CN1775794A - Azitromycin double salts and their preparing method and use - Google Patents
Azitromycin double salts and their preparing method and use Download PDFInfo
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- CN1775794A CN1775794A CN 200510126577 CN200510126577A CN1775794A CN 1775794 A CN1775794 A CN 1775794A CN 200510126577 CN200510126577 CN 200510126577 CN 200510126577 A CN200510126577 A CN 200510126577A CN 1775794 A CN1775794 A CN 1775794A
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- fudosteine
- azythromycin
- double salt
- azithromycin
- molecular formula
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Abstract
The invention relates to an azithromycin fudosteine compound salt. Its feature is that it combines azithromycin and fudosteine, which is double to azithromycin. And its molecular formula is that C38H72N2O12.2C6H13NO3S.nH2O, n=0,1,2,3,4,5. Its advantages are that it has good water solubility and is uneasy to absorption of moisture; the aqueous solution pH value acidity is close to human-body. Using the azithromycin fudosteine compound salt as the main medicine can make various pre oral and injection preparation. The preparations are mainly used to treat abundant expectoration type infection of the respiratory.
Description
Technical field
The present invention relates to medicine and preparation method thereof, relate in particular to a kind of Azythromycin double salt and its production and use.
Background technology
(-)-(R)-amino-3-(3-hydroxypropyl sulfydryl) propionic acid is called as " Fudosteine " (English name: fudosteine CAS:13189-98-5) go on the market in Japan first October calendar year 2001, bronchitis is a kind of common disease, frequently-occurring disease, all higher in domestic its incidence and mortality of world's model, and the trend of increase arranged, often show as cough, expectoration, or with breathing hard, pant etc., severe patient can concurrent pulmonary emphysema, pulmonary heart disease etc.Fudosteine is a kind of novel expectorant, for the glutinous phlegm dissolved substance of a new generation, belongs to cysteine derivative.The many difficulties of phlegm that the indication of Fudosteine almost contains all respiratory system diseases that comprise bronchitis are coughed symptom.Normal and anti-asthmatic, antimicrobial drug of expectorant share clinically, and pharmaceutical chemicals with phlegm-dispelling functions that goes on the market such as bromhexine, acetylcysteine, Carbocisteine etc. all have sticking phlegm regulating effect in various degree at present.And the Fudosteine clinical effective rate is better than similar medicine greatly, can merge to be used for respiratory system disease.
Azythromycin is the popular name of 9a-azepine-9a-methyl-9-deoxidation-9a-a-homoerythromycin A (homoerythromycinA), and it is by Erythromycin A deutero-broad-spectrum micro-organisms compound.Azythromycin is found by (US4517359) such as Bright (US4474768) and Kobrehel is independent.These two pieces of patent disclosures Azythromycin therefore have antibacterial properties and and as microbiotic, clinical have anti-inflammatory curative effect preferably, but when treatment abundant expectoration type inflammation, because the obstruction of sticking phlegm, Azythromycin itself is difficult for reaching inflammation part, thereby is difficult for reaching effective treatment concentration.French Patent (FR8503679) has been invented a kind of salt of being made up of erythromycin and Erdosteine, treatment abundant expectoration type inflammation, but erythromycin itself is unstable to acid, can make himself structure deteriorate with sour salify.Can form salt and stable to acid with acid because Azythromycin is a basic cpd, it is acidic cpd that latest generation goes phlegm medicine Fudosteine, so the double salt of Azythromycin and Fudosteine generation is significant in clinical practice.Still there are not at present Azythromycin and Fudosteine in conjunction with the open report that generates double salt.
Summary of the invention
One of purpose of the present invention is at disadvantages of background technology, and providing a kind of is double salt of making of raw material and uses thereof with Azythromycin and Fudosteine; Two of purpose provides the preparation method of this Azythromycin double salt.
One of purpose of the present invention can realize by following technical measures
Azythromycin Fudosteine double salt is that (molecule is C by Azythromycin
38H
72N
2O
12NH
2O, n=0,1,2) (molecular formula is C with Fudosteine
6H
13NO
3S)=1: 2 (mol ratio) [its molecular formula is the Azythromycin Fudosteine mixture of Sheng Chenging: C
38H
72N
2O
122C
6H
13NO
3SnH
2O, n=0,1,2,3,4,5].
Azythromycin Fudosteine double salt of the present invention, two bases in the Azythromycin molecule become the molecules of salt mol ratio with Fu Sitan be 1: 2, and molecular weight ratio is 749: 358, and the dosage during with clinical being used is suitable, and Azythromycin is more stable to acid.
Can be made into the medicine of said various formulations on any pharmaceutics with Azythromycin Fudosteine double salt of the present invention; Described formulation is various oral preparations or intravenous administration formulation.Clinical being mainly used in of Azythromycin double salt of the present invention treated the abundant expectoration type respiratory tract infection.
Azythromycin double salt of the present invention can improve the water-soluble of Azythromycin; Fudosteine has very strong phlegm-dispelling functions and can coordinate with the Azythromycin anti-microbial effect in the Azythromycin double salt of the present invention, Azythromycin is improved in the concentration at bronchitis position, both promoted and improved the curative effect of Azythromycin, can reduce the trouble of taking two kinds of medicines again the abundant expectoration type inflammation.
Two of purpose of the present invention can realize by following technical measures
(molecule is C by Azythromycin
38H
72N
2O
12NH
2O, n=0,1,2) (molecular formula is C with Fudosteine
6H
13NO
3S)=1: 2 (mol ratio) in 1～40 times solvent (mixture of the organic solvent of one or more in water, methyl alcohol, ethanol, acetone, the methylene dichloride), react to raw material and all dissolve, reaction soln concentrating under reduced pressure or spraying drying or lyophilize, [its molecular formula is the Azythromycin Fudosteine mixture that all can be made into: C
38H
72N
2O
122C
6H
13NO
3SnH
2O, n=0,1,2,3,4,5].
With the Azythromycin Fudosteine double salt good stability of method for preparing, pH value of water solution near the pH value of blood of human body, little to the pungency of blood vessel.See following test result for details:
A, stability influence factorial experiments
High temperature test
It is an amount of to get Azythromycin Fudosteine double salt, is paved into thin layer＜5mm, puts in 60 ℃ of constant temperature vacuum drying ovens, respectively at sampling in the 5th, 10 day, investigates outward appearance, related substance and content.
High wet test
It is an amount of to get Azythromycin Fudosteine double salt, is paved into thin layer＜5mm, put in the constant humidity encloses container, relative humidity 90% ± 5% (25 ℃, saturated KNO
3Solution) placed 10 days,, investigate outward appearance, related substance and content respectively at sampling in the 5th, 10 day.
The strong illumination test
It is an amount of to get this product, is paved into thin layer＜5mm, puts under the lamp of YB-2 type clarity detector (light intensity is 4500Lux) and places 10 days, respectively at sampling in the 5th, 10 day, investigates outward appearance, related substance and content.The results are shown in following table
The influence factor test-results
| Condition | Time | Outward appearance | Related substance (%) | Content (%) | Moisture absorption weightening finish (%) |
| Hot and humid high light | 0 5 10 0 5 10 0 5 10 | White crystalline powder white crystalline powder white crystalline powder white crystalline powder white crystalline powder white crystalline powder white crystalline powder white crystalline powder white crystalline powder | 3.65 3.69 3.71 3.65 3.72 3.72 3.65 3.76 3.75 | 96.8 96.7 96.8 96.7 96.8 96.7 96.8 96.7 96.8 | - - - - 0.31 0.31 - - - |
B, Azythromycin Fudosteine double salt are tested the rabbit blood vessel irritation
Getting 8 of rabbit, to be divided into 2 groups at random be test group and control group, and test group is by the rabbit ear edge vein Azythromycin Fudosteine double salt that slowly instils, and once a day, dosage 80mg/kg adds 5% glucose injection 40ml, drips fast 1ml/min, successive administration three days; Control group gives 10% Glacial acetic acid, in the negative contrast of 5% glucose injection of instiling to picking up the ears, and 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 10% Glacial acetic acid group visible vessels contrafluxion, ooze out, thickening.
Below in conjunction with embodiment the present invention is described in further detail, but should understands the non-scope that only limits to these embodiment of scope of the present invention.
Embodiment 1
The 749g Azythromycin is dissolved in 2 liters of methylene dichloride, dichloromethane solution in 5～10 ℃ of Dropwise 35 8g Fudosteine, after adding, stirring at room half an hour, the pressure reducing and steaming methylene dichloride, get Azythromycin Fudosteine double salt crude product, get highly finished product with methylene dichloride/normal hexane recrystallization, 40 ℃ of vacuum-dryings get white crystalline powder.
Embodiment 2
749g Azythromycin, 358g Fudosteine are added in 10 premium on currency, and stirring at room to raw material all dissolves, and pH is 7.3, and spraying drying gets white powder, i.e. Azythromycin Fudosteine double salt.
Embodiment 3
749g Azythromycin, 358g Fudosteine are added in 10 premium on currency, and stirring at room to raw material all dissolves, and pH is 7.4, and Sterile Filtration gets clear liquid, with lyophilize under the clear liquid aseptic condition (30 ℃), gets quantitative salt crystal, i.e. Azythromycin Fudosteine double salt.
Embodiment 4
The transfusion prescription:
Azythromycin Fudosteine double salt 1.11g
Sodium-chlor 4.2g
Water for injection 500ml
Azythromycin Fudosteine double salt adds sodium-chlor, water, needle-use activated carbon mixes after carbon removal, Sterile Filtration (0.22 μ m), and the sterilization embedding can be made into the transfusion of Azythromycin Fudosteine double salt.
Embodiment 5
The transfusion prescription:
Azythromycin Fudosteine double salt 1.11g
Water for injection 10ml
Azythromycin Fudosteine double salt with adding needle-use activated carbon absorption 30 minutes after the water for injection dissolving after carbon removal, Sterile Filtration (0.22 μ m), after testing, be sub-packed in after filtrate is up to specification in the control microbiotic cillin bottle, place in the vacuum freezing drying oven and carried out lyophilize 48 hours, add a cover butyl rubber plug, and roll the envelope aluminium lid promptly get azithromycin injection Fudosteine double salt.
Claims (4)
1. Azythromycin Fudosteine double salt is characterized in that it is that molecular formula is: C by Azythromycin and the Fudosteine be combined into that doubles Azythromycin
38H
72N
2O
122C
6H
13NO
3SnH
2O, n=0,1,2,3,4,5; The Azythromycin molecule is C
38H
72N
2O
12NH
2O, n=0,1,2; The Fudosteine molecular formula is C
6H
13NO
3S.
2. Azythromycin Fudosteine double salt pharmaceutical preparation wherein mainly contains Azythromycin Fudosteine double salt as activeconstituents.
3. the described pharmaceutical preparation of claim 2, its described preparation is oral preparations or intravenous administration formulation.
4. the described Azythromycin Fudosteine of claim 2 double salt pharmaceutical preparation is characterized in that clinical main application is the respiratory tract infection of treatment abundant expectoration type.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510126577 CN1775794A (en) | 2005-11-30 | 2005-11-30 | Azitromycin double salts and their preparing method and use |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510126577 CN1775794A (en) | 2005-11-30 | 2005-11-30 | Azitromycin double salts and their preparing method and use |
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| Publication Number | Publication Date |
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| CN1775794A true CN1775794A (en) | 2006-05-24 |
Family
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| CN 200510126577 Pending CN1775794A (en) | 2005-11-30 | 2005-11-30 | Azitromycin double salts and their preparing method and use |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103768011A (en) * | 2012-10-23 | 2014-05-07 | 天津药物研究院 | Fudosteine injection and preparation method thereof |
-
2005
- 2005-11-30 CN CN 200510126577 patent/CN1775794A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103768011A (en) * | 2012-10-23 | 2014-05-07 | 天津药物研究院 | Fudosteine injection and preparation method thereof |
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Addressee: Su Hongjun Document name: Notification before expiration of term |
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