CN104958318A - Medicinal sulbactam sodium composition for treating infectious diseases - Google Patents
Medicinal sulbactam sodium composition for treating infectious diseases Download PDFInfo
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- CN104958318A CN104958318A CN201510467811.7A CN201510467811A CN104958318A CN 104958318 A CN104958318 A CN 104958318A CN 201510467811 A CN201510467811 A CN 201510467811A CN 104958318 A CN104958318 A CN 104958318A
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- sulbactam sodium
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Abstract
The invention discloses a medicinal sulbactam sodium composition for treating infectious diseases, and belongs to the technical field of medicaments. The composition comprises sulbactam sodium and sodium dihydrogen phosphate; the sulbactam sodium is crystal; the X-ray powder diffraction diagram obtained by Cu-Ka ray measurement is shown as Figure. 1; the main granularity of the sulbactam sodium crystal is 40-60 microns, and the distribution width is 25-75 microns. The new crystal form of the sulbactam sodium is different from the crystal form structure of the prior art, and tests verify that the sulbactam sodium composition is unlikely to absorb moisture, can be stored stably for a long term and greatly improves the medication safety.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine sulbactam sodium composition for the treatment of infectious disease.
Background technology
Sulbactam sodium Chinese another name: (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid sodium-4,4-dioxide; (2S-CIS)-3,3-dimethyl-7-oxo-4-sulfo--1-azabicyclo [3,2,0] heptane-2-carboxylic acid 4,4-dioxide sodium salt; English name Sulbactam Sodium; Molecular formula: C8H10NNaO5S; Molecular weight: 255.22; Molecular structural formula is as follows:
Sulbactam sodium is irreversible competitive beta-lactamase inhibitor, all inhibitory action is had to the beta-lactamase that Grain-positive and negative bacterium (except bacillus pyocyaneus) produce, make enzyme deactivation after there is irreversible reaction with enzyme, inhibitor can not make the activity of enzyme be restored after removing.Sulbactam sodium has very strong and irreversible inhibitory action to the beta-lactamase that S. aureus L-forms and most gram negative bacilli produce.2 μ g/ml concentration are very strong to the inhibitory action of Richmond-Syks II, III, IV and V type beta-lactamase, but to I type beta-lactamase without effect.Can there is cooperative phenomenon when share in penicillins and cephalosporins and sulbactam sodium, the MIC of S. aureus L-forms, hemophilus influenza, escherichia coli, bacteroides fragilis etc. to front two class antibiotics resistances is dropped within sensitive range.
CN200910169645.7 discloses a kind of process for purification of sulbactam sodium compound, and the method comprises the following steps: first the pH value of its aqueous solution by water-soluble for sulbactam sodium crude product, is adjusted to acidity by a., collects the solid of separating out in solution; B. the solid obtained by step a, with after the organic solvent dissolution mixed with it, obtains solution to be refined; C. solution to be refined is placed in macroporous adsorbent resin, eluent purification, collects eluent; D. the eluent pH value that regulating step c obtains is neutrality, collects the solid of separating out, obtains sulbactam sodium highly finished product.The sulbactam sodium compound highly finished product purity adopting the method to obtain reaches more than 99.8%, and yield is more than 90%.
The storage stability of sulbactam sodium of the prior art is poor, in illumination and moist environment, its related substance can significantly increase, and long term storage impurity content is higher, and safety in utilization is poor, in order to obtain a kind of sulbactam sodium compound of more excellent performance, special proposition the present invention.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine sulbactam sodium composition for the treatment of infectious disease.
In order to complete object of the present invention, the technical scheme of employing is:
Treat a medicine sulbactam sodium composition for infectious disease, consisting of of described compositions: sulbactam sodium 1 weight portion, sodium dihydrogen phosphate 0.005-0.015 weight portion; Described sulbactam sodium 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: sulbactam sodium 1 weight portion, sodium dihydrogen phosphate 0.01 weight portion.
Preferably, the main granularity of crystal of described sulbactam sodium is 40-60 μm, and the dispersion of distribution is 25-75 μm.
The main granularity of crystal of described sulbactam sodium is 45-55 μm, and the dispersion of distribution is 30-70 μm.
The dosage form of described compositions is injection, and the preparation method of described injection comprises the following steps:
(1) take sulbactam sodium crystal and sodium dihydrogen phosphate 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 crystal of described sulbactam sodium comprises the following steps:
(1) joined by sulbactam sodium crude product in the mixed solution of water that volume is 5 times of sulbactam sodium weight, acetonitrile, the volume ratio of water, acetonitrile is 3:1, is warming up to 30 DEG C, is stirred to and dissolves completely;
(2) frequency be 25KHz, under output is the sound field of 40W, add the mixed solution of ethanol that volume is sulbactam sodium weight 10 times, ethyl acetate, cyclohexane extraction while stirring, the volume ratio of ethanol, ethyl acetate, cyclohexane extraction is 1:2:1, mixing speed is 150 revs/min, and adding speed is 80 ml/min;
(3) after the mixed solution of ethanol, ethyl acetate, cyclohexane extraction adds, frequency be 15KHz, under output is the sound field of 10W, be cooled to 0 DEG C with 5 DEG C/h, growing the grain 3 hours, washing, vacuum drying, obtains sulbactam sodium compound.
Below technical scheme of the present invention is made further explanation:
Different solution polarity, Crystal solubility, crystallization condition, comprise crystallization temperature, mixing speed etc. and have a great impact nucleus formation tool.In order to improve the stability of sulbactam sodium, first the applicant has carried out the crystallization processes research of sulbactam sodium, in the present invention, inventor is by experiment repeatedly, continuous change recrystallisation solvent, method for crystallising and crystallization condition, finally obtain that crystal formation is even, the good sulbactam sodium crystal form of mobile performance.
The present invention is by the precise controlling to crystallization condition, and prepared a kind of novel crystal forms unlike the prior art, the X-ray powder diffraction pattern of this sulbactam sodium crystal unlike the prior art.Simultaneously due to the ins and outs of this crystal formation, the stability of sulbactam sodium compound of the present invention increases substantially, and utilizes composition injection prepared by sulbactam sodium compound of the present invention, not easily moisture absorption, and storage stability is good, and security performance is higher.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction that the sulbactam 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 sulbactam sodium crystal
(1) joined by sulbactam sodium crude product in the mixed solution of water that volume is 5 times of sulbactam sodium weight, acetonitrile, the volume ratio of water, acetonitrile is 3:1, is warming up to 30 DEG C, is stirred to and dissolves completely;
(2) frequency be 25KHz, under output is the sound field of 40W, add the mixed solution of ethanol that volume is sulbactam sodium weight 10 times, ethyl acetate, cyclohexane extraction while stirring, the volume ratio of ethanol, ethyl acetate, cyclohexane extraction is 1:2:1, mixing speed is 150 revs/min, and adding speed is 80 ml/min;
(3) after the mixed solution of ethanol, ethyl acetate, cyclohexane extraction adds, frequency be 15KHz, under output is the sound field of 10W, be cooled to 0 DEG C with 5 DEG C/h, growing the grain 3 hours, washing, vacuum drying, obtains sulbactam sodium compound.
The X-ray powder diffraction pattern that the sulbactam sodium crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1, measure through sem observation and particle size analyzer, the main granularity of this sulbactam sodium crystal is 40-60 μm, the dispersion of distribution is 25-75 μm, the main granularity of preferred crystal is 45-55 μm, and the dispersion of distribution is 30-70 μm.Its purity of high-performance liquid chromatogram determination is 99.8%.
embodiment 2:the preparation of sulbactam sodium composition
Consist of: sulbactam sodium crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.005 weight portion.
Preparation method is:
(1) take sulbactam sodium crystal and sodium dihydrogen phosphate 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 sulbactam sodium composition
Consist of: sulbactam sodium crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.01 weight portion.
Preparation method is:
(1) take sulbactam sodium crystal and sodium dihydrogen phosphate 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 method of sulbactam sodium composition, step is as follows:
Consist of: sulbactam sodium crystal 1 weight portion prepared by the present invention, sodium dihydrogen phosphate 0.015 weight portion.
Preparation method is:
(1) take sulbactam sodium crystal and sodium dihydrogen phosphate in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
test example 1:related substance is checked
This test example detects related substance in sulbactam sodium 3 batch sample prepared by embodiment 1, this test is carried out according to Chinese Pharmacopoeia 2010 editions second annex VIII P residual solvent algoscopy, annex XIX F medicine impurity analysis guideline, and it the results are shown in Table 1:
Table 1 related substance assay
test example 2:raw material stability test
This experiment is carried out according to the method in Pharmacopoeia of the People's Republic of China version in 2010 two annex XIX C medicine stability test guidelines.Embodiment 1 sample is placed respectively under high temperature (30 ± 2 DEG C) and high humidity (RH is 65% ± 5%) condition, respectively at 0 month, January, February, March, June samples detection respectively, to investigate its stability, the results are shown in Table 2:
Table 2 accelerated test result
Can find out that sulbactam sodium crystal provided by the invention has good stability by table 2 result, and still lower through accelerating 6 months rear impurity content, ensure that drug safety.
test example 3:hygroscopicity is investigated
This test example is respectively under the condition of humidity 80% and 90%, and each sample thief 1g is placed on electronic balance, and time recording weight, to detect moisture absorption degree, the results are shown in Table 3.
Table 3 hygroscopicity testing result
Sulbactam sodium 3 batch sample of sample 1-3 prepared by embodiment 1, sample 4 is commercially available HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory product.Can be found out by result of the test, compared with prior art, sulbactam sodium crystal not easily moisture absorption prepared by the present invention, good stability.
test example 4:compositions long-time stability are investigated
The composition sample and the commercially available injection sulbactam sodium injectable powder that the inventive method are obtained embodiment 2,3,4 carry out long-time stability investigation, at 25 ± 2 DEG C, place 36 months, the results are shown in 4 under relative humidity 60% ± 10% condition.
Table 4 long-term stable experiment result
As can be seen from Table 4, the stability of embodiment of the present invention product is obviously better than commercially available injection sulbactam sodium injectable powder, sample every quality index after long-term 30 months of the embodiment of the present invention has no significant change, all meet quality criteria requirements, and commercially available product occurs that under long term test condition impurity increases and degradation significant change under content, therefore adopt the product quality of the injection sulbactam sodium of sulbactam sodium crystal preparation of the present invention more stable, substantially increase drug safety.
Claims (6)
1. treat a medicine sulbactam sodium composition for infectious disease, it is characterized in that, consisting of of described compositions: sulbactam sodium 1 weight portion, sodium dihydrogen phosphate 0.005-0.015 weight portion; Described sulbactam sodium 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 sulbactam sodium composition for the treatment of infectious disease according to claim 1, is characterized in that, consisting of of described compositions: sulbactam sodium 1 weight portion, sodium dihydrogen phosphate 0.01 weight portion.
3. the medicine sulbactam sodium composition for the treatment of infectious disease according to claim 1 and 2, is characterized in that: the main granularity of crystal of described sulbactam sodium is 40-60 μm, and the dispersion of distribution is 25-75 μm.
4. the medicine sulbactam sodium composition for the treatment of infectious disease according to claim 3, is characterized in that: the main granularity of crystal of described sulbactam sodium is 45-55 μm, and the dispersion of distribution is 30-70 μm.
5. the medicine sulbactam sodium composition for the treatment of infectious disease according to claim 1 and 2, 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 sulbactam sodium crystal and sodium dihydrogen phosphate in proportion, fully mix;
(2) to divide in the cillin bottle after being filled to sterilizing and to jump a queue.
6. the medicine sulbactam sodium composition for the treatment of infectious disease according to claim 1, is characterized in that, the preparation method of the crystal of described sulbactam sodium comprises the following steps:
(1) joined by sulbactam sodium crude product in the mixed solution of water that volume is 5 times of sulbactam sodium weight, acetonitrile, the volume ratio of water, acetonitrile is 3:1, is warming up to 30 DEG C, is stirred to and dissolves completely;
(2) frequency be 25KHz, under output is the sound field of 40W, add the mixed solution of ethanol that volume is sulbactam sodium weight 10 times, ethyl acetate, cyclohexane extraction while stirring, the volume ratio of ethanol, ethyl acetate, cyclohexane extraction is 1:2:1, mixing speed is 150 revs/min, and adding speed is 80 ml/min;
(3) after the mixed solution of ethanol, ethyl acetate, cyclohexane extraction adds, frequency be 15KHz, under output is the sound field of 10W, be cooled to 0 DEG C with 5 DEG C/h, growing the grain 3 hours, washing, vacuum drying, obtains sulbactam sodium compound.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432277A (en) * | 2016-09-21 | 2017-02-22 | 陕西顿斯制药有限公司 | Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition |
| CN108926706A (en) * | 2018-09-30 | 2018-12-04 | 温州市中心医院 | A kind of pharmaceutical composition and preparation method thereof for treating infection |
| CN109134498A (en) * | 2017-07-19 | 2019-01-04 | 梁怡 | 1/20 water sulbactam sodium compound of one kind and its pharmaceutical composition |
| CN109160919A (en) * | 2017-07-28 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/10 water sulbactam sodium compound of one kind and its drug combination preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4432987A (en) * | 1982-04-23 | 1984-02-21 | Pfizer Inc. | Crystalline benzenesulfonate salts of sultamicillin |
| WO2009053256A2 (en) * | 2007-10-22 | 2009-04-30 | Sandoz Ag | Process for the production of beta lactam crystals |
| CN102898438A (en) * | 2012-09-14 | 2013-01-30 | 北京新天宇科技开发有限公司 | Eutectic of Piperacillin sodium and Sulbactam sodium, preparation method thereof, pharmaceutical composition containing eutectic and application of pharmaceutical composition |
| CN103113390A (en) * | 2013-03-12 | 2013-05-22 | 四川省惠达药业有限公司 | Sulbactam sodium compound and medical composition of sulbactam sodium compound and mezlocillin sodium |
-
2015
- 2015-08-04 CN CN201510467811.7A patent/CN104958318A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4432987A (en) * | 1982-04-23 | 1984-02-21 | Pfizer Inc. | Crystalline benzenesulfonate salts of sultamicillin |
| WO2009053256A2 (en) * | 2007-10-22 | 2009-04-30 | Sandoz Ag | Process for the production of beta lactam crystals |
| CN102898438A (en) * | 2012-09-14 | 2013-01-30 | 北京新天宇科技开发有限公司 | Eutectic of Piperacillin sodium and Sulbactam sodium, preparation method thereof, pharmaceutical composition containing eutectic and application of pharmaceutical composition |
| CN103113390A (en) * | 2013-03-12 | 2013-05-22 | 四川省惠达药业有限公司 | Sulbactam sodium compound and medical composition of sulbactam sodium compound and mezlocillin sodium |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432277A (en) * | 2016-09-21 | 2017-02-22 | 陕西顿斯制药有限公司 | Cefoperazone sodium compound and sulbactam sodium compound prepared with strong-field coupling crystallization technology as well as prepared composition |
| CN109134498A (en) * | 2017-07-19 | 2019-01-04 | 梁怡 | 1/20 water sulbactam sodium compound of one kind and its pharmaceutical composition |
| CN109160919A (en) * | 2017-07-28 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/10 water sulbactam sodium compound of one kind and its drug combination preparation |
| CN108926706A (en) * | 2018-09-30 | 2018-12-04 | 温州市中心医院 | A kind of pharmaceutical composition and preparation method thereof for treating infection |
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