CN102697739A - Preparation method of powder injection for reducing tigecycline epimer - Google Patents
Preparation method of powder injection for reducing tigecycline epimer Download PDFInfo
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- CN102697739A CN102697739A CN2012101864149A CN201210186414A CN102697739A CN 102697739 A CN102697739 A CN 102697739A CN 2012101864149 A CN2012101864149 A CN 2012101864149A CN 201210186414 A CN201210186414 A CN 201210186414A CN 102697739 A CN102697739 A CN 102697739A
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Abstract
The invention discloses a preparation method of a powder injection for reducing tigecycline epimer. The preparation method comprises the following steps of: taking the tigecycline and fined lactose, adding water for injection to dissolve the materials, firstly dissolving the materials by using acid, enabling the pH of the solution to be proper, then readjusting the pH to be proper by using alkaline, filtering with a 0.22mum microfiltration membrane, carrying out subpackage, semi-plug-pressing, freeze-drying, plug pressing and rolled covering to obtain the powder injection. The pH adjusting agent is one or more of inorganic acids; and the pH readjusting agent is one or more of inorganic alkalines. The tigecycline powder injection prepared by the preparation method disclosed by the invention has the advantages that the content of impurities is low, the mass is stable in the putting process and the clinical use is safer and more effective.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of method for preparing of tigecycline injectable powder, relate in particular to a kind of injectable powder method for preparing that can reduce the tigecycline epimerization.
Background technology
Tigecycline is first approved novel used for intravenous injection glycyl TCs, contains a glycyl amino, is replaced in 9 of minocycline.This replacement form is not shown in any natural or semi-synthetic tetracycline compound, thereby gives tigecycline unique Microbiological Characteristics.Tigecycline does not receive the influence of Tetracyclines two big resistance mechanisms (mechanism is protected and effluxed to ribosome).Correspondingly, external have broad spectrum antibiotic activity with in vivo test confirmation tigecycline.Do not find that as yet there are crossing drug resistant in tigecycline and other antibiotic.Tigecycline does not receive beta lactamase (comprising extended spectrum), target position modification, Macrolide efflux pump or enzyme target position to change the influence of resistance mechanisms such as (like gyrase/topoisomerases).In vitro study does not confirm that there are antagonism in tigecycline and other antibacterials commonly used.Its mechanism of action is to combine with 30S ribosome A position, stops amino acid transport RNA to get into ribosome, thereby has stoped amino acid residue to form peptide chain, and then kills or suppress bacterial reproduction.
Tigecycline be mainly used in treatment by the complexity intracavity that Grain-negative or positive pathogen, anaerobe and methicillin-resistant gold Portugal bacterium and methicillin-sensitivity can the Portugal bacterium cause infect, in the lung coccus infect, complicated skin and soft tissue infection thereof etc.Compare advantage such as tigecycline has has a broad antifungal spectrum, be difficult for to produce drug resistance, long half time, consumption are little with other antibiotic.Tigecycline Xiang doctors provide a kind of new, can be at treatment initial stage selective broad ectrum antibiotic when the cause of disease is clear as yet, and do not need to adjust dosage according to the impaired renal function situation, easy to use, use in per 12 hours once gets final product.
Tigecycline is by former the grinding of Hui Shi (Wyeth), and in granted listing in 2005, trade name Tygacil, dosage form is a lyophilized injectable powder.This drug stabilisation property is relatively poor, and its solution is oxidative degradation and generation epimerization very easily, therefore, when the preparation freeze-dried powder, should do one's utmost to avoid the generation of above-mentioned impurity.
Research shows; When tigecycline in the water of pH about 7.8 during lyophilizing, the lyophilizing block major impurity that obtains is the oxidation Decomposition product, and in the water of low pH value during lyophilizing; Epimerization occurs as main degradation pathway; Simultaneously, tigecycline has different epimerization characteristics with other TCses, and the epimerization of tigecycline is more remarkable under the condition of low pH value.Therefore, at present main through control epimerization product in the lyophilizing tigecycline under the situation of low pH value, or pH be under the situation of 7.7-8.2 in the lyophilizing tigecycline method of controlled oxidation catabolite increase the stability of tigecycline.
The Chinese invention patent application 200680006447.3 of Wyeth provide a kind of under acid condition the lyophilizing tigecycline, add the method that carbohydrate such as lactose, glucose wait the stability that increases tigecycline simultaneously.Because under the tart condition of pH value, oxidative degradation has been reduced to minimum degree, therefore adding carbohydrate is mainly used in the generation of avoiding epimer.Yet the tigecycline lyophilized formulations that uses the preparation of this method is after carrying out 6 months 40 ℃ of accelerated tests that keep sample; Its epimerism body burden has increased about 1.5%; Therefore; As in the tigecycline production do not hope to exist or exist the few more good more impurity of content, the epimerism body burden of strict control tigecycline more is to increase the stability of tigecycline lyophilized formulations.
It is the method for lyophilizing tigecycline under the situation of 7.7-8.2 at pH that the Chinese invention patent application 200680021384.9 of Wyeth discloses a kind of; Be reduced at epimerization reaction under the situation of minimum degree; Be lower than 5ppm and keep the temperature of water to reduce oxidative breakdown product with the control oxygen content through spraying noble gases such as a large amount of nitrogen in the preparation, reach the purpose of the stable tigecycline lyophilized formulations of preparation in the method for about 2-8 degree.Chinese invention patent application 200610098366.2 also points out, thereby it is not oxidized to reach in the preparation process protection tigecycline through the oxygen in the water for injection that charges into noble gases replacement dissolving tigecyclines such as a large amount of nitrogen or argon.Yet these two kinds of method complex process are with high costs.
Chinese invention patent 200610096514.7 provides a kind of antioxidant that adds to solve tigecycline oxidative degradation problem, generally has the clinical drug safety potential problem owing in injection, add oxidant, and is unworthy advocating.
Summary of the invention:
The objective of the invention is to, a kind of lyophilized injectable powder method for preparing that reduces tigecycline epimerism body burden through the method for regulating pH value is provided; Another object of the present invention is, the tigecycline injectable powder method for preparing that provides is when the control epimer increases, and the basic zero growth of all the other known impurities and unknown impuritie has significantly reduced because of impurity and increased the hidden danger of bringing to patient's drug safety.
The method for preparing of tigecycline freeze-dried powder provided by the invention; Tigecycline epimer growth rate is obviously reduced; Keep sample at 40 ℃ and to quicken that the epimer increment can be controlled at below 1.0% in the experiment in six months, under optimal conditions even can be controlled in 0.3%.
The present invention realizes through following technical proposals:
A kind of injectable powder method for preparing that reduces the tigecycline epimerization may further comprise the steps: get tigecycline, refined lactose, add the dissolving of injection water; Transfer the pH that makes material dissolution and make solution to suitable with acid earlier, return with alkali then and transfer pH, the 0.22um filtering with microporous membrane to suitable; Packing, half tamponade, lyophilizing; Tamponade, Zha Gai promptly gets.
A kind of injectable powder method for preparing that reduces the tigecycline epimerization, said acid be medicinal hydrochloric acid, sulphuric acid, phosphoric acid, etc. mineral acid.Said alkali is inorganic bases such as medicinal sodium hydroxide, potassium hydroxide.
A kind of injectable powder method for preparing that reduces the tigecycline epimerization, it is 1.0 to 4.4 that the pH scope is transferred in described acid, it is 1.0-1.5 that preferred acid is transferred the pH scope
A kind of injectable powder method for preparing that reduces the tigecycline epimerization, described alkali are returned and transferred the pH scope is 4.5 to 6.3, and preferred bases is returned and transferred the pH scope is 5.2-6.3
Because the present invention is the preparation tigecycline lyophilized formulations under the condition of 4.5-6.3 at pH value; Therefore epimerism turns to the main degradation pathway of tigecycline, minimumly reduces to 0.11% and through above-mentioned alkali readjustment technology the content of 40 ℃ of trimestral epimers that keep sample of this product is increased from 1.0%; The content of 40 ℃ of epimers that kept sample six months increases from 1.0% minimumly reduces to 0.25%.
The embodiment of the invention 1 is with reference to the method for preparing of tigecycline injectable powder technology in the Wyeth patent (ZL 200680006447.3); Prepare pH respectively and be 5.60,5.20,4.80 tigecycline solution, 40 ℃ of epimer increments that kept sample six months of this product are all about 1.5%.Compare with the lyophilized formulations of alkali readjustment technology of the present invention preparation; The lyophilized formulations for preparing keeps sample experiment in the time of 0 day at 40 ℃; Both differences are not remarkable, and along with the time of 40 ℃ of experiments that keep sample extends, the recruitment of both epimers has the difference of significance.
Through product research of the present invention is found; The increase of the epimer under 40 ℃ of accelerated tests of this technology mainly occurs in the first two months, and per 6 months quality that keeps sample for a long time simultaneously slightly is superior to 40 ℃ of characteristics of one month, under the condition of optimum; The epimer recruitment that this product quickened after 6 months is lower than 0.3%; Therefore can foresee, the recruitment of the epimer that this product is long-term 24 months can be lower than the recruitment of quickening 4 months, also can be lower than 0.3%.
Therefore, can find out that the present invention is superior to Wyeth patent (ZL 200680006447.3) part and is that the present invention can slow down the epimer rate of transition significantly, has improved the stability in the tigecycline long term store process largely.
Research shows; The present invention is through carrying out alkali readjustment technology under the environment of acid ph value; The increase of product stability is not to be that simple adding inorganic salt can't make its stability improve because when regulating pH value, introduced inorganic salts such as sodium chloride, sodium sulfate, potassium sulfate.The salt (like sodium chloride, potassium sulfate, sodium phosphate) that possibly bring into when regulating pH value through adding, it is as shown in table 1 below to the concrete outcome of the influence of the epimerism body burden of freeze dried tigecycline under the pH5.2 condition to investigate salt:
Group 1 is the content of the sodium chloride that produced to 4.8 o'clock through alkali readjustment in 4.0 o'clock for pH value, and group 4 and group 5 are to adjust back the potassium sulfate that produced to 4.8 o'clock and the content of sodium phosphate through alkali at 4.0 o'clock for pH value.
| | Inventory | 0 day | One month | Two months | Three months | Six months | |
| 1 | (0.02mg sodium chloride) | 0.253％ | 0.697％ | 1.037％ | 1.277％ | 1.819％ | |
| 2 | (0.1mg sodium chloride) | 0.246％ | 0.687％ | 1.054％ | 1.282％ | 1.857％ | |
| 3 | (0.5mg sodium chloride) | 0.275％ | 0.689％ | 1.033％ | 1.254％ | 1.825％ | |
| 4 | (0.03mg potassium sulfate) | 0.261％ | 0.708％ | 1.041％ | 1.285％ | 1.834％ | |
| 5 | (0.02mg sodium phosphate) | 0.258％ | 0.716％ | 1.068％ | 1.269％ | 1.849％ |
Can find out by last table; Even than group 1 drop into more the sodium chloride of volume (as organize 2 with group 3); Also can't slow down advancing the speed of tigecycline epimer; Therefore, under the situation of not using alkali readjustment technology, add the stability that salt (like sodium chloride, potassium sulfate and potassium phosphate) can't improve product significantly separately.
When the alkali readjustment technology that the present invention uses prepares the tigecycline lyophilized formulations, in control epimerism body burden, the basic zero growth of all the other known impurities and unknown impuritie.Can know by accompanying drawing 1-3, through by pH value 1.5 through alkali adjust back to pH5.2 the tigecycline lyophilized formulations of method preparation, tangible impurity peaks does not appear on 40 ℃ of accelerated tests HPLC collection of illustrative plates of 0 day, 3 months, 6 months.
Research shows, through alkali readjustment technology preparation tigecycline lyophilized formulations, difference is returned the formulation and technology of transferring starting point, and the growth of epimer is also had tangible influence.Alkali transfers the starting point pH value between 1.0-1.5, and stability can reach optimum, and tigecycline epimer recruitment can be controlled in 0.3%, and alkali transfers the starting point pH value to be lower than 1.0, and the freeze-dried powder molding, color and luster is not good enough.
The invention provides a kind of method for preparing the tigecycline lyophilized formulations through alkali readjustment technology; Through this method; Can slow down advancing the speed of tigecycline epimer significantly; All the other known impurities of tigecycline and the basic zero growth of unknown impuritie have improved the stability in the tigecycline storage process largely simultaneously, make patient's medication safer, effective; And need not the inflated with nitrogen processing in the production process, reduced cost.
Description of drawings:
Fig. 1 for by pH value 1.5 through alkali adjust back to pH5.2 40 ℃ of HPLC collection of illustrative plates that kept sample 0 day of tigecycline lyophilized formulations of method preparation.
Fig. 2 for by pH value 1.5 through alkali adjust back to pH5.2 40 ℃ of trimestral HPLC collection of illustrative plates that keep sample of tigecycline lyophilized formulations of method preparation.
Fig. 3 for by pH value 1.5 through alkali adjust back to pH5.2 40 ℃ of HPLC collection of illustrative plates that kept sample six months of tigecycline lyophilized formulations of method preparation.
Fig. 4 is 40 ℃ of trimestral HPLC collection of illustrative plates that keep sample of 5.2 tigecycline lyophilized formulations for pH value
The specific embodiment:
Embodiment 1:
With reference to the method for preparing of tigecycline injectable powder technology in the Wyeth patent (ZL 200680006447.3), prepare pH respectively and be 5.60,5.20,4.80 tigecycline solution, like group 1, the group 2 of table 2 with organize shown in 3.
Use alkali readjustment technology preparation tigecycline injectable powder, concrete technology is following:
Get tigecycline 10.03g, refined lactose 20.00g, add the about 700ml dissolving of injection water, extremely suitable with the hydrochloric acid conditioning solution pH of 5mol/L, return with the 2mol/L sodium hydroxide solution then and transfer pH to suitable; Add water for injection and be diluted to 800ml, shake up, use the 0.22um filtering with microporous membrane; Packing, half tamponade, lyophilizing; Tamponade, Zha Gai promptly gets these article.Specifically shown in the group 4-group 13 of table 2.
Table 2: tigecycline injectable powder stability test:
| Experimental | PH value | 0 day | 40 ℃ one month | 40 ℃ two months | 40 ℃ three months | 40 ℃ six months | |
| 1 | 4.8 | 0.364 | 0.654 | 1.010 | 1.206 | 1.805 | |
| 2 | 5.2 | 0.415 | 0.788 | 1.131 | 1.311 | 1.866 | |
| 3 | 5.6 | 0.388 | 0.823 | 1.120 | 1.373 | 1.926 | |
| 4 | 4.0 readjustment is to 5.2 | 0.226 | 0.494 | 0.702 | 0.867 | 1.241 | |
| 5 | 3.5 readjustment is to 5.2 | 0.230 | 0.455 | 0.541 | 0.728 | 1.116 | |
| 6 | 3.0 readjustment is to 5.2 | 0.223 | 0.433 | 0.515 | 0.593 | 0.977 | |
| 7 | 1.5 readjustment is to 5.2 | 0.205 | 0.329 | 0.336 | 0.369 | 0.479 | |
| 8 | 1.0 readjustment is to 5.2 | 0.204 | 0.275 | 0.339 | 0.415 | 0.495 | |
| 9 | 1.2 readjustment is to 5.2 | 0.211 | 0.281 | 0.308 | 0.322 | 0.457 | |
| 10 | 1.3 readjustment is to 5.2 | 0.220 | 0.288 | 0.315 | 0.335 | 0.465 | |
| 11 | 1.4 readjustment is to 5.2 | 0.200 | 0.311 | 0.328 | 0.361 | 0.472 | |
| 12 | 3.0 readjustment is to 6.3 | 0.201 | 0.418 | 0.476 | 0.553 | 0.952 | |
| 13 | 1.2 readjustment is to 6.3 | 0.208 | 0.277 | 0.331 | 0.386 | 0.501 |
Can know by last table: through the tigecycline injectable powder of pH alkali readjustment technology preparation; Its epimer recruitment can basic controlling below 1.0%; When pH value readjustment starting point was 1.0-1.5, tigecycline epimer recruitment can be controlled at below 0.3%.
Embodiment 2:
Get tigecycline 10.03g, refined lactose 20.00g, add the about 700ml dissolving of injection water, extremely suitable with the sulfuric acid regulation solution pH of 5mol/L, return with the 2mol/L potassium hydroxide solution then and transfer pH to suitable; Add water for injection and be diluted to 800ml, shake up, use the 0.22um filtering with microporous membrane; Packing, half tamponade, lyophilizing; Tamponade, Zha Gai promptly gets these article.Shown in the table 3 specific as follows.
Table 3: tigecycline injectable powder stability test:
| Experimental | PH value | 0 day | 40 ℃ one month | 40 ℃ two months | 40 ℃ three months | 40 ℃ six months | |
| 1 | 4.4 readjustment is to 5.6 | 0.221 | 0.489 | 0.695 | 0.871 | 1.302 | |
| 2 | 1.0 readjustment is to 4.5 | 0.192 | 0.360 | 0.462 | 0.513 | 0.558 |
Embodiment 3:
Get tigecycline 10.03g, refined lactose 20.00g, add the about 700ml dissolving of injection water, extremely suitable with the phosphoric acid regulator solution pH of 5mol/L, return with the 2mol/L sodium hydroxide solution then and transfer pH to suitable; Add water for injection and be diluted to 800ml, shake up, use the 0.22um filtering with microporous membrane; Packing, half tamponade, lyophilizing; Tamponade, Zha Gai promptly gets these article.Shown in the table 4 specific as follows.
Table 4: tigecycline injectable powder stability test:
| Experimental | PH value | 0 day | 40 ℃ one month | 40 ℃ two months | 40 ℃ three months | 40 ℃ six months | |
| 1 | 1.5 readjustment is to 5.6 | 0.210 | 0.298 | 0.332 | 0.358 | 0.472 | |
| 2 | 2.0 readjustment is to 6.3 | 0.221 | 0.353 | 0.438 | 0.492 | 0.735 |
Claims (6)
1. an injectable powder method for preparing that reduces the tigecycline epimerization is characterized in that may further comprise the steps: get tigecycline, refined lactose, add the dissolving of injection water; Transfer the pH that makes material dissolution and make solution to suitable with acid earlier, return with alkali then and transfer pH, the 0.22um filtering with microporous membrane to suitable; Packing, half tamponade, lyophilizing; Tamponade, Zha Gai promptly gets.
2. injectable powder method for preparing according to claim 1 is characterized in that: said acid is mineral acids such as medicinal hydrochloric acid, sulphuric acid, phosphoric acid.Said alkali is inorganic bases such as medicinal sodium hydroxide, potassium hydroxide.
3. injectable powder method for preparing according to claim 1 is characterized in that: it is that pH is 1.0 to 4.4 that the pH scope is transferred in described acid.
4. injectable powder method for preparing according to claim 3 is characterized in that: it is 1.0 to 1.5 that described acid transfers the pH scope to be preferably pH.
5. according to the injectable powder method for preparing of claim 1-4 described in each, it is characterized in that: described alkali returns and transfers the pH scope is that pH is 4.5 to 6.3.
6. injectable powder method for preparing according to claim 5 is characterized in that: described alkali returns and transfers the pH scope is that pH is preferably 5.2 to 6.3.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104107170A (en) * | 2013-04-22 | 2014-10-22 | 上海汇伦生命科技有限公司 | Tigecycline composition |
| WO2014191552A1 (en) * | 2013-05-31 | 2014-12-04 | Xellia Pharmaceuticals Aps | A method for stabilizing tigecycline |
| CN105079816A (en) * | 2015-08-17 | 2015-11-25 | 江苏豪森药业股份有限公司 | Tigecycline pharmaceutical composition and preparation method thereof |
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| CN101401812A (en) * | 2008-11-14 | 2009-04-08 | 江苏奥赛康药业有限公司 | Tigecycline freeze-dried injection |
| WO2011143503A2 (en) * | 2010-05-12 | 2011-11-17 | Rempex Pharmaceuticals, Inc. | Tetracycline compositions |
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| CN101132775A (en) * | 2005-03-14 | 2008-02-27 | 惠氏公司 | Tigecycline compositons and methods of preparation |
| CN101152152A (en) * | 2006-09-28 | 2008-04-02 | 南京华威医药科技开发有限公司 | Lgecycline composition for injection and processes for producing same |
| CN101167732A (en) * | 2007-10-22 | 2008-04-30 | 合肥信风科技开发有限公司 | Method for preparing glycylcycline freezing-dried powder injection |
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| CN104107170A (en) * | 2013-04-22 | 2014-10-22 | 上海汇伦生命科技有限公司 | Tigecycline composition |
| WO2014191552A1 (en) * | 2013-05-31 | 2014-12-04 | Xellia Pharmaceuticals Aps | A method for stabilizing tigecycline |
| CN105079816A (en) * | 2015-08-17 | 2015-11-25 | 江苏豪森药业股份有限公司 | Tigecycline pharmaceutical composition and preparation method thereof |
| CN105079816B (en) * | 2015-08-17 | 2018-09-07 | 江苏豪森药业集团有限公司 | Tigecycline pharmaceutical composition and preparation method thereof |
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