CN1820760A - Method for preparing kitasamycin tartrate injection - Google Patents
Method for preparing kitasamycin tartrate injection Download PDFInfo
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- CN1820760A CN1820760A CN 200610054867 CN200610054867A CN1820760A CN 1820760 A CN1820760 A CN 1820760A CN 200610054867 CN200610054867 CN 200610054867 CN 200610054867 A CN200610054867 A CN 200610054867A CN 1820760 A CN1820760 A CN 1820760A
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- kitasamycin
- tartrate
- kitasamycin tartrate
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Abstract
The present invention solves the difficult problem of microlide medicine kitasamycin tartrate in unstable structure, and provides preparation process of kitasamycin tartrate injection. The kitasamycin tartrate injection consists of kitasamycin tartrate or kitasamycin as main medicine component, solvent for injection, pH stabilizer, chemical structure stabilizer, metal ion complexing agent, isosmotic regulator and other auxiliary components. The kitasamycin tartrate injection has high stability, high safety and effectiveness, simplified clinical use and other advantages.
Description
Technical field
The present invention relates to the preparation method of Macrocyclolactone lactone kind medicine kitasamycin tartrate injection.
Background technology
Kitasamycin (kitasamycin) is the Macrolide of first generation Macrolide-16 yuan ring.Mechanism of action is similar to erythromycin with antimicrobial spectrum, but gram positive bacteria is had stronger antibacterial action, and staphylococcus, Hemolytic streptococcus, streptococcus pneumoniae, diphtheria corynebacterium, clostridium tetani, anthrax bacillus etc. are all had effect.Gram negative bacterias such as gonococcus, bordetella pertussis also there is antibacterial action.The staphylococcus aureus of the anti-erythromycin of part also has quite active still to the kitasamycin sensitivity to leptospira, rickettsia, mycoplasma etc.
At present, both at home and abroad the kitasamycin of the drug administration by injection approach of listing is Kitasamycin tartrate powder pin, and its pH value is 3.0～5.0, Kitasamycin tartrate in fact itself by some mixture that row kitasamycin A1～the A9 tartrate is formed.Because first generation Macrolide lactone structure instability, acid and alkali-resistance is not easy to decompose in aqueous solution, especially needs high temperature sterilize in preparation injection process, and macrolide structure is easy to be hydrolyzed destruction.Through our test, to sterilize 30 minutes for 100 ℃, pH value equals at 4.0 o'clock, and the Kitasamycin tartrate activity is reduced to 68%; PH value equals at 9.0 o'clock, and activity is reduced to 74%, all can't reach medicinal requirements.
The medicine of drug administration by injection approach divides solution-type and powder pin type, and every structural unstable medicine just must be made powder injection formulation, so that keep medicines structure stable, meets medicinal requirement.Injectable powder and solution dosage relatively have some shortcomings, for example; (1) complex process, the chance of microbiological contamination is big; Need prepare when (2) using, inconvenience, and be difficult to find the problems such as clarity of solution.
Therefore, if can solve kitasamycin structural instability shortcoming, provide a kind of fast, safety, effectively, Kitasamycin tartrate liquid injection solution more easily, will give the patient and socially bring huge Gospel.The kitasamycin injection has solved first generation Macrocyclolactone lactone kind medicine unsettled shortcoming in high temperature sterilize and long-term storage process of generally acknowledging both at home and abroad, indicate that this medicine has had breakthrough progress aspect preparation stability, domestic and foreign literature is not seen the report that this technology is arranged.
Summary of the invention
The objective of the invention is to have solved the structural unstable difficult problem of Macrocyclolactone lactone kind medicine Kitasamycin tartrate, the method of the stable kitasamycin tartrate injection of preparation quality is provided, has made that the kitasamycin tartrate injection energy is safe, effective, it is clinical to be conveniently used in.
Another object of the present invention is for the kitasamycin tartrate injection dosage form is provided clinically, and this just has remarkable advantages than powder needle set the injection dosage form on dosage form, and technology simply, quality is more controlled, easy to use safer.
Solved the structural unstable difficult problem of Macrocyclolactone lactone kind medicine Kitasamycin tartrate, realized by non-water-soluble matchmaker, strict pH value and stabilizing agent tween 80 three approach or combination in twos.The research the whole bag of tricks is to the influence of kitasamycin stability, because kitasamycin itself is a multicomponent mixture, so experimental study adopts antibiotic-microbial assays (2005 editions appendix XIA of Chinese Pharmacopoeia) to investigate the activity of kitasamycin injection.
Kitasamycin injection of the present invention uses water for injection and nonaqueous solvent mixture as the injection solvent, and non-water-soluble matchmaker can singly use, mix usefulness or constitute certain ratio with water for injection.Wherein non-water-soluble matchmaker's ratio is 0～100%, preferred 50～100%.Non-water-soluble matchmaker comprises: ethanol, propylene glycol, glycerol, Polyethylene Glycol, polyoxyethylene castor oil, the Semen sojae atricolor wet goods that can use for the human injection.
Consumption according to the recipe quantity screening injection solvent described in the table keeps other prescription condition constant, and as PH=7.0, the stabilizing agent tween 80 is 1%, and complexing of metal ion agent etc. are constant, according to the preparation method preparation of sterile preparation, and 100 ℃ of sterilization 30min.Adopt antibiotic-microbial assays to measure kitasamycin content, the character of observing medicine simultaneously.
The screening of injection solvent
| Prescription | Water for injection | Ethanol | Propylene glycol | Glycerol | Polyethylene Glycol | Content |
| 1 | 100％ | 99.2％ | ||||
| 2 | 10％ | 90％ | 99.4％ | |||
| 3 | 30％ | 70％ | 98.5％ | |||
| 4 | 50％ | 50％ | 94.6％ | |||
| 5 | 60％ | 40％ | 90.1％ | |||
| 6 | 50％ | 50％ | 99.4％ | |||
| 7 | 50％ | 50％ | 98.9％ | |||
| 8 | 50％ | 50％ | 98.8％ |
See that by injection solvent The selection result to adopt non-water-soluble matchmaker's amount many more, kitasamycin content is high more, but considers that the viscosity of some solvent such as propylene glycol, glycerol is bigger, adopts blended non-water-soluble matchmaker or adds a spot of water and mix proper.
The pH value of the strict control of kitasamycin injection of the present invention solution, preferred 6.5～7.5.Adopt and the same screening technique of injection solvent, the screening pH value, when PH less than 6.5 the time, reduce rapidly through the content of sterilization back kitasamycin injection, therefore, 6.5～7.5th, only pH value.
The selection of stabilizers of kitasamycin injection of the present invention, we attempt having screened multiple stabilizing agents such as tween 80, organic acid, antioxidant, the result finds that unexpectedly tween 80 has extraordinary Stabilization, particularly when being prepared into the high capacity kitasamycin tartrate injection, show extraordinary Stabilization, its consumption is in 0.1～5.0% consumption the best.It has, and obvious Stabilization may to form micelle in solution relevant with tween.
Other added substance is with reference to the material commonly used of general injection, as isoosmotic adjusting agent sodium chloride, glucose, mannitol or sorbitol.The complexing of metal ion agent has EDTA-CaNa or EDTA-2Na etc., can further guarantee the stability of kitasamycin.
It below is the stability test result of our kitasamycin tartrate injection two batch samples that prepare: temperatures involved factorial experiments: get this product, the simulation commercially available back, in 60 ℃ ± 2 ℃ of temperature, the calorstat condition under placed 10 days, respectively at sampling in 1,3,5,10 day once, measure by the high spot reviews project, the results are shown in following table:
The accelerated test measurement result
| Lot number | Time | Character | PH value | Clarity | Endotoxin | Aseptic | Content % |
| Injection with small volume | 0 day 1 day 3 days 5 days 10 days | The yellowish clear liquid of the yellowish clear liquid of the yellowish clear liquid of the yellowish clear liquid of yellowish clear liquid | 7.25 7.28 7.20 7.18 7.10 | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification | 99.5 99.3 99.0 99.0 98.6 |
| High-capacity injection | 0 day 1 day 2 days 3 days 10 days | Colourless clear liquid colourless clear liquid colourless clear liquid colourless clear liquid colourless clear liquid | 7.36 7.35 7.31 7.25 7.20 | Up to specification up to specification | Up to specification up to specification | Up to specification up to specification | 96.8 96.6 96.2 95.4 95.0 |
The result shows, places 10 days under 60 ℃ ± 2 ℃ calorstat conditions of temperature, and this product quality is basicly stable.
The specific embodiment
Example 1: the preparation of low capacity kitasamycin tartrate injection
Prescription:
Kitasamycin tartrate 200g
Ethanol 500ml
Propylene glycol 500ml
The PH regulator is an amount of
Amount to 1000ml
Be divided into and dress up 1000 bottles
In 10000 grades of clean areas, measure Kitasamycin tartrate, ethanol and mixed with propylene glycol dissolving according to prescription.The PH regulator is transferred PH to 6.5-7.5, press amount of liquid 0.03% and add activated carbon, room temperature decoloured 30 minutes down, sent into behind the coarse filtration activated carbon in 100 grades of clean areas, through the microporous filter membrane fine straining of 0.22um, getting fine straining liquid inspects by ready samples in right amount, calculate loading amount after the assay was approved, packing, sterilization, lamp inspection, packing and the aseptic parenteral solution made makes finished product.
Example 2: the preparation of high capacity kitasamycin tartrate injection
Prescription:
Kitasamycin tartrate 200g
Ethanol 1000ml
Propylene glycol 1000ml
Polysorbas20 0g
The PH regulator is an amount of
Water for injection adds to 100000ml
Be divided into and dress up 1000 bottles
In 10000 grades of clean areas, measure Kitasamycin tartrate, ethanol, propylene glycol and 30% water for injection mixed dissolution according to prescription.The PH regulator is transferred PH to 6.5-7.5, presses amount of liquid 0.05% and adds activated carbon, and room temperature decoloured 30 minutes down, behind the coarse filtration activated carbon, send in 100 grades of clean areas, through the microporous filter membrane fine straining of 0.22um, replenish water for injection to full dose, regulate pH value, getting fine straining liquid inspects by ready samples in right amount, calculate loading amount after the assay was approved, packing, sterilization, lamp inspection, packing and the aseptic parenteral solution made makes finished product.
Claims (5)
1, a kind of kitasamycin tartrate injection, its feature mainly is: this injection uses water for injection and nonaqueous solvent mixture as the injection solvent, and wherein non-water-soluble matchmaker's ratio is 0～100%; The pH of injection is 6.5-7.5; Stabilizing agent is a tween 80, and consumption is 0.1-5%.
2. kitasamycin tartrate injection according to claim 1 is characterized in that: the ratio of nonaqueous solvent is 50～100%.
3, kitasamycin tartrate injection according to claim 1 and 2, wherein nonaqueous solvent is selected from ethanol, propylene glycol, glycerol, Polyethylene Glycol, polyoxyethylene castor oil, soybean oil.
4. kitasamycin tartrate injection according to claim 1 is characterized in that: this injection also contains sodium chloride, glucose, mannitol or sorbitol, as isoosmotic adjusting agent.
5. kitasamycin tartrate injection according to claim 1 is characterized in that: this injection also contains EDTA-CaNa or EDTA-2Na metal ion chelation agent, further improves the stability of injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610054867 CN1820760A (en) | 2006-03-07 | 2006-03-07 | Method for preparing kitasamycin tartrate injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610054867 CN1820760A (en) | 2006-03-07 | 2006-03-07 | Method for preparing kitasamycin tartrate injection |
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| Publication Number | Publication Date |
|---|---|
| CN1820760A true CN1820760A (en) | 2006-08-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200610054867 Pending CN1820760A (en) | 2006-03-07 | 2006-03-07 | Method for preparing kitasamycin tartrate injection |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103463623A (en) * | 2013-09-03 | 2013-12-25 | 长春海伯尔生物技术有限责任公司 | Pegylated interferon injection and preparation method thereof |
| CN103720645A (en) * | 2013-12-06 | 2014-04-16 | 鼎正动物药业（天津）有限公司 | Thiocyanate erythromycin injection and preparation method thereof |
-
2006
- 2006-03-07 CN CN 200610054867 patent/CN1820760A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103463623A (en) * | 2013-09-03 | 2013-12-25 | 长春海伯尔生物技术有限责任公司 | Pegylated interferon injection and preparation method thereof |
| CN103720645A (en) * | 2013-12-06 | 2014-04-16 | 鼎正动物药业（天津）有限公司 | Thiocyanate erythromycin injection and preparation method thereof |
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