CN102697739B - 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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- CN102697739B CN102697739B CN201210186414.9A CN201210186414A CN102697739B CN 102697739 B CN102697739 B CN 102697739B CN 201210186414 A CN201210186414 A CN 201210186414A CN 102697739 B CN102697739 B CN 102697739B
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- tigecycline
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- epimer
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- 239000000843 powder Substances 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical class C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 title claims abstract 6
- 238000002347 injection Methods 0.000 title abstract description 5
- 239000007924 injection Substances 0.000 title abstract description 5
- 229960004089 tigecycline Drugs 0.000 claims abstract description 62
- 239000002253 acid Substances 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000000243 solution Substances 0.000 claims abstract description 12
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 7
- 239000008101 lactose Substances 0.000 claims abstract description 7
- 239000008215 water for injection Substances 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000012982 microporous membrane Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 2
- 150000007529 inorganic bases Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 21
- 239000012535 impurity Substances 0.000 abstract description 9
- 230000008569 process Effects 0.000 abstract description 5
- 230000008901 benefit Effects 0.000 abstract description 2
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- 238000004108 freeze drying Methods 0.000 abstract 1
- 239000012528 membrane Substances 0.000 abstract 1
- 238000001471 micro-filtration Methods 0.000 abstract 1
- 150000007522 mineralic acids Chemical class 0.000 abstract 1
- 239000003002 pH adjusting agent Substances 0.000 abstract 1
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical class C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 72
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 16
- 238000009472 formulation Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000011780 sodium chloride Substances 0.000 description 8
- 230000007115 recruitment Effects 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000006345 epimerization reaction Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 5
- 229910052939 potassium sulfate Inorganic materials 0.000 description 5
- 235000011151 potassium sulphates Nutrition 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000010525 oxidative degradation reaction Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 230000006652 catabolic pathway Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- -1 glycyl amino Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229910052756 noble gas Inorganic materials 0.000 description 2
- 150000002835 noble gases Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000008261 resistance mechanism Effects 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 206010062237 Renal impairment Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
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- 238000000354 decomposition reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 231100000857 poor renal function Toxicity 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 229940061267 tygacil Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 preparation method of tigecycline injectable powder, relate in particular to a kind of injectable powder preparation method that can reduce tigecycline epimer.
Background technology
Tigecycline is first approved intravenous injection Tigecycline class antibiotic, contains a glycyl amino, is replaced in 9 of minocycline.This replacement form does not see any natural or semi-synthetic tetracycline compound, thereby gives the Microbiological Characteristics of tigecycline uniqueness.Tigecycline is not subject to the impact of the large resistance mechanism of Tetracyclines two (ribosome protection and outer row's mechanism).Correspondingly, in vitro and in vivo test confirms that tigecycline has broad spectrum antibiotic activity.Not yet find that tigecycline and other antibiotic exist crossing drug resistant.Tigecycline is not subject to beta lactamase (comprising extended spectrum β lactamases), target position modification, Macrolide efflux pump or enzyme target position to change the impact of resistance mechanisms such as (as gyrase/topoisomerases).In vitro study does not confirm that tigecycline and other Common Antibiotics exist antagonism.Its mechanism of action is to be combined with 30S ribosome A position, stops amino acid transport RNA to enter ribosome, thereby has stoped amino acid residue to form peptide chain, and then kills or anti-bacteria breeding.
Tigecycline is mainly used in that the complexity intracavity that treatment can Portugal bacterium causes by Grain-negative or positive pathogen, anaerobe and Methicillin-resistant Staphylococcus aureus and methicillin-sensitivity infects, in lung coccus infect, complicated skin and soft tissue infection thereof etc.Compare the 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 not yet understands, and do not need to adjust dosage according to impaired renal function situation, easy to use, use in every 12 hours once.
Tigecycline is by former the grinding of Hui Shi (Wyeth), and in granted listing in 2005, trade name Tygacil, dosage form is lyophilized injectable powder.This drug stabilisation is poor, and its solution is oxidative degradation and generation epimer very easily, therefore, should do one's utmost to avoid the generation of above-mentioned impurity when preparing freeze-dried powder.
Research shows, when tigecycline is in the water of pH approximately 7.8 during lyophilizing, the lyophilizing block major impurity obtaining is oxidation Decomposition product, and in the water of lower pH value during lyophilizing, epimerism is turned to main degradation pathway and occurs, meanwhile, tigecycline has different epimerization characteristics from other tetracycline antibiotics, and under the condition of lower pH value, the epimerization of tigecycline is more remarkable.Therefore, in the time of at present mainly by lyophilizing tigecycline the lower pH value in the situation that, control epimerization product, or the method for controlling oxidative breakdown product in the situation that pH is 7.7-8.2 when lyophilizing tigecycline increases the stability of tigecycline.
The Chinese invention patent application 200680006447.3 of Wyeth provide a kind of under acid condition lyophilizing tigecycline, add carbohydrate simultaneously and increase the method for the stability of tigecycline as lactose, glucose etc.Under the condition in pH value acidity, oxidative degradation has been reduced to minimum degree, therefore adds the generation that carbohydrate is mainly used in avoiding epimer.Yet use tigecycline lyophilized formulations prepared by the method carry out 6 months 40 ℃ keep sample after accelerated test, its epimerism body burden has increased approximately 1.5%, therefore, in producing as tigecycline, do not wish to exist or exist the more few better impurity of content, the epimerism body burden of control tigecycline that should be stricter, to increase the stability of tigecycline lyophilized formulations.
The Chinese invention patent application 200680021384.9 of Wyeth disclose a kind of in the situation that pH is 7.7-8.2 the method for lyophilizing tigecycline, in the situation that epimerization reaction is reduced to minimum degree, by spraying in the preparation the noble gases such as a large amount of nitrogen to control oxygen content lower than 5ppm and to keep the temperature of water to reduce oxidative breakdown product in the method for about 2-8 degree, reach the object of the stable tigecycline lyophilized formulations of preparation.Chinese invention patent application 200610098366.2 also points out, thereby replaces oxygen in the water for injection that dissolves tigecycline and reach and in preparation process, protect tigecycline not oxidized by being filled with the noble gases 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, owing to adding oxidant generally to have Hidden Trouble In Clinical Medication Security problem in injection, and is unworthy advocating.
Summary of the invention:
The object of the invention is to, provide a kind of by regulating the method for pH value to reduce the lyophilized injectable powder preparation method of tigecycline epimerism body burden; Another object of the present invention is, the tigecycline injectable powder preparation method providing is when controlling epimer and increasing, and the basic zero growth of all the other known impurities and unknown impuritie, has greatly reduced and increased the hidden danger of bringing to patient's drug safety because of impurity.
The preparation method of tigecycline freeze-dried powder provided by the invention, can make tigecycline epimer growth rate obviously reduce, in 40 ℃ keep sample acceleration experiment in six months, epimer increment can be controlled at below 1.0%, under optimal conditions, even can be controlled in 0.3%.
The present invention is achieved through the following technical solutions:
A kind of injectable powder preparation method that reduces tigecycline epimer, comprise the following steps: get tigecycline, refined lactose, be dissolved in water for injection, first with acid, adjust and make material dissolution and make the pH of solution to suitable, then with alkali, return and adjust pH to suitable, 0.22um filtering with microporous membrane, subpackage, half tamponade, lyophilizing, tamponade, Zha Gai, obtains.
Reduce an injectable powder preparation method for tigecycline epimer, described acid be medicinal hydrochloric acid, sulphuric acid, phosphoric acid, etc. mineral acid.Described alkali is the inorganic bases such as medicinal sodium hydroxide, potassium hydroxide.
Reduce an injectable powder preparation method for tigecycline epimer, it is 1.0 to 4.4 that pH scope is adjusted in described acid, and it is 1.0-1.5 that preferred acid is adjusted pH scope
Reduce an injectable powder preparation method for tigecycline epimer, described alkali returns and adjusts pH scope is 4.5 to 6.3, and preferred bases is returned and adjusted pH scope is 5.2-6.3
Owing to preparing tigecycline lyophilized formulations under the present invention's condition that is 4.5-6.3 at pH value, therefore epimerism turns to the main degradation pathway of tigecycline, and can make the content of 40 ℃ of trimestral epimers that keep sample of this product increase from 1.0% by above-mentioned alkali callbacks, is minimumly down to 0.11%; The content of 40 ℃ of epimers that keep sample six months increases from 1.0% is minimumly down to 0.25%.
The embodiment of the present invention 1 is with reference to the preparation method of tigecycline injectable powder technique in Wyeth patent (ZL 200680006447.3), prepare respectively pH and be 5.60,5.20,4.80 tigecycline solution, 40 ℃ of epimer increments that keep sample six months of this product are all in 1.5% left and right.Compare with lyophilized formulations prepared by alkali callbacks of the present invention, the lyophilized formulations 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 lengthens, the recruitment of both epimers has the difference of significance.
By product research of the present invention is found, 40 ℃ of increases of accelerating the epimer under experiment of this technique mainly occur in the first two months, the quality keeping sample for a long time every 6 months is slightly better than 40 ℃ of characteristics of month simultaneously, under optimum condition, the epimer recruitment of this product acceleration after 6 months is lower than 0.3%, therefore can predict, the recruitment of this product epimer of long-term 24 months can be lower than the recruitment of accelerating 4 months, also can be lower than 0.3%.
Therefore, can find out, the present invention is better than Wyeth patent (ZL 200680006447.3) part and is, the present invention can slow down the speed that epimerization changes significantly, has improved largely the stability in the long-term storage process of tigecycline.
Research shows, the present invention by carrying out alkali callbacks under the environment of acid ph value, the increase of product stability is not because introduced the inorganic salts such as sodium chloride, sodium sulfate, potassium sulfate when regulating pH value, and the simple inorganic salt that adds cannot make its stability improve.The salt (as sodium chloride, potassium sulfate, sodium phosphate) that may bring into while regulating pH value by adding, investigate salt as shown in table 1 below on the concrete outcome of the impact of the epimerism body burden of the tigecycline of lyophilizing under pH5.2 condition:
Group is 1 for pH value is to pull back to the content of the sodium chloride producing at 4.0 o'clock at 4.8 o'clock by alkali, group 4 and organize 5 for pH value be by alkali, to pull back to the potassium sulfate that produces and the content of sodium phosphate at 4.8 o'clock at 4.0 o'clock.
| Group | 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％ |
As can be seen from the above table, even than group 1 drop into more the sodium chloride of volume (as organize 2 and group 3), also cannot slow down advancing the speed of tigecycline epimer, therefore, in the situation that not using alkali callbacks, add separately salt (as sodium chloride, potassium sulfate and potassium phosphate) cannot improve significantly the stability of product.
When the alkali callbacks that the present invention uses is prepared tigecycline lyophilized formulations, when controlling epimerism body burden, the basic zero growth of all the other known impurities and unknown impuritie.From accompanying drawing 1-3, by by pH value 1.5 by alkali pull back to pH5.2 the tigecycline lyophilized formulations prepared of method, 0 day, 3 months, 6 months 40 ℃, accelerate not occur obvious impurity peaks on experiment HPLC collection of illustrative plates.
Research shows, by alkali callbacks, prepares tigecycline lyophilized formulations, and difference is returned the formulation and technology of adjusting starting point, and the growth of epimer is also had to obvious impact.Alkali adjusts 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 adjusts starting point pH value lower than 1.0, and freeze-dried powder molding, color and luster is not good enough.
The invention provides a kind of method of preparing tigecycline lyophilized formulations by alkali callbacks, pass through the method, can slow down significantly advancing the speed of tigecycline epimer, while all the other known impurities of tigecycline and the basic zero growth of unknown impuritie, improved largely the stability in tigecycline storage process, made patient's medication safer, effective; And without inflated with nitrogen, process in production process, reduced cost.
Accompanying drawing explanation:
Fig. 1 for by pH value 1.5 by alkali pull back to pH5.2 40 ℃ of HPLC collection of illustrative plates that keep sample 0 day of the tigecycline lyophilized formulations prepared of method.
Fig. 2 for by pH value 1.5 by alkali pull back to pH5.2 40 ℃ of trimestral HPLC collection of illustrative plates that keep sample of the tigecycline lyophilized formulations prepared of method.
Fig. 3 for by pH value 1.5 by alkali pull back to pH5.2 40 ℃ of HPLC collection of illustrative plates that keep sample six months of the tigecycline lyophilized formulations prepared of method.
Fig. 4 is that pH value is 40 ℃ of trimestral HPLC collection of illustrative plates that keep sample of 5.2 tigecycline lyophilized formulations
The specific embodiment:
Embodiment 1:
With reference to the preparation method of tigecycline injectable powder technique in Wyeth patent (ZL 200680006447.3), prepare respectively pH and be 5.60,5.20,4.80 tigecycline solution, as shown in the group 1 of table 2, group 2 and group 3.
Use alkali callbacks to prepare tigecycline injectable powder, concrete technology is as follows:
Get tigecycline 10.03g, refined lactose 20.00g, inject the about 700ml of water and dissolve, extremely suitable with the hydrochloric acid conditioning solution pH of 5mol/L, then with 2mol/L sodium hydroxide solution, return and adjust pH to suitable, add water for injection to be diluted to 800ml, shake up, use 0.22um filtering with microporous membrane, subpackage, half tamponade, lyophilizing, tamponade, Zha Gai, obtains this product.Specifically as shown in the group 4-group 13 of table 2.
Table 2: tigecycline injectable powder stability test:
| Experimental group | 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 pull back to 5.2 | 0.226 | 0.494 | 0.702 | 0.867 | 1.241 |
| 5 | 3.5 pull back to 5.2 | 0.230 | 0.455 | 0.541 | 0.728 | 1.116 |
| 6 | 3.0 pull back to 5.2 | 0.223 | 0.433 | 0.515 | 0.593 | 0.977 |
| 7 | 1.5 pull back to 5.2 | 0.205 | 0.329 | 0.336 | 0.369 | 0.479 |
| 8 | 1.0 pull back to 5.2 | 0.204 | 0.275 | 0.339 | 0.415 | 0.495 |
| 9 | 1.2 pull back to 5.2 | 0.211 | 0.281 | 0.308 | 0.322 | 0.457 |
| 10 | 1.3 pull back to 5.2 | 0.220 | 0.288 | 0.315 | 0.335 | 0.465 |
| 11 | 1.4 pull back to 5.2 | 0.200 | 0.311 | 0.328 | 0.361 | 0.472 |
| 12 | 3.0 pull back to 6.3 | 0.201 | 0.418 | 0.476 | 0.553 | 0.952 |
| 13 | 1.2 pull back to 6.3 | 0.208 | 0.277 | 0.331 | 0.386 | 0.501 |
As seen from the above table: the tigecycline injectable powder of preparing by pH alkali callbacks, its epimer recruitment can basic controlling below 1.0%, when pH value readjustment starting point is 1.0-1.5, tigecycline epimer recruitment can be controlled at below 0.3%.
Embodiment 2:
Get tigecycline 10.03g, refined lactose 20.00g, inject the about 700ml of water and dissolve, extremely suitable with the sulfuric acid regulation solution pH of 5mol/L, then with 2mol/L potassium hydroxide solution, return and adjust pH to suitable, add water for injection to be diluted to 800ml, shake up, use 0.22um filtering with microporous membrane, subpackage, half tamponade, lyophilizing, tamponade, Zha Gai, obtains this product.Shown in table 3 specific as follows.
Table 3: tigecycline injectable powder stability test:
| Experimental group | PH value | 0 day | 40 ℃ one month | 40 ℃ two months | 40 ℃ three months | 40 ℃ six months |
| 1 | 4.4 pull back to 5.6 | 0.221 | 0.489 | 0.695 | 0.871 | 1.302 |
| 2 | 1.0 pull back to 4.5 | 0.192 | 0.360 | 0.462 | 0.513 | 0.558 |
Embodiment 3:
Get tigecycline 10.03g, refined lactose 20.00g, inject the about 700ml of water and dissolve, extremely suitable with the phosphoric acid regulator solution pH of 5mol/L, then with 2mol/L sodium hydroxide solution, return and adjust pH to suitable, add water for injection to be diluted to 800ml, shake up, use 0.22um filtering with microporous membrane, subpackage, half tamponade, lyophilizing, tamponade, Zha Gai, obtains this product.Shown in table 4 specific as follows.
Table 4: tigecycline injectable powder stability test:
| Experimental group | PH value | 0 day | 40 ℃ one month | 40 ℃ two months | 40 ℃ three months | 40 ℃ six months |
| 1 | 1.5 pull back to 5.6 | 0.210 | 0.298 | 0.332 | 0.358 | 0.472 |
| 2 | 2.0 pull back to 6.3 | 0.221 | 0.353 | 0.438 | 0.492 | 0.735 |
Claims (6)
1. an injectable powder preparation method that reduces tigecycline epimer, is characterized in that comprising the following steps: get tigecycline, refined lactose, be dissolved in water for injection, first with acid, adjust and make material dissolution and make the pH of solution to suitable, then with alkali, return and adjust pH to suitable, 0.22 μ m filtering with microporous membrane, subpackage, half tamponade, lyophilizing, tamponade, Zha Gai, obtains, wherein, it is that pH is 1.0 to 4.4 that pH scope is adjusted in described acid, and described alkali returns and adjusts pH scope is that pH is 4.5 to 6.3.
2. injectable powder preparation method according to claim 1, is characterized in that: described acid is mineral acid, and described alkali is inorganic base.
3. injectable powder preparation method according to claim 2, is characterized in that: described acid is medicinal hydrochloric acid, sulphuric acid or phosphoric acid.
4. injectable powder preparation method according to claim 2, is characterized in that: described alkali is medicinal sodium hydroxide or potassium hydroxide.
5. injectable powder preparation method according to claim 1, is characterized in that: it is that pH is 1.0 to 1.5 that pH scope is adjusted in described acid.
6. injectable powder preparation method according to claim 1, is characterized in that: described alkali returns and adjusts pH scope is that pH is 5.2 to 6.3.
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