CN104940130A - Children type azlocillin sodium and low-sodium carrier pharmaceutical composition - Google Patents
Children type azlocillin sodium and low-sodium carrier pharmaceutical composition Download PDFInfo
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- CN104940130A CN104940130A CN201510283092.3A CN201510283092A CN104940130A CN 104940130 A CN104940130 A CN 104940130A CN 201510283092 A CN201510283092 A CN 201510283092A CN 104940130 A CN104940130 A CN 104940130A
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Abstract
The present invention relates to a children type azlocillin sodium pharmaceutical composition, especially to a combination application package, wherein the composition is an azlocillin sodium and low-sodium carrier infusion pharmaceutical combination preparation, which comprises azlocillin sodium for injection and a low-sodium carrier infusion, wherein the low-sodium carrier infusion contains a glucose and sodium chloride injection (15-200:1), a glucose, sodium chloride and potassium chloride injection (15-200:1:0-1) and the like. According to the present invention, the clinical application steps are simplified compared with the compatible mixing use of the azlocillin sodium and the low-sodium carrier infusion; and the clinical risk caused by the excessive sodium positioned in the blood and incapable of being metabolized due to the children kidney achieving the immature development state is reduced so as to improve the clinical application quality and the safety of the children medication are improved.
Description
Technical field
The present invention relates to a kind of child form azlocillin sodium and low sodium carrier pharmaceutical composition, belong to medicinal chemistry art.
Background technology
Azlocillin sodium; English name: AzlocillinSodium; the former name of an article of consulting and deliberating: Sai Ke is friend such; by visiing, Delhi is uncommon to list a company, and Chinese is (2S, 5R; 6R)-3; 3-dimethyl-6-[[[[(2-oxo-1-imidazolidinyl) carbonyl] is amino] phenyl acetyl] is amino]-7-oxo-4-thia-1-azabicyclo [3,2,0] heptane-2-carboxylic acid sodium salt.This product is Penicillin antibiotics, third generation wide spectrum semisynthetic penicillin, effective to G+ bacterium, G-bacterium and anaerobe, can consumingly to anti Bacillus pyocyaneu Flugge.Be applicable to G+ bacterium, G-bacterium and the microbial infection of anaerobism.Effective to charrin disease.Be applied to responsive gram-negative bacteria and the various infection caused by positive bacteria clinically, and charrin's disease, comprise septicemia, meningitis, endocarditis, purulent pleurisy, peritonitis and lower respiratory tract, gastrointestinal tract, biliary tract, kidney and ureter, bone and soft tissue and genitals's infection, gynecological, Obstetrics infection, external otitis, burn, skin and postoperative infection.
In Chinese patent 200410096008.9, azlocillin acid is suspended in the solution of water or water and organic solvent alcohols, C3-6 lower aliphatic ketone, C2-6 nitrile, ethers a kind of formation wherein, add organic or inorganic alkali reaction and obtain azlocillin sodium solution, and then add organic solvent alcohols, C3-6 lower aliphatic ketone, C2-6 nitrile, ethers wherein a kind of or their mixture, separate out to crystalline azlocillin sodium, be separated, dry, pulverize to obtain crystalline azlocillin sodium.But the azlocillin sodium of preparation still shows less stable, all unstable to heat, meta-acid environment, meta-alkali environment, show that outward appearance is easy to change, content reduces, occurs the problems such as catabolite, the reason of appearance may be the partial impurities cannot removed by the crystallization impact in azlocillin sodium finished product.Children's torso each side is still in growth stage, and the side effect that Drug-related causes can show particularly evident, controls Drug-related content in pediatric pharmaceuticals, seems particularly important.The purity how improving children's's azlocillin sodium is current problem demanding prompt solution, has great Social benefit and economic benefit.Therefore, high-purity is prepared and stable azlocillin sodium is those skilled in the art always makes great efforts.
Because child's kidney is not reached maturity, there is no sodium too much in ability metabolism blood.If hypernatremia, be difficult to recover to the injury of child, and the age is less, and to receive injury larger, particularly neonate.Neonate and infant kidney are poor to acid, alkali and water metabolism regulating power, and the filtration rate of glomerule is only adult's 1/4 ~ 1/2.
For the physiological characteristics of child, reduce the clinical risk that azlocillin sodium is in use possible, invent and a kind ofly can meet the child form azlocillin sodium of child's stage physiological characteristics and low sodium carrier pharmaceutical composition, namely the carrier transfusion of low sodium is packed with azlocillin sodium Combination application.
Need in Clinical practice to buy use in conjunction respectively, the assembly packaging of the carrier flow of infusate combination preparation of azlocillin sodium and low sodium does not occur commercially with in medical institutions.
Summary of the invention
The object of this invention is to provide the medicine composition that a kind of child form Azlocillin sodium drug composition and azlocillin sodium and low sodium carrier are infused, especially Combination application packaging, with a kind of azlocillin sodium preparation method, it can solve above-mentioned shortcoming of the prior art.
For achieving the above object, the present invention is by the following technical solutions:
A kind of child form azlocillin sodium and low sodium carrier pharmaceutical composition are azlocillin sodium glucose sodium chloride potassium injection or azlocillin sodium Dextrose and Sodium Chloride Inj..
Preferably, this azlocillin sodium glucose sodium chloride potassium injection comprises each component of following quality:
Azlocillin sodium 0.25g-1.0g;
Glucose 5-9g;
Sodium chloride 0.1-0.2g;
Potassium chloride 0.1-0.2g;
Add water to 100mL.
This azlocillin sodium Dextrose and Sodium Chloride Inj. comprises each component of following quality:
Azlocillin sodium 0.25g-1.0g;
Glucose 5-9g;
Sodium chloride 0.1-0.2g;
Add water to 100mL.
Preferably, this pharmaceutical composition can be packed for Combination application.
Preferably, this azlocillin sodium is prepared by following steps:
(1) add acetone, purified water and azlocillin acid in the reactor, be stirred to dissolving, in stirring, drip sodium acetate alcoholic solution; Continue to stir, growing the grain, sucking filtration, washing with acetone, vacuum drying, obtains azlocillin sodium crude product;
(2) azlocillin sodium crude product is dissolved in purified water, adds active carbon, stir decolouring, filter;
(3) under agitation add extractant in filtrate, be transferred to and be full of in pressure vessel, remove sealing vibration after bubble, the freezing rear taking-up of temperature control;
(4) by solid-liquor separation, discard extractant, solid drips acetone at 5 DEG C, low rate mixing, growing the grain after melting, and filters, and washing, vacuum drying, obtains azlocillin sodium finished product.
As preferably, the weight ratio of the acetone added in described step (1), purified water and azlocillin acid is 2 ~ 4:0.8 ~ 1.5:1, the concentration of sodium acetate alcoholic solution is 0.2g/ml, azlocillin acid is 1:1.1 ~ 1.4 with the mol ratio of sodium acetate, and vacuum drying temperature is 40 ~ 50 DEG C.
As preferably, in described step (2), azlocillin sodium solution concentration is 0.1 ~ 0.3g/ml, and activated carbon dosage is 3 ~ 10% of azlocillin sodium crude product.
As preferably, in described step (3), extractant is several mixture of ethyl acetate, chloroform, ether or more.
As preferably, in described step (3), extractant is 1:100 ~ 200 with the volume ratio of the middle purified water of step (2).
As preferably, in described step (3), temperature control cryogenic temperature is-20 ~-10 DEG C, and cooling time is 2 ~ 8 hours.
As preferably, in described step (4), the dripping quantity of acetone is 3 ~ 5 times of purified water consumption, and the low rate mixing time is 30 minutes, and rearing crystal time is 1 hour.
A kind of children's of the present invention with the beneficial effect of azlocillin sodium chemical entities and pharmaceutical preparation thereof is:
(1) produce azlocillin sodium crude product by agitation and dropping sodium acetate alcoholic solution in acetone, purified water and azlocillin acid mixed liquor, the azlocillin sodium impurity obtained is less, and purity is higher.
(2) azlocillin sodium crude product is dissolved in purified water, with activated carbon decolorizing, and can remove portion impurity.
(3) azlocillin sodium solution under agitation extracts with immiscible with it and also immiscible with water extractant, dissolve organic contaminants can be removed in extractant, improves the purity of azlocillin sodium.
(4) mixed solution be transferred to and be full of in pressure vessel, after removing bubble, sealing is vibrated, carry out temperature control freezing, in refrigerating process, aqueous solvent is frozen into ice, and volumetric expansion increases, and the internal pressure in airtight pressure vessel is increased, thus the dissolubility of the organic impurities that improve in azlocillin sodium in extractant, reduce the impurity content in azlocillin sodium finished product.
(5) aqueous solvent is frozen in the process of ice, and organic impurities is extruded from ice, further increases extraction efficiency, reduces impurity content.
(6) injectable powder prepared with azlocillin sodium chemical entities of children's provided by the invention, has dissolubility good, the advantages such as clarity is good, good stability, and impurity is low, and toxic and side effects is little.
(7) simultaneously, have employed the carrier flow of infusate assembly packaging of azlocillin sodium and low sodium, used in combination relative to the compatibility of the two, simplify step, improve the safety of children; Decrease because child's kidney is not reached maturity, there is no the clinical risk that in ability metabolism blood, too much sodium brings, improve the clinical practice quality of children.
Detailed description of the invention
Set forth the specific embodiment of the present invention further below:
Embodiment 1
Add 400ml acetone, 80ml water and azlocillin acid 100g in the reactor, temperature control 25 DEG C is stirred to dissolving, drips 0.2g/ml Glacial acetic acid sodium ethoxide solution 100ml in stirring in 30 minutes; Continue to stir 30min, growing the grain, sucking filtration, with washing with acetone, 40 DEG C of vacuum dryings, obtain azlocillin sodium crude product.
Take azlocillin sodium crude product 100g, add purified water 1000ml, being warming up to 30 DEG C to all dissolving, adding 10g active carbon, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 5ml ethyl acetate, be transferred in 1000ml pressure vessel, guarantee to be full of and bubble removal, sealed container, vibration, takes out after the freezing 2h of temperature control-20 DEG C.
By solid-liquor separation, discard ethyl acetate solution, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 5000ml acetone, low rate mixing 30min, continue growing the grain 1h, sucking filtration, with washing with acetone, obtain azlocillin sodium finished product after vacuum drying, purity is 99.89%.
Embodiment 2
Add 300ml acetone, 100ml water and azlocillin acid 100g in the reactor, temperature control 25 DEG C is stirred to dissolving, drips 0.2g/ml Glacial acetic acid sodium ethoxide solution 110ml in stirring in 30 minutes; Continue to stir 30min, growing the grain, sucking filtration, with washing with acetone, 45 DEG C of vacuum dryings, obtain azlocillin sodium crude product.
Take azlocillin sodium crude product 100g, add purified water 500ml, being warming up to 30 DEG C to all dissolving, adding 7g active carbon, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 5ml chloroform, be transferred in 500ml pressure vessel, guarantee to be full of and bubble removal, sealed container, vibration, takes out after the freezing 5h of temperature control-15 DEG C.
By solid-liquor separation, discard chloroformic solution, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 2000ml acetone, low rate mixing 30min, continue growing the grain 1h, sucking filtration, with washing with acetone, obtain azlocillin sodium finished product after vacuum drying, purity is 99.95%.
Embodiment 3
Add 200ml acetone, 150ml water and azlocillin acid 100g in the reactor, temperature control 25 DEG C is stirred to dissolving, drips 0.2g/ml Glacial acetic acid sodium ethoxide solution 124ml in stirring in 30 minutes; Continue to stir 30min, growing the grain, sucking filtration, with washing with acetone, 50 DEG C of vacuum dryings, obtain azlocillin sodium crude product.
Take azlocillin sodium crude product 100g, add purified water 350ml, being warming up to 30 DEG C to all dissolving, adding 3g active carbon, stir decolouring, filter and obtain filtrate.
Under agitation in above-mentioned filtrate, add 2.3ml ethyl acetate and 2.3ml chloroform mixed solvent, be transferred in 350ml pressure vessel, guarantee to be full of and bubble removal, sealed container, vibration, takes out after the freezing 8h of temperature control-10 DEG C.
By solid-liquor separation, discard the mixed solution of ethyl acetate and chloroform, after ice-out, be transferred to crystallizer, within at 5 DEG C about 1 hour, drip 1050ml acetone, low rate mixing 30min, continue growing the grain 1h, sucking filtration, with washing with acetone, obtain azlocillin sodium finished product after vacuum drying, purity is 99.87%.
Embodiment 4 (comparative example)
In reaction bulb, add 10ml water and 10ml acetone, stir 5 minutes, then add 5 grams of azlocillin acid, stir and be cooled to 0 ~ 5 DEG C, add 0.58 gram of natrium carbonicum calcinatum, insulation reaction 4 hours.Filter, filtrate under agitation adds 250ml acetone, continues to stir half an hour, leaves standstill 4 hours.Filter, with 25ml washing with acetone 2 times, drain, drying under reduced pressure, obtain crystalline azlocillin sodium 4.3 grams.Purity 99.05%.
Embodiment 5
The preparation of glucose sodium chloride potassium injection:
Configuration 1: glucose 8g, sodium chloride 0.18g, potassium chloride 0.15g, inject water to 100mL, with 0.22 μm of microporous filter membrane aseptic filtration.
Configuration 2: glucose 5g, sodium chloride 0.11g, potassium chloride 0.1g, inject water to 100mL, with 0.22 μm of microporous filter membrane aseptic filtration.
Embodiment 6
The preparation of Dextrose and Sodium Chloride Inj.:
Configuration 3: glucose 8g, sodium chloride 0.18g, inject water to 100mL, with 0.22 μm of microporous filter membrane aseptic filtration.
Configuration 4: glucose 5g, sodium chloride 0.11g, inject water to 100mL, with 0.22 μm of microporous filter membrane aseptic filtration.
Embodiment 7
The preparation of assembly packaging medicine:
The glucose sodium chloride potassium injection of the azlocillin sodium of embodiment 1-3 and embodiment 5-6 or Dextrose and Sodium Chloride Inj. are carried out assembly packaging according to 0.25g:100ml, 0.5g:100ml, 0.75g:100ml, 1.0g:100ml respectively.
Get the azlocillin sodium that the azlocillin sodium prepared by embodiment 1-3 and embodiment 4 traditional handicraft produce at random each a collection of, temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, investigate the projects such as appearance character, color level, content, related substance, and with 0 month results contrast, result of the test is in table 1.
Table 1
Result shows: the azlocillin sodium that the present invention prepares is in accelerated test, and character, solution colour, related substance etc. are without significant change, and its stability is good, significantly better than the azlocillin sodium of comparative example.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art just design according to the present invention can make many modifications and variations without the need to creative work.Therefore, all technical staff in the art, all should by the determined protection domain of claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (9)
1. child form azlocillin sodium and a low sodium carrier pharmaceutical composition, is characterized in that, described pharmaceutical composition is azlocillin sodium glucose sodium chloride potassium injection or azlocillin sodium Dextrose and Sodium Chloride Inj.; Described azlocillin sodium glucose sodium chloride potassium injection comprises each component of following quality:
Azlocillin sodium 0.25g-1.0g;
Glucose 5-9g;
Sodium chloride 0.1-0.2g;
Potassium chloride 0.1-0.2g;
Add water to 100mL.
Described azlocillin sodium Dextrose and Sodium Chloride Inj. comprises each component of following quality:
Azlocillin sodium 0.25g-1.0g;
Glucose 5-9g;
Sodium chloride 0.1-0.2g;
Add water to 100mL.
2. child form azlocillin sodium as claimed in claim 1 and low sodium carrier pharmaceutical composition, it is characterized in that, described pharmaceutical composition can be packed for Combination application.
3. child form azlocillin sodium as claimed in claim 1 and low sodium carrier pharmaceutical composition, it is characterized in that, described azlocillin sodium compound is prepared by following steps:
(1) add acetone, purified water and azlocillin acid in the reactor, be stirred to dissolving, in stirring, drip sodium acetate alcoholic solution; Continue to stir, growing the grain, sucking filtration, washing with acetone, vacuum drying, obtains azlocillin sodium crude product;
(2) azlocillin sodium crude product is dissolved in purified water, adds active carbon, stir decolouring, filter;
(3) under agitation add extractant in filtrate, be transferred to and be full of in pressure vessel, remove sealing vibration after bubble, the freezing rear taking-up of temperature control;
(4) by solid-liquor separation, discard extractant, solid drips acetone at 5 DEG C, low rate mixing, growing the grain after melting, and filters, and washing, vacuum drying, obtains azlocillin sodium finished product.
4. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, it is characterized in that, the weight ratio of the acetone added in described step (1), purified water and azlocillin acid is 2 ~ 4:0.8 ~ 1.5:1, the concentration of sodium acetate alcoholic solution is 0.2g/ml, azlocillin acid is 1:1.1 ~ 1.4 with the mol ratio of sodium acetate, and vacuum drying temperature is 40 ~ 50 DEG C.
5. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, is characterized in that, in described step (2), azlocillin sodium solution concentration is 0.1 ~ 0.3g/ml, and activated carbon dosage is 3 ~ 10% of azlocillin sodium crude product.
6. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, is characterized in that, in described step (3), extractant is several mixture of ethyl acetate, chloroform, ether or more.
7. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, is characterized in that, in described step (3), the volume ratio of extractant and the middle purified water of step (2) is 1:100 ~ 200.
8. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, is characterized in that, in described step (3), temperature control cryogenic temperature is-20 ~-10 DEG C, and cooling time is 2 ~ 8 hours.
9. child form azlocillin sodium as claimed in claim 3 and low sodium carrier pharmaceutical composition, it is characterized in that, in described step (4), the dripping quantity of acetone is 3 ~ 5 times of purified water consumption, and the low rate mixing time is 30 minutes, and rearing crystal time is 1 hour.
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| CN201510283092.3A CN104940130A (en) | 2015-05-28 | 2015-05-28 | Children type azlocillin sodium and low-sodium carrier pharmaceutical composition |
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| CN201510283092.3A CN104940130A (en) | 2015-05-28 | 2015-05-28 | Children type azlocillin sodium and low-sodium carrier pharmaceutical composition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1751751A (en) * | 2005-09-07 | 2006-03-29 | 华北制药集团有限责任公司 | Immediate dispensing infusion |
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
-
2015
- 2015-05-28 CN CN201510283092.3A patent/CN104940130A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1751751A (en) * | 2005-09-07 | 2006-03-29 | 华北制药集团有限责任公司 | Immediate dispensing infusion |
| CN102179063A (en) * | 2011-03-23 | 2011-09-14 | 苏州汇通色谱分离纯化有限公司 | High pressure liquid-liquid extraction method |
Non-Patent Citations (2)
| Title |
|---|
| 国家药典委员会: "《中华人民共和国药典2010年版第一增补本》", 31 August 2012 * |
| 迟延青等: "《最新临床用药必备》", 31 January 2011 * |
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