CN104107170A - Tigecycline composition - Google Patents
Tigecycline composition Download PDFInfo
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- CN104107170A CN104107170A CN201310140974.5A CN201310140974A CN104107170A CN 104107170 A CN104107170 A CN 104107170A CN 201310140974 A CN201310140974 A CN 201310140974A CN 104107170 A CN104107170 A CN 104107170A
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- tigecycline
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- lactose
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- 229960004089 tigecycline Drugs 0.000 title claims abstract description 89
- 239000000203 mixture Substances 0.000 title claims abstract description 70
- 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 29
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 62
- 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 39
- 239000008101 lactose Substances 0.000 claims abstract description 39
- 239000011780 sodium chloride Substances 0.000 claims abstract description 31
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000002347 injection Methods 0.000 claims description 25
- 239000007924 injection Substances 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000007909 solid dosage form Substances 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 22
- 239000002253 acid Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 4
- 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 abstract description 2
- 239000003513 alkali Substances 0.000 abstract description 2
- 238000009835 boiling Methods 0.000 abstract description 2
- 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 compound 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 61
- 238000006345 epimerization reaction Methods 0.000 description 19
- 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 description 15
- 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 12
- 229960004023 minocycline Drugs 0.000 description 12
- 239000004098 Tetracycline Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 235000019364 tetracycline Nutrition 0.000 description 10
- 150000003522 tetracyclines Chemical class 0.000 description 10
- 239000000523 sample Substances 0.000 description 9
- 229960002180 tetracycline Drugs 0.000 description 9
- 229930101283 tetracycline Natural products 0.000 description 9
- 238000002512 chemotherapy Methods 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 7
- 238000011203 antimicrobial therapy Methods 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 6
- 238000010525 oxidative degradation reaction Methods 0.000 description 6
- 230000015556 catabolic process Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 230000006652 catabolic pathway Effects 0.000 description 4
- 208000035473 Communicable disease Diseases 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 210000004907 gland Anatomy 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 229940080435 lactose 250 mg Drugs 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 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 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 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 2
- 239000000872 buffer Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 239000002905 metal composite material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000194033 Enterococcus Species 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 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
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 108010059993 Vancomycin Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical class [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- -1 carbon water ring compound Chemical class 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000002560 therapeutic procedure 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
- 210000003462 vein Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A tigecycline composition disclosed by the invention is prepared from the following raw materials in parts by weight: 1.0 part of tigecycline, 0.2-4 parts of lactose, and 0.1-1 part of sodium chloride. The pH value of the tigecycline composition is 4-6. Lactose and sodium chloride are dissolved in water cooled after boiling, then tigecycline is added and stirred to be dissolved, the solution is adjusted by an acid or an alkali to a corresponding pH value, the solution is freeze-dried, a plug is pressed, and a cover is pressed. The validity period of the composition is longer than that of a commercially available product. In addition, because Asians have poorer lactose tolerance, the composition significantly reduces the amount of lactose under a condition of achieving the same stability, so as to reduce generation of side effects.
Description
Technical field
The present invention relates to improved tigecycline (tigecycline) compositions.
Background technology
Tigecycline is a kind of well-known tetracycline antibiotics, and is the analog of minocycline.This material can be used for overriding resistance element, and has found that it is still effective in the time of other antibiotic therapy failure.
Tigecycline has activity to following microorganism, comprise the staphylococcus aureus (Staphylococcus aureus) of methicillin resistance, the streptococcus pneumoniae (Staphylococcus pneumoniae) of Penicillin-resistant, the enterococcus (people such as D.J.Beidenbach, diagnostic microbiology and infectious disease (Diagnostic Microbiology and Infectious Disease) 40:173-177(2001) of drug resistance of vancomycin; The people such as H.W.Boucher, antimicrobial and chemotherapy (Antimicrobial Agents and Chemotherapy) 44:2225-2229(2000);
P.A.Bradford Clinical microorganism current events wall bulletins (Clin.Microbiol.Newsett.) 26:163-168(2004); The people such as D.Milatovic, antimicrobial and chemotherapy 47:400-404(2003); The people such as R.Patel, diagnostic microbiology and infectious disease 38:177-179(2000); The people such as P.J.Petersen, antimicrobial and chemotherapy 46:2595-2601(2002); The people such as P.J.Petersen, antimicrobial and chemotherapy 43:738-744(1999)), and with the microorganism of one of four kinds of main resistance mechanisms of tetracycline (discharge and ribosome protect) people such as (, antimicrobial and chemotherapy 48:323-325(2004) C.Betriu; The people such as T.Hirata, antimicrobial and chemotherapy 48:2179-2184(2004); With the people such as P.J.Petersen, antimicrobial and chemotherapy 43:738-744(1999)).
Because tigecycline bioavailability in the time of oral administration is conventionally very poor, so tigecycline was intravenously administrable in the past.The solution of intravenously administrable is mainly using (for example, to patient's administration) front freeze dried powder that is prepared into.Tigecycline is mainly degraded by being oxidized in solution.Preferably have and need to have and need not use immediately, and can in solution, keep the stable tigecycline intravenous formulations up to 24 hours.
Tigecycline is produced as lyophilized powder at present.Because tigecycline has propensity for degradation, so these lyophilized powders are produced under hypoxia and cryogenic conditions, minimize so that degrade.
The classical way of preparing tigecycline compositions comprises that slurry tigecycline is dissolved in water and by solution lyophilizing to form amorphous tigecycline solid mass, then under nitrogen environment, these blocks are packed in band plug glass vial, and be transported to the terminal use as hospital pharmacy.Before to patient's administration, these blocks are reconstructed (conventionally using 0.9% saline) and arrive the concentration of 10mg/mL according to appointment.Under this concentration, tigecycline is fast degradation in solution, therefore must use immediately.Like this, with saline or other pharmaceutically acceptable diluent, these reconstituted solutions are diluted in patient's administrable venous pocket immediately, and are diluted to about 1mg/mL.
Under this diluted state, tigecycline is easy to intravenously administrable patient, but under 1mg/mL concentration, tigecycline should use in 6 hours after dilution.Because venous transfusion may spend several hours, medical personnel must be swift in motion, so that start to be no more than 6 hours to the time that tigecycline preparation is given to patient from mixing.Should more preferably provide motility and the benefit brought by the mixing of more growing and reconstitution time to medical personnel, thereby for example hospital pharmacist can need to prepare solution to the previous day of patient's administration.
Tigecycline incorporation time is so short, and reconstitution time is substantially zero, and is that oxidation due to tigecycline in solution is than very fast.Under current production, storage and administration condition, the reason of the oxidation of topmost degraded form is relevant with the chemical constitution of tigecycline.Tigecycline contains powder group, and it is well-known that phenol is easy to oxidation especially in organic chemistry filed.When time tigecycline is soluble in water before lyophilizing, pH is alkalescence (approximately 7.8), and this is higher than the pKa of the phenolic group group on tigecycline.Therefore, in water and saline solution, phenolic group group sloughs proton and is more easy to react with oxygen, and this is that tigecycline is in the reason of mixing and lyophilizing will be carried out under nitrogen environment.Therefore,, in reconstruct and dilution, medical personnel must live to avoid contacting of unnecessary and oxygen.
If the pH of tigecycline solution is lower than the pKa of phenolic group group on tigecycline, oxidation can occur, but it drops to compared with low degree.In fact, having observed the oxidative degradation of tigecycline in the time that pH is lower reduces really.But in the time of low pH value, another degradation process occurs, i.e. epimerization.In the time of lower pH value, epimerism is turned to topmost degradation pathway and occurs.
Tigecycline and its epimerization structurally only have not same.
In tigecycline, the N-dimethyl group on 4 carbon and adjacent hydrogen are Cis formulas, and as above shown in facial I, and in its epimer (formula II), their are trans each other mutually, the mode as shown in formula II.Although tigecycline epimerization is considered to avirulent, it lacks the antibacterial effectiveness of tigecycline.Therefore, it is undesirable catabolite.
Under lyophilised state, tigecycline is followed and degradation pathway identical in solution, but degradation speed is relatively slow.So, when tigecycline is in the time that pH is about in 7.8 water lyophilizing, obtain lyophilizing block generation oxidative degradation, although its speed is slower than in solution.Similarly, when tigecycline is during in acid solution lyophilizing, main degradation pathway is epimerization, and its epimerization speed is also slower than in solution.
Epimerization is the known general degradation pathway of tetracycline, although degradation speed can change according to different tetracyclines.Comparatively speaking, the epimerization speed of tigecycline is fast especially.Tetracycline pertinent literature has reported that several scientists are in order to attempt and to make tetracycline epimer generate the direction minimizing.In certain methods, the generation of calcium, magnesium, zinc or the aluminum metal salt of tetracycline has limited the epimer generation occurring in the anhydrous solution of alkaline pH and limited the epimer generation (Gordon occurring in the anhydrous solution of alkaline pH, P.N., Stephens Jr, C.R., Noseworthy, M.M., Teare, F.W., U.K. patent 901107).In other method, (Tobkes, U.S. patent 4038315) generates metal composite under acid pH, follows stable solid form medicine and prepared.
Being included in whole process for other method that reduces epimerization keeps pH to be approximately greater than 6.0; Avoid and contact as formates, acetate, phosphate or boratory weak acid conjugate; And avoid contacting with the dampness that comprises aqueous solution.For being protected from influence of moisture, Noseworthy and Spiegel(U.S. patent 3026248) and Nash and Haeger(U.S. patent 3219529) non-water-soluble matchmaker's preparation of tetracycline analogue has been proposed, to improve the stability of medicine.But, compared with using with parenteral, the most of solvents that comprise in these inventions are more suitable for local use.Tetracycline epimerization temperature dependency moral is also known, therefore produces at low temperatures and store tetracycline and also can reduce formation speed (Yuen, the P.H. of epimerization, Sokoloski, T.D., pharmaceutical science magazine) (J.Pharm.Sci) 66:1648-1650,1977; Pawelczyk, E., Matlak., Matlak, B, Pol. pharmacology and to learn magazine (J.Pharmacol.Pharm) 34::409-421,1982).With several in these methods, tigecycline is attempted, generated and oxidative degradation but do not have method can reduce epimer, do not introduce again other degradation product simultaneously.Metal composite, for example, finding under alkaline pH, its epimer to be generated or degraded does not almost affect conventionally.
Although the use of phosphate, acetate and citrate buffer agent has improved the stability of solution state, they are as the degraded of having accelerated lyophilised state tigecycline.But, even in the time existing without buffer agent, as compared with minocycline, be even more serious problem for replacing the plain epimerization of ring with other tetracycline.
Other method in these methods can not reduce epimerization and oxidative degradation simultaneously.Although as mentioned above, to find to keep to be approximately greater than 6.0 pH and can help reduce epimer and generate, this condition causes higher oxygen sensitivity.For non-water dissolution, although think that water accelerates the degraded of tigecycline, it will be unpractical that above-mentioned non-water-soluble matchmaker prepares intravenous pharmacy.
Although determined at the temperature lower than room temperature (as being less than about 10 DEG C) and processed the degradation speed that can reduce tigecycline, but this processing method is expensive, it will be useful that use does not need to carry out the high freezing compositions spending in the course of processing.
Chinese patent application CN1390550A discloses minocycline can combine to improve the stability to oxidative degradation with acid, and further proposes as the application of the coagulating agent of mannitol.But this reference paper had not both been mentioned replacement ring element, also not proposing carbohydrate in the pH environment reducing can be for reducing oxidation or the epimerization of minocycline.In fact, minocycline can be made to vein product formulation with its hydrochlorate, and there is no significant epimerization.But replacing in the plain hydrochlorate of ring, can find significant epimerization.Therefore, minocycline and tigecycline have different epimerization characteristics.
In another experiment, minocycline is carried out to lyophilizing approximately 5.0 times at pH, lyophilizing piece is deposited 20 days under 40 DEG C and 75% relative humidity.At 20 days ends, lyophilizing piece is analyzed with HPLC.Epimer to minocycline is measured, and calculating is by mass 2.65%.Comparatively speaking, tigecycline is carried out to lyophilizing approximately 5.0 times at pH, sample is deposited under identical condition, within 4 days, then carry out HPLC analysis but only deposit, measuring tigecycline epimer is 5.40%, more than the doubling dose in minocycline, 1/5 long-time although tigecycline has only deposited that minocycline deposits.Therefore, tigecycline is than the easier epimerization of minocycline, and it is for minocycline relatively, and epimerization is even more important problem for tigecycline.
In order to solve the problems of the technologies described above, China Patent Publication No. CN101132775 discloses a kind of replacement ring promotor composition and preparation method, the aqueous solution that it contains tigecycline and suitable carbon water ring compound by lyophilizing under acid pH, has been worth comparing oxidative degradation and the more stable tigecycline compositions of epimerization with compositions.This tigecycline comprises at least one suitable carbohydrate of tigecycline and acid or buffer agent.Its suitable carbohydrate is selected from newborn mannose, sucrose and glucose.It also comprises pharmaceutically can receive diluent.Diluent is saline, sodium lactate ringer's injection or glucose solution.The pH value scope of compositions is 3.0～7.0, and acid is hydrochloric acid or DHB.But the embodiment providing from it, the sample that its pH that contains lactose that is 4.5 times preparations at about pH is 4.5 was placed after 25 days in the chamber of 40 DEG C/75%/RH, and the content of tigecycline only has 97.17%.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of tigecycline for the existing deficiency of prior art, and the stability of said composition has exceeded the compositions of tigecycline lyophilizing together with lactose, and therefore the effect duration of this combination will be longer than commercially available product.Because there is toleration in Aisan to lactose, under the condition that reaches same stable, the present invention can reduce the consumption of lactose in addition, to reduce the generation of side reaction.
Technical problem to be solved by this invention can be achieved through the following technical solutions:
A compositions for tigecycline, its raw material by following weight portion is prepared from: 1.0 parts of tigecyclines, 0.2～4 part of lactose, 0.1～1 part, sodium chloride.
In a preferred embodiment of the invention, the weight portion of described lactose is 0.5～2 part.
In a preferred embodiment of the invention, the weight portion of described sodium chloride is 0.2～0.4 part.
In a preferred embodiment of the invention, the pH value of the compositions of described tigecycline is 4～6.
In a preferred embodiment of the invention, the composition for injection that the compositions of described tigecycline is tigecycline.
In a preferred embodiment of the invention, the composition for injection of described tigecycline is injection solution preparation compositions or solid dosage forms for injection compositions, is preferably solid dosage forms for injection compositions; As freeze-dried powder.
The present invention, taking lactose as proppant, adds sodium chloride can make tigecycline more stable simultaneously.
Compositions of the present invention can be by many acceptable method preparations.Method described below is exemplary, does not mean limitation of the present invention.
The present invention is dissolved in lactose and sodium chloride in the boiled water letting cool, and then adds after tigecycline stirring and dissolving and is adjusted to corresponding pH value with acid or alkali, by solution lyophilizing, tamponade, gland.
The effect duration of this combination will be longer than commercially available product.Because Aisan is poor to lactose toleration, under the condition that reaches same stable, the present invention reduces the consumption of lactose significantly in addition, to reduce the generation of side reaction.
Detailed description of the invention
The following examples exemplify explanation different embodiments of the present invention, but to the present invention without any restriction.In each embodiment, compositions is a lyophilizing in same freeze dryer, in same drying baker, places, and raw materials used is same batch.
Numeric ratio in bracket is weight ratio herein, and TGC is tigecycline abbreviation.
Embodiment 1: lactose+TGC(0.5:1), pH4.5
Take lactose 250mg and be dissolved in 20mL deoxidized water (after boiling pure water, let cool, below identical), adjust pH to 4.5 with 1mol/LHCl after adding TGC500mg to dissolve, then divide and be filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 2: lactose+sodium chloride+TGC(0.5:0.2:1), pH4.5
Take lactose 250mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 3: lactose+sodium chloride+TGC(0.5:0.4:1), pH4.5
Take lactose 250mg, sodium chloride 200mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 4: lactose+TGC(1:1), pH4.5
Take lactose 500mg and be dissolved in 20mL deoxidized water, add TGC500mg dissolve after with 1mol/LHCl adjust pH to 4.5, then divide and be filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 5: lactose+sodium chloride+TGC(1:0.2:1), pH4.5
Take lactose 500mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 6: lactose+sodium chloride+TGC(1:0.4:1), pH4.5
Take lactose 500mg, sodium chloride 200mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 7: lactose+TGC(2:1), the patent CN101132775A of pH4.5(Wyeth advantage prescription)
Take lactose 1000mg and be dissolved in 20mL deoxidized water, add TGC500mg dissolve after with 1mol/LHCl adjust pH to 4.5, then divide and be filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 8: lactose+sodium chloride+TGC(2:0.2:1), pH4.5
Take lactose 1000mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 9: lactose+sodium chloride+TGC(2:0.4:1), pH4.5
Take lactose 1000mg, sodium chloride 200mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Above-mentioned all cillin bottles that sample solution is housed are placed in to the lyophilizing of " Dong Fulong " freezer dryer, after lyophilizing, tamponade, gland.Measure moisture content and purity in 0 day, then remaining sample is placed in to 60 DEG C of drying baker, measured purity in 10 days.Experimental result is in table 1.
Table 1
More above-mentioned sample 60 degree are placed 10 days to such an extent that purity is known, add prescription sample (2,3,5,6,8, the 9) stability of sodium chloride to be all better than not adding the sample (1,4,7) of sodium chloride.
Embodiment 10: lactose+TGC(2:1), pH4.5
Take lactose 1000mg and be dissolved in 20mL deoxidized water, add TGC500mg dissolve after with 1mol/LHCl adjust pH to 4.5, then divide and be filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 11: lactose+sodium chloride+TGC(2:0.2:1), pH4.0
Take lactose 500mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.0 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 12: lactose+sodium chloride+TGC(1:0.2:1), pH4.5
Take lactose 500mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 4.5 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Embodiment 13: lactose+sodium chloride+TGC(1:0.2:1), pH6.0
Take lactose 500mg, sodium chloride 100mg is dissolved in 20mL deoxidized water, adds TGC500mg, after dissolving, adjusts pH to 6.0 with 1mol/LHCl, then divides and is filled in 10 10mL cillin bottles, 2mL/ bottle.
Above-mentioned all cillin bottles that sample solution is housed are placed in to the lyophilizing of " Dong Fulong " freezer dryer, after lyophilizing, tamponade, gland.Measure moisture content and purity in 0 day, then remaining sample is placed in to 60 DEG C of drying baker, measured purity in 10 days.Experimental result is in table 2
Table 2
More above-mentioned sample 60 degree are placed 10 days to such an extent that purity is known, and the prescription sample that adds sodium chloride o'clock has good stability in pH4～6.
Claims (17)
1. a compositions for tigecycline, is characterized in that, is prepared from by the raw material of following weight portion: 1.0 parts of tigecyclines, 0.2～4 part of lactose, 0.1～1 part, sodium chloride.
2. the compositions of tigecycline as claimed in claim 1, is characterized in that, the weight portion of described lactose is 0.5～2 part.
As claim 12 or as described in the compositions of tigecycline, it is characterized in that, the weight portion of described sodium chloride is 0.2～0.4 part.
4. the compositions of tigecycline as claimed in claim 1 or 2, is characterized in that, the pH value of the compositions of described tigecycline is 4～6.
5. the compositions of tigecycline as claimed in claim 3, is characterized in that, the pH value of the compositions of described tigecycline is 4～6.
6. the compositions of tigecycline as claimed in claim 1 or 2, is characterized in that, the composition for injection that the compositions of described tigecycline is tigecycline.
7. the compositions of tigecycline as claimed in claim 6, is characterized in that, the composition for injection of described tigecycline is injection solution preparation compositions or solid dosage forms for injection compositions.
8. the compositions of tigecycline as claimed in claim 7, is characterized in that, described solid dosage forms for injection compositions is freeze-dried powder.
9. the compositions of tigecycline as claimed in claim 3, is characterized in that, the composition for injection that the compositions of described tigecycline is tigecycline.
10. the compositions of tigecycline as claimed in claim 9, is characterized in that, the composition for injection of described tigecycline is injection solution preparation compositions or solid dosage forms for injection compositions.
The compositions of 11. tigecyclines as claimed in claim 10, is characterized in that, described solid dosage forms for injection compositions is freeze-dried powder.
The compositions of 12. tigecyclines as claimed in claim 4, is characterized in that, the composition for injection that the compositions of described tigecycline is tigecycline.
The compositions of 13. tigecyclines as claimed in claim 12, is characterized in that, the composition for injection of described tigecycline is injection solution preparation compositions or solid dosage forms for injection compositions.
The compositions of 14. tigecyclines as claimed in claim 13, is characterized in that, described solid dosage forms for injection compositions is freeze-dried powder.
The compositions of 15. tigecyclines as claimed in claim 5, is characterized in that, the composition for injection that the compositions of described tigecycline is tigecycline.
The compositions of 16. tigecyclines as claimed in claim 15, is characterized in that, the composition for injection of described tigecycline is injection solution preparation compositions or solid dosage forms for injection compositions.
The compositions of 17. tigecyclines as claimed in claim 16, is characterized in that, described solid dosage forms for injection compositions is freeze-dried powder.
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| CN201310140974.5A CN104107170A (en) | 2013-04-22 | 2013-04-22 | Tigecycline composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101132775A (en) * | 2005-03-14 | 2008-02-27 | 惠氏公司 | Tigecycline compositons and methods of preparation |
| CN102641249A (en) * | 2012-05-06 | 2012-08-22 | 江苏奥赛康药业股份有限公司 | Preparation method of tigecycline composition |
| CN102697739A (en) * | 2012-05-31 | 2012-10-03 | 丽珠医药集团股份有限公司 | Preparation method of powder injection for reducing tigecycline epimer |
| CN103356662A (en) * | 2012-03-27 | 2013-10-23 | 浙江医药股份有限公司新昌制药厂 | Injection tigecycline composition and preparation method thereof |
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2013
- 2013-04-22 CN CN201310140974.5A patent/CN104107170A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101132775A (en) * | 2005-03-14 | 2008-02-27 | 惠氏公司 | Tigecycline compositons and methods of preparation |
| CN103356662A (en) * | 2012-03-27 | 2013-10-23 | 浙江医药股份有限公司新昌制药厂 | Injection tigecycline composition and preparation method thereof |
| CN102641249A (en) * | 2012-05-06 | 2012-08-22 | 江苏奥赛康药业股份有限公司 | Preparation method of tigecycline composition |
| CN102697739A (en) * | 2012-05-31 | 2012-10-03 | 丽珠医药集团股份有限公司 | Preparation method of powder injection for reducing tigecycline epimer |
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Application publication date: 20141022 |