CN1208060C - Compound of ceferamet used for injection - Google Patents
Compound of ceferamet used for injection Download PDFInfo
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- CN1208060C CN1208060C CN 03101990 CN03101990A CN1208060C CN 1208060 C CN1208060 C CN 1208060C CN 03101990 CN03101990 CN 03101990 CN 03101990 A CN03101990 A CN 03101990A CN 1208060 C CN1208060 C CN 1208060C
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- Prior art keywords
- cefetamet
- hydrochloric acid
- acid
- arginine
- injection
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- 238000002347 injection Methods 0.000 title claims abstract description 21
- 239000007924 injection Substances 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 title abstract 3
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 claims abstract description 94
- 229960004041 cefetamet Drugs 0.000 claims abstract description 93
- -1 inorganic acid salt Chemical class 0.000 claims abstract description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 11
- 150000001413 amino acids Chemical class 0.000 claims abstract description 11
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 66
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 18
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 18
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 17
- 235000014852 L-arginine Nutrition 0.000 claims description 17
- 229930064664 L-arginine Natural products 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229940024606 amino acid Drugs 0.000 claims description 10
- 235000001014 amino acid Nutrition 0.000 claims description 10
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 claims description 2
- 229930028154 D-arginine Natural products 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229940110377 dl- arginine Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims 1
- 125000005587 carbonate group Chemical group 0.000 claims 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract description 9
- 150000001342 alkaline earth metals Chemical class 0.000 abstract description 9
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 229940088710 antibiotic agent Drugs 0.000 abstract description 3
- 229930186147 Cephalosporin Natural products 0.000 abstract description 2
- 229940124587 cephalosporin Drugs 0.000 abstract description 2
- 150000001780 cephalosporins Chemical class 0.000 abstract description 2
- 239000002253 acid Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 239000000126 substance Substances 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- 235000017550 sodium carbonate Nutrition 0.000 description 15
- 239000000243 solution Substances 0.000 description 9
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000007670 refining Methods 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 241000194017 Streptococcus Species 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229920005549 butyl rubber Polymers 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 108020004256 Beta-lactamase Proteins 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
- 230000002950 deficient Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002949 hemolytic effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 208000014540 Functional gastrointestinal disease Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000293871 Salmonella enterica subsp. enterica serovar Typhi Species 0.000 description 1
- 241000607762 Shigella flexneri Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- FMRLDPWIRHBCCC-UHFFFAOYSA-L Zinc carbonate Chemical compound [Zn+2].[O-]C([O-])=O FMRLDPWIRHBCCC-UHFFFAOYSA-L 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 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
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 description 1
- 229910000020 calcium bicarbonate Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- QWDJLDTYWNBUKE-UHFFFAOYSA-L magnesium bicarbonate Chemical compound [Mg+2].OC([O-])=O.OC([O-])=O QWDJLDTYWNBUKE-UHFFFAOYSA-L 0.000 description 1
- 239000002370 magnesium bicarbonate Substances 0.000 description 1
- 229910000022 magnesium bicarbonate Inorganic materials 0.000 description 1
- 235000014824 magnesium bicarbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011667 zinc carbonate Substances 0.000 description 1
- 235000004416 zinc carbonate Nutrition 0.000 description 1
- 229910000010 zinc carbonate Inorganic materials 0.000 description 1
- PCHQDTOLHOFHHK-UHFFFAOYSA-L zinc;hydrogen carbonate Chemical compound [Zn+2].OC([O-])=O.OC([O-])=O PCHQDTOLHOFHHK-UHFFFAOYSA-L 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The present invention relates to a ceferamet compound for injection. The ceferamet compound for injection is prepared from cefetamet or cefetamet hydrochloride which is third generation cephalosporin antibiotics and is used as an effective component, alkaline amino acid or alkali metal, and inorganic acid salt and organic acid salt of alkaline earth metal, which are used as hydrotropy components.
Description
Technical field:
The present invention relates to third generation cephalosporin antibiotics cefetamet or hydrochloric acid cefetamet is inorganic, the medicinal composition for injections that acylate is made of effective ingredient and hydrotropy composition basic amino acid or alkali metal, alkaline-earth metal.
Background technology:
Special pentyl ester (the Cefetamet Piuil Hydrochloride C of antibiotic hydrochloric acid cefetamet
20H
25N
5O
7.HCl) be third generation oral cephalosporin antibiotics, its mechanism of action mainly is the oral performance antibacterial action that enters gastrointestinal tract after form active cefetamet acid after the intestinal wall esterase hydrolyzed.Cefetamet acid has strong antimicrbial power to the streptococcus in the gram positive bacteria, streptococcus pneumoniae, and is very stable to multiple beta-lactamases such as penicillinase that aerobe and anaerobe produced, cephalosporinase, oxygen imido cephalosporinases.It has characteristics such as wide spectrum, efficient, anti-enzyme, low toxicity, is the infection oral drugs of extensive use clinically.
Yet, find after deliberation, still there is following some shortcoming in this medicine: (1) dosage form of listing at present is tablet and syrup, but because this medicine dissolubility in water is little, cause the bioavailability of these oral formulations lower, the absolute bioavailability of tablet is 50%, and the absolute bioavailability of syrup is only between 38-47%, remainder is excreted, and causes very big waste; In addition just because dissolubility is less, and it can't directly make injection, (2) this medicine comprises functional gastrointestinal disorder owing to orally cause occurring a series of untoward reaction, especially based on diarrhoea, and with phenomenons such as nauseating, vomitings; (3) in the production process of the special pentyl ester of hydrochloric acid cefetamet, by the cefetamet free acid through becoming ester, acidify salify again, its yield is the highest can only to reach 80%, causes cost higher; (4) the synthetic of the special pentyl ester of hydrochloric acid cefetamet is that the product related substance that present technology obtains easily exceeds standard by cefetamet acid and pivalic acid bromine methyl ester generation esterification gained, is difficult to control; (5) most beta-lactam antibiotics are in reacting solution, there is degraded to produce the trend of high polymer, high polymer can bring sizable toxicity to preparation, thereby reduces the advantageous property of preparation, and unavoidably there is same problem in cefetamet in becoming ester, the salifiable process of acidify.
Summary of the invention:
The invention provides a kind of cefetamet preparation that can be used for injecting, said preparation can be given full play to the antibacterial action of cefetamet, has overcome the defective that the cefetamet oral formulations brings.
The invention provides a kind of cefetamet compositions, said composition comprises following component:
Component a. cefetamet or hydrochloric acid cefetamet
Components b. inorganic, the acylate of basic amino acid or alkali metal, alkaline-earth metal.
Compositions of the present invention, wherein inorganic the or acylate of the basic amino acid of components b, alkali metal or alkaline-earth metal is a cosolvent, compositions of the present invention is that component a and components b are mixed and made into.Preparation of the present invention has the water solublity height, and cost is low, good stability, and the characteristics that pH value of water solution is moderate, and be convenient to suitability for industrialized production and can be used for medical application.
Contain acidic-group in the molecular structure of cefetamet and hydrochloric acid cefetamet, can with the alkaline matter salify, but use the strong alkaline substance salify, can make this salt in the preparation process, produce harmful components.The present invention finds, the inorganic or acylate of cefetamet or hydrochloric acid cefetamet and basic amino acid or alkali metal, alkaline-earth metal is mixed, and can be made into the cefetamet complex of direct injection, need not make salt earlier, and the while can be avoided harmful components.The present invention finds, the cefetamet complex of injection of the present invention and cefetamet (being that the cefetamet free acid also claims cefetamet acid) are by the thin layer inspection, the result show injection the cefetamet complex apparent principal spot identical with the Rf value of cefetamet free acid, the aqueous solution that they are described is easy to discharge cefetamet, brings into play antibacterial action in vivo.
Inorganic or the acylate of employed basic amino acid, alkali metal or alkaline-earth metal is the adjuvant that pharmaceutically allows use in the compositions of the present invention, toxicity is very little, and it can generate with cefetamet acid or hydrochloric acid cefetamet has enough water miscible salt, pH value of aqueous solution is 7.0～9.5, pH value near blood of human body, to several nonirritants of blood vessel, the cefetamet complex of made injection is easy to discharge cefetamet in aqueous solution, can bring into play drug effect rapidly and fully, can be used for whole indications of cefetamet.
The components b of compositions of the present invention is basic amino acid or alkali metal, inorganic or the acylate of alkaline-earth metal, basic amino acid wherein, it is the L-arginine, the D-arginine, the DL-arginine, histidine, lysine etc., the alkali metal wherein or the inorganic acid salt of alkaline-earth metal, it is sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, calcium bicarbonate, magnesium carbonate, magnesium bicarbonate, zinc carbonate, bicarbonate zinc etc., acylate is respectively citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, the sodium of oxalates, potassium, calcium, magnesium, zinc salt, preferably: the L-arginine, lysine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, most preferably: the L-arginine, sodium carbonate.
The present invention is from technical standpoint, tangible advantage is arranged: one, the inorganic or acylate with basic amino acid, alkali metal or alkaline-earth metal is a cosolvent, the preparation dissolubility that mixes with cefetamet or hydrochloric acid cefetamet aseptic powder improves greatly, is more conducive to absorption of human body; Two, the related substance in the said preparation (harmful components) has obvious reduction than the special pentyl ester of hydrochloric acid cefetamet.
Compositions of the present invention, wherein the ratio of component a and components b can be 1-5: 1,1-3 preferably: 1, most preferred ratio is 8: 1 (mass ratio) as the ratio of the acid of: cefetamet and sodium carbonate, dissolubility is 16.4023g/100ml, and pH value of water solution is 7.45, related substance 0.27%; The arginic ratio of hydrochloric acid cefetamet and L-is 1.25: 1 (mass ratio), and dissolubility is 17.548g/100ml, and pH value of water solution is 5.74, and related substance is less than 1%; The ratio of hydrochloric acid cefetamet and sodium carbonate is 2.4: 1 (mass ratio), and dissolubility is 21.332g/100ml, and pH value of water solution is 8.47, and related substance is less than 1%.
Below solubility experiment by different proportion beneficial effect of the present invention is described:
Solubility test
One, gets cefetamet acid aseptic powder and mix detection dissolubility, pH value and related substance by different proportion, the results are shown in Table with the aseptic powder of sodium carbonate;
Table one: cefetamet acid: sodium carbonate
| Mass ratio | Dissolubility (g/100ml) | PH value | Related substance (%) |
| 24∶1 | 6.8159 | 6.44 | 0.26 |
| 12∶1 | 14.9793 | 6.67 | 0.22 |
| 8∶1 | 16.4023 | 7.45 | 0.27 |
| 6∶1 | 18.2646 | 8.10 | 0.37 |
| 3∶1 | 10.0722 | 9.36 | 0.56 |
| 2.8∶1 | 10.5075 | 9.23 | 0.54 |
| 2.6∶1 | 14.0463 | 9.28 | 0.47 |
| 2.4∶1 | 16.0171 | 9.20 | 0.53 |
| 2.2∶1 | 21.4826 | 9.59 | 1.08 |
Last table and Fig. 1 show that (cefetamet acid: sodium carbonate 3: 1) good dissolubility is arranged in water, and pH value is moderate, related substance is qualified for the cefetamet complex of injection.Two, get hydrochloric acid cefetamet aseptic powder and mix detection dissolubility, pH value and related substance with the aseptic powder of L-arginine, sodium carbonate by different proportion respectively, the results are shown in Table:
Table two: hydrochloric acid cefetamet: L-arginine
| Mass ratio | Dissolubility (g/100ml) | PH value | Related substance (%) |
| 2∶1 | 0.380 | 4.66 | Qualified |
| 1.33∶1 | 16.575 | 5.29 | |
| 1.25∶1 | 17.548 | 5.74 | |
| 1.14∶1 | 15.811 | 7.94 | |
| 1.07∶1 | 16.102 | 8.21 | |
| 1∶1 | 16.932 | 8.38 | |
| 0.8∶1 | 21.144 | 8.76 | Defective |
| 0.67∶1 | 12.204 | 8.96 | |
| 0.62∶1 | 15.722 | 9.01 | |
| 0.57∶1 | 14.324 | 9.14 | |
| 0.53∶1 | 12.504 | 9.14 | |
| 0.5∶1 | 11.135 | 9.20 | |
| 0.44∶1 | 9.756 | 9.28 | |
| 0.4∶1 | 8.269 | 9.35 | |
| 0.36∶1 | 8.503 | 9.31 | |
| 0.33∶1 | 9.113 | 9.31 | |
| 0.25∶1 | 7.028 | 9.46 |
Table three: hydrochloric acid cefetamet: sodium carbonate
| Mass ratio | Dissolubility (g/100ml) | PH value | Related substance (%) |
| 4∶1 | 3.612 | 6.55 | Qualified |
| 3∶1 | 4.169 | 7.21 | |
| 2.4∶1 | 21.332 | 8.47 | |
| 2∶1 | 38.792 | 9.45 | |
| 1.6∶1 | 30.748 | 9.56 | |
| 1.333∶1 | 36.279 | 9.57 | |
| 1.143∶1 | 18.91 | 9.45 | |
| 1∶1 | 17.25 | 9.46 | Defective |
| 0.5∶1 | 1.182 | 9.98 | |
| 0.25∶1 | 0.813 | 10.18 |
Above table two, three and Fig. 2, Fig. 3 show that (hydrochloric acid cefetamet: L-arginine 1.25: 1 and hydrochloric acid cefetamet: sodium carbonate 2.4: 1) good dissolubility is arranged in water, and pH value is moderate, related substance is qualified for the cefetamet complex of injection.
Thin layer, crystallize experiment
With cefetamet acid: L-arginine 1: 1 (mass ratio) is an example
One, TLC experiment
Material: the silica GF254 lamellae, methanol: ethyl acetate (1: 1) is developing solvent, the iodine colour developing.
It is an amount of to get this product solution, thin up becomes the solution of (being equivalent to the 20mg cefetamet) of about 40mg among every 1ml, as test sample, it is an amount of that other gets cefetamet acid (highly finished product), add absolute methanol and make the solution that contains the 20mg cefetamet among every 1ml approximately, product in contrast, test according to thin layer chromatography (two appendix VB of Chinese Pharmacopoeia nineteen ninety-five version), draw above-mentioned solution 5 μ l, point is on the silica GF254 lamellae, with methanol: ethyl acetate (1: 1) is developing solvent, dries after the expansion, place the colour developing of iodine cylinder, the result shows that test sample is identical with the principal spot Rf value of reference substance.
By above-mentioned experimental result as can be seen the cefetamet complex of injection in water, easily be decomposed into cefetamet acid and corresponding L-arginine, illustrate the cefetamet free acid through with the L-arginine mixed powder after, its stability is unaffected.
Three, drug effect and toxicological experiment are relatively:
Experimental drug: the cefetamet complex of injection is as test sample; With the special pentyl ester raw material of hydrochloric acid cefetamet and tablet thereof product in contrast.
(1) effect experiment:
The in-vitro antibacterial result of the test shows: the cefetamet complex of injection has stronger antibacterial activity, its MIC to Bacillus typhi, shigella flexneri, bloodthirsty hemophilus influenza, Hemolytic streptococcus, Ke Shi pneumobacillus etc.
50Be respectively 0.5,0.25 ,≤0.03125,0.25mg/L.The antibacterial tests result shows in the body: the cefetamet complex of injection has the obvious treatment protective effect to Hemolytic streptococcus and coli-infection in the mice body; It is to the ED of two strain Hemolytic streptococcuss
50Be respectively 0.74 (0.56～0.96) and 0.94 (0.68～1.29) mg/kg with 95% fiducial limit, to the colibacillary ED of two strains
50Be respectively 2.54 (1.84～3.49) and 2.72 (1.98～3.72) mg/kg with 95% fiducial limit, the cefetamet complex of injection has significant protective effect to two kinds of bacterial infections.
(2) acute toxicity testing:
The special pentyl ester mice of hydrochloric acid cefetamet oral administration LD
50Value is greater than 4000mg/kg, the LD of cefetamet L-arginine mixed powder drug administration by injection
50Be 2074.3mg/kg, the 95% credible 1867.3～2304.2mg/kg that is limited to illustrates that the toxicity of cefetamet complex of injection is little.
(3) local application's toxicity test:
The cefetamet complex of injection does not have blood vessel irritation, can not cause allergy and haemolysis.
The specific embodiment:
Further specify the present invention by the following examples
Embodiment 1
Prescription:
The material name consumption
Cefetamet acid 100g
L-arginine 100g
Make 1000
Preparation technology:
Under the gnotobasis, cefetamet acid aseptic refining product (refining methanol is through the aseptic washing of 75% ethanol, dry gained) 100g and L-arginine sterilized powder 100g are fully mixed in aseptic Aluminum Drum, be distributed into 1000, seal with the butyl rubber chock plug.
Prescription:
The material name consumption
Cefetamet acid 100g
Natrium carbonicum calcinatum 33.3g
Make 1000
Preparation technology:
Under the gnotobasis, with cefetamet free acid sterile highly finished product (refining methanol is through the aseptic washing of 75% ethanol, dry gained) 100g and anhydrous Na
2CO
3Sterilized powder 33.3g fully mixes in aseptic Aluminum Drum, is distributed into 1000, seals with the butyl rubber chock plug.
Embodiment 3
Prescription:
The material name consumption
Hydrochloric acid cefetamet 109g (containing cefetamet 100g)
L-arginine 109g
Make 1000
Preparation technology:
Under the gnotobasis, hydrochloric acid cefetamet aseptic refining product (refining methanol is through the aseptic washing of 75% ethanol, dry gained) 109g and L-arginine sterilized powder 109g are fully mixed in aseptic Aluminum Drum, be distributed into 1000, seal with the butyl rubber chock plug.
Embodiment 4
Prescription:
The material name consumption
Hydrochloric acid cefetamet 109g (containing cefetamet 100g)
Natrium carbonicum calcinatum 45.4g
Make 1000
Preparation technology:
Under the gnotobasis, with hydrochloric acid cefetamet aseptic refining product (refining methanol is through the aseptic washing of 75% ethanol, dry gained) 109g and anhydrous Na
2CO
3Sterilized powder 45.4g fully mixes in aseptic Aluminum Drum, is distributed into 1000, seals with the butyl rubber chock plug.
Description of drawings:
Fig. 1 is that cefetamet acid aseptic powder is mixed the curve that detects dissolubility, pH value and related substance with the aseptic powder of sodium carbonate by different proportion, and wherein, X-axis is represented cefetamet acid: the mass ratio of sodium carbonate
Fig. 2 is that hydrochloric acid cefetamet aseptic powder is mixed detection dissolubility, pH value and related substance curve with the arginic aseptic powder of L-by different proportion, and wherein, X-axis is represented the hydrochloric acid cefetamet: L-arginine mass ratio
Fig. 3 hydrochloric acid cefetamet aseptic powder is mixed detection dissolubility, pH value and related substance with the aseptic powder of sodium carbonate by different proportion, and wherein, X-axis is represented the hydrochloric acid cefetamet: the sodium carbonate mass ratio
Claims (5)
1, a kind of injection cefetamet compositions is characterized in that, comprises following component:
Component a. cefetamet or hydrochloric acid cefetamet
Components b. basic amino acid or alkali-metal inorganic acid salt
Basic amino acid wherein is selected from L-arginine, D-arginine, DL-arginine, and alkali metal is selected from sodium, potassium, and inorganic acid salt is selected from carbonate, bicarbonate.
2, compositions as claimed in claim 1, component a is the hydrochloric acid cefetamet, and components b is the L-arginine, and wherein the arginic mass ratio of hydrochloric acid cefetamet: L-is 1-5: 1.
3, compositions as claimed in claim 1, component a is cefetamet or hydrochloric acid cefetamet, components b is sodium carbonate, wherein cefetamet: the mass ratio of sodium carbonate is 1-24: 1; The mass ratio of hydrochloric acid cefetamet and sodium carbonate is 1-3: 1.
4, the described compositions of claim 1 is characterized in that, good dissolubility is arranged in water, and its pH value of aqueous solution is 7.0～9.5.
5, the described preparation of compositions method of claim 1 is characterized in that, component a and components b are mixed.
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|---|---|---|---|
| CN 03101990 CN1208060C (en) | 2003-01-30 | 2003-01-30 | Compound of ceferamet used for injection |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03101990 CN1208060C (en) | 2003-01-30 | 2003-01-30 | Compound of ceferamet used for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1430961A CN1430961A (en) | 2003-07-23 |
| CN1208060C true CN1208060C (en) | 2005-06-29 |
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|---|---|---|---|
| CN 03101990 Expired - Fee Related CN1208060C (en) | 2003-01-30 | 2003-01-30 | Compound of ceferamet used for injection |
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| Country | Link |
|---|---|
| CN (1) | CN1208060C (en) |
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2003
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