CN1157824A - Azrinomycin dihydric phosphate complex salt and its preparation - Google Patents
Azrinomycin dihydric phosphate complex salt and its preparation Download PDFInfo
- Publication number
- CN1157824A CN1157824A CN 96116135 CN96116135A CN1157824A CN 1157824 A CN1157824 A CN 1157824A CN 96116135 CN96116135 CN 96116135 CN 96116135 A CN96116135 A CN 96116135A CN 1157824 A CN1157824 A CN 1157824A
- Authority
- CN
- China
- Prior art keywords
- azrinomycin
- azythromycin
- complex salt
- phosphate complex
- dihydric phosphate
- Prior art date
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- Granted
Links
Abstract
A double salt of azimycin dihydrogen phosphate is prepared from azimycin and dihydrogen phosphate salt whose mole number is equal to or 2 times higher than that of azimycin, and has a molecular formula: C38H72N2O12.Mm(H2PO4)x.yH2O, where M=Na, K, Ca, or NH4, m=1 or 2, x=2 and y=0, 1,2,3,4,5, or 6. It features good water solubility, not sucking moisture easily, and the pH value of its aqueous solution near the pH value of human blood. Said double salt can be used to prepare oral medicine or injection suitable for all the diseases originally cured by azimycin.
Description
The present invention relates to new macrolide antibiotics Azrinomycin dihydric phosphate complex salt and be the preparation that main ingredient is made, belong to chemistry and medicine field with this double salt.
Azythromycin (Azithromyin) is new macrolide antibiotics, it is strong to have anti-microbial effect, long action time, characteristics such as untoward reaction is few, because its solubleness in water is very little, can't directly make solution and injection, so this medicine listing formulation mostly is capsule at present, solid orally ingestibles such as granule, and there are not solution and injection, therefore since the eighties, there has been the people researching and solving the way of the problems referred to above always, main result of study is as follows: (1) Azythromycin and sour salify, this salt is water-soluble fine, but the moisture absorption very easily, in humidity is to place suction in 24 hours under 75% condition to become liquid, and aqueous solution acidity is big (pH value majority＜6.0), are lower than the pH value (7.4) of blood of human body; (2) muriate of Azythromycin and metal ion forms title complex (also claiming complex compound), but the metal ion of formation complex compound mostly is transition metal such as Cu
2+, Zn
2+, Co
2+, Ni
2+Deng, the toxicity of its muriate own is bigger, though the title complex of formation keeps anti-microbial activity, and is not suitable for the medication of conducting oneself.
The objective of the invention is at the problems referred to above a kind of good water solubility be provided, be difficult for the moisture absorption, aqueous ph value acidity is that main ingredient adds the preparation that suitable auxiliary material is made near the little Azrinomycin dihydric phosphate complex salt of blood of human body pH value and toxicity and with it.
The present invention is achieved in that Azrinomycin dihydric phosphate complex salt is by Azythromycin (C
38H
72N
2O
12NH
2O, n=0,1,2) and 1 times or 2 times [M (H of the dihydrogen phosphate to it of mole number
2PO
4) xyH
2O is M=Na, K, Ca, NH wherein
4X=1,2; Y=0,1,2,3,4] in the solvent of 4-47 (any or more than one mixture of organic solvent in water or water and methyl alcohol, ethanol, the acetone), react to raw material and all dissolve, add organic solvent such as ethanol, Virahol, methyl-sulphoxide crystallization or directly decompressing and extracting or spraying drying or lyophilize behind the reaction soln concentrating under reduced pressure, all can make Azrinomycin dihydric phosphate complex salt, its molecular formula is [C
38H
72N
2O
12Mm (H
2PO
4) xyH
2O], wherein M=Na, K, Ca, NH
4M=1,2; X=2; Y=0,1,2,3,4,5,6.Because above-mentioned dihydrogen phosphate is the auxiliary material (wherein SODIUM PHOSPHATE, MONOBASIC is freeze-dried excipient commonly used) that pharmaceutically allows use, toxicity is very little (to It is generally accepted to being safe, FDA Food and Drug Administration 1985), combine the formation Azrinomycin dihydric phosphate complex salt with Azythromycin after, aqueous ph value is 7.0-8.0, very approaching with the pH value (7.4) of blood of human body, to the effect of blood vessel nonirritant.
Be that main ingredient adds suitable auxiliary material and can be made into oral and injection formulationss such as tablet, capsule, granule, dry syrup, solution, syrup, liquid drugs injection, transfusion, powder pin with the Azrinomycin dihydric phosphate complex salt.Azrinomycin dihydric phosphate complex salt adding thinner, tackiness agent, disintegrating agent, lubricant, glidant can be made into the Azrinomycin dihydric phosphate complex salt tablet after mixing, make softwood, system particle, drying, whole grain, compressing tablet; Azrinomycin dihydric phosphate complex salt adding thinner, correctives, tackiness agent, disintegrating agent, lubricant, glidant can be made into Azrinomycin dihydric phosphate complex salt capsule, granule and dry syrup after mixing, make softwood, system particle, drying, whole grain, embedding; Azrinomycin dihydric phosphate complex salt can be made into Azrinomycin dihydric phosphate complex salt solution and syrup after adding sugar, correctives, acidic flavoring agent, water etc.; Thinner can be selected starch, Icing Sugar, lactose, dextrin, Microcrystalline Cellulose etc. for use in the above-mentioned pharmaceutical adjunct, tackiness agent can be selected starch slurry, syrup, jelly etc. for use, disintegrating agent can be selected dry starch, sodium starch glycolate, L-hydroxypropyl cellulose etc. for use, lubricant can be selected Magnesium Stearate, talcum powder etc. for use, glidant can be selected micropowder silica gel etc. for use, correctives can be selected sweeting agent (as aspartame, soluble saccharin etc.), perfume compound (as peppermint, fruity flavor etc.) etc. for use, and capsule can not add correctives.The various oral preparations disintegrations of using Azrinomycin dihydric phosphate complex salt to make are fast, scattered, absorption is complete, and being better than with the Azythromycin bulk drug is the oral preparations that main ingredient is made.Azrinomycin dihydric phosphate complex salt is biphosphate Azythromycin sodium salt preferably, adds suitable quantity of water, needle-use activated carbon mixing after carbon removal, Sterile Filtration, embedding can be made into the Azrinomycin dihydric phosphate complex salt liquid drugs injection; Azrinomycin dihydric phosphate complex salt is biphosphate Azythromycin sodium salt preferably, adds in right amount isotonic aqueous solution with sodium-chlor or glucose preparation, needle-use activated carbon mixing after carbon removal, Sterile Filtration, embedding can be made into the Azrinomycin dihydric phosphate complex salt transfusion; Azrinomycin dihydric phosphate complex salt is biphosphate Azythromycin sodium salt preferably, adds suitable quantity of water, needle-use activated carbon mixing after make Azrinomycin dihydric phosphate complex salt powder pin after spraying drying or the lyophilize after the carbon removal, Sterile Filtration.
With the Azrinomycin dihydric phosphate complex salt whole indications that various preparations that raw material is made all can be used for Azythromycin.
Azrinomycin dihydric phosphate complex salt has good water solubility, is difficult for the moisture absorption, aqueous ph value acidity is near the blood of human body pH value, to characteristics such as blood vessel irritation are little; The various oral preparations disintegrations of using Azrinomycin dihydric phosphate complex salt to make are fast, scattered, absorption is complete, and being better than with the Azythromycin bulk drug is the oral preparations that main ingredient is made; Use injection formulations good stability that Azrinomycin dihydric phosphate complex salt makes, the aqueous ph value acidity near blood of human body pH value, little, solved the difficult problem that the Azythromycin bulk drug can not directly be made injection blood vessel irritation.See following test result for details:
One, humidity sees the following form to the influence of Azrinomycin dihydric phosphate complex salt and the pH value of the Azrinomycin dihydric phosphate complex salt aqueous solution: bar relative humidity (75%) part
10 days white powders 7.7 of 10 days white powder 7.6 biphosphate Azythromycin sylvite 10 days white powder 7.2 biphosphate Azythromycin ammonium salts of 10 days white powder 7.8 biphosphate Azythromycin calcium salts of aqueous ph value compound outward appearance storage period (10%W/V) biphosphate Azythromycin sodium salt
Two, biphosphate Azythromycin sodium salt is tested the rabbit blood vessel irritation
Getting 8 of rabbit, to be divided into two groups at random be test group and control group, and test group is by the rabbit ear edge vein biphosphate Azythromycin sodium salt that slowly instils, once a day, dosage is 62.5mg/kg, add 5% glucose injection 40ml, drip fast 1.5ml/min, successive administration three days; Control group gives 10% Glacial acetic acid, at the negative contrast of 5% glucose injection of instiling of the offside rabbit ear, successive administration three days; The result shows: test group continuous use three days, the local no abnormality seen of administration, with the same to side injection 5% glucose injection, and inject visible vessels contrafluxion behind 10% Glacial acetic acid, ooze out, thickening.
Three, tire (Azythromycin unit) biphosphate Azythromycin sodium salt 700 biphosphate Azythromycin sylvite 690 biphosphate Azythromycin calcium salts 704 biphosphate Azythromycin ammonium salts 689 1, embodiment of biphosphate Azythromycin double salt titration result (bacillus pumilus, two dish methods) double salt title
Embodiment 1
Azythromycin 74.9g, sodium dihydrogen phosphate dihydrate 31.2g add 2000ml water, and stirring at room to raw material all dissolves, PH=7.6, and spraying drying gets white powder, i.e. biphosphate Azythromycin sodium salt [C
38H
72N
2O
12Na
2(H
2PO
4)
2].
Embodiment 2
Azythromycin 0.75g, sodium dihydrogen phosphate dihydrate 0.312g add 8ml water, 1ml acetone, stirring at room to raw material all dissolves, PH=7.6, decompression is evacuated to when making an appointment with half water, add the 5ml Virahol put into vacuumize under 45 ℃ of the refrigerator cold-storage after-filtration crystallizations in 4 hours do after quick-fried white solid, i.e. biphosphate Azythromycin sodium salt [C
38H
72N
2O
12Na
2(H
2PO
4)
22H
2O].
Embodiment 3
Tablet formulation: 100,000 consumptions
Biphosphate Azythromycin sodium salt (among the embodiment 2) 35.4kg
Starch 8.0kg
Icing Sugar 1.5kg
Starch (dashing slurry 10%) is an amount of
Dry starch 0.5kg
Magnesium Stearate 0.5kg
Take by weighing biphosphate Azythromycin sodium salt, starch, Icing Sugar and sieve respectively, mix, make tackiness agent with 10% starch slurry, behind the mixing, cross 14 mesh sieves and make particle, 40 ℃ of following cryodryings, add dry starch and Magnesium Stearate, through the whole grain of 12 mesh sieves, compressing tablet promptly.
Embodiment 4
Capsule prescription: 100,000 consumptions
Biphosphate Azythromycin sodium salt (among the embodiment 2) 35.4kg
Starch 8.0kg
Icing Sugar 2.5kg
Starch (dashing slurry 10%) is an amount of
Dry starch 0.2kg
Magnesium Stearate 0.2kg
Take by weighing biphosphate Azythromycin sodium salt, starch, Icing Sugar and sieve respectively, mix, make tackiness agent with 10% starch slurry, behind the mixing, cross 20 mesh sieves and make particle, 40 ℃ of following cryodryings, add dry starch and Magnesium Stearate,, incapsulate promptly through the whole grain of 20 mesh sieves.
Embodiment 5
The granule prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 17.7kg
Lactose 5.0kg
Icing Sugar 28.5kg
Aspartame 0.8kg
Vanilla is an amount of
Tangerine flavor essence is an amount of
Distilled water is an amount of
Take by weighing biphosphate Azythromycin sodium salt, lactose, Icing Sugar and sieve respectively, mix, granulate with wetting mistake 12 mesh sieves of suitable quantity of water, 40 ℃ of following cryodryings, through the whole grain of 12 mesh sieves, filling and sealing promptly.
Embodiment 6
The dry syrup prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 17.7kg
Icing Sugar 88.5kg
Aspartame 0.8kg
Vanilla is an amount of
Tangerine flavor essence is an amount of
Distilled water is an amount of
Take by weighing biphosphate Azythromycin sodium salt, lactose, Icing Sugar and sieve respectively, mix, granulate with wetting mistake 12 mesh sieves of suitable quantity of water, 40 ℃ of following cryodryings, through the whole grain of 12 mesh sieves, filling and sealing promptly.
Embodiment 7
The solution prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 70.7g
Citric acid 8.0g
Sucrose 200 g
Aspartame 1.0g
Sodium-chlor 1.0g
Spearmint oil is an amount of
Tangerine flavor essence is an amount of
Water for injection is an amount of
Be made into 1000ml
Sucrose adds 700ml water heated and boiled, and sugar is dissolving back filtered while hot all, is cooled to below 40 ℃, adds other main ingredient mixing, adds water to 1000ml, and can promptly.
Embodiment 8
The syrup prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 70.7g
Sucrose 700 g
Aspartame 0.3g
Sodium-chlor 1.0g
Spearmint oil is an amount of
Tangerine flavor essence is an amount of
Water for injection is an amount of
Be made into 1000ml
Sucrose adds 950m1 water heated and boiled, and sugar is dissolving back filtered while hot all, is cooled to below 40 ℃, adds other main ingredient mixing, adds water to 1000ml, and can promptly.
Embodiment 9
The liquid drugs injection prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 176.8g
Water for injection is an amount of
Be made into 1000ml
Biphosphate Azythromycin sodium salt adds entry, needle-use activated carbon mixing after carbon removal, remove that embedding can be made into the Azrinomycin dihydric phosphate complex salt liquid drugs injection under (0.22 μ m), the aseptic condition with filtering.
Embodiment 10
The transfusion prescription:
Biphosphate Azythromycin sodium salt (among the embodiment 2) 1.77g
Sodium-chlor 9.0g
Water for injection is an amount of
Be made into 1000ml
Biphosphate Azythromycin sodium salt, add sodium-chlor, water, needle-use activated carbon mixing after under the carbon removal, Sterile Filtration (0.22 μ m), aseptic condition embedding can be made into the Azrinomycin dihydric phosphate complex salt transfusion.
Embodiment 11
Biphosphate Azythromycin sodium salt 250g adds needle-use activated carbon 0.05% (W/V) absorption 20 minutes after adding injection water 2500ml mixing among the embodiment 2, carbon removal, Sterile Filtration (0.22 μ m) lyophilize under aseptic condition get white powder, are the powder pin after aseptic subpackaged.
Claims (5)
1. Azrinomycin dihydric phosphate complex salt is characterized in that it equals Azythromycin by Azythromycin and mole number or doubles the dihydrogen phosphate be combined into of Azythromycin, and molecular formula is C
38H
72N
2O
12Mm (H
2PO
4) xyH
2O, wherein M=Na, K, Ca, NH
4M=1,2; X=2; Y=0,1,2,3,4,5,6.
2. the Azrinomycin dihydric phosphate complex salt preparation is characterized in that with the Azrinomycin dihydric phosphate complex salt being that main ingredient adding auxiliary material can be made into tablet, capsule, granule, dry syrup, solution, syrup, liquid drugs injection, transfusion, powder pin.
3. the Azrinomycin dihydric phosphate complex salt described in claim 1, the molecular formula that it is characterized in that said Azythromycin is C
38H
72N
2O
12NH
2O, n=0 wherein, 1,2.
4. the Azrinomycin dihydric phosphate complex salt described in claim 1, the molecular formula that it is characterized in that said dihydrogen phosphate is M (H
2PO
4) xyH
2O, wherein M=Na, K, Ca, NH
4X=1,2; Y=0,1,2,3,4.
5. the dihydrogen phosphate described in claim 4 is characterized in that dihydrogen phosphate is one or more a mixture of dihydrogen phosphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96116135 CN1046945C (en) | 1996-12-28 | 1996-12-28 | Azrinomycin dihydric phosphate complex salt and its preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 96116135 CN1046945C (en) | 1996-12-28 | 1996-12-28 | Azrinomycin dihydric phosphate complex salt and its preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1157824A true CN1157824A (en) | 1997-08-27 |
| CN1046945C CN1046945C (en) | 1999-12-01 |
Family
ID=5123311
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 96116135 Expired - Fee Related CN1046945C (en) | 1996-12-28 | 1996-12-28 | Azrinomycin dihydric phosphate complex salt and its preparation |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1046945C (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096468C (en) * | 1998-11-27 | 2002-12-18 | 何广卫 | Adriamycin polybasic acid sodium salt complex salt |
| 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 |
| CN101092440B (en) * | 2007-07-19 | 2010-05-26 | 浙江尖峰药业有限公司 | Method for preparing Azithromycin Sulfate |
| CN102755287A (en) * | 2012-07-20 | 2012-10-31 | 天津药业集团新郑股份有限公司 | Azithromycin oral liquid and preparation method thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1652851A1 (en) | 2001-05-22 | 2006-05-03 | Pfizer Products Inc. | New crystal form of Azithromycin |
-
1996
- 1996-12-28 CN CN 96116135 patent/CN1046945C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096468C (en) * | 1998-11-27 | 2002-12-18 | 何广卫 | Adriamycin polybasic acid sodium salt complex salt |
| 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 |
| CN101092440B (en) * | 2007-07-19 | 2010-05-26 | 浙江尖峰药业有限公司 | Method for preparing Azithromycin Sulfate |
| CN102755287A (en) * | 2012-07-20 | 2012-10-31 | 天津药业集团新郑股份有限公司 | Azithromycin oral liquid and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1046945C (en) | 1999-12-01 |
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| PB01 | Publication | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
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| CF01 | Termination of patent right due to non-payment of annual fee |