CN101125871A - Sulfuric acid azithromycin, application thereof, freeze dried of the sulfuric acid azithromycin and preparation method for the freeze dried - Google Patents
Sulfuric acid azithromycin, application thereof, freeze dried of the sulfuric acid azithromycin and preparation method for the freeze dried Download PDFInfo
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- CN101125871A CN101125871A CNA2007100710693A CN200710071069A CN101125871A CN 101125871 A CN101125871 A CN 101125871A CN A2007100710693 A CNA2007100710693 A CN A2007100710693A CN 200710071069 A CN200710071069 A CN 200710071069A CN 101125871 A CN101125871 A CN 101125871A
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Abstract
The invention relates to medicine field, in particular to azithromycin sulfate and application thereof, and a freeze-drying powder injection thereof and a preparation method of the freeze-drying powder injection. The invention discloses a structure formula of the azithromycin sulfate that can be used for preparing drugs used for treating acute pharyngitis, tonsillitis and pneumonia caused by streptococcus pyogenes, urethritis and cervicitis caused by chlamydia as well as acute bronchitis, acute attack of chronic bronchitis and infection of skin tissue caused by sensitive bacteria. The invention further discloses the freeze-drying powder injection of the azithromycin sulfate and the preparation method thereof. The freeze-drying powder injection of the azithromycin sulfate of the invention is characterized in that the injection is easily dissolved by using ordinary menstruum for injection, the preparation used for mainline has anhemolytic characteristic, the stability is good and the chronobioavailability is high.
Description
Technical field
The present invention relates to field of medicaments, relate in particular to the preparation method of Azithromycin Sulfate and its application and lyophilized injectable powder and lyophilized injectable powder.
Background technology
Azythromycin (Azithromycin)
Chemical name: (2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)-13-[(2, the pyrans glycosyl of 6-dideoxy-3-C-methyl-3-O-methyl-a-L-nuclear-) oxygen]-2-ethyl-3,4,10-trihydroxy--3,5,6,8,10,12,14-seven methyl isophthalic acid 1-[[3,4, the pyrans glycosyl of 6-three deoxidations-3-(dimethylamino)-β-D-wood-] oxygen]-1-oxa--6-nitrogen heterocyclic pentadecane-15 ketone
Structural formula is as follows:
Molecular formula: C
38H
72N
2O
12
Molecular weight: 749.0
Azythromycin changes the phthalein process by hindering bacterium, thereby suppresses the synthetic of bacterioprotein.In vitro tests proof Azythromycin comprises Gram-positive aerophil, streptococcus aureus, A group β Hemolytic streptococcus, pneumonia (chain) coccus, alpha-Hemolytic streptococcus (Streptococcus viridans group) and other suis, diphtheria (bar-shaped) bacillus to multiple common pathogen is effective clinically.Azythromycin comprises that for the gram positive bacterium of anti-erythromycin the multiple aureus strains of streptococcus faecium (faecalis) and methicillin-resistant presents cross resistance.
The Zitromax prime system is at first gone on the market in Belgium in 1988 by Yugoslavic Pliva company, goes on the market in Russia and preceding Czechoslovakia in 1992.U.S. Pfizer company has except that Yugoslavia; production and selling license licensed licenser licence outside Eastern Europe and some Asian countries; go on the market in the Britain and the U.S. respectively in 1991 and 1992 with trade(brand)name Zithromax; went on the market in Turkey with trade(brand)name Zitromax in 1993; Pfizer company in November, 1993 respectively with the administrative protection of trade(brand)name Azithromax capsule and dry syrup at China's application medicine, its specification is 0.25g.
Because Azythromycin is almost insoluble in water, so the water soluble preparation of this medicine of exploitation has certain difficulty, using more clinically is the azithromycin oral preparation, but there is the not high weak point of gastrointestinal side effect and bioavailability in oral medication.Owing to injection has advantages such as onset is determined, gastrointestinal side effect is few, at present, more the research focus adopts suitable acid and Azythromycin reaction to generate and makes azithromycin injection after salt solves its solvability.
Summary of the invention
In order to solve above-mentioned technical problem, an object of the present invention is to provide a kind of salify good stability, the bioavailability height is fit to make the Azithromycin Sulfate of lyophilized injectable powder.Azithromycin Sulfate can be used for the treatment of acute pharyngitis, acute tonsillitis, the pneumonia that micrococcus scarlatinae causes, the acute bronchitis, acute episode of chronic bronchitis and the skin histology that have urethritis, cervicitis and sensitive bacterial due to the chlamydozoan to cause infect.
Another object of the present invention provides above-mentioned Azithromycin Sulfate lyophilized injectable powder, and it has good stability, characteristics that bioavailability is high.
The 3rd purpose of the present invention provides the preparation method of above-mentioned Azithromycin Sulfate lyophilized injectable powder.
In order to realize above-mentioned first purpose, the present invention has adopted following technical scheme:
Azithromycin Sulfate, its structural formula is as follows:
The Azithromycin Sulfate pharmacological action:
Azithromycin Sulfate is similar to the Azythromycin effect, changes the peptide process by hindering bacterium, thereby suppresses the synthetic of bacterioprotein.In vitro tests proof Azythromycin comprises Gram-positive aerophil, streptococcus aureus, A group β Hemolytic streptococcus, pneumonia (chain) coccus, alpha-Hemolytic streptococcus (Streptococcus viridans group) and other suis, diphtheria (bar-shaped) bacillus to multiple common pathogen is effective clinically.Azythromycin comprises that for the gram positive bacterium of anti-erythromycin the multiple aureus strains of streptococcus faecium (faecalis) and methicillin-resistant presents cross resistance.
Gram-negative aerobic bacteria: influenza (bloodthirsty) bacillus, parainfluenza (bloodthirsty) bacillus, catarrh (not drawing) bacterium, acinetobacter, yersinia's genus, legionella pneumophilia, bordetella pertussis, parapertussis bacillus, Shigella, Pasteurella, vibrio cholerae, secondary Bacillus hemolyticus, class will Hayes pyrrole Plesiomonas.
Anerobe: bacteroides fragilis, Bacteroides, aerogenesis capsule bacillus, Peptostreptococcus, seat sore propionibacterium etc.
The sexually transmitted disease (STD) microorganism: Azythromycin has activity " chlamydia trachomatis, Tyreponema pallidum, gonococcus, shape gram (bloodthirsty) bacillus for following sexually transmitted disease (STD) microorganism.
Other microorganism: comprise special southern borrelia vincentii (Lyme pathogenic agent), mycoplasma pneumoniae, mycoplasma hominis, Ureaplasma urealyticum, Pneumocystis carinii, mycobacterium avium genus, Campylobacter, monocytosis Li Side bacillus.
Following Gram-negative bacteria is normally drug-fast: proteus, Serratia, Morganella, green pus (false unit cell) bacillus.
Therefore, above-mentioned Azithromycin Sulfate is used to prepare acute pharyngitis, acute tonsillitis, the pneumonia that treatment is caused by micrococcus scarlatinae; The application of the medicine that infects by the urethritis due to the chlamydozoan, cervicitis and the acute bronchitis that causes by sensitive bacterial, acute episode of chronic bronchitis and skin histology.Described medicine is lyophilized injectable powder or oral preparations.
The preparation method of above-mentioned Azithromycin Sulfate at first is dissolved in organic solvent with Azythromycin, and controlled temperature-10 ℃～10 ℃ adds hydrosulfate, and it is fully reacted, and obtains Azithromycin Sulfate, and its reaction equation is as follows: C
38H
72N
2O
12+ 2AHSO
4=C
38H
72N
2O
12H
2SO
4+ A
2SO
4, wherein, C
38H
72N
2O
12Be Azythromycin, A be can with the salifiable positively charged ion of bisulfate ion.As preferably, above-mentioned A is Na ion or K ion.As most preferably, above-mentioned A is the Na ion.As preferably, after above-mentioned abundant reaction, add gac again and vitriol decolours, dewaters, filter crystallization.Above-mentioned crystallization can adopt low polarity or nonpolar organic solvent crystallization.Above-mentioned low polar organic solvent or non-polar organic solvent can be selected from anhydrous diethyl ether, sherwood oil, methane or the mixed solution between them.As preferably,, dry then to constant weight and obtain Azithromycin Sulfate the Azithromycin Sulfate organic solvent washing that crystallization obtains.As preferably, the above-mentioned Azythromycin and the charging capacity of hydrosulfate are 1: 1～20 in molar ratio.As preferred again, the charging capacity of Azythromycin and hydrosulfate is 1: 2～3 in molar ratio.As preferably, above-mentioned organic solvent is dehydrated alcohol, anhydrous diethyl ether, sherwood oil, methane or the mixed solution between them.
In order to realize second above-mentioned purpose, the present invention has adopted following technical scheme:
The Azithromycin Sulfate lyophilized injectable powder, Azithromycin Sulfate is fully dissolved with water for injection, regulate PH, add gac and stirring, filtration, packing, carry out lyophilize then and make, every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.1～1g after the packing.
As preferably, every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.25～0.5g after the packing.
As most preferably, every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.25g or 0.5g after the packing.
In order to realize the 3rd purpose, the preparation method of Azithromycin Sulfate preparation lyophilized injectable powder of the present invention is at first fully dissolved Azithromycin Sulfate with water for injection, regulates PH, adds gac and stirring, filtration, packing, carries out lyophilize then; Described cryodesiccated step is as follows:
1. pre-freeze 2～10 hours behind the inlet, products temperature is to-50 ℃～-20 ℃;
2. open the vacuum pump goods then and begin distillation, the sublimation stage products temperature is controlled at-25 ℃～-15 ℃;
3. after treating that waterline on earth, products temperature slowly is warming up to 30～36 ℃, is incubated 2～8 hours;
4. tamponade outlet under the vacuum then.
As preferably, above-mentioned step shelf temperature 1. is-60 ℃～-40 ℃.
As preferably, above-mentioned step shelf temperature 3. is 37～42 ℃.
The present invention is owing to adopted above technical scheme, and Azithromycin Sulfate is easily molten in water, and every ml water dissolvable Azithromycin Sulfate is greater than 285mg.The invention solves the problem of Azythromycin poorly water-soluble in the prior art, adopt freeze drying technology, it is good self to be shaped after the Azithromycin Sulfate freeze-drying, do not need to add other binder, solubleness, stability and the bioavailability of Azythromycin have been improved, in the acute infection treatment, bring into play important effect, guaranteed the security and the accessibility of medication.
Azithromycin Sulfate lyophilized injectable powder of the present invention has following characteristics: a, is easy to use general solvent for injection dissolving (for example G/W, physiological saline, water for injection and other known aqueous diluent); B, be used for intravenous preparation and should do not have hemolytic; C, good stability, the characteristics that bioavailability is high.Azithromycin Sulfate lyophilized injectable powder by preparation method's gained of the present invention has outward appearance preferably, and weight loss on drying is less.
Embodiment
Embodiment 1
Take by weighing the 25kg dehydrated alcohol, take by weighing the 12.5kg Azythromycin, be added to 100L and become salt cellar, stirring makes molten entirely, below 5 ℃, slowly add anhydrous slufuric acid hydrogen sodium 4.05kg reaction 90 minutes, add the 0.25kg gac, the decolouring of 2kg sodium sulfate, dehydration 30 minutes, blowing takes off the charcoal press filtration, former through desuperheating through the smart filter of 0.8um, 0.22um, as to take off charcoal, smart filter, Sterile Filtration anhydrous diethyl ether 85.8kg crystallization jar to being equipped with, stirring and crystallizing 30 minutes, suction filtration, wash with anhydrous diethyl ether, drain, change double cone dryer over to, oven dry about 60 ℃, packing.The weight yield of elaboration is 97.8%.
Embodiment 2.
Take by weighing the 250g dehydrated alcohol, take by weighing the 125g Azythromycin, be added in the 1000ml there-necked flask, stirring makes molten entirely, below 5 ℃, slowly adds anhydrous slufuric acid hydrogen sodium 400g reaction 90 minutes, add the 25g gac, the decolouring of 200g sodium sulfate, dehydration 30 minutes are through the smart filter of 0.8um, 0.22um, pour in the there-necked flask that anhydrous diethyl ether 858g is housed stirring and crystallizing 30 minutes, suction filtration into, wash with anhydrous diethyl ether, drain, change vacuum drying oven over to, oven dry about 60 ℃, packing.The weight yield of elaboration is 101.0%.
Embodiment 3.
Take by weighing the 250g dehydrated alcohol, take by weighing the 125g Azythromycin, be added in the 1000ml there-necked flask, stirring makes molten entirely, below 5 ℃, slowly adds anhydrous slufuric acid hydrogen sodium 300g reaction 90 minutes, add the 25g gac, the decolouring of 200g sodium sulfate, dehydration 30 minutes are through the smart filter of 0.8um, 0.22um, pour in the there-necked flask that anhydrous diethyl ether 858g is housed stirring and crystallizing 30 minutes, suction filtration into, wash with anhydrous diethyl ether, drain, change vacuum drying oven over to, oven dry about 60 ℃, packing.The weight yield of elaboration is 98.2%.
Embodiment 4.
Take by weighing Azithromycin Sulfate by prescription, add water and make Azithromycin Sulfate solution, transfer pH value of solution to 6.0～7.0, add water to 1000ml with 0.1mol/L hydrochloric acid and sodium hydroxide solution; Add gac 3g and stir 30min, filtration sterilization is distributed into every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.25g.
Then, prepare the Azithromycin Sulfate lyophilized injectable powder according to following freezing step lyophilize:
1. pre-freeze 4 hours behind the inlet, products temperature is to-30 ℃, and shelf temperature is-50 ℃.
2. open the vacuum pump goods then and begin distillation, the sublimation stage products temperature is controlled at-25 ℃～-15 ℃;
3. after treating that waterline on earth, adjusting shelf temperature is 37～42 ℃, and products temperature slowly is warming up to 30～36 ℃, is incubated 2～4 hours, gets white freeze-drying block;
4. tamponade outlet under the vacuum then.
Embodiment 5.
Take by weighing Azithromycin Sulfate by prescription, add water and make Azithromycin Sulfate solution, transfer pH value of solution to 6.0-7.0, add water to 1000ml with 0.1mol/L hydrochloric acid and sodium hydroxide solution; Add gac 9.31g and stir 30min, filtration sterilization is distributed into every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.5g.
Then, prepare the Azithromycin Sulfate lyophilized injectable powder according to following freezing step lyophilize:
1. pre-freeze 4～10 hours behind the inlet, products temperature is to-40 ℃, and shelf temperature is-50 ℃.
2. open the vacuum pump goods then and begin distillation, the sublimation stage products temperature is controlled at-25 ℃～-15 ℃;
3. after treating that waterline on earth, adjusting shelf temperature is 37～42 ℃, and products temperature slowly is warming up to 30～36 ℃, is incubated 4～8 hours, gets white freeze-drying block;
4. tamponade outlet under the vacuum then.
Test example 1.
Infrared absorption spectrum (IR) is measured Azithromycin Sulfate
1, instrument model and condition determination: instrument Magna-IR 750, Nicolet U.S.A.Sweep limit 4000～5000cm
-1
2, instrumental correction and calibrating are carried out instrumental correction and calibrating by two appendix IVC of Chinese Pharmacopoeia nineteen ninety-five version infrared spectrophotometry.
3, specimen preparation can be compiled " medicine infrared spectra collection " with reference to Ministry of Health's pharmacopeia, gets Azithromycin Sulfate and Azythromycin 2mg, Potassium Bromide 200mg, and in the presence of Vanadium Pentoxide in FLAKES, drying under reduced pressure 12 hours mixes sample and Potassium Bromide, grinds evenly compressing tablet.
4, determination data.
Azithromycin Sulfate infrared absorption spectrum data
| Absorption peak (cm -1) | Oscillatory type | Group | Absorption peak strength |
| 3408 2970-2730 1714 1464-1300 1383 1200-1000 | γO-H γC-H γC＝O γC-H γCH 3 γC-O-C | -OH -CH 3 -C＝0 -CH 2- N-CH 3 C-O-C | s s，m s s s s |
Azythromycin infrared absorption spectrum data
| Absorption peak (cm -1) | Oscillatory type | Group | Absorption peak strength |
| 3559，3495 2970-2730 1727 1459-1300 1379 1200-1000 | γO-H γC-H γC＝O γC-H γCH 3 γC-O-C | -OH -CH 3 -C＝0 -CH 2- N-CH 3 C-O-C | s s，m s s s s |
5, parsing and the infrared absorption pattern of Azithromycin Sulfate and Azythromycin reference substance is basic identical as a result, Azithromycin Sulfate is at 3600～3400cm
-1, 2970～2730cm
-1, 1700～1730cm
-1, 1460～1300cm
-1, 1383cm
-1, 1200～I000cm
-1There is the charateristic avsorption band of Azythromycin at the place, shows that Azithromycin Sulfate and Azythromycin have identical basic structure.
Test example 2.
The stability of Azithromycin Sulfate.
The Azithromycin Sulfate that the foregoing description 1～3 is made carries out preliminary study on the stability (3600Lux illumination placement 10 days down, high temperature were placed 10 days down for 60 ℃), and in the tenth day sampling and measuring, the result was as table 1-1～table 1-3.
Table 1-1: embodiment 1 study on the stability result
| Fate | Proterties | pH | Content (%) | Degraded product |
| 0 | White powder | 6.31 | 100.32 | ＜2％ |
| 3600Lux illumination in 10 days | White powder | 6.15 | 100.00 | ＜2％ |
| High temperature was 60 ℃ in 10 days | White powder | 6.68 | 101.19 | ＜2％ |
Table 1-2: embodiment 2 study on the stability results
| Fate | Proterties | pH | Content (%) | Degraded product |
| 0 | White powder | 6.25 | 100.14 | ＜2％ |
| 3600Lux illumination in 10 days | White powder | 6.10 | 99.8 | ＜2％ |
| High temperature was 60 ℃ in 10 days | White powder | 6.53 | 101.00 | ＜2％ |
Table 1-3: embodiment 3 study on the stability results
| Fate | Proterties | pH | Content (%) | Degraded product |
| 0 | White powder | 6.25 | 100.10 | ＜2％ |
| 3600Lux illumination in 10 days | White powder | 6.10 | 99.7 | ＜2％ |
| High temperature was 60 ℃ in 10 days | White powder | 6.53 | 100.90 | ＜2％ |
Test example 3.
Azithromycin Sulfate pharmacology, toxicity part, pharmacodynamics
Acute toxicity.Azithromycin Sulfate mouse peritoneal injection LD
50Be 1203.1mg/kg, the 95% credible 1106.1～1308.7mg/kg that is limited to; The tail vein is annotated LD
50Value is for 461.7mg/kg, the 95% credible 403.3～528.5mg/kg that is limited to, and mouse writhing, tic, convulsions death during poisoning, death concentrated on after the administration in 2 hours, and the tangible pathological change of main organs is not all found in the dead animal postmortem.
Pungency, haemolysis, sensitivity test.This product does not have tangible blood vessel irritation.The hemolytic experiment result shows that Azithromycin Sulfate was through 1 hour, and after 37 ℃ of insulations, haemolysis, part haemolysis or agglutination reaction appear in each Guan Junwei before the 5th pipe, show that Azithromycin Sulfate does not have tangible haemolysis or agglutination phenomenon, but injection for intravenous is used.Sensitivity test is the result show, Azithromycin Sulfate does not have tangible sensitization.
The test of mouse endogenous protective.With the Azythromycin is contrast, has measured the antibacterial activity in vivo of Azithromycin Sulfate.Experimental result shows that oral Azithromycin Sulfate has endogenous protective effect preferably to streptococcus aureus and pneumococcal infection mouse, its ED
50Be respectively 47.28mg/kg and 17.28mg/kg, (53.67mg/kg, 19.65mg/kg) lower slightly, possibility is good because of the solubleness of Azithromycin Sulfate, the bioavailability height than Azythromycin.The tail vein injection Azithromycin Sulfate has endogenous protective effect preferably to streptococcus aureus and pneumococcal infection mouse, its ED
50Be respectively 36.49mg/kg and 11.27mg/kg, similar to Azythromycin.
The antibacterial activity in vitro experiment.With the Azythromycin is contrast, has measured the antibacterial activity in vitro of Azithromycin Sulfate.Experimental result shows that the MBC of Azithromycin Sulfate and Azythromycin, MIC and ratio thereof are close, does not have obviously difference between the two; Streptococcus aureus, faecalis, micrococcus scarlatinae different vaccination amount have certain influence to the bacteriostatic action (MIC) of Azithromycin Sulfate, along with the increase MIC of inoculum size also increases, but all in sensitive range; Different pH are to the influence of the anti-microbial effect of Azithromycin Sulfate, the anti-microbial effect of Azithromycin Sulfate under acidic conditions a little less than, anti-microbial effect is strong in pH7～9 scopes, ED
50Less than 0.032mg/L.(356 strain) has stronger anti-microbial activity to Azithromycin Sulfate to clinical isolating common pathogen, and be suitable with the anti-microbial effect of Azythromycin.
The clinical study part is responsible for by Yi Ji mountain hospital of Wannan Medical College, simultaneously carry out clinical verification in Tongling City Peple's Hospital, No.1 Reople's Hospital, Hefei City and Yi Ji mountain hospital, adopt random pair, multicenter, parallel check experiment design synchronously, clinical efficacy and the untoward reaction of research evaluation injection Azithromycin Sulfate in treatment respiratory tract, skin soft-tissue infection.Checking is the result show: injection Azithromycin Sulfate group 60 examples, and clinical effective rate is 86.67%, and bacteria clearance is 98.11%, and adverse reaction rate is 6.67%; Control group lincomycin inj 60 examples, clinical effective rate are 81.67%, and bacteria clearance is 98.00%, and adverse reaction rate is 6.67%, and credit is analysed by statistics, both no significant differences.
Test example 4.
The stability of the Azithromycin Sulfate lyophilized injectable powder of embodiment 4 preparations.
One, factor is investigated
1, illumination.Get the Azithromycin Sulfate lyophilized injectable powder, put under the 3000LX illumination condition, outward appearance, color and luster, content %, potential of hydrogen, degraded product, clarity, aseptic (table 2-1) are investigated in the sampling respectively in the 1st, 3,5,10 day.
Table 2-1 illumination is to the influence of Azithromycin Sulfate lyophilized injectable powder quality
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 5 10 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 100.88％ 100.49％ 99.20％ 98.03％ | 7.35 7.18 7.43 7.22 6.90 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.3％ 2.3％ 2.2％ |
2, high temperature.Get the Azithromycin Sulfate lyophilized injectable powder, place in 40,60,80 ℃ the encloses container,, investigate outward appearance, color and luster, content %, potential of hydrogen, related substance, clarity, aseptic (table 2-2 is to table 2-4) respectively at sampling respectively in the 1st, 3,5,10 day.
Table 2-2 high temperature (40 ℃) is to the influence of Azithromycin Sulfate lyophilized injectable powder quality
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 5 10 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 99.88％ 100.16％ 100.22％ 99.17％ | 7.35 7.10 7.38 7.16 7.02 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.3％ 2.3％ 2.4％ |
Table 2-3 high temperature (60 ℃) is to the influence of Azithromycin Sulfate lyophilized injectable powder quality
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 5 10 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 99.25％ 99.16％ 101.68％ 97.76％ | 7.35 7.26 7.40 7.21 6.93 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.3％ 2.3％ 2.1％ |
Table 2-4 high temperature (80 ℃) is to the influence of Azithromycin Sulfate lyophilized injectable powder quality
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 5 10 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 100.96％ 98.79％ 97.52％ 89.25％ | 7.35 7.30 7.43 6.92 6.58 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.3％ 2.3％ 2.2％ |
3, air at room temperature.Get the Azithromycin Sulfate lyophilized injectable powder, put in room temperature, the air and place, investigated outward appearance, color and luster, content %, potential of hydrogen, degraded product, clarity, weight loss on drying (table 2-5) in the 0th, 1,3,5,10 day respectively.
In the table 2-5 air at room temperature to the influence of Azithromycin Sulfate lyophilized injectable powder quality
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 5 10 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 98.38％ 100.12％ 99.32％ 98.92％ | 7.35 7.28 7.41 7.15 7.24 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.3％ 2.3％ 2.1％ |
Factor investigation Azithromycin Sulfate lyophilized injectable powder as a result is stable to light, stable in air at room temperature, (40 ℃, 60 ℃) are stable under hot conditions, 80 ℃ of little Huangs of appearance color of placing the 5th day, the tenth day sample, related substance increases, content slightly descends, and illustrates that high temperature is the influence factor of this product stability.
Two, accelerated test
Adopt simulation listing packing, carry out accelerated test sampling and measuring in March under 40 ℃, RH75% condition, experimental result shows, the sample in accelerated tests March and the 0th month is respectively at the 0th, 1,2, outward appearance, content, pH, degraded product, clarity, aspect such as aseptic do not have noticeable change (table 2-6).
Table 2-6 accelerated test data
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 2 3 | White loose piece white loose piece white loose piece white loose piece | 99.30％ 98.28％ 100.66％ 97.61％ | 7.35 7.22 7.07 6.92 | Qualified | Qualified | ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.3％ 2.1％ 2.5％ |
Three, the room temperature investigation that keeps sample.Simulation listing packing (2ml cillin bottle packing, rubber plug, aluminium lid sealing) is placed at ambient temperature, respectively at the 0th, 1, and 3,6,12,24 months sampling and measuring.Experimental result shows, room temperature keeps sample the 1st, 3,6, the sample in December and the 0th month, do not have the long-term room temperature of noticeable change (table 2-7) the examination well afoot that keeps sample at aspects such as outward appearance, content, pH, degraded products.
The table 2-7 room temperature examination data that keep sample
| Time (my god) | The investigation project | ||||||
| Appearance luster | Content % | PH | Clarity | Aseptic | Degraded product | Weight loss on drying | |
| 0 1 3 6 12 | White loose piece white loose piece white loose piece white loose piece white loose piece | 99.30％ 101.68％ 98.24％ 100.64％ 99.37％ | 7.35 7.21 7.43 7.08 7.23 | Qualified qualified | Qualified qualified | ＜2％ ＜2％ ＜2％ ＜2％ ＜2％ | 2.3％ 2.2％ 2.4％ 2.3％ 2.5％ |
Conclusion:, carried out influence factor test, accelerated test and the room temperature setting-out of Azithromycin Sulfate lyophilized injectable powder and investigated according to the relevant regulations of " provisions for new drugs approval ".Influence factor test Azithromycin Sulfate lyophilized injectable powder is stable to light, stable in air at room temperature, (40 ℃, 60 ℃, 80 ℃) are basicly stable under hot conditions, but the little Huang of appearance color of 80 ℃ the 5th day, the tenth day sample, degraded product increases, content descends, and illustrates that high temperature is the influence factor of this product stability.Accelerated tests result shows, is 75% in relative humidity, places 3 months under 40 ℃ of conditions of temperature, and Azithromycin Sulfate lyophilized injectable powder physico-chemical property is stable, and its validity period can be fixed tentatively 2 years.Room temperature keeps sample and investigates the room temperature carried out 12 months investigations that keep sample, and assay shows that sample is stablized at ambient temperature.
Test example 5.
The checking of the Azithromycin Sulfate lyophilized injectable powder pharmaceutics index of embodiment 4.
1, measure its clarity, weight loss on drying, the result meets 1995 editions two general requirements to sterile powder for injection of Chinese Pharmacopoeia.
2, irritant experiment, result of study show that this product muscle irritation is strong; Family's rabbit ear vein instils, and once a day, continuous seven days, situations such as vessel wall loss did not have significant difference with 5% glucose injection that instils with method.
3, hemolytic experiment, result of study show that this product do not have tangible hemolytic action, suitable intravenously administrable.Above test-results explanation, this prescription basic feasible solution, processing condition can reach the general requirement of Chinese Pharmacopoeia to sterile powder for injection.
4, the stability of Azithromycin Sulfate lyophilized injectable powder in transfusion.Get the Azithromycin Sulfate lyophilized injectable powder, add the dissolving of 5% glucose injection, make about 4mg/ml solution and be divided into two parts, respectively at room temperature, 4 ℃ of placements of refrigerator, respectively at 0,1,2,3,4, the 6h sampling, adopt the HPLC method to measure the variation of the related substance of different time, and relatively (table 3-1).
Stability in table 3-1 Azithromycin Sulfate lyophilized injectable powder 5% glucose injection
| The placement condition | Related substance (%) | |||||
| 0 | 1 | 2 | 3 | 4 | 6(h) | |
| 4 ℃ of room temperatures | 2.11 2.11 | 2.75 2.51 | 2.06 2.75 | 2.43 2.61 | 2.11 2.26 | 2.34 2.92 |
The result shows that this product was placed 6 hours under room temperature or 4 ℃ of conditions in 5% glucose injection, relatively, related substance does not all have obvious increase with zero the time, show 4 hours with interior use, this product is solution-stabilized.
Claims (10)
1. Azithromycin Sulfate, its structural formula is as follows:
2. Azithromycin Sulfate lyophilized injectable powder according to claim 1, it is characterized in that Azithromycin Sulfate is fully dissolved with water for injection, regulate PH, add gac and stirring, filtration, packing, carry out lyophilize then and make, every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.1～1g after the packing.
3. Azithromycin Sulfate lyophilized injectable powder according to claim 2 is characterized in that every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.25～0.5g after the packing.
4. Azithromycin Sulfate lyophilized injectable powder according to claim 2 is characterized in that every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.25g after the packing.
5. Azithromycin Sulfate lyophilized injectable powder according to claim 2 is characterized in that every Azithromycin Sulfate amount that contains with respect to Azythromycin 0.5g after the packing.
6. the preparation method of Azithromycin Sulfate preparation lyophilized injectable powder according to claim 2 is characterized in that comprising Azithromycin Sulfate is fully dissolved with water for injection, regulates PH, adds gac and stirring, filtration, packing, carries out lyophilize then; Described cryodesiccated step is as follows:
1. pre-freeze 2～10 hours behind the inlet, products temperature is to-50 ℃～-20 ℃;
2. open the vacuum pump goods then and begin distillation, the sublimation stage products temperature is controlled at-25 ℃～-15 ℃;
3. after treating that waterline on earth, products temperature slowly is warming up to 30～36 ℃, is incubated 2～8 hours;
4. tamponade outlet under the vacuum then.
7. the preparation method of Azithromycin Sulfate preparation lyophilized injectable powder according to claim 6 is characterized in that step shelf temperature 1. is-60 ℃～-40 ℃.
8. the preparation method of Azithromycin Sulfate preparation lyophilized injectable powder according to claim 6 is characterized in that step shelf temperature 3. is 37～42 ℃.
9. Azithromycin Sulfate is used to prepare acute pharyngitis, acute tonsillitis, the pneumonia that treatment is caused by micrococcus scarlatinae; By the application in the medicine of the urethritis due to the chlamydozoan, cervicitis and the acute bronchitis that causes by sensitive bacterial, acute episode of chronic bronchitis and skin histology infection.
10. according to the described application of claim 9, it is characterized in that medicine is lyophilized injectable powder or oral preparations.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101856335A (en) * | 2010-07-08 | 2010-10-13 | 山东罗欣药业股份有限公司 | Azithromycin composite freeze-dried powder for injection |
| CN101940555B (en) * | 2009-07-10 | 2012-02-22 | 华北制药股份有限公司 | Method for preparing azithromycin freeze-dried powder injection for injection |
| CN101433519B (en) * | 2008-12-19 | 2013-01-23 | 沈阳药科大学 | Azithromycin eye drops and preparation method thereof |
| CN106188218A (en) * | 2016-07-14 | 2016-12-07 | 江苏诺泰生物制药股份有限公司 | A kind of method improving polypeptide raw material drug stabilisation |
-
2007
- 2007-09-03 CN CNB2007100710693A patent/CN100569789C/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101433519B (en) * | 2008-12-19 | 2013-01-23 | 沈阳药科大学 | Azithromycin eye drops and preparation method thereof |
| CN101940555B (en) * | 2009-07-10 | 2012-02-22 | 华北制药股份有限公司 | Method for preparing azithromycin freeze-dried powder injection for injection |
| CN101856335A (en) * | 2010-07-08 | 2010-10-13 | 山东罗欣药业股份有限公司 | Azithromycin composite freeze-dried powder for injection |
| CN106188218A (en) * | 2016-07-14 | 2016-12-07 | 江苏诺泰生物制药股份有限公司 | A kind of method improving polypeptide raw material drug stabilisation |
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Denomination of invention: Sulfuric acid azithromycin, application thereof, freeze dried of the sulfuric acid azithromycin and preparation method for the freeze dried Effective date of registration: 20150128 Granted publication date: 20091216 Pledgee: Bank of Communications Ltd Jinhua branch Pledgor: Zhejiang Jiafeng Pharmaceutical Co., Ltd. Registration number: 2015990000078 |
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