CN102145001A - Stable aztreonam composition and preparation method thereof - Google Patents
Stable aztreonam composition and preparation method thereof Download PDFInfo
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- CN102145001A CN102145001A CN 201110025127 CN201110025127A CN102145001A CN 102145001 A CN102145001 A CN 102145001A CN 201110025127 CN201110025127 CN 201110025127 CN 201110025127 A CN201110025127 A CN 201110025127A CN 102145001 A CN102145001 A CN 102145001A
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- aztreonam
- composition
- arginine
- injection
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Abstract
The invention belongs to the field of drug synthesis and preparations thereof, relates to a preparation method of an antibacterial drug, and particularly relates to a stable aztreonam composition and a preparation method thereof. The preparation method comprises the following steps: directly suspending aseptic beta-aztreonam in water, adding aseptic L-arginine to regulate the pH value for complete dissolution to obtain an aztreonam/arginine water solution, adding hydroxypropyl-beta-cyclodextrin (HP-beta-CD) into the water solution for clathration, subpackaging, and freeze-drying to obtain aztreonam for injection. The preparation method provided by the invention is simple and suitable for industrial production. After the aztreonam/arginine salt is clathrated by HP-beta-CD, the water solubility and stability of aztreonam are improved, the toxic and side effects of aztreonam are reduced, and the availability of aztreonam is improved.
Description
Technical field
The present invention relates to a kind of antibacterials and preparation method thereof, relate in particular to a kind of stable aztreonam composition and preparation method thereof.
Background technology
Aztreonam is the complete synthesis monocycle beta-lactam antibiotics of first listing, chemical name is: [2S-[2 α, 3 β (z)]]-2-[[[1-(2-amino-4-thiazolyl)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid, molecular formula C
13H
17N
5O
8S
2, molecular weight 435.43.The earliest by Shi Guibao (Squibb) company exploitation, at first in Italy's listing,, went on the market in Japan in 1987 subsequently in the listing of the many countries of America and Europe in 1984.Because aztreonam better tolerance, the side effect chance of occurrence is few, and penicillins and the common anaphylactic reaction of cephalosporins do not take place itself, also with blue or green class and the reaction of class generation cross allergy, thereby for seek real no anaphylactic reaction, efficiently, the broad-spectrum beta-lactam antibiotic opened up a new direction.Clinical research thinks that aztreonam has the good clinical curative effect to pulmonary infection, abdominal cavity infection, biliary tract infection, bone and the infection of joint, skin and the soft tissue inflammation 5 diseases infection that gram negative bacteria caused, especially be applicable to urinary tract infection, also be used for septicemia, widely-used clinically.
Aztreonam has multiple crystal structure form, is divided into α, β, γ, types such as δ, wherein the dissolubility of α type in water is bigger, but moisture absorption easily, and mobile relatively poor, storage stability is poor, therefore can not be used for doing preparation, the β type is not easy moisture absorption, and good fluidity, its solid-state stability is better, so medicinal aztreonam is generally the β type, but the dissolubility of β type aztreonam in water is very little, so has a lot of effort that it is prepared into various salt to improve its water solublity in the prior art.
World patent file WO2005/005424 has reported a kind of method for preparing the aztreonam lysinate, be that aztreonam is water-soluble, again lysine solution is added dropwise to and makes, this method preparation process is simple, also need not special installation, but since aztreonam lysinate less stable in aqueous solution have partly to be decomposed into aztreonam and lysine, make its reaction yield not high, less than 70%.
Disclose the preparation method of aztreonam amino acid salt among the Chinese patent file CN200710092994, this method is dissolved in organic solvent with aztreonam, drips amino acid whose aqueous solution, and after having reacted, cold filtration obtains aztreonam amino acid salt.Utilize organic solvent as reaction solution in this application, make the salt-forming reaction of aztreonam more thorough, the reaction yield height.But the product of gained is subjected to the pollution of organic solvent easily.
Chinese patent file 200810088955.1 discloses a kind of aztreonam liposomes freeze-dry preparations and preparation method thereof, but its preparation process more complicated, and the preparation yield of liposome is very low, is not suitable for suitability for industrialized production.
Chinese patent file 200910014974.4 discloses a kind of sub-micro emulsion frozen preparation of aztreonam, and wherein employed biological degradation polyalcohol is not suitable for injection and uses, and human body is had very big harm, so said preparation can not be by clinical use.
Chinese patent file CN1030238A discloses the arginic mixture of a kind of preparation aztreonam L-, be that L-arginine and aztreonam are mixed, again with it water-soluble and lyophilization and the mixture of L-arginine and aztreonam, but this mixture exists stability of formulation poor, and being placed with related substance for a long time increases problems such as a lot.
Existing in the market aztreonam for injection mainly is aztreonam and the arginic mixture of L-, aztreonam and these the two kinds of easy layerings of composition of L-arginine cause mixing inhomogeneous in vibration processes such as production, transportation, storage, present in addition aztreonam stability of formulation is relatively poor, being placed with related substance for a long time increases a lot, pH value alters a great deal, the prescription in the time that can not satisfy the prescriptive period.Urgent need provides the aztreonam pharmaceutical preparation that has good stability and be suitable for clinical use.
Summary of the invention
In order to overcome the deficiencies in the prior art, aztreonam and these the two kinds of easy layerings of composition of L-arginine cause mixing inhomogeneous in the solution prior art for preparing aztreonam for injection, and present aztreonam for injection stability of formulation is relatively poor, being placed with related substance for a long time increases a lot, pH value alters a great deal, the problem of the prescription in the time can not satisfy the prescriptive period, the invention provides a kind of stable aztreonam/arginine composite preparation and preparation method thereof, solved above problem, for the use of aztreonam for injection provides reliable technique support more.
Technical scheme of the present invention is as follows:
An object of the present invention is to provide simple, the steady quality of a kind of prescription and preparation technology, can the aztreonam pharmaceutical composition of preserving steady in a long-term.Aztreonam pharmaceutical composition of the present invention only contains β-aztreonam, L-arginine and HP-(HP-β-CD).
Further preferably, aztreonam pharmaceutical composition of the present invention contains the component of following weight proportion:
β-aztreonam 1～2
L-arginine 0.5～1
(HP-β-CD) 1～4 for HP-
Preferably, aztreonam pharmaceutical composition of the present invention contains the component of following weight proportion:
β-aztreonam 1～1.5
L-arginine 0.5～0.8
(HP-β-CD) 1～3 for HP-
Further preferably, aztreonam pharmaceutical composition of the present invention contains the component of following weight proportion:
β-aztreonam 1～1.2
L-arginine 0.5～0.7
(HP-β-CD) 1～2 for HP-
Most preferably, aztreonam pharmaceutical composition of the present invention contains the component of following weight proportion:
β-aztreonam 1～1.2
L-arginine 0.5～0.6
(HP-β-CD) 1～1.8 for HP-
Still more preferably, aztreonam pharmaceutical composition of the present invention contains the component of following weight proportion:
β-aztreonam 1
L-arginine 0.6
(HP-β-CD) 1 for HP-
(β-CD) there is the banded hydroxyl of C2 on the glucose molecule, C3 at an end opening place in molecule hole to beta-schardinger dextrin-, other end opening is the banded hydroxyl of C6, so the two ends of tubular structure are hydrophilic, and its hole have the glucosyl group oxo bridge and-the CH-group, so be hydrophobic in the hole.Some sizeable drug molecules form inclusion complex often by Van der Waals force with its inclusion in hydrophobic region.HP-(HP-β-CD) be beta-schardinger dextrin-(β-CD) in alkaline aqueous solution with the ethylene chlorhydrin condensation polytype CD.HP-tool safe dose is big, good with blood compatibility, do not change characteristics such as drug effect, the water solublity that increases medicine, stability, is considered to more promising drug carrier material.Pharmaceutical composition of the present invention coats the active component aztreonam with HP-, prepares the stable aztreonam pharmaceutical preparation that formulation and technology is simplified.
Aztreonam pharmaceutical composition of the present invention is an ejection preparation, and this ejection preparation comprises injection and lyophilized injectable powder.Therefore, aztreonam composition of the present invention must use water for injection in preparation process, and the consumption of water for injection is not particularly limited, and determines corresponding water for injection use amount according to product specification.If lyophilized injectable powder, then the composition of above-mentioned composition is meant that said preparation is the composition content of lyophilized injectable powder, at this moment, and by because factor such as technology, it also is understandable existing pharmacy to allow the water of content in the final preparation, for example may contain the water of weight percentage 0～6% in the preparation.If said preparation is an injection, then the weight ratio of aztreonam and water for injection changes in 1: 5～100 scope, preferred 1: 10～80, more preferably 1: 10-50, further preferred 1: 15～50.If final preparation is a lyophilized injectable powder, the water for injection that uses in preparation process also changes in above-mentioned scope.
Another object of the present invention provides a kind of described aztreonam preparation of drug combination method, this method directly is suspended in aseptic β-aztreonam in the water for injection, add aseptic L-arginine and regulate pH value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine, (HP-β-CD) carries out enclose to add HP-in this aqueous solution, through packing, promptly get aztreonam injecta composition of the present invention, if desired, the injection lyophilization is promptly got aztreonam for injection lyophilized injectable powder compositions.
Preparation method of the present invention adopts inclusion technique to prepare stable aztreonam/arginine compositions, comprises the steps:
1) adding aseptic β-aztreonam in the room temperature downhill reaction still is suspended in the water for injection; Add aseptic L-arginine and regulate the ph value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine; Adding finishes, and regulates ph value 5～7, preferred 6～7; Wherein the weight of aseptic β-aztreonam is in C13H17N5O8S2.
2) reaction back adds HP-(HP-β-CD), stirring at room enclose 0.5～2.0 hour in reactor; Add injection and be diluted with water to required mass concentration, the filtering with microporous membrane of reuse 0.45 μ m, by the filtering with microporous membrane of 0.22 μ m, packing promptly gets the aztreonam for injection freeze-dried powder through lyophilization at last.
Preferably, described step 2) the stirring at room enclose is 0.5～2.0 hour, preferred 1.0～1.5 hours;
The present invention directly suspends in water aseptic β-aztreonam, add aseptic L-arginine and regulate the ph value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine, (HP-β-CD) carries out enclose to add HP-in this aqueous solution, through packing, lyophilization promptly gets aztreonam for injection.The preparation method that this invention provided is simple, and the aztreonam arginine salt increases the water solublity and the stability of aseptic β-aztreonam medicine behind the HP-enclose, reduced its toxic and side effects, has improved the drug utilization degree.
The specific embodiment
The present invention will be further described with the test example below in conjunction with embodiment, but be not limited thereto.
Embodiment 1:
β-aztreonam 100g
L-arginine 70g
HP-(the 120g of HP-β-CD)
Water for injection 5000ml
Preparation technology:
Adding aseptic β-aztreonam in the room temperature downhill reaction still is suspended in the water for injection; Add aseptic L-arginine and regulate pH value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine; Adding finishes, and regulates pH value 6.0 β-aztreonam is all dissolved; In reactor, add HP-(HP-β-CD), stirred enclose 1.0 hours; Add injection and be diluted with water to required mass concentration, the filtering with microporous membrane of reuse 0.45 μ m, by the filtering with microporous membrane of 0.22 μ m, packing promptly gets the aztreonam for injection freeze-dried powder through lyophilization at last.
Embodiment 2:
β-aztreonam 100g
L-arginine 75g
HP-(the 150g of HP-β-CD)
Water for injection 2500ml
Preparation technology:
Adding aseptic β-aztreonam in the room temperature downhill reaction still is suspended in the water for injection; Add aseptic L-arginine and regulate the ph value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine; Adding finishes, and regulates pH value 6.5 aseptic β-aztreonam is all dissolved; In reactor, add HP-(HP-β-CD), stirred enclose 1.5 hours; Add injection and be diluted with water to required mass concentration, the filtering with microporous membrane of reuse 0.45 μ m, by the filtering with microporous membrane of 0.22 μ m, packing obtains the aztreonam injection at last.
Embodiment 3:
β-aztreonam 200g
L-arginine 120g
HP-(the 200g of HP-β-CD)
Water for injection 2000ml
Preparation technology:
Adding aseptic β-aztreonam in the room temperature downhill reaction still is suspended in the water for injection; Add aseptic L-arginine and regulate the ph value, make its whole dissolvings, get the aqueous solution of aztreonam/arginine; Adding finishes, and regulates pH value 7.0 aseptic β-aztreonam is all dissolved; In reactor, add HP-(HP-β-CD), stirred enclose 2.0 hours; Add injection and be diluted with water to required mass concentration, the filtering with microporous membrane of reuse 0.45 μ m, by the filtering with microporous membrane of 0.22 μ m, packing promptly gets the aztreonam for injection freeze-dried powder through lyophilization at last.
Test example: (stability experiment)
1, sample preparation: the method according to embodiment 2 is prepared respectively; Control sample is commercially available sample aztreonam for injection (ChongQing LaiMei Pharmacy Co., Ltd produces, lot number 20101006)
2, influence factor: sample is placed room temperature (25 ℃) respectively, high temperature (60 ℃), relative humidity 75% is under six kinds of conditions of relative humidity 92.5% and illumination 4500Lx.
3, investigate the result: investigate every index in sampling in the 5th day, 10 days, and be contrast, the results are shown in following table 1: factors influencing result with 0 day result
As seen from the above table, the sample of embodiment 2 and control sample contrast are as can be known, placed 5 days, 10 days under the condition of 25 ℃ of room temperatures, 60 ℃ of high temperature, relative humidity 75%, relative humidity 92.5% and illumination 4500Lx, the every index of the sample of embodiment 2 does not have significant change; The control sample related substance slightly raises, and under 60 ℃ of conditions of high temperature, related substance raises very fast, therefore the aztreonam arginine salt is behind the HP-enclose, increase the aztreonam stability of drug, reduced its toxic and side effects, improved the drug utilization degree, and preparation technology is simple, is fit to suitability for industrialized production.
Content disclosed according to the present invention, those skilled in the art can use the present invention to greatest extent.Therefore, above-mentioned preferred embodiment only illustrates, but not limits the scope of the invention by any way.
Claims (10)
1. aztreonam composition it is characterized in that said composition contains the component of following weight proportion, and said composition is an injection:
β-aztreonam 1～2
L-arginine 0.5～1
HP-1～4.
2. according to the aztreonam composition of claim 1, it is characterized in that said composition contains the component of following weight proportion:
β-aztreonam 1～1.5
L-arginine 0.5～0.8
HP-1～3.
3. according to the aztreonam composition of claim 2, it is characterized in that said composition contains the component of following weight proportion:
β-aztreonam 1～1.2
L-arginine 0.5～0.7
HP-1～2.
4. according to the aztreonam composition of claim 3, it is characterized in that said composition contains the component of following weight proportion:
β-aztreonam 1～1.2
L-arginine 0.5～0.6
HP-1～1.8.
5. according to the aztreonam composition of claim 4, it is characterized in that said composition contains the component of following weight proportion:
β-aztreonam 1
L-arginine 0.6
HP-1.
6. any one aztreonam composition among the claim 1-5 is characterized in that said composition adds the injection water by β-aztreonam, L-arginine and HP-and is prepared from, and wherein the weight proportion of aztreonam and water for injection is 1: 5～100.
7. as aztreonam composition as described in the claim 6, wherein the weight proportion of aztreonam and water for injection is 1: 10～50.
8. the preparation method of any one aztreonam composition among the claim 1-7 is characterized in that this method comprises the steps:
1) in the room temperature downhill reaction still aseptic β-aztreonam is suspended in the water for injection; Add aseptic L-arginine and regulate pH value, adding finishes, and regulates pH value 5～7; Make its whole dissolvings, get the aqueous solution of aztreonam/arginine;
2) the reaction back adds HP-, stirring at room enclose 0.5～2.0 hour in reactor; Add injection and be diluted with water to required mass concentration, the filtering with microporous membrane of reuse 0.45 μ m, by the filtering with microporous membrane of 0.22 μ m, packing gets the aztreonam injection at last; If desired, gained filtrate is promptly got the aztreonam for injection freeze-dried powder through lyophilization.
9. the preparation method of stable aztreonam composition as claimed in claim 8 is characterized in that described step 1) regulates pH value to 6～7.
10. the preparation method of stable aztreonam composition as claimed in claim 8 is characterized in that described step 2) stirring at room enclose 1.0～1.5 hours.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106924179A (en) * | 2015-12-29 | 2017-07-07 | 成都康弘药业集团股份有限公司 | A kind of liquid preparation containing Vonoprazan fumarate and preparation method thereof |
| CN113244170A (en) * | 2021-06-09 | 2021-08-13 | 苏州天马医药集团天吉生物制药有限公司 | Aztreonam injection preparation and preparation method thereof |
| CN113876722A (en) * | 2021-11-04 | 2022-01-04 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
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| CN101172974A (en) * | 2007-11-16 | 2008-05-07 | 西南合成制药股份有限公司 | Method for producing aztreonam amino acid salt |
| CN101579336A (en) * | 2009-07-07 | 2009-11-18 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN101773469A (en) * | 2010-02-05 | 2010-07-14 | 陶灵刚 | Aztreonam/arginine medicament composition suspension injection |
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
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2011
- 2011-01-24 CN CN2011100251275A patent/CN102145001B/en active Active
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| CN101172974A (en) * | 2007-11-16 | 2008-05-07 | 西南合成制药股份有限公司 | Method for producing aztreonam amino acid salt |
| CN101579336A (en) * | 2009-07-07 | 2009-11-18 | 重庆市庆余堂制药有限公司 | Aztreonam for injection and production method thereof |
| CN101773469A (en) * | 2010-02-05 | 2010-07-14 | 陶灵刚 | Aztreonam/arginine medicament composition suspension injection |
| CN101912356A (en) * | 2010-08-02 | 2010-12-15 | 王明 | Aztreonam/arginine medicinal composition lipid microsphere injection |
Non-Patent Citations (1)
| Title |
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| 《药剂学》 20030228 毕殿洲 包合技术 108-114 , 1 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106924179A (en) * | 2015-12-29 | 2017-07-07 | 成都康弘药业集团股份有限公司 | A kind of liquid preparation containing Vonoprazan fumarate and preparation method thereof |
| CN106924179B (en) * | 2015-12-29 | 2021-04-30 | 成都康弘药业集团股份有限公司 | Liquid preparation containing Vonoprazan fumarate and preparation method thereof |
| CN113244170A (en) * | 2021-06-09 | 2021-08-13 | 苏州天马医药集团天吉生物制药有限公司 | Aztreonam injection preparation and preparation method thereof |
| CN113876722A (en) * | 2021-11-04 | 2022-01-04 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
| CN113876722B (en) * | 2021-11-04 | 2022-12-02 | 海南皇隆制药股份有限公司 | Aztreonam for injection and preparation method thereof |
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| CN102145001B (en) | 2012-03-28 |
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