CN1123279A - Azithmycin water-soluble salt, injection thereof and their usage - Google Patents
Azithmycin water-soluble salt, injection thereof and their usage Download PDFInfo
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- CN1123279A CN1123279A CN 95106702 CN95106702A CN1123279A CN 1123279 A CN1123279 A CN 1123279A CN 95106702 CN95106702 CN 95106702 CN 95106702 A CN95106702 A CN 95106702A CN 1123279 A CN1123279 A CN 1123279A
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- acid
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- water soluble
- azythromycin
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Abstract
The azithromycin and equivalent required organic acid are mixed together, then stirred in requisited amount water at normal temp. until the raw materials are completely dissolved, then the obtained aqueous solution can be made into aqueous injection or powdered injection dosage form after freeze-drying treatment. USE-ADVANTAGE- can be used for curing several indications, and can quickly obtain results, its dose is small and side effect is less.
Description
And their purposes
The present invention relates to water-soluble salt, its aqueous injection and powder needle injection type and their purposes of pharmaceutical antibiotics.More particularly, relate to water soluble Azithromycin salt, its aqueous injection and powder needle injection type, and their purposes.
Azythromycin (Azithromycin, C
38H
72N
2O
12, molecular weight 748.99) and be a kind of semisynthetic azepine fifteen-membered ring macrolide antibiotics, its structural formula is as follows:
PKa=8.1 and 8.5 (referring to Fiese EF, et al:J Antimicrobial Chemotherapy
1990，25(suppl?A)，39)
Compare advantage such as that Azythromycin has is more stable to acid, concentration height, acting duration length, has a broad antifungal spectrum, side effect be low in body tissue with the parent stock Erythromycin A.Yet the same with erythromycin, its solubleness in water is very little, can't directly make injection type.According to the literature: when azithromycin capsule or tablet oral administration, only account for 37% (Foulds G of dosage through the medicine of stomach and intestine absorption, et al:The Pharmacokinetics of azithromycin inhuman serum and tissues.Journal of Antimicrobial Chemotherapy.1990,25 (Suppl A:73～82), rest part all is excreted, and causes very big waste.
Purpose of the present invention is that a kind of muscle or intravenous water soluble Azithromycin salt, its formulation that is suitable for injecting and their purposes of being directly used in will be provided.This salt and injection type thereof also can use the patient who can not per os takes medicine.
The inventor considers, because Azythromycin has two amino in its molecular structure, therefore might make one mole Azythromycin and two normal acid-responss become salt.The inventor finds through behind the various condition tests, needs only the various organic acid reactions with Azythromycin and equivalent, can make it become soluble salt.Here said equivalent is for residue carboxyl in the organic acid.For example, some have the amino acid of the amino and carboxyl of similar number owing to there is remaining carboxyl can not with Azythromycin reaction generation soluble salt.But L-glutamic acid and aspartic acid belong to acidic amino acid, they all have an amino and two carboxyls, just have a residue carboxyl to combine with the amino of Azythromycin, therefore one mole Azythromycin can generate soluble salt with two moles L-glutamic acid or aspartic acid reaction.Other situations are analogized.The inventor finds that also the aqueous solution that is formed by these soluble salts and water very is easy to disengage the former medicine of Azythromycin again, when for example carrying out thin-layer chromatography, can obtain the spot with the identical Rf of free Azythromycin.As seen the salt of this class Azythromycin can play the anti-microbial effect same with oral Azythromycin after being made into the injection liquid administration.And animal test results shows that medicine directly enters blood during owing to injection, therefore can bring into play therapeutic action rapidly, can fully be absorbed by living organism again, all is being much better than existing azithromycin oral formulation aspect instant effect and low-consuming two.
Thereby, the invention provides a kind of water soluble Azithromycin salt, it is characterized in that it is formed by the equivalent reaction by Azythromycin and the organic acid that pharmaceutically allows.
Said organic acid will be done suitable selection among the present invention, and it must be the organic acid that pharmaceutically allows, and it wants to generate with Azythromycin and have the enough salt of water-soluble degree, and for example, the concentration of Azythromycin can reach more than the 250mg/ml in the aqueous solution.The pH of the aqueous solution of its formation simultaneously is moderate, and for example the pH value so just can guarantee that contained Azythromycin is not damaged in 5.5～6.5 scopes.In addition, formed salt also will be easy to disengage Azythromycin in the aqueous solution, can bring into play drug effect rapidly and fully to guarantee it.
Show that behind overtesting preferable organic acid comprises acidic amino acid, alcohol acid and C
1～12(be preferably C
1～6) straight chain and/or branched chain fatty acid etc.
The preferred example of said acidic amino acid has: L-glutamic acid and aspartic acid.It also can be the mixture of the two.
The preferred example of said alcohol acid has: lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid and lactobionic acid.It also can be any mixture more than 2 kinds in them.
The preferred example of said lipid acid has: acetate, propionic acid and butyric acid.It also can be any mixture more than 2 kinds in them.
In addition, the present invention also provides a kind of Azythromycin aqueous injection and powder needle injection, it is characterized in that, the aqueous injection that the aqueous solution that it is formed by above-mentioned water soluble Azithromycin salt and water makes, with and through lyophilize and the powder injection type made.
The above-mentioned aqueous solution can be that Azythromycin and organic acid react in water and the aqueous solution of the water soluble Azithromycin salt that directly forms, also can be again that it is the soluble in water and aqueous solution that forms after obtaining the water-soluble fluidity salt of Azythromycin.
In addition, the present invention also provides water soluble Azithromycin salt, its aqueous injection and powder needle injection type to be used for the treatment of the purposes of all indications of Azythromycin.Said indication is modal to be various bacterial and chlamydozoan, mycoplasma infection.
In the aqueous solution that forms by water soluble Azithromycin salt of the present invention, even Azythromycin concentration up to 250mg/ml, store at normal temperatures and also do not separate out solid, and composition is still stablized.But when drug level is too high, direct injection will cause pain.Therefore must be made into the injection type of proper concn and proper volume usually with physiological saline.Yet according to the present invention, the preferably aqueous solution freeze-drying of the water soluble Azithromycin salt that will generate through reaction and make powder injection, from several respects such as storage, transportation and uses bigger benefit is arranged all like this, the water of injection specified amount faces with preceding as long as promptly can be used for injection or add in the intravenous infusion using after the thixotropy.As for its consumption, can calculate according to the specific absorption of oral dosage, but preferably determine as the case may be by the doctor.
Compare with the azithromycin oral agent of prior art, the invention has the beneficial effects as follows: the good water solubility of medicine, the Azythromycin concentration in solution can reach more than the 250mg/kg.And because medicine can directly enter blood, therefore can bring into play therapeutic action rapidly, can fully be absorbed by the body again, all play more significant effect aspect instant effect and low-consuming two.
Enumerate embodiment, test case and application examples below and further explain the present invention, but be not subjected to the restriction of these examples.
One, embodiment
The preparation of water soluble Azithromycin salt and injection type thereof
Embodiment 1
7.5g Azythromycin, 3g L-glutamic acid and 30ml water are added in the 100ml vial, and at room temperature stir about is 30 minutes, dissolves fully to raw material.Gained solution is water white transparency, and the pH that records solution with pH meter is 5.83.
Obtaining salts solution is under reduced pressure concentrated, in moisture eliminator, place in the dislocation plate then, allow its volatilization moisture, become transparent glass shape solid after anhydrating, continue again to place and allow moisture volatilize fully, gradually become white solid, the heavy 10.6g of institute's product that obtains.Fusing point: 126～127 ℃ of these products are water soluble Azithromycin salt of the present invention.Add 30ml water in this solid, stir with glass stick, less than 1 minute, solid i.e. all dissolvings.
Solution is pressed the predetermined concentration dilute with water, and through Sterile Filtration, the ampoule fusion sealing of packing under aseptic condition promptly gets aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.
Embodiment 2
7.5g Azythromycin, 2.7g aspartic acid and 30ml water are added in the 100ml vial, and at room temperature stir about is 30 minutes, dissolves fully to raw material, and gained solution is water white transparency, and the pH value that records solution with pH meter is 5.67.
Obtaining salts solution is under reduced pressure concentrated, in moisture eliminator, place in the dislocation plate then, allow its volatilization moisture, become transparent glass shape solid after anhydrating, continue again to place and allow moisture volatilize fully, gradually become white solid, the heavy 10.3g of institute's product that obtains.Fusing point: 115～117 ℃ of these products are water soluble Azithromycin salt of the present invention.Add 30ml water in this solid, stir with glass stick, less than 1 minute, solid i.e. all dissolvings.
Solution is pressed the predetermined concentration dilute with water, and through Sterile Filtration, the ampoule fusion sealing of packing under aseptic condition promptly gets aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.
Embodiment 3
7.5g Azythromycin, 1.8g are newly distilled in purified lactic acid and 100ml vial of 30ml water adding, at room temperature stirred 10 minutes, raw material dissolves rapidly, and gained solution is water white transparency, and the pH value that records solution with pH meter is 5.81.
Obtaining salts solution is under reduced pressure concentrated, in moisture eliminator, place in the dislocation plate then, allow its volatilization moisture, become transparent glass shape solid after anhydrating, continue again to place and allow moisture volatilize fully, gradually become white solid, the heavy 9.4g of institute's product that obtains.Fusing point: 108～109 ℃ of these products are water soluble Azithromycin salt of the present invention.Add 30ml water in this solid, stir with glass stick, less than 1 minute, solid i.e. all dissolvings.
Solution is pressed the predetermined concentration dilute with water, and through Sterile Filtration, the ampoule fusion sealing of packing under aseptic condition promptly gets aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.
Embodiment 4
7.5g Azythromycin, 1.3g citric acid and 30ml water are added in the 100ml vial, at room temperature stirred 10 minutes, raw material dissolves rapidly, and solution is water white transparency.The pH value that records solution with pH meter is 6.03.
Obtaining salts solution is under reduced pressure concentrated, in moisture eliminator, place in the dislocation plate then, allow its volatilization moisture, become transparent glass shape solid after anhydrating.Continue again to place to allow moisture volatilize fully, gradually become white solid, the heavy 9.0g of institute's product that obtains.Fusing point: 154～156 ℃ of these products are water soluble Azithromycin salt of the present invention.Add 30ml water in this solid, stir with glass stick, less than 1 minute, solid i.e. all dissolvings.
Solution is pressed the predetermined concentration dilute with water, and through Sterile Filtration, the ampoule fusion sealing of packing under aseptic condition promptly gets aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.
Embodiment 5
7.5g Azythromycin, 1.2g acetate and 30ml water are added in the 100ml vial, at room temperature stirred 10 minutes, raw material dissolves rapidly, and solution is water white transparency.The pH value that records solution with pH meter is 5.81.
Obtaining salts solution is under reduced pressure concentrated, in moisture eliminator, place in the dislocation plate then, allow its volatilization moisture, become transparent glass shape solid after the dehydration.Continue again to place to allow moisture volatilize fully, gradually become white solid, the heavy 8.9g of institute's product that obtains.Fusing point: 98～99 ℃ of these products are water soluble Azithromycin salt of the present invention.Add 30ml water in this solid, stir with glass stick, less than 1 minute, solid i.e. all dissolvings.
Solution is pressed the predetermined concentration dilute with water, and through Sterile Filtration, the ampoule fusion sealing of packing under aseptic condition promptly gets aqueous injection; Be sub-packed in freeze-drying in the vial by predetermined dose in addition, promptly obtain powder needle injection of the present invention.Face water, can use after the thixotropy with preceding adding predetermined amount.
Two, test case
1. water-soluble salt solution thin-layer chromatography experiment
As matrix, is developping agent with ether/methylene chloride (14/12/1) with silica gel thin sheet.
The 0.5g Azythromycin is dissolved in the 2ml ethanol, with this solution in contrast.In addition, the solution of 5 water soluble Azithromycin salts that embodiment 1～5 is made, and the pressed powder that after drying, obtains 10 solution that form soluble in water again, totally 15 solution examples, with above-mentioned contrast solution, put the different positions on same silica gel thin sheet respectively, use developping agent (ether: methylene dichloride: methyl alcohol=14: 12: 1) launch these 17 the Azythromycin spots that all presented identical Rf value by test agent then.These results show that the combination of these water-soluble salts in water of Azythromycin is also insecure, very easily resolve into Azythromycin and corresponding organic acid on as the silica-gel plate of sorbent material, thereby can play the anti-microbial effect of the former medicine of Azythromycin.
2, separate out the experiment of acid from water-soluble salt solution
The glutaminate solution of the Azythromycin that makes by embodiment 1 method from wherein pipetting 1ml to another 10ml test tube, drips ethanol in this test tube, the adularescent precipitation is separated out; Till continuation dropping ethanol to white precipitate is separated out fully.Filter, solids washs with small amount of ethanol, and is dry then.This solids is carried out infrared measurement, the ir data of acquisition and L-glutamic acid identical.
3, separate out the experiment of Azythromycin from water-soluble salt solution
The glutaminate solution of the Azythromycin that the method by embodiment 1 that pipettes makes, from wherein moving 1ml to another 10ml test tube, toward dropping ammonia wherein, the adularescent precipitation is separated out; Till continuation dropping ammonia to white precipitate is separated out fully.Suction filtration, solids washs with less ammonia, then drying under reduced pressure.This solids is carried out infrared measurement, the spectroscopic data of acquisition and Azythromycin identical.
By the foregoing description 1～5 as can be seen, Azythromycin can form water-soluble salt with organic acids such as L-glutamic acid, aspartic acid, lactic acid, citric acid, acetic acid, and from test case 1～3 as can be seen, these azithromycins resolve into Azythromycin and corresponding acid easily in water.And since the pH value of solution value all in 5.6～6.1 scope, the unlikely stability that influences Azythromycin, this just provides experimental basis for the injection type of manufacturing Azythromycin.
Three, application examples
The laboratory animal mouse is divided into three groups, and 10 every group, all each is measured with streptococcus aureus abdominal injection 0.5ml minimum 100% deadly bacterium.Behind the mouse infection, give ED with first group of per os immediately
50Dosage, i.e. the Azythromycin of 55mg/kg contains the water-soluble salt solution of 1/2 this dosage, i.e. 27.5mg/kg Azythromycin with second group from tail vein injection.The 3rd group of not administration in contrast.
Result: first group of 5/10 animals survived
Second group of 6/10 animals survived
The 3rd treated animal is all dead
The curative effect of as seen injecting 1/2 dosage Azythromycin is better than oral full ED
50The curative effect of dosage.
The water-soluble salt property list
| Water-soluble salt | Potency of azithromycin (%) | Fusing point (℃) | PH value of water solution |
| The L-glutamic acid Azythromycin | 71 | ?126～127 | ?5.83 |
| Asparagus fern is pacified sour Azythromycin | 73 | ?115～117 | ?5.67 |
| The lactic acid Azythromycin | 80 | ?108～109 | ?5.81 |
| The citric acid Azythromycin | 85 | ?154～156 | ?6.03 |
| The acetic acid Azythromycin | 86 | ?98～99 | ?5.77 |
Claims (10)
1, water soluble Azithromycin salt is characterized in that, it is formed by the equivalent reaction by Azythromycin and the organic acid that pharmaceutically allows.
2, water soluble Azithromycin salt as claimed in claim 1 is characterized in that, wherein said organic acid is an acidic amino acid.
3, water soluble Azithromycin salt as claimed in claim 2 is characterized in that, wherein said acidic amino acid is the mixture of any or the two in L-glutamic acid and the aspartic acid.
4, water soluble Azithromycin salt as claimed in claim 1 is characterized in that, wherein said organic acid is an alcohol acid.
5, water soluble Azithromycin salt as claimed in claim 4 is characterized in that, wherein said alcohol acid is: any in lactic acid, hydroxybutyric acid, oxysuccinic acid, tartrate, citric acid and the lactobionic acid or any mixture more than 2 kinds.
6, water soluble Azithromycin salt as claimed in claim 1 is characterized in that, wherein said organic acid is C
1～12Straight chain and or branched chain fatty acid.
7, water soluble Azithromycin salt as claimed in claim 6 is characterized in that, wherein said organic acid is any or any mixture more than 2 kinds in acetate, propionic acid and the butyric acid.
8, the water needle injection of water soluble Azithromycin salt is characterized in that, the sterile preparation of the injection that it is formed by the water soluble Azithromycin salt and the water of claim 1.
9, the powder needle injection of water soluble Azithromycin salt is characterized in that, it is made through lyophilize by the aqueous solution that the water soluble Azithromycin salt and the water of claim 1 forms.
10, the water soluble Azithromycin salt of claim 1 is used for the treatment of all indications of Azythromycin with the injection type of claim 8 or 9.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95106702 CN1123279A (en) | 1995-06-15 | 1995-06-15 | Azithmycin water-soluble salt, injection thereof and their usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95106702 CN1123279A (en) | 1995-06-15 | 1995-06-15 | Azithmycin water-soluble salt, injection thereof and their usage |
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| Publication Number | Publication Date |
|---|---|
| CN1123279A true CN1123279A (en) | 1996-05-29 |
Family
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95106702 Pending CN1123279A (en) | 1995-06-15 | 1995-06-15 | Azithmycin water-soluble salt, injection thereof and their usage |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1075837A3 (en) * | 1999-08-09 | 2001-05-16 | S.I.F.I. Società Industria Farmaceutica Italiana S.p.A. | Process for the preparation of aqueous formulations for ophthalmic use |
| CN1081037C (en) * | 1997-12-29 | 2002-03-20 | 锦州九天药业有限公司 | Azithromycin suppository and ointment |
| CN1096468C (en) * | 1998-11-27 | 2002-12-18 | 何广卫 | Adriamycin polybasic acid sodium salt complex salt |
| JP2003522108A (en) * | 1998-07-09 | 2003-07-22 | メリアル，インコーポレイテッド | Macrolide aqueous solution |
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| CN1313476C (en) * | 2003-09-09 | 2007-05-02 | 上海新先锋药业有限公司 | Injection preparation of arjimycin water soluble phosphate and its preparation method |
| CN100343267C (en) * | 2005-08-05 | 2007-10-17 | 新昌国邦化学工业有限公司 | Azithromycin tartrate preparation method |
| CN100427499C (en) * | 2005-12-20 | 2008-10-22 | 山东诚创医药技术开发有限公司 | Soluble salt of azithromycin and its preparation process |
| CN1697648B (en) * | 2003-12-04 | 2010-06-23 | 辉瑞产品公司 | Azithromycin dosage forms with reduced side effects |
| CN102772374A (en) * | 2012-08-06 | 2012-11-14 | 浙江亚太药业股份有限公司 | Lyophilized preparation of citric acid and azithromycin, and preparation method thereof |
| CN103462910A (en) * | 2013-09-22 | 2013-12-25 | 悦康药业集团有限公司 | Azithromycin composition for injection and preparation method thereof |
-
1995
- 1995-06-15 CN CN 95106702 patent/CN1123279A/en active Pending
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1081037C (en) * | 1997-12-29 | 2002-03-20 | 锦州九天药业有限公司 | Azithromycin suppository and ointment |
| JP4987187B2 (en) * | 1998-07-09 | 2012-07-25 | メリアル，インコーポレイテッド | Macrolide aqueous solution |
| JP2003522108A (en) * | 1998-07-09 | 2003-07-22 | メリアル，インコーポレイテッド | Macrolide aqueous solution |
| EP1094822A4 (en) * | 1998-07-09 | 2004-03-31 | Merial Inc | Water miscible macrolide solutions |
| CN1096468C (en) * | 1998-11-27 | 2002-12-18 | 何广卫 | Adriamycin polybasic acid sodium salt complex salt |
| EP1075837A3 (en) * | 1999-08-09 | 2001-05-16 | S.I.F.I. Società Industria Farmaceutica Italiana S.p.A. | Process for the preparation of aqueous formulations for ophthalmic use |
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
| CN1313476C (en) * | 2003-09-09 | 2007-05-02 | 上海新先锋药业有限公司 | Injection preparation of arjimycin water soluble phosphate and its preparation method |
| CN1697648B (en) * | 2003-12-04 | 2010-06-23 | 辉瑞产品公司 | Azithromycin dosage forms with reduced side effects |
| CN100343267C (en) * | 2005-08-05 | 2007-10-17 | 新昌国邦化学工业有限公司 | Azithromycin tartrate preparation method |
| CN100427499C (en) * | 2005-12-20 | 2008-10-22 | 山东诚创医药技术开发有限公司 | Soluble salt of azithromycin and its preparation process |
| CN102772374A (en) * | 2012-08-06 | 2012-11-14 | 浙江亚太药业股份有限公司 | Lyophilized preparation of citric acid and azithromycin, and preparation method thereof |
| CN102772374B (en) * | 2012-08-06 | 2014-08-20 | 浙江亚太药业股份有限公司 | Lyophilized preparation of citric acid and azithromycin, and preparation method thereof |
| CN103462910A (en) * | 2013-09-22 | 2013-12-25 | 悦康药业集团有限公司 | Azithromycin composition for injection and preparation method thereof |
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