CN101167732A - Method for preparing glycylcycline freezing-dried powder injection - Google Patents
Method for preparing glycylcycline freezing-dried powder injection Download PDFInfo
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- CN101167732A CN101167732A CNA2007101348093A CN200710134809A CN101167732A CN 101167732 A CN101167732 A CN 101167732A CN A2007101348093 A CNA2007101348093 A CN A2007101348093A CN 200710134809 A CN200710134809 A CN 200710134809A CN 101167732 A CN101167732 A CN 101167732A
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Abstract
The invention relates to a tigecycline freeze dried for injection and a process for preparation, which comprises taking some tigecycline, charging injection water in proper temperature to dissolve the tigecycline, regulating the pH level of the solution to acidity with pH modifier, charging 0.1%(g/100ml) cubage of activated charcoal for pin, churning up for 15-30 minutes, preliterating and decarbonizing, then filtrating by filter membrane with micropores of 0.45mum, 0.22mum split charging, pre freezing, cryodesiccating, stressing the top, and putting aluminium cover. The pH modifier is one or multiple kind of inorganic acid or organic acid. The tigecycline freeze dried for injection has the advantages of more steady, safe clinical application, and simple operational process.
Description
Technical field
The present invention relates to a kind of preparation method of tigecycline, be specifically related to the preparation method of a kind of injection tigecycline (Tigecycline I) freeze-dried powder.
Background technology
Tigecycline is the new class antibiotic---glycyl tetracycline (glycylcycline), be mainly used in treatment by Grain-negative and positive pathogenic bacterium, anaerobe, methicillin-resistant staphylococcus aureus (MRSA) infects and MSSA (MSSA) infects complexity intra-abdominal infection, skin and the skin histology infection (cSSSI) that causes, pneumococcal infection etc.This product is succeeded in developing by Wyeth (Wyeth), and dosage form is the injection freeze-dried powder.
Tigecycline is orange-yellow crystalline powder, and exsiccant pressed powder stores relatively stable in the room temperature lower seal, but its aqueous solution is extremely unstable, mainly is because of the phenolic hydroxyl group among the I easily produces oxidative degradation, and solution colour is deepened.The necessary process conditions of freeze-dried powder preparation is: after certain density solution was made in water (water for injection) dissolving, solution was again through pretreatment, packing, pre-freeze, lyophilization.For guaranteeing safety of clinical administration, should adopt an effective measure in the above-mentioned operation process and prevent the degraded of this product, and then make stable freeze-dried powder.
At present, " effective measures " that solve easy oxidative degradation problem in the unstable drug production process in the pharmaceuticals industry mainly are to add such as protective agents such as antioxidant, chelating agent, air displacement agent, medicinal antioxidant commonly used mainly comprises: sulfites such as sodium sulfite, sodium sulfite, sodium pyrosulfite, amido classes such as cysteine, glycine, phenylalanine; Chelating agent is mainly disodium edetate; The air displacement agent mainly comprises noble gases such as nitrogen, carbon dioxide gas and argon.
Adopt the method for adding antioxidant to solve the oxidative degradation problem, must consider following two problems: 1, the kind of antioxidant is selected, characteristic solvable, that consumption is low, antioxidation efficient is high that selected antioxidant must have can not produce compatibility with this product simultaneously and change; 2, safety issue, selected antioxidant is except that requiring to have the characteristic of general injection pharmaceutic adjuvant, also require its product behind redox reaction must be nontoxic to human body, simultaneously, directly contact as intravenous injection with blood, selected antioxidant reply blood and blood vessel nonirritant are to guarantee drug safety.And antioxidant be applied to preparation particularly injection generally all have certain clinical drug safety hidden danger, be unworthy advocate using.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, designed and developed out a kind of stable, clinical drug safety, method that technological operation simply prepares glycylcycline freezing-dried powder injection.
The present invention is achieved through the following technical solutions:
A kind of preparation method of glycylcycline freezing-dried powder injection may further comprise the steps preparation: get tigecycline, add the water for injection dissolving of preference temperature, to slant acidity, add the needle-use activated carbon of 0.1% (g/100ml) volume with PH regulator regulator solution pH value, stirred 15～30 minutes, coarse filtration is taken off charcoal, again respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, packing, pre-freeze, lyophilization, gland is pricked aluminium lid, promptly.
A kind of preparation method of glycylcycline freezing-dried powder injection, the temperature of described water for injection are 5～30 ℃.
A kind of preparation method of glycylcycline freezing-dried powder injection, described PH regulator be in mineral acid, the organic acid any one or multiple.
A kind of preparation method of glycylcycline freezing-dried powder injection, described mineral acid can be in hydrochloric acid, carbonic acid, sulphuric acid, nitric acid, the hydrobromic acid wherein any one or multiple.
A kind of preparation method of glycylcycline freezing-dried powder injection, described organic acid are that molecular formula is water-soluble organic monoacid of R-COOH, wherein R be carbon number be in 2～6 the straight or branched alkyl any one or multiple.As propanoic acid etc.
A kind of preparation method of glycylcycline freezing-dried powder injection, described organic acid are that molecular formula is water-soluble organic monoacid of R-CH (OH)-COOH, wherein R be H or carbon number be in 1～5 the straight or branched alkyl any one or multiple.As glycolic, lactic acid etc.
A kind of preparation method of glycylcycline freezing-dried powder injection, described organic acid be in the organic multicomponent acid any one or multiple.As tartaric acid, succinic acid, malic acid, maleic acid, fumaric acid etc.
A kind of preparation method of glycylcycline freezing-dried powder injection, described organic acid be ascorbic acid, nicotinic acid, alkyl sulfonic acid apoplexy due to endogenous wind any one or multiple.
A kind of preparation method of glycylcycline freezing-dried powder injection, described solution pH value range of accommodation is 3.5～7.0.
Tigecycline is very easily oxidative degradation under aqueous solution state, its pure water solution was oxidation stain in 30 minutes, and preparation injection tigecycline all is its aqueous solution states from the pre-freeze process of preparing burden, this process can not be finished at short notice, size according to preparation amount, generally need 2～4 hours at least, therefore must adopt necessary effective measures to solve.The invention provides a kind of preparation method of stable, clinical drug safety, the simple glycylcycline freezing-dried powder injection of technological operation.At the tigecycline construction features, dimethylamino is intensive electron-donating group, makes active the increasing of phenolic hydroxyl group of its para-position, easily produce oxidative degradation, and acid condition can suppress the oxidative degradation of phenolic hydroxyl group.The present invention has adopted the PH regulator to come regulator solution pH value (to slant acidity), thereby has improved the stability of tigecycline in aqueous solution.With respect to adding antioxidant process and chelating agent, the prepared injection tigecycline of the present invention has the safer real advantage of clinical application; With respect to the air displacement Protection Code, adopt the injection tigecycline of the present invention's preparation, its preparation technology is simple and easy to control, is more suitable for suitability for industrialized production.
At this preparation method, we have done experiment and have detected, detection the results are shown in following table:
| Detection time and result | |||||||||
| The PH regulator | Detect index | 0 hour | 0.5 hour | 1 hour | 2 hours | 4 hours | 5 hours | 6 hours | 8 hours |
| Do not regulate (PH=8.06) | The solution character | Orange-yellow | Color burn | Pale brown color | Pale brown color | Sepia | Green black | Green black | Green black |
| Related substance | 1.05 | 3.89 | 5.76 | 7.88 | 15.34 | / | / | / | |
| 0.3mol/L hydrochloric acid solution (PH=4.02) | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow |
| Related substance | 1.03 | 1.05 | 1.02 | 1.03 | 1.16 | 1.24 | 1.27 | 1.33 | |
| 0.3mol/L hydrochloric acid solution (PH=5.55) | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow |
| Related substance | 0.97 | 0.95 | 0.99 | 1.03 | 1.02 | 1.04 | 1.11 | 1.16 | |
| 0.5mol/L tartaric acid solution (PH=5.43) | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow |
| Related substance | 0.98 | 1.01 | 1.06 | 1.12 | 1.18 | 1.21 | 1.27 | 1.38 | |
| 0.5mol/L tartaric acid solution (PH=4.91) | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow |
| Related substance | 1.02 | 1.07 | 1.08 | 1.10 | 1.21 | 1.29 | 1.34 | 1.44 | |
| 0.3mol/L | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow |
| Lactic acid solution (PH=5.36) | Related substance | 1.05 | 1.01 | 1.10 | 1.15 | 1.18 | 1.17 | 1.22 | 1.31 |
| 0.3mol/L lactic acid solution (PH=6.62) | The solution character | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Orange-yellow | Pale brown color |
| Related substance | 1.01 | 1.11 | 1.16 | 1.23 | 1.31 | 1.46 | 1.68 | 1.98 |
The specific embodiment
The following examples can specifically be illustrated the present invention, but do not limit the present invention in any way.
Embodiment 1 gets tigecycline 2.5g, add the about 80ml of injection water (20.4 ℃ of water temperatures), stirring and dissolving, hydrochloric acid solution regulator solution pH value to 5.48 with 0.3mol/L, add the injection water to 100ml, shake up, add the needle-use activated carbon of 100mg (0.1% water for injection volume), stir about 30 minutes, coarse filtration is taken off charcoal, respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, be sub-packed in the control antibiotic bottle of 10ml again, loading amount is the 2.0ml/ bottle, entered freezer dryer lyophilization 36 hours after the pre-freeze through 4 hours, gland is pricked aluminium lid, promptly gets this product.
Embodiment 2 gets tigecycline 2.5g, add the about 80ml of injection water (20.4 ℃ of water temperatures), stirring and dissolving, sulfuric acid solution regulator solution pH value to 5.46 with 0.2mol/L, add the injection water to 100ml, shake up, add the needle-use activated carbon of 100mg (0.1% water for injection volume), stir about 30 minutes, coarse filtration is taken off charcoal, respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, be sub-packed in the control antibiotic bottle of 10ml again, loading amount is the 2.0ml/ bottle, entered freezer dryer lyophilization 36 hours after the pre-freeze through 4 hours, gland is pricked aluminium lid, promptly gets this product.
Embodiment 3 gets tigecycline 2.5g, add the about 80ml of injection water (20.4 ℃ of water temperatures), stirring and dissolving, tartaric acid solution regulator solution pH value to 5.40 with 0.5mol/L, add the injection water to 100ml, shake up, add the needle-use activated carbon of 100mg (0.1% water for injection volume), stir about 30 minutes, coarse filtration is taken off charcoal, respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, be sub-packed in the control antibiotic bottle of 10ml again, loading amount is the 2.0ml/ bottle, entered freezer dryer lyophilization 36 hours after the pre-freeze through 4 hours, gland is pricked aluminium lid, promptly gets this product.
Embodiment 4 gets tigecycline 2.5g, add the about 80ml of injection water (20.4 ℃ of water temperatures), stirring and dissolving, lactic acid solution regulator solution pH value to 5.53 with 0.5mol/L, add the injection water to 100ml, shake up, add the needle-use activated carbon of 100mg (0.1% water for injection volume), stir about 30 minutes, coarse filtration is taken off charcoal, respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, be sub-packed in the control antibiotic bottle of 10ml again, loading amount is the 2.0ml/ bottle, entered freezer dryer lyophilization 36 hours after the pre-freeze through 4 hours, gland is pricked aluminium lid, promptly gets this product.
Embodiment 5 PH regulators are ascorbic acid solution, and all the other preparation methoies are with embodiment 1.
Embodiment 6 PH regulators are propanoic acid solution, and all the other preparation methoies are with embodiment 1.
Embodiment 7 PH regulators are maleic acid solution, and all the other preparation methoies are with embodiment 1.
Embodiment 8 PH regulators are methanesulfonic acid solution, and all the other preparation methoies are with embodiment 1.
Embodiment 9 PH regulators are nicotinic acid solution, and all the other preparation methoies are with embodiment 1.
Claims (9)
1. the preparation method of a glycylcycline freezing-dried powder injection is characterized in that may further comprise the steps preparation: get tigecycline, add the water for injection dissolving of preference temperature, to slant acidity, add the needle-use activated carbon of 0.1% (g/100ml) volume with PH regulator regulator solution pH value, stirred 15～30 minutes, coarse filtration is taken off charcoal, again respectively through 0.45 μ m, 0.22 μ m filtering with microporous membrane, packing, pre-freeze, lyophilization, gland is pricked aluminium lid, promptly.
2. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 1, the temperature that it is characterized in that described water for injection is 5～30 ℃.
3. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 1, it is characterized in that described PH regulator be in mineral acid, the organic acid any one or multiple.
4. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 3, it is characterized in that described mineral acid can be in hydrochloric acid, carbonic acid, sulphuric acid, nitric acid, the hydrobromic acid wherein any one or multiple.
5. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 3, it is characterized in that described organic acid is that molecular formula is water-soluble organic monoacid of R-COOH, wherein R be carbon number be in 2～6 the straight or branched alkyl any one or multiple.
6. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 3, it is characterized in that described organic acid is that molecular formula is water-soluble organic monoacid of R-CH (OH)-COOH, wherein R be H or carbon number be in 1～5 the straight or branched alkyl any one or multiple.
7. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 3, it is characterized in that described organic acid be in the organic multicomponent acid any one or multiple.
8. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 3, it is characterized in that described organic acid be ascorbic acid, nicotinic acid, alkyl sulfonic acid apoplexy due to endogenous wind any one or multiple.
9. the preparation method of a kind of glycylcycline freezing-dried powder injection according to claim 1 is characterized in that described solution pH value range of accommodation is 3.5～7.0.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101348093A CN101167732A (en) | 2007-10-22 | 2007-10-22 | Method for preparing glycylcycline freezing-dried powder injection |
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| CNA2007101348093A CN101167732A (en) | 2007-10-22 | 2007-10-22 | Method for preparing glycylcycline freezing-dried powder injection |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101401812B (en) * | 2008-11-14 | 2011-03-23 | 江苏奥赛康药业有限公司 | Tigecycline freeze-dried injection |
| CN102138925A (en) * | 2010-01-29 | 2011-08-03 | 江苏正大天晴药业股份有限公司 | Tigecycline composition and preparation method thereof |
| CN102697739A (en) * | 2012-05-31 | 2012-10-03 | 丽珠医药集团股份有限公司 | Preparation method of powder injection for reducing tigecycline epimer |
| CN103202814A (en) * | 2013-04-23 | 2013-07-17 | 成都百裕科技制药有限公司 | Method for preparing tigecycline for injection |
| WO2014191552A1 (en) * | 2013-05-31 | 2014-12-04 | Xellia Pharmaceuticals Aps | A method for stabilizing tigecycline |
| CN108014099A (en) * | 2017-12-15 | 2018-05-11 | 武汉兴华智慧医药科技有限公司 | A kind of suction tobramycin solution and preparation method thereof |
-
2007
- 2007-10-22 CN CNA2007101348093A patent/CN101167732A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101401812B (en) * | 2008-11-14 | 2011-03-23 | 江苏奥赛康药业有限公司 | Tigecycline freeze-dried injection |
| CN102138925A (en) * | 2010-01-29 | 2011-08-03 | 江苏正大天晴药业股份有限公司 | Tigecycline composition and preparation method thereof |
| CN102138925B (en) * | 2010-01-29 | 2014-06-25 | 正大天晴药业集团股份有限公司 | Tigecycline composition and preparation method thereof |
| CN102697739A (en) * | 2012-05-31 | 2012-10-03 | 丽珠医药集团股份有限公司 | Preparation method of powder injection for reducing tigecycline epimer |
| CN103202814A (en) * | 2013-04-23 | 2013-07-17 | 成都百裕科技制药有限公司 | Method for preparing tigecycline for injection |
| WO2014191552A1 (en) * | 2013-05-31 | 2014-12-04 | Xellia Pharmaceuticals Aps | A method for stabilizing tigecycline |
| CN108014099A (en) * | 2017-12-15 | 2018-05-11 | 武汉兴华智慧医药科技有限公司 | A kind of suction tobramycin solution and preparation method thereof |
| CN108014099B (en) * | 2017-12-15 | 2019-03-01 | 武汉兴华智慧医药科技有限公司 | A kind of sucking tobramycin solution and preparation method thereof |
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Open date: 20080430 |