%.Improved novel process adopts acetate trihydrate sodium salt-forming agent, acetone, methanol as solvent, cefoxitin sodium of doing all has a clear superiority in more former techniques of each side such as quality and stability, crystal formation and product granularities, simple to operate, with low cost, be more suitable for suitability for industrialized production.
CN102358744A discloses a kind of cefoxitin sodium crystalline compounds and composition powder injection thereof.This cefoxitin sodium crystalline compounds steady dissolution is good, and long-time placement can not separate out solid, and bioavailability is higher.
The present inventor is after carrying out large quantifier elimination to raw material of cefoxitin sodium medicine, and obtained a kind of Cefoxitin sodium compound crystal being different from prior art crystal formation, this crystal has satisfactory stability, substantially non-hygroscopic, thus completes the present invention.
Summary of the invention
The first object of the present invention is just to provide a kind of Cefoxitin sodium compound crystal, and this crystal has satisfactory stability, substantially non-hygroscopic.
The second object of the present invention is the preparation method providing described Cefoxitin sodium compound crystal, the method simple possible, and the Cefoxitin sodium compound crystal adopting this method to prepare has satisfactory stability, substantially non-hygroscopic.
The third object of the present invention is to provide a kind of pharmaceutical composition containing Cefoxitin sodium compound.
For realizing the first object of the present invention, the present invention adopts following technical scheme:
A kind of Cefoxitin sodium compound crystal, wherein, described Cefoxitin sodium compound crystal has the X-ray diffracting spectrum shown in Fig. 1.
The particle diameter of described Cefoxitin sodium compound crystal is 80 ~ 120 μm.
Research shows, the medicine of same chemical structure, because crystallization condition is as the difference of solvent, temperature, speed of cooling etc., and obtains the crystallization of different crystalline lattice arrangement, is called polymorphic.Polymorphism extensively exists in organic drug.The same medicine of different crystal forms may have significant difference in solubleness, fusing point, density, stability etc., and then has influence on stability, homogeneity, bioavailability, the efficacy and saferry of medicine.Accordingly, the present inventor is after having carried out a large amount of tests to crystallization condition etc., obtain a kind of Cefoxitin sodium compound crystal, its X-ray powder diffraction to this axonometry, as shown in Figure 1, its X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle is at 3.50 °, 4.00 °, 4.25 °, 5.50 °, 7.00 °, 8.75 °, 9.00 °, 12.00 °, 12.50 °, 12.75 °, 13.25 °, 14.50 °, 16.25 °, 16.75 °, 17.25 °, 18.00 °, 18.25 °, 19.75 °, 21.25 °, 21.75 °, 22.00 °, 23.25 °, 24.50 °, 26.25 °, 26.50 °, 27.75 °, 29.00 ° and 29.75 ° of places demonstrate characteristic diffraction peak.
CN102358744A discloses a kind ofly has the X-ray powder diffraction cefoxitin sodium crystalline compounds shown in Fig. 2 and composition powder injection thereof.This cefoxitin sodium crystalline compounds steady dissolution is good, and long-time placement can not separate out solid, and bioavailability is higher.
Through comparing discovery, have the X-ray powder diffraction cefoxitin sodium crystalline compounds shown in Fig. 2 disclosed in the Cefoxitin sodium compound crystal obtained by the present invention and CN102358744A and to take on a different character peak, both are different crystal formations.
The shortcoming, particularly its look level and content of raw material of cefoxitin sodium medicine existence and stability difference are always comparatively large, affect drug quality.For improving its stability, " cefoxitin sodium stability improvement " [Wei Qingjie. cefoxitin sodium stability improvement [J], Hebei chemical industry, 2011(34): 14:16] in conjunction with the preparation method of CN101007812A and CN101235045A, filtered out by repetition test that crystallization is more satisfactory, the good preparation technology of stability.
In the present invention, show further by stability comparison test, the crystallization filtered out with above-mentioned document is more satisfactory, compared with Cefoxitin sodium compound obtained by the good preparation technology of stability, Cefoxitin sodium compound crystal of the present invention has more excellent stability, and substantially non-hygroscopic.
For realizing the second object of the present invention, the present invention adopts following technical scheme:
A preparation method for Cefoxitin sodium compound crystal, the preparation method described in the method comprises the steps:
1) added by cefoxitin sodium crude product in the mixed solvent of the propyl carbinol of 55 ~ 85 DEG C and tetrahydrofuran (THF), stirring and dissolving, obtains propyl carbinol and the tetrahydrofuran solution of cefoxitin sodium;
2) under ultrasonic field, in the propyl carbinol of the cefoxitin sodium of step 1) gained and tetrahydrofuran solution, ether is dripped, to crystallization;
3) close ultrasonic field, cooling, leave standstill, filter, filter cake washing with alcohol, dry, obtain described Cefoxitin sodium compound crystal.
In the present invention, adopting the mixed solvent with certain temperature---the mixed solvent of propyl carbinol and tetrahydrofuran (THF) dissolves cefoxitin sodium, and introduce ultrasonic field, anti-solvent is dripped under ultrasonic field---after ether to crystallization, close ultrasonic field, lower the temperature subsequently, leave standstill, obtain Cefoxitin sodium compound crystal of the present invention, show through stability test, Cefoxitin sodium compound crystal of the present invention has satisfactory stability, and substantially non-hygroscopic.
The volume of the mixed solvent of the propyl carbinol described in step 1) and tetrahydrofuran (THF) is 10 ~ 20 times of cefoxitin sodium crude product weight.
In the present invention alleged " weight " unit be gram or kilogram, " volume " unit corresponding is with it milliliter or liter, and namely when the weight unit of cefoxitin sodium use is gram, in operating process, the volume unit of mixed solvent is milliliter; When the weight unit that cefoxitin sodium uses be kilogram, in operating process mixed solvent volume unit for liter.
In the present invention, described cefoxitin sodium crude product is commercially available cefoxitin sodium, or the cefoxitin sodium adopting the method for prior art to synthesize, as adopted the cefoxitin sodium of the method synthesis disclosed in CN101235045A.
In the mixed solvent of described propyl carbinol and tetrahydrofuran (THF), the volume ratio of propyl carbinol and tetrahydrofuran (THF) is 5:1 ~ 8:1.
In preparation method of the present invention, step 2) described in the power of ultrasonic field be 0.4 ~ 0.6KW.
Cooling described in step 3) is for being cooled to 0 ~ 5 DEG C.
Leaving standstill as leaving standstill 4 ~ 8 hours described in step 3).
For realizing the third object of the present invention, the present invention adopts following technical scheme:
Containing the pharmaceutical composition of Cefoxitin sodium compound, this pharmaceutical composition contains the Cefoxitin sodium compound crystal that Cefoxitin sodium compound crystal of the present invention or above-mentioned preparation method obtain.
Pharmaceutical composition of the present invention can be prepared into acceptable formulation, preferred powder injection according to method conventional in pharmaceutics.
Consisting of of described powder injection: Cefoxitin sodium compound crystal 80 ~ 120 weight part, N.F,USP MANNITOL 10 ~ 20 weight part.
" the anaphylactoid progress of β-lactam antibitics " [Jin Shaohong, Hu Changqin. the anaphylactoid progress of β-lactam antibitics [J]. Chinese Journal of New Drugs, 1994,4(3): 38] report that β-lactam antibitics is anti-infectives the most frequently used clinically at present, but they are normal Anaphylactic shock attributed reaction clinically, and the safety of patient in serious threat.Research for many years proves, and the type Ⅰ hypersensitivity reaction caused by microbiotic is not caused by medicine itself, but relevant with the high molecular polymer existed in medicine.In addition, the high molecular polymer in some antibacterials is also relevant with the toxic reaction of medicine.Test example 2 of the present invention has investigated the thermal stability difference of cefoxitin composition of sodium prepared by the present invention and cefoxitin sodium of the prior art.Test shows, cefoxitin sodium powder-needle agent of the present invention has excellent thermostability, and the content of high molecular polymer is little, and changes not obvious.
Compared with prior art, tool of the present invention has the following advantages:
(1) of the present invention provided Cefoxitin sodium compound crystal, this crystal has satisfactory stability, substantially non-hygroscopic;
(2) preparation method of described Cefoxitin sodium compound crystal provided by the present invention, the method simple possible, and the Cefoxitin sodium compound crystal adopting this method to prepare has good stability, substantially non-hygroscopic;
(3) pharmaceutical composition containing cefoxitin sodium provided by the present invention has excellent thermostability, and the content of high molecular polymer is little, and changes not obvious
Accompanying drawing explanation
The X-ray powder diffraction figure of the Cefoxitin sodium compound crystal of Fig. 1 prepared by the present invention;
The X-ray powder diffraction figure of Fig. 2 cefoxitin sodium crystalline compounds disclosed in CN102358744A.
Embodiment
Be below the specific embodiment of the present invention, described embodiment is to further describe the present invention, instead of restriction the present invention.
The preparation of [embodiment 1] Cefoxitin sodium compound crystal
1) cefoxitin sodium crude product is added in the mixed solvent of propyl carbinol and tetrahydrofuran (THF), stirring and dissolving, obtain propyl carbinol and the tetrahydrofuran solution of cefoxitin sodium;
2) under ultrasonic field, in the propyl carbinol of the cefoxitin sodium of step 1) gained and tetrahydrofuran solution, ether is dripped, to crystallization;
3) close ultrasonic field, cooling, leave standstill, filter, filter cake washing with alcohol, dry, obtain described Cefoxitin sodium compound crystal.
The particle diameter of the Cefoxitin sodium compound crystal of gained is 105 μm, this crystal uses Cu-K alpha-ray to measure, the X-ray powder diffraction pattern obtained as shown in Figure 1, its X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle is at 3.50 °, 4.00 °, 4.25 °, 5.50 °, 7.00 °, 8.75 °, 9.00 °, 12.00 °, 12.50 °, 12.75 °, 13.25 °, 14.50 °, 16.25 °, 16.75 °, 17.25 °, 18.00 °, 18.25 °, 19.75 °, 21.25 °, 21.75 °, 22.00 °, 23.25 °, 24.50 °, 26.25 °, 26.50 °, 27.75 °, 29.00 ° and 29.75 ° of places demonstrate characteristic diffraction peak.
Be below embodiment 2-9, preparation method is with embodiment 1, and its concrete processing parameter is in table 1:
Table 1
The multiple of note: A to be the volume of the mixed solvent of propyl carbinol and tetrahydrofuran (THF) be cefoxitin sodium crude product weight;
B is the volume ratio of propyl carbinol and tetrahydrofuran (THF) in the mixed solvent of propyl carbinol and tetrahydrofuran (THF).
The X-ray powder diffraction pattern using the measurement of Cu-K alpha-ray to obtain to the Cefoxitin sodium compound crystal obtained by embodiment 2-9 is similar with embodiment 1.
[example of formulations 1] cefoxitin sodium powder-needle agent
Cefoxitin sodium compound crystal 80g and N.F,USP MANNITOL 20g is aseptically distributed into 1000 bottles, obtains cefoxitin sodium powder-needle agent.
[example of formulations 2] cefoxitin sodium powder-needle agent
Cefoxitin sodium compound crystal 120g and N.F,USP MANNITOL 10g is aseptically distributed into 1000 bottles, obtains final product.
[example of formulations 3] cefoxitin sodium powder-needle agent
Cefoxitin sodium compound crystal 100g and N.F,USP MANNITOL 15g is aseptically distributed into 1000 bottles, obtains final product.
Test example 1
Stability comparison test
Cefoxitin sodium compound crystal of the present invention is as follows through excess temperature, humidity, light durability, product purity and 6 months 30 DEG C of accelerated tests investigation results:
Control sample A: according to the cefoxitin sodium crystalline compounds that the method for CN102358744A embodiment 1 is obtained.
Control sample B: according to " cefoxitin sodium stability improvement " [Wei Qingjie. cefoxitin sodium stability improvement [J], Hebei chemical industry, crystallization 2011(34): 14-15] filtered out is more satisfactory, the good preparation technology of stability, and namely " test portion 1.1 preparation method " obtains;
Test sample: the Cefoxitin sodium compound crystal prepared by the embodiment of the present invention 1.
1, humid test:
Condition: 75% relative humidity, 40 DEG C of dew put ten days.
Content result:
| Before placement (%) | After ten days (%) | Content declines (%) | |
| Control sample A | 98.5 | 96.3 | 2.2 |
| Control sample B | 94.5 | 93.2 | 1.3 |
| Test sample | 99.7 | 99.3 | 0.4 |
Note: measure content with HPLC, measure moisture content by Ka Shi method, content calculates with dry product.
2, humid test:
Condition: 60 DEG C of glass are airtight, two weeks.
Content result:
| Before placement (%) | After two weeks (%) | Content declines (%) | |
| Control sample A | 98.5 | 96.7 | 1.8 |
| Control sample B | 94.5 | 93.2 | 1.3 |
| Test sample | 99.7 | 99.5 | 0.2 |
Note: content assaying method: HPLC
3, exposure experiments to light:
Condition: 2000nX, one week
Content result:
| Before placement (%) | Illumination one Zhou Houhou (%) | Content declines (%) | |
| Control sample A | 98.5 | 94.9 | 3.6 |
| Control sample B | 94.5 | 92.8 | 1.7 |
| Test sample | 99.7 | 98.9 | 0.8 |
Note: content assaying method: HPLC
4, product purity contrast:
| Content (%) | Impurity spot | |
| Control sample A | ＜98.5 | Have |
| Control sample B | ＜99.0 | Have |
| Test sample | ＞99.5 | Nothing |
Note: content assaying method: HPLC, impurity determination method: TLC
5,6 months 30 DEG C of accelerated tests
Shown by above-mentioned test-results: Cefoxitin sodium compound crystal of the present invention is obviously better than the cefoxitin sodium of prior art to the stability of humidity; Stability under temperature, illumination and 6 months 30 DEG C of accelerated tests is also better than the cefoxitin sodium of prior art.Product purity is apparently higher than the cefoxitin sodium of prior art.
Also carried out above-mentioned test to the Cefoxitin sodium compound crystal prepared by other embodiment of the present invention, its result obtained is similar.
Test example 2
The heat stability test of cefoxitin sodium powder-needle agent
Have and report that β-lactam antibitics is anti-infectives the most frequently used clinically at present, but their normal Anaphylactic shock attributed reactions clinically, the safety of patient in serious threat.Research for many years proves, and the type Ⅰ hypersensitivity reaction caused by microbiotic is not caused by medicine itself, but relevant with the high molecular polymer existed in medicine.In addition, the high molecular polymer in some antibacterials is also relevant with the toxic reaction of medicine.Therefore, carry out control to High-molecular weight polymer impurity in microbiotic to have great significance.
This test example has investigated the thermal stability difference of cefoxitin composition of sodium prepared by the present invention and cefoxitin sodium of the prior art.
In this test example, each sample is numbered:
Trial target 1: the cefoxitin sodium powder-needle agent prepared by invention formulation embodiment 1;
Trial target 2: the cefoxitin sodium powder-needle agent prepared by invention formulation embodiment 3;
Reference substance 1: the cefoxitin sodium composition powder injection prepared according to the embodiment 8 of CN102358744A;
Reference substance 2: prepare cefoxitin sodium powder-needle agent according to the prescription of invention formulation embodiment 1 and technique, with invention formulation embodiment 1 unlike adopted cefoxitin sodium be according to " cefoxitin sodium stability improvement " [Wei Qingjie. cefoxitin sodium stability improvement [J], Hebei chemical industry, crystallization 2011(34): 14-15] filtered out is more satisfactory, the good preparation technology of stability, and namely " test portion 1.1 preparation method " is obtained.
Each sample is exposed to respectively relative humidity is 75%, temperature is under the environment of 60 DEG C, after adopting high performance liquid chromatography test different time, the content of cefoxitin sodium and size exclusive chromatography measure the content of high molecular polymer (high performance liquid chromatography and size exclusive chromatography are according to pharmacopeia in 2005 second, the related conditions of annex VD and annex VH carries out measuring), the results are shown in Table 2.
Table 2, thermostability comparative result
As can be seen from the above table, the thermostability of the cefoxitin sodium powder-needle agent prepared by method of the present invention is adopted significantly to be better than the cefoxitin composition of sodium adopting the method for prior art to obtain.
Also carried out above-mentioned test to the cefoxitin sodium powder-needle agent prepared by other embodiment of the present invention, its result obtained is similar.
Claims (4)
1. a Cefoxitin sodium compound crystal, is characterized in that, described Cefoxitin sodium compound crystal has the X-ray diffracting spectrum shown in Fig. 1.
2. Cefoxitin sodium compound crystal according to claim 1, is characterized in that, the particle diameter of described Cefoxitin sodium compound crystal is 80 ~ 120 μm.
3. the pharmaceutical composition containing Cefoxitin sodium compound, it is characterized in that, described pharmaceutical composition contains the Cefoxitin sodium compound crystal described in claim 1 or 2.
4. pharmaceutical composition according to claim 3, is characterized in that, described pharmaceutical composition is powder injection, and it consists of: Cefoxitin sodium compound crystal 80 ~ 120 weight part, N.F,USP MANNITOL 10 ~ 20 weight part.
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| CN103304582B (en) * | 2013-06-28 | 2015-02-11 | 四川省惠达药业有限公司 | Cefoxitin sodium compound, preparation method and pharmaceutical composition thereof |
| CN103601739A (en) * | 2013-11-26 | 2014-02-26 | 悦康药业集团有限公司 | Cefoxitin sodium compound and preparation method thereof |
| CN104402908B (en) * | 2014-10-23 | 2017-10-27 | 胡梨芳 | Cefoxitin sodium compound entity and combinations thereof and purposes |
| CN109134509A (en) * | 2017-06-16 | 2019-01-04 | 李双喜 | A kind of 1/5 water Cefoxitin sodium compound |
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| US4210750A (en) * | 1972-07-27 | 1980-07-01 | Merck & Co., Inc. | Process for the preparation of 3-carbamoyl cephalosporins using isocyanates |
| WO2004083217A1 (en) * | 2003-03-20 | 2004-09-30 | Orchid Chemicals & Pharmaceuticals Ltd | An improved process for the preparation of cefoxitin |
| CN102358744B (en) * | 2011-09-02 | 2013-11-06 | 山东罗欣药业股份有限公司 | Cefoxitin sodium crystal compound and cefoxitin sodium composition powder injection |
| CN102399234A (en) * | 2011-12-06 | 2012-04-04 | 苏州中联化学制药有限公司 | Preparation method for Cefoxintin sodium |
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Application publication date: 20130227 Assignee: Fujian Kang Cheng Pharmaceutical Co., Ltd. Assignor: Luo Cheng Contract record no.: 2018990000073 Denomination of invention: Cefoxitin sodium compound-containing pharmaceutical composition Granted publication date: 20150325 License type: Common License Record date: 20180329 |
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