CN101919816B - Tigecycline-containing sterile packaged preparation for injection - Google Patents
Tigecycline-containing sterile packaged preparation for injection Download PDFInfo
- Publication number
- CN101919816B CN101919816B CN2010102225266A CN201010222526A CN101919816B CN 101919816 B CN101919816 B CN 101919816B CN 2010102225266 A CN2010102225266 A CN 2010102225266A CN 201010222526 A CN201010222526 A CN 201010222526A CN 101919816 B CN101919816 B CN 101919816B
- Authority
- CN
- China
- Prior art keywords
- tigecycline
- aseptic
- hydrochloric acid
- powder
- stir
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound 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 description 124
- 229960004089 tigecycline Drugs 0.000 title claims abstract description 113
- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- 238000002347 injection Methods 0.000 title abstract description 16
- 239000007924 injection Substances 0.000 title abstract description 16
- 239000000843 powder Substances 0.000 claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 88
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 23
- 239000002994 raw material Substances 0.000 claims description 23
- 239000013078 crystal Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 238000001914 filtration Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 210000004907 gland Anatomy 0.000 claims description 14
- 238000005303 weighing Methods 0.000 claims description 13
- 238000004140 cleaning Methods 0.000 claims description 12
- 238000012856 packing Methods 0.000 claims description 12
- 238000010298 pulverizing process Methods 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- 230000001954 sterilising effect Effects 0.000 description 12
- 239000012467 final product Substances 0.000 description 10
- 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 description 9
- 239000008101 lactose Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000004475 Arginine Substances 0.000 description 6
- 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 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 239000008103 glucose Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 229940011858 tigecycline 50 mg Drugs 0.000 description 5
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 239000005715 Fructose Substances 0.000 description 3
- 229930091371 Fructose Natural products 0.000 description 3
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000001509 sodium citrate Substances 0.000 description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000000811 xylitol Substances 0.000 description 3
- 235000010447 xylitol Nutrition 0.000 description 3
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 3
- 229960002675 xylitol Drugs 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 241000194033 Enterococcus Species 0.000 description 1
- 206010021143 Hypoxia Diseases 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
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940041476 lactose 100 mg Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(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 DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the field of pharmaceuticals and relates to a tigecycline-containing sterile packaged preparation for injection. The sterile powder of tigecycline is prepared by a solvent crystallization method. Each preparation contains 10 to 500mg of sterile powder of tigecycline or sterile powder of tigecycline salt.
Description
Technical field
The invention belongs to pharmaceutical field, relate to a kind of sterile packaged preparation for injection that contains tigecycline.
Background technology
Tigecycline is a kind of TCs, is the analog of minocycline, can be used for antimicrobial agent, and is still effective when concurrent present other antibiotic therapy is failed.Like enterococcus of methicillin resistant staphylococcus aureus, penicillin-fast streptococcus pneumoniae, vancomycin resistance etc., it still has activity.
Tigecycline is the antibiotic with broad spectrum antibiotic activity.Yet tigecycline is not quite stable, and the patent CN200680021384.9 of Wyeth's application points out that tigecycline is difficult to make, because it is easy to degraded (comprise by aerial oxygen and carry out oxidative degradation) and is prone to form epimer.Preparation injection tigecycline prepares in the process, need tigecycline be dissolved in through nitrogen jet to make oxygen content be lower than 5ppm and maintain the temperature in the water of about 2-8 degree, and lyophilizing then in the water of low temperature and hypoxia, technology is very complicated, the production cost costliness.
Can see the tigecycline preparation of Hui Shi listing from PDR (Physicians ' Desk Reference); Trade name;
generation writes out a prescription and is: tigecycline 50mg, the water lyophilizing is removed.
In 2 generations,, prescription was: tigecycline 50mg, and lactose 100mg, hydrochloric acid is transferred ph, and the water lyophilizing is removed.
Wherein, 1 generation prescription is the tigecycline directly lyophilizing of back that is dissolved in water.
In 2 generations,, prescription was after tigecycline is dissolved in water, and added hydrochloric acid and transferred ph, added the lactose lyophilizing.
After adding the adjuvant lactose stability is improved, but lactose derives from Lac Bovis seu Bubali, may contain and remove unclean protein, anaphylaxis is increased.Anaphylaxis is a kind of serious adverse effects, and serious meeting causes life danger.And the adjuvant lactose generally only is used to make oral formulations, and (referring to the pharmaceutic adjuvant handbook, Chemical Industry Press publishes, P32; The lactose classification is; Lactose is used for the diluent of powder inhalation, the diluent of tablet and capsule), and the rule of making preparation is exactly, and adjuvant is few more good more.
We find that through experiment accident ground the tigecycline solvent crystal can form stable crystal formation, and water-soluble lyophilizing afterwards just becomes the amorphous state of no crystal formation.
Summary of the invention
The object of the present invention is to provide a kind of Injectable sterile preparation that contains tigecycline or its salt.The quality of the pharmaceutical preparations of the present invention is stable, and clinical easy to use, cost is low.
Preparation of the present invention, every contains the aseptic powder of tigecycline or the aseptic powder 10-500mg of tigecycline salt.
Preferably, every preparation contains the aseptic powder 25-100mg of tigecycline aseptic powder or tigecycline salt.
Preferred, every preparation contains tigecycline aseptic powder 50mg or is equivalent to the aseptic powder of the tigecycline salt of tigecycline 50mg.
Tigecycline salt of the present invention is selected from: hydrochloric acid tigecycline, acetic acid tigecycline, sulphuric acid tigecycline, methanesulfonic acid tigecycline, benzenesulfonic acid tigecycline or lactic acid tigecycline.Be preferably the hydrochloric acid tigecycline.
1, preparation of the present invention; Only contain the aseptic powder of tigecycline or the aseptic powder of tigecycline salt; Do not contain other composition; If but the amount of tigecycline aseptic powder and tigecycline salt aseptic powder is too little in every injection; Make when producing the said preparation inconvenience and can consider to add some aseptic addns to gain in weight, like arginine, sodium carbonate, glucose, mannitol, sorbitol, sodium chloride, sodium citrate, sodium carbonate, arginine, glucose, fructose, sucrose, xylitol, dextran.
Tigecycline and tigecycline salt aseptic powder are prepared from through the solvent crystal method.
The present invention also provides the method for preparing of tigecycline aseptic powder and tigecycline salt aseptic powder.
Wherein, the tigecycline aseptic powder is prepared from through following method:
(1) taking by weighing the tigecycline bullion adds in the agitated reactor; Added the mixed solution of methanol and acetone in 1: 1 by volume, 25 ℃ are stirred after 1 hour, slowly are cooled to 0 ℃; Keeping 0 ℃ continues to stir 1 hour; Aseptic filtration, with the mixed solution washing leaching cake of above-mentioned cold acetone and methanol, drying under reduced pressure gets refined products one time;
(2) take by weighing an above-mentioned refined products, added dichloromethane in 1: 50 by volume, agitating heating refluxed 0.5 hour; Aseptic filtration filters out insoluble matter, and filtrating is slowly stirred and is cooled to 0 ℃ after separate out crystallization; Continue 0 ℃ and stirred 4 hours, cold washed with dichloromethane is used in aseptic filtration; Drying under reduced pressure gets the aseptic raw material of tigecycline.
Wherein, the aseptic powder of tigecycline salt is prepared from through following method:
The preparation of the aseptic powder of hydrochloric acid tigecycline:
Take by weighing the tigecycline elaboration and add in the agitated reactor, added dichloromethane in 1: 12 by volume, 25 ℃ were stirred after 1 hour; Add hydrogen chloride methanol solution in 1: 1.1 in molar ratio, continue to stir after 3 hours, carry out aseptic filtration; Drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline
Perhaps,
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 10 by volume adding 2-butanone; Keep 25 ℃ to stir after 1 hour, added concentrated hydrochloric acid in 1: 1 in molar ratio, continue to stir after 4 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline.
Other salt can be by above-mentioned same procedure preparation, as long as change hydrochloric acid into corresponding acid.As:
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 10 by volume adding 2-butanone; Keep 25 ℃ to stir after 1 hour, added corresponding acid in 1: 1 in molar ratio, continue to stir after 4 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of tigecycline salt.
Above preparation process all needs to accomplish in sterilizing room, and solvent all needs after aseptic filtration, to use, and the vessel of use all need aseptic process.
Aseptic; Under the production environment of local laminar flow; After tigecycline that makes or the pulverizing of hydrochloric acid tigecycline sterile solid, place the racking machine hopper, contain tigecycline 50mg according to every; The dose of hydrochloric acid tigecycline 53mg is loaded in the aseptic cillin bottle of cleaning oven dry, and gland, packing promptly get.
Further specify beneficial effect of the present invention through following experiment.
We find that through experiment the tigecycline solvent crystal can form stable crystal formation, but in case water-soluble back lyophilizing; Just become the amorphous state of no crystal formation; Accelerated test result shows that the Pickering property of tigecycline solvent crystal significantly is better than freeze dried amorphous solid, sees the following form 1
Table 1, tigecycline solvent crystal solid and lyophilized solid stability is (60 degree, 5 days) relatively
Annotate: tigecycline solvent crystal sample preparation methods:, be sub-packed in the cillin bottle every dress 50mg referring to embodiment 1 preparation tigecycline solvent crystal solid.
The secondary prescription of listing article tigecycline is to transfer PH earlier, just adds the lactose lyophilizing then, and medical substance comes down to the hydrochloric acid tigecycline; Therefore we have also prepared the solvent crystal article of hydrochloric acid tigecycline; And also made the lyophilized solid of hydrochloric acid tigecycline, the X-diffraction shows identical with tigecycline, and the hydrochloric acid tigecycline is crystallization; But water-soluble back lyophilizing just becomes amorphous state; Accelerated test shows that the Pickering property of hydrochloric acid tigecycline solvent crystal significantly is better than freeze dried amorphous solid, sees the following form 2.
Wherein, hydrochloric acid tigecycline solvent crystal solids method:, be sub-packed in the cillin bottle every dress 50mg referring to embodiment 2 preparation hydrochloric acid tigecycline solvent crystal solids.
Hydrochloric acid tigecycline lyophilized solid method for preparing: get hydrochloric acid tigecycline 250mg and be dissolved in the 25ml water, be sub-packed in five cillin bottles, every dress 5ml puts into the freeze dryer lyophilizing then, and gland promptly gets.
The commercially available prescription own product of hydrochloric acid tigecycline method for preparing: get hydrochloric acid tigecycline 250mg and lactose 500mg is dissolved in the 25ml water, be sub-packed in five cillin bottles, every dress 5ml puts into the freeze dryer lyophilizing then, and gland promptly gets.
Table 2, hydrochloric acid tigecycline solvent crystal solid and lyophilized solid stability is (60 degree, 5 days) relatively
Experimental result shows that the stability of tigecycline aseptic powder and hydrochloric acid tigecycline aseptic powder is better, the tigecycline that is superior to selling on the existing market.
In addition, preparation dissolution velocity of the present invention has solved the difficult problem of clinical practice soon.
| Sample | Dissolution velocity |
| Embodiment 4 preparations | In 10 seconds |
| Embodiment 5 preparations | In 10 seconds |
| Commercially available tigecycline lyophilizing (containing lactose) | In 30 seconds |
Injectable sterile preparation of the present invention, dissolution velocity is fast, and good stability is safe, few side effects, long shelf-life, clinical easy to use, its preparation technology is simple in addition, and cost is low.
The specific embodiment:
To do further description to the present invention through embodiment below, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what content of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
Below experiment all needs in sterilizing room, to accomplish, and solvent all needs after aseptic filtration, to use, and the vessel of use all need aseptic process.
The preparation of embodiment 1, tigecycline solvent crystal solid (aseptic raw material)
Taking by weighing 10g tigecycline bullion adds in the reaction bulb; The mixed solution that adds 10ml methanol and 10ml acetone keeps 25 ℃ to stir after 1 hour, slowly is cooled to 0 ℃; Keeping 0 ℃ continues to stir 1 hour; Aseptic filtration, with mixed solution (1: the 1) washing leaching cake of small amount of cold acetone and methanol, drying under reduced pressure gets refined products one time.
Take by weighing the above-mentioned refined products of 5g, add 250ml dichloromethane agitating heating and reflux half an hour aseptic filtration; Filter out insoluble matter, filtrate for later use, filtrating is slowly stirred and is cooled to 0 ℃ after separate out crystallization; Continue 0 ℃ and keep stirring 4 hours, aseptic filtration, small amount of cold washed with dichloromethane; Drying under reduced pressure gets the aseptic raw material of tigecycline.
The preparation of embodiment 2, hydrochloric acid tigecycline solvent crystal solid (aseptic raw material)
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 12 by volume adding dichloromethane; Keep 25 ℃ to stir after 1 hour, added hydrogen chloride methanol solution in 1: 1.1 in molar ratio, continue to stir after 3 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline.
The preparation of embodiment 3, hydrochloric acid tigecycline solvent crystal solid (aseptic raw material)
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 10 by volume adding 2-butanone; Keep 25 ℃ to stir after 1 hour, added concentrated hydrochloric acid in 1: 1 in molar ratio, continue to stir after 4 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline.
The preparation of embodiment 4, injection tigecycline
The aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 50mg.Gland, packing get final product.
The preparation of embodiment 5, hydrochloride for injection tigecycline
The aseptic raw material of hydrochloric acid tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 53mg.Gland, packing get final product.
The preparation of embodiment 6, injection tigecycline
The aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 10mg.Gland, packing get final product.
The preparation of embodiment 7, injection tigecycline
The aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 25mg.Gland, packing get final product.
The preparation of embodiment 8, injection tigecycline
The aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 50mg.Gland, packing get final product.
The preparation of embodiment 9, injection tigecycline
With the aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow; Be selected from arginine, sodium carbonate, glucose; Behind the additive mixing of mannitol, sorbitol, sodium chloride, sodium citrate, sodium carbonate, arginine, glucose, fructose, sucrose, xylitol, dextran; Be sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress tigecycline 50mg, additive 50-200mg together.Gland, packing get final product.
The preparation of embodiment 9, injection tigecycline
The aseptic raw material of the tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 100mg.Gland, packing get final product.
The preparation of embodiment 10, hydrochloride for injection tigecycline
The aseptic raw material of hydrochloric acid tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 26.5mg.Gland, packing get final product.
The preparation of embodiment 11, hydrochloride for injection tigecycline
The aseptic raw material of hydrochloric acid tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow, is sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress 53mg.Gland, packing get final product.
The preparation of embodiment 12, hydrochloride for injection tigecycline
With the aseptic raw material of hydrochloric acid tigecycline that makes after pulverizing under the production environment of aseptic, local laminar flow; Be selected from arginine, sodium carbonate, glucose; Behind the additive mixing of mannitol, sorbitol, sodium chloride, sodium citrate, sodium carbonate, arginine, glucose, fructose, sucrose, xylitol, dextran; Be sub-packed in the cillin bottle of cleaning behind the drying and sterilizing every dress hydrochloric acid tigecycline 53mg, additive 50-200mg together.Gland, packing get final product.
Claims (3)
1. method for preparing that contains the Injectable sterile preparation of tigecycline; Every in said preparation contains the aseptic powder of tigecycline or the aseptic powder 10-500mg of hydrochloric acid tigecycline; It is characterized in that; The aseptic powder of tigecycline aseptic powder or hydrochloric acid tigecycline is prepared from through the solvent crystal method, and said tigecycline aseptic powder is prepared from through following method:
(1) taking by weighing the tigecycline bullion adds in the agitated reactor; Added the mixed solution of methanol and acetone in 1: 1 by volume, 25 ℃ are stirred after 1 hour, slowly are cooled to 0 ℃; Keeping 0 ℃ continues to stir 1 hour; Aseptic filtration, with the mixed solution washing leaching cake of above-mentioned cold acetone and methanol, drying under reduced pressure gets refined products one time;
(2) take by weighing an above-mentioned refined products, added dichloromethane in 1: 50 by volume, agitating heating refluxed 0.5 hour; Aseptic filtration filters out insoluble matter, and filtrating is slowly stirred and is cooled to 0 ℃ after separate out crystallization; Continue 0 ℃ and stirred 4 hours, cold washed with dichloromethane is used in aseptic filtration; Drying under reduced pressure gets the aseptic raw material of tigecycline;
Said hydrochloric acid tigecycline aseptic powder is prepared from through following method:
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 12 by volume adding dichloromethane; Keep 25 ℃ to stir after 1 hour, added hydrogen chloride methanol solution in 1: 1.1 in molar ratio, continue to stir after 3 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline;
Or
Take by weighing the tigecycline elaboration and add in the agitated reactor, 1: 10 by volume adding 2-butanone; Keep 25 ℃ to stir after 1 hour, added concentrated hydrochloric acid in 1: 1 in molar ratio, continue to stir after 4 hours, carry out aseptic filtration, drying under reduced pressure gets the aseptic raw material of hydrochloric acid tigecycline;
After tigecycline that makes or the pulverizing of hydrochloric acid tigecycline aseptic powder, place the racking machine hopper, be loaded on according to every dose that contains in the aseptic cillin bottle of cleaning oven dry, gland, packing promptly get.
2. the described method for preparing of claim 1 is characterized in that, every preparation contains hydrochloric acid tigecycline aseptic powder 25-100mg.
3. the described method for preparing of claim 1 is characterized in that, every preparation contains tigecycline aseptic powder 50mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102225266A CN101919816B (en) | 2010-07-02 | 2010-07-02 | Tigecycline-containing sterile packaged preparation for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102225266A CN101919816B (en) | 2010-07-02 | 2010-07-02 | Tigecycline-containing sterile packaged preparation for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101919816A CN101919816A (en) | 2010-12-22 |
| CN101919816B true CN101919816B (en) | 2012-07-25 |
Family
ID=43335207
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102225266A Active CN101919816B (en) | 2010-07-02 | 2010-07-02 | Tigecycline-containing sterile packaged preparation for injection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101919816B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102258476B (en) * | 2011-05-16 | 2012-11-14 | 赵军旭 | Method for preparing tigecycline for injection |
| CN103315947B (en) * | 2012-03-22 | 2016-01-20 | 上海汇伦生命科技有限公司 | A kind of tigecycline for injection compositions |
| US20140323443A1 (en) * | 2013-04-30 | 2014-10-30 | Fresenius Kabi Usa, Llc | Tigecycline formulations |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228113A (en) * | 2005-05-27 | 2008-07-23 | 惠氏公司 | Tigecycline and methods of preparing 9-aminominocycline |
-
2010
- 2010-07-02 CN CN2010102225266A patent/CN101919816B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101228113A (en) * | 2005-05-27 | 2008-07-23 | 惠氏公司 | Tigecycline and methods of preparing 9-aminominocycline |
Non-Patent Citations (1)
| Title |
|---|
| 张建新等.静脉注射抗生素新药：替加环素.《河北医药》.2006,第28卷(第12期),第1207-1208. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101919816A (en) | 2010-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101919816B (en) | Tigecycline-containing sterile packaged preparation for injection | |
| KR102375444B1 (en) | Applications and drugs of isovaleryl spiramycin I, II and/or III in the manufacture of drugs to treat and/or prevent tumors | |
| EP3607952A1 (en) | Use of carrimycin and pharmaceutically acceptable salt thereof for manufacture of medicament for treatment and/or prevention of tumors | |
| KR880002087B1 (en) | Process for preparing salts of antimicrobial naphthyridine and quinoline compounds | |
| CN106795159B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| WO2018130063A1 (en) | (r)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof | |
| CN102228444B (en) | N(2)-L-alanyl-L-glutamine preparation for injection and preparation method thereof | |
| CN104945453B (en) | The polymorph of pyrazole derivatives | |
| CN113893221A (en) | High-water-solubility tylosin premix | |
| CN107595782A (en) | A kind of Linezolid dry suspensoid agent and preparation method thereof | |
| CN109588724A (en) | A kind of probiotic powder and preparation method thereof improving stomach trouble | |
| CN101744831B (en) | Preparation method of tylosin tartrate-doxycycline hydrochloride pharmaceutical composition | |
| CN102302462A (en) | Gemcitabine hydrochloride lyophilized preparation | |
| CN102942577A (en) | Cefoxitin sodium compound-containing pharmaceutical composition | |
| CN103145735A (en) | Cefmenoxime hydrochloride compound for injection and pharmaceutical composition thereof | |
| CN102942576A (en) | New crystal form composition of cefminox sodium and preparation method thereof | |
| CN102258476B (en) | Method for preparing tigecycline for injection | |
| CN105596345A (en) | Drug composition of cefoperazone sodium and sulbactam sodium | |
| JPH0614862B2 (en) | Bifidobacterium growth promoter | |
| CN104887632B (en) | A kind of preparation method of decitabine freeze-dried preparation and products thereof | |
| CN106310286B (en) | Tosufloxacin tosylate composition | |
| CN101744800B (en) | Nedaplatin medical composition and application | |
| CN105030804B (en) | - 3 β-N- methoxyl groups-N- β of Bufalin-application of the D-Glucose glycosides in preparing cardiac drug | |
| CN110551038A (en) | Novel antitumor compound and application thereof | |
| CN102335137A (en) | Medicinal composition containing meropenem |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHIJIAZHUANG ZHITONG PHARMACEUTICAL TECHNOLOGY CO. Free format text: FORMER OWNER: ZHAO JUNXU Effective date: 20140210 |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 050011 SHIJIAZHUANG, HEBEI PROVINCE TO: 050035 SHIJIAZHUANG, HEBEI PROVINCE |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20140210 Address after: Taishan high tech Zone of Hebei Province, Shijiazhuang City, 050035 street, No. 219 Patentee after: HEBEI ZHITONG PHARMACEUTICAL GROUP CO., LTD. Address before: 050011 dormitory 9-1-401, provincial medical college, 222 Dongfeng East Road, Hebei, Shijiazhuang Patentee before: Zhao Junxu |
|
| ASS | Succession or assignment of patent right |
Owner name: SHIJIAZHUANG ZHIHENG PHARMACEUTICAL TECHNOLOGY CO. Free format text: FORMER OWNER: SHIJIAZHUANG ZHITONG PHARMACEUTICAL TECHNOLOGY CO., LTD. Effective date: 20150407 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 050035 SHIJIAZHUANG, HEBEI PROVINCE TO: 050011 SHIJIAZHUANG, HEBEI PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20150407 Address after: 050011 Hebei Shijiazhuang Zhai Yingnan Street No. 73 building 3 floor business Williams Patentee after: SHIJIANGZHUANG ZHIHENG PHARMACY TECHNOLOGY CO., LTD. Address before: Taishan high tech Zone of Hebei Province, Shijiazhuang City, 050035 street, No. 219 Patentee before: HEBEI ZHITONG PHARMACEUTICAL GROUP CO., LTD. |
|
| C56 | Change in the name or address of the patentee |
Owner name: HEBEI ZHIHENG PHARMACEUTICAL TECHNOLOGY CO., LTD. Free format text: FORMER NAME: SHIJIAZHUANG ZHIHENG PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: 050011 Hebei city of Shijiazhuang province Yingnan Zhai Street No. 73 building 3 floor business Williams Patentee after: Hebei Zhi Heng pharmaceutical Polytron Technologies Inc Address before: 050011 Hebei Shijiazhuang Zhai Yingnan Street No. 73 building 3 floor business Williams Patentee before: SHIJIANGZHUANG ZHIHENG PHARMACY TECHNOLOGY CO., LTD. |