CN101773469B - Aztreonam/arginine medicament composition suspension injection - Google Patents
Aztreonam/arginine medicament composition suspension injection Download PDFInfo
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- CN101773469B CN101773469B CN2010101063692A CN201010106369A CN101773469B CN 101773469 B CN101773469 B CN 101773469B CN 2010101063692 A CN2010101063692 A CN 2010101063692A CN 201010106369 A CN201010106369 A CN 201010106369A CN 101773469 B CN101773469 B CN 101773469B
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- Prior art keywords
- aztreonam
- arginine
- suspensoid injectio
- surfactant
- suspension grain
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- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 title claims abstract description 126
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 title claims abstract description 126
- 229960003644 aztreonam Drugs 0.000 title claims abstract description 126
- 239000000203 mixture Substances 0.000 title claims abstract description 73
- 239000004475 Arginine Substances 0.000 title claims abstract description 62
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 239000000725 suspension Substances 0.000 title claims abstract description 41
- 238000002347 injection Methods 0.000 title abstract description 10
- 239000007924 injection Substances 0.000 title abstract description 10
- 239000003814 drug Substances 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 37
- 239000004094 surface-active agent Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 10
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 9
- 238000001694 spray drying Methods 0.000 claims abstract description 9
- 238000004945 emulsification Methods 0.000 claims abstract description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 34
- 239000000839 emulsion Substances 0.000 claims description 21
- 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 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 235000010265 sodium sulphite Nutrition 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000012856 packing Methods 0.000 claims description 10
- 239000008215 water for injection Substances 0.000 claims description 10
- 235000006708 antioxidants Nutrition 0.000 claims description 9
- 238000013019 agitation Methods 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 3
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 3
- 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 claims description 2
- 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 claims description 2
- 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 claims 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 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 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 description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 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 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims 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 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 11
- 239000008187 granular material Substances 0.000 abstract 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 abstract 1
- 229960003964 deoxycholic acid Drugs 0.000 abstract 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 abstract 1
- 229940069328 povidone Drugs 0.000 abstract 1
- 235000009697 arginine Nutrition 0.000 description 52
- 229920003081 Povidone K 30 Polymers 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000005374 membrane filtration Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 229930064664 L-arginine Natural products 0.000 description 4
- 235000014852 L-arginine Nutrition 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 241000894006 Bacteria Species 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 150000003952 β-lactams Chemical class 0.000 description 3
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 229920002521 macromolecule Polymers 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 description 1
- 241000588653 Neisseria Species 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- -1 amino 4-thiazolyl Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000000680 avirulence Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000001408 fungistatic effect Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 238000005360 mashing Methods 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
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- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an aztreonam/arginine medicament composition suspension injection and a preparation method thereof. The aztreonam/arginine medicament composition suspension injection is characterized by comprising the mixture of aztreonam suspension granules and arginine, wherein the weight ratio of the aztreonam suspension granules (metering in aztreonam) to the arginine is 1:0.66-0.72; specifically, the aztreonam suspension granules comprises the following components in parts by weight: 1 part of aztreonam, 3.5-6 parts of surfactant, 0.05-0.1 part of antioxidant and 4-8 parts of excipients; and in particular, the surfactant contains sodium deoxycholate and povidone with the weight ratio of 2:1. Because the aztreonam suspension granules are prepared by applying an emulsification technique through spray drying and then are mixed with the arginine for split charging, the the problems of poor stability and short validity period of the aztreonam are solved, and a satisfactory technical effect is achieved.
Description
Technical field
The present invention relates to a kind of aztreonam/arginine medicinal composition suspensoid injectio, belong to medical technical field.
Background technology
Aztreonam, chemical name is: [2S-[2 α, 3 β (z)]]-2-[[[1-(the amino 4-thiazolyl of 2-)-2-[(2-methyl-4-oxo-1-sulfo group-3-azetidinyl) amino]-2-oxo ethylidene] amino] oxo]-2 Methylpropionic acid, molecular formula is: C
13H
17N
5O
8S
2, molecular weight: 435.43, structural formula:
Aztreonam is a kind of monocycle beta-lactam antibiotic of synthetic, the antibacterial activity that most of aerobic gram-negative bacterias is had height, comprise enterobacteriaceae lactobacteriaceaes such as the pneumobacillus of escherichia coli, Klebsiella and OKCY holder bacterium, aerobacteria, bacillus cloacae, Proteus, Serratia, citric acid bacterium genus, Shigella, and hemophilus influenza, gonococcus, meningococcus etc., it also has good antibacterial action to Pseudomonas aeruginosa.
On medicament, aztreonam is an alkalescence, is insoluble in water, often uses with basic amino acids such as arginine, lysines, L-arginine is wherein being played the part of important effect in aztreonam for injection, at first it has the effect that increases aztreonam dissolubility and dissolution velocity, adjusting pH, if arginine is very few, the pH of solution is low excessively, the aztreonam dissolving is not clarified, arginine is too much, and the pH of solution raises, and zest is bigger during injection.Secondly the L-arginine has the stable effect of the aztreonam of promotion, the L-arginine can reduce the open loop impurity of aztreonam, aztreonam is the same with other Beta-lactam medicines, its monoamides ring mixes uneven or wet at aztreonam with arginine, also open loop easily under the situation of heat, form ring-opening aztreonam, ring-opening aztreonam is a kind of major impurity of aztreonam, his existence has reduced content of medicines on the one hand, cause the reduction of tiring of medicine, sterilization and the fungistatic effect of using aztreonam are reduced, on the other hand, similar with other Beta-lactam medicines, after the beta-lactam open loop, form active target spot, self-polymerization takes place easily, forms high polymer (macromolecule impurity).The content of the assorted son of high polymer or macromolecule directly influences anaphylactoid incidence rate, reduces the ring-opening aztreonam impurity content, just can control endogenous anaphylaxis incidence rate.
The list marketing preparation of aztreonam is injectable powder aseptic subpackaged or that lyophilizing makes, crystal formation to environment and aztreonam raw material is had relatively high expectations, be preferably the beta crystal aztreonam, aztreonam and these the two kinds of easy layerings of composition of L-arginine cause mixing inhomogeneous in vibration processes such as production, transportation, storage, present in addition aztreonam stability of formulation is relatively poor, being placed with related substance for a long time increases a lot, and pH value alters a great deal, the prescription in the time that can not satisfy the prescriptive period.
Because aztreonam is unstable in aqueous solution, thereby Chinese patent 200810088955.1 discloses a kind of aztreonam liposomes freeze-dry preparations and preparation method thereof, but its preparation process more complicated, and the preparation yield of liposome is very low, is not suitable for present suitability for industrialized production.Chinese patent 200910014974.4 discloses a kind of sub-micro emulsion frozen preparation of aztreonam, and its used component biological degradation polyalcohol is not suitable for injection and uses, and human body is had very big harm.Chinese patent 200910150076.1 discloses a kind of aztreonam for injection and production method thereof, the same with traditional production technology, under the process conditions of harshness, directly aztreonam and arginine packing are made poor stability, the prescription that can not satisfy the prescriptive period.
Therefore, still there is demand in superior in quality aztreonam/arginine preparation.The invention provides a kind of stable aztreonam/arginine medicinal composition suspensoid injectio, solved short problem of aztreonam poor stability, effect duration, obtained gratifying technique effect, satisfied the market demand.
Summary of the invention
The inventor finds unexpectedly that through long-term conscientious research using emulsion technique is made the aztreonam mix suspension grain by spray drying, with arginine mixing packing, has solved the aztreonam poor stability again, and the problem that effect duration is short has been finished the present invention thus.
The object of the present invention is to provide a kind of stable aztreonam/arginine medicinal composition suspensoid injectio, specifically, the combination of surfactant, antioxidant, excipient and active component by certain content, adopt emulsifying technology to make the aztreonam mix suspension grain, make the aztreonam/arginine medicinal composition suspensoid injectio with arginine mixing packing again, obtained gratifying technique effect.
The technical scheme that the present invention solves is as follows:
A kind of aztreonam/arginine medicinal composition suspensoid injectio, it is set up jointly with arginine mixed by the aztreonam mix suspension grain, and wherein said aztreonam mix suspension grain (in aztreonam) and arginic weight ratio are 1: 0.66-0.72 is preferably 1: 0.7.
Aztreonam/arginine medicinal composition suspensoid injectio provided by the invention, wherein the aztreonam mix suspension grain is made by the component of following weight portion:
1 part of aztreonam
Surfactant 3.1-8.8 part
Antioxidant 0.01-1.6 part
Excipient 3.5-15 part.
As the present invention's one preferred embodiment, its aztreonam mix suspension grain is made by the component of following weight portion:
1 part of aztreonam
Surfactant 3.5-6 part
Antioxidant 0.05-0.1 part
Excipient 4-8 part.
In the above-mentioned described component, the applicant has carried out the screening trial test to the surfactant of routine, find that independent a kind of surfactant is difficult to obtain stability preferably, carried out a large amount of composite test of surfactant for this reason, be surprisingly found out that the complexed surfactant by NaTDC and polyvidone combination has gratifying technique effect.Most preferably, described surfactant is made up of with weight ratio NaTDC and polyvidone at 2: 1, and wherein polyvidone is preferably from K30, K15 model.
In the above-mentioned described component, antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, the ascorbic acid, is preferably sodium sulfite.
In the above-mentioned described component, excipient is selected from one or more in mannitol, lactose, trehalose, glucose, sucrose, sorbitol, sodium chloride, the glycine, is preferably mannitol and trehalose, most preferably is mannitol.
The technical scheme that the present invention solves also comprises:
A kind of method for preparing the aztreonam mix suspension grain comprises the steps:
(1) agricultural surface-active agent and antioxidant are added in the water for injection, add the aztreonam mix homogeneously again, 70-90 ℃ of heating in water bath is stirred to suspension;
(2) aforesaid liquid is adopted tissue mincer's shear agitation under 70-90 ℃ of condition of insulation, get colostric fluid,, get emulsion again through high pressure dispersing emulsification machine circulating emulsion;
(3) in emulsion, add excipient, the dissolving after-filtration, spray drying gets the aztreonam mix suspension grain.
The preparation method of aztreonam/arginine medicinal composition suspensoid injectio provided by the invention is mixed aztreonam mix suspension grain and the arginine of crossing 60 sieves evenly, packing under the aseptic condition, and lid is rolled in tamponade, gets the aztreonam/arginine suspensoid injectio.
The preparation method of above-mentioned described suspensoid injectio, wherein aztreonam and arginic weight ratio are 1: 0.7.
The preparation method of above-mentioned described aztreonam mix suspension grain, wherein the amount of water for injection be all supplementary material weight summations 10-20 doubly; Tissue mincer is a JJ-2B type high-speed tissue mashing machine, and rotating speed is 12000-15000r/min, shear agitation 20-30 minute; High pressure dispersing emulsification machine model is NS1001L, by the import of Italian GEA Niro Soavi company, maximum working pressure (MWP) 1500bar, output 10L/hr, circulating emulsion 4-5 time.
Do not wish to be subjected to theoretical constraint, because the present invention carries out the emulsifying modification to the character of aztreonam and makes up with arginine, thereby aztreonam/arginine medicinal composition suspensoid injectio provided by the invention, compared with prior art, have beyond thought effect, major advantage is as follows:
(1) improved the stability of aztreonam, placing every detection index does not for a long time have significant change, guarantees that product quality is qualified in effect duration;
(2) suspensoid injectio of the present invention slowly administration has for a long time in vivo improved bioavailability greatly;
(3) used surfactant degradation in vivo, avirulence and non-immunogenicity, and can improve the Drug therapy index, reduce drug toxicity and reduce drug side effect;
(4) production technology is simple, and cost is low, can industrial-scale production.
The specific embodiment
Further specify the present invention by the following examples, but should not be construed as limitation of the present invention.Concerning the art technology people, can carry out multiple variation or modification in the embodiment described herein.Do not depart from the scope of the present invention or spirit in can obtain these variations.
Embodiment 1
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 50g
NaTDC 116.7g
30 POVIDONE K 30 BP/USP 30 58.3g
Sodium sulfite 2.5g
Mannitol 200g
Arginine 35g
Preparation technology
(1) 116.7g NaTDC, 58.3g 30 POVIDONE K 30 BP/USP 30,2.5g sodium sulfite are added in the 5000ml water for injection, add 50g aztreonam mix homogeneously again, 80 ℃ of heating in water bath are stirred to suspension;
(2) aforesaid liquid is adopted the shear agitation 20min of tissue mincer under 70-90 ℃ of condition of insulation, rotating speed 15000r/min, colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion;
(3) add 200g mannitol in emulsion, with 0.45 μ m membrane filtration, spray drying gets the aztreonam mix suspension grain after the dissolving;
(4) with aztreonam mix suspension grain that makes and the arginine 35g mix homogeneously of crossing 60 mesh sieves, packing under the aseptic condition, lid is rolled in tamponade, gets the aztreonam/arginine medicinal composition suspensoid injectio.
Embodiment 2
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 100g
NaTDC 400g
30 POVIDONE K 30 BP/USP 15 200g
Sodium sulfite 10g
Mannitol 800g
Arginine 66g
Preparation technology
(1) 400g NaTDC, 200g 30 POVIDONE K 30 BP/USP 15,10g sodium sulfite are added in the 18000ml water for injection, add 100g aztreonam mix homogeneously again, 90 ℃ of heating in water bath are stirred to suspension;
(2) aforesaid liquid is adopted the shear agitation 10min of tissue mincer under 70-90 ℃ of condition of insulation, rotating speed 15000r/min, colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion;
(3) add 800g mannitol in emulsion, with 0.45 μ m membrane filtration, spray drying gets the aztreonam mix suspension grain after the dissolving;
(4) with aztreonam mix suspension grain that makes and the arginine 66g mix homogeneously of crossing 60 mesh sieves, packing under the aseptic condition, lid is rolled in tamponade, gets the aztreonam/arginine medicinal composition suspensoid injectio.
Embodiment 3
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 50g
NaTDC 160g
30 POVIDONE K 30 BP/USP 30 80g
Sodium pyrosulfite 2.5g
Mannitol 300g
Arginine 36g
Preparation technology
(1) 160g NaTDC, 80g 30 POVIDONE K 30 BP/USP 30,2.5g sodium pyrosulfite are added in the 9000ml water for injection, add 50g aztreonam mix homogeneously again, 70 ℃ of heating in water bath are stirred to suspension;
(2) aforesaid liquid is adopted the shear agitation 20min of tissue mincer under 70-90 ℃ of condition of insulation, rotating speed 15000r/min, colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion;
(3) add 300g mannitol in emulsion, with 0.45 μ m membrane filtration, spray drying gets the aztreonam mix suspension grain after the dissolving;
(4) with aztreonam mix suspension grain that makes and the arginine 36g mix homogeneously of crossing 60 mesh sieves, packing under the aseptic condition, lid is rolled in tamponade, gets the aztreonam/arginine medicinal composition suspensoid injectio.
Embodiment 4
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 100g
NaTDC 300g
30 POVIDONE K 30 BP/USP 30 150g
Sodium sulfite 5g
Mannitol 500g
Arginine 68g
Preparation technology one:
(1) 300g NaTDC, 150g 30 POVIDONE K 30 BP/USP 30,5g sodium sulfite are added in the 13000ml water for injection, add 100g aztreonam mix homogeneously again, 80 ℃ of heating in water bath are stirred to suspension;
(2) aforesaid liquid is adopted the shear agitation 20min of tissue mincer under 70-90 ℃ of condition of insulation, rotating speed 15000r/min, colostric fluid, again through high pressure dispersing emulsification machine circulating emulsion 5 times, emulsion;
(3) add 500g mannitol in emulsion, with 0.45 μ m membrane filtration, spray drying gets the aztreonam mix suspension grain after the dissolving;
(4) with aztreonam mix suspension grain that makes and the arginine 68g mix homogeneously of crossing 60 mesh sieves, packing under the aseptic condition, lid is rolled in tamponade, gets the aztreonam/arginine medicinal composition suspensoid injectio.
Alternatively, preparation technology two is:
(1) 300g NaTDC, 150g 30 POVIDONE K 30 BP/USP 30,5g sodium sulfite are added in the 13000ml water for injection, add 100g aztreonam mix homogeneously again, stirring at room 60min;
(2) the aforesaid liquid room temperature condition is adopted the shear agitation 20min of tissue mincer down, rotating speed 15000r/min gets colostric fluid;
(3) add 500g mannitol in emulsion, with 0.45 μ m membrane filtration, spray drying gets the aztreonam mix suspension grain after the dissolving;
(4) with aztreonam mix suspension grain that makes and the arginine 68g mix homogeneously of crossing 60 mesh sieves, packing under the aseptic condition, lid is rolled in tamponade, gets the aztreonam/arginine medicinal composition suspensoid injectio.
Be similar to the preparation method of above embodiment 1-4, make following examples:
Embodiment 5
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 50g
NaTDC 166g
30 POVIDONE K 30 BP/USP 30 83g
Sodium sulfite 3g
Mannitol 300g
Arginine 35g
Embodiment 6
The preparation of aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 100g
NaTDC 380g
30 POVIDONE K 30 BP/USP 15 190g
Sodium sulfite 8g
Mannitol 740g
Arginine 70g
The preparation of Comparative Examples 1 aztreonam/arginine medicinal composition suspensoid injectio
Prescription (100 bottles): aztreonam 50g
30 POVIDONE K 30 BP/USP 30 175g
Sodium sulfite 2.5g
Mannitol 200g
Arginine 35g
Preparation technology is with embodiment 1, but the identical 30 POVIDONE K 30 BP/USP 30 of application surface activating agent gross weight umber replaces the complexed surfactant of NaTDC and polyvidone, makes the aztreonam/arginine medicinal composition suspensoid injectio.
The preparation of Comparative Examples 2 aztreonam/arginine medicinal composition suspensoid injectios
Prescription (100 bottles): aztreonam 100g
NaTDC 150g
30 POVIDONE K 30 BP/USP 15 50g
Sodium sulfite 10g
Mannitol 800g
Arginine 66g
Preparation technology chooses the extraneous components by weight percent of preferred ingredient of the present invention and forms with embodiment 2, makes the aztreonam/arginine medicinal composition suspensoid injectio.
The preparation of Comparative Examples 3 aztreonam/arginine medicinal composition suspensoid injectios
Prescription (100 bottles): aztreonam 100g
NaTDC 450g
Sodium sulfite 5g
Mannitol 500g
Arginine 68g
Preparation technology is with embodiment 4 preparation technologies one, but the identical NaTDC of application surface activating agent gross weight umber replaces the complexed surfactant of NaTDC and polyvidone, makes the aztreonam/arginine medicinal composition suspensoid injectio.
Test example 1
The distribution of particle diameter
Suspensoid injectio water for injection dissolved dilution with embodiment of the invention 1-4 and Comparative Examples 1-3 preparation, with the suspensoid injectio granular size homogeneous of JSM-5900 sem observation to embodiment of the invention 1-4 preparation, be irregular spherical or oval spherical, and the suspensoid injectio granular size heterogeneity of Comparative Examples 1-3 preparation, present different shape, disorderly and unsystematic.
Test example 2
The size of particle diameter
Suspensoid injectio water for injection dissolved dilution with embodiment of the invention 1-4 and Comparative Examples 1-3 preparation, measure size with the zetasizer3000HS laser particle size analyzer, embodiment 1-4 sample is about 150-280nm, and Comparative Examples 1-3 sample size heterogeneity does not have stable scope.The results are shown in Table 1:
Table 1 particle size determination result
Test example 3
Study on the stability
With the sample of above each embodiment and Comparative Examples preparation and aztreonam for injection (ChongQing LaiMei Pharmacy Co., Ltd's production of listing, lot number 20081106) under 40 ℃ of high temperature, relative humidity 75% ± 5% condition 6 month, carry out accelerated test and investigate, the results are shown in Table 2.Wherein the content measuring item is the content of aztreonam.The assay of following aztreonam and related substance can adopt routine techniques well known in the art, for example referring to Lv Luyang etc. different process prepares the stability study of aztreonam for injection, " Central-South pharmacy " 2007,12,5 (6): 516-518 is introduced into as a reference at this.
Table 2 accelerated test result
Found that by above the aztreonam for injection visible foreign matters of Comparative Examples and listing is against regulation when quickening June, pH value descends bigger, and content reduces obviously, and related substance raises; And sample appearance character, visible foreign matters, pH value, content and the related substance of embodiment of the invention 1-4 preparation all do not have obvious variation; Prove absolutely the superiority of the present invention aspect product stability, unexpectedly had gratifying beneficial effect.
Claims (8)
1. aztreonam/arginine medicinal composition suspensoid injectio, it is characterized in that setting up jointly with arginine mixed by the aztreonam mix suspension grain, wherein said aztreonam mix suspension grain is 1 in aztreonam and arginic weight ratio: 0.66-0.72, and wherein the aztreonam mix suspension grain is made by the component of following weight portion:
1 part of aztreonam
Surfactant 3.1-8.8 part
Antioxidant 0.01-1.6 part
Excipient 3.5-15 part,
Wherein said surfactant is made up of NaTDC and polyvidone.
2. suspensoid injectio according to claim 1 is characterized in that the aztreonam mix suspension grain made by the component of following weight portion:
1 part of aztreonam
Surfactant 3.5-6 part
Antioxidant 0.05-0.1 part
Excipient 4-8 part,
Wherein said surfactant is made up of NaTDC and polyvidone.
3. according to the arbitrary described suspensoid injectio of claim 1-2, it is characterized in that surfactant is made up of with weight ratio NaTDC and polyvidone at 2: 1.
4. according to the arbitrary described suspensoid injectio of claim 1-2, it is characterized in that antioxidant is selected from one or more in sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, thiourea, the ascorbic acid.
5. according to the arbitrary described suspensoid injectio of claim 1-2, it is characterized in that excipient is selected from one or more in mannitol, lactose, trehalose, glucose, sucrose, sorbitol, sodium chloride, the glycine.
6. according to the arbitrary described suspensoid injectio of claim 1, it is characterized in that wherein said aztreonam mix suspension grain is 1: 0.7 in aztreonam and arginic weight ratio.
7. according to the arbitrary described suspensoid injectio of claim 1-2, wherein the preparation of aztreonam mix suspension grain comprises the steps:
(1) surfactant and antioxidant are added in the water for injection, add the aztreonam mix homogeneously again, 70-90 ℃ of heating in water bath is stirred to suspension;
(2) aforesaid liquid is adopted tissue mincer's shear agitation under 70-90 ℃ of condition of insulation, get colostric fluid,, get emulsion again through high pressure dispersing emulsification machine circulating emulsion;
(3) in emulsion, add excipient, the dissolving after-filtration, spray drying gets the aztreonam mix suspension grain.
8. a method for preparing the arbitrary described suspensoid injectio of claim 1-2 is wherein mixed aztreonam mix suspension grain and the arginine of crossing 60 mesh sieves evenly, packing under the aseptic condition, and lid is rolled in tamponade, gets the aztreonam/arginine suspensoid injectio.
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| CN2010101063692A CN101773469B (en) | 2010-02-05 | 2010-02-05 | Aztreonam/arginine medicament composition suspension injection |
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| CN101953834B (en) * | 2010-08-20 | 2013-05-15 | 海南海灵化学制药有限公司 | Formula and preparation process of aztreonam for injection |
| CN102145001B (en) * | 2011-01-24 | 2012-03-28 | 山东鲁抗立科药物化学有限公司 | Stable aztreonam composition and preparation method thereof |
| CN102218059B (en) * | 2011-04-07 | 2012-07-25 | 罗诚 | Aztreonam-compound-containing composition |
| RU2455989C1 (en) * | 2011-05-11 | 2012-07-20 | Лимонов Виктор Львович | Pharmaceutical composition for treatment of infectious diseases caused by multi-resistant bacteria |
| CN104546836B (en) * | 2014-12-19 | 2017-10-10 | 重庆福安药业(集团)股份有限公司 | One kind contains AZT and arginic pharmaceutical composition |
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