CN115737573A - Latamoxef sodium freeze-dried powder for injection and preparation method thereof - Google Patents
Latamoxef sodium freeze-dried powder for injection and preparation method thereof Download PDFInfo
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- CN115737573A CN115737573A CN202211533054.5A CN202211533054A CN115737573A CN 115737573 A CN115737573 A CN 115737573A CN 202211533054 A CN202211533054 A CN 202211533054A CN 115737573 A CN115737573 A CN 115737573A
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- drying
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- latamoxef sodium
- dried powder
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- 229960000433 latamoxef Drugs 0.000 title claims abstract description 133
- 239000000843 powder Substances 0.000 title claims abstract description 90
- 238000002347 injection Methods 0.000 title claims abstract description 44
- 239000007924 injection Substances 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- GRIXGZQULWMCLU-HUTAOCTPSA-L disodium;(6r,7r)-7-[[2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C([O-])=O)=O)C(=O)C(C([O-])=O)C1=CC=C(O)C=C1 GRIXGZQULWMCLU-HUTAOCTPSA-L 0.000 title claims abstract 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 132
- 238000004108 freeze drying Methods 0.000 claims abstract description 92
- 229940006091 aloe polysaccharide Drugs 0.000 claims abstract description 56
- 239000007853 buffer solution Substances 0.000 claims abstract description 46
- 239000012752 auxiliary agent Substances 0.000 claims abstract description 32
- 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 abstract description 29
- 229930195725 Mannitol Natural products 0.000 claims abstract description 29
- 239000000594 mannitol Substances 0.000 claims abstract description 29
- 235000010355 mannitol Nutrition 0.000 claims abstract description 29
- ALSPKRWQCLSJLV-UHFFFAOYSA-N azanium;acetic acid;acetate Chemical compound [NH4+].CC(O)=O.CC([O-])=O ALSPKRWQCLSJLV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000001035 drying Methods 0.000 claims description 51
- 230000001954 sterilising effect Effects 0.000 claims description 46
- 239000000243 solution Substances 0.000 claims description 40
- 229930182555 Penicillin Natural products 0.000 claims description 35
- 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 claims description 35
- 229940049954 penicillin Drugs 0.000 claims description 35
- 239000008215 water for injection Substances 0.000 claims description 35
- 241001116389 Aloe Species 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 235000011399 aloe vera Nutrition 0.000 claims description 26
- 239000000706 filtrate Substances 0.000 claims description 24
- 238000002156 mixing Methods 0.000 claims description 24
- 238000004659 sterilization and disinfection Methods 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 22
- 238000007710 freezing Methods 0.000 claims description 21
- 230000008014 freezing Effects 0.000 claims description 21
- 239000008213 purified water Substances 0.000 claims description 21
- 238000004140 cleaning Methods 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000007789 gas Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 238000000108 ultra-filtration Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- 239000012528 membrane Substances 0.000 claims description 9
- 230000001105 regulatory effect Effects 0.000 claims description 9
- 238000011049 filling Methods 0.000 claims description 8
- 238000004806 packaging method and process Methods 0.000 claims description 8
- 238000007689 inspection Methods 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000004033 plastic Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000006228 supernatant Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims 2
- 239000011148 porous material Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 16
- 230000007062 hydrolysis Effects 0.000 abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 8
- 239000000872 buffer Substances 0.000 abstract description 5
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 description 111
- 150000004676 glycans Chemical class 0.000 description 16
- 229920001282 polysaccharide Polymers 0.000 description 16
- 239000005017 polysaccharide Substances 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 10
- -1 alkyl cyanoacrylate Chemical compound 0.000 description 9
- 239000003223 protective agent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000007974 sodium acetate buffer Substances 0.000 description 3
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LUEWUZLMQUOBSB-FSKGGBMCSA-N (2s,3s,4s,5s,6r)-2-[(2r,3s,4r,5r,6s)-6-[(2r,3s,4r,5s,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,4r,5s,6r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol 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]2[C@H](O[C@@H](OC3[C@H](O[C@@H](O)[C@@H](O)[C@H]3O)CO)[C@@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O LUEWUZLMQUOBSB-FSKGGBMCSA-N 0.000 description 2
- SATHPVQTSSUFFW-UHFFFAOYSA-N 4-[6-[(3,5-dihydroxy-4-methoxyoxan-2-yl)oxymethyl]-3,5-dihydroxy-4-methoxyoxan-2-yl]oxy-2-(hydroxymethyl)-6-methyloxane-3,5-diol Chemical compound OC1C(OC)C(O)COC1OCC1C(O)C(OC)C(O)C(OC2C(C(CO)OC(C)C2O)O)O1 SATHPVQTSSUFFW-UHFFFAOYSA-N 0.000 description 2
- 239000001904 Arabinogalactan Substances 0.000 description 2
- 229920001503 Glucan Polymers 0.000 description 2
- 229920002581 Glucomannan Polymers 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 235000019312 arabinogalactan Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940046240 glucomannan Drugs 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000012792 lyophilization process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000000859 sublimation Methods 0.000 description 2
- 230000008022 sublimation Effects 0.000 description 2
- 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 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 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 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- OZZOVSQSDIWNIP-UHFFFAOYSA-N acetic acid;azane Chemical compound [NH4+].[NH4+].CC([O-])=O.CC([O-])=O OZZOVSQSDIWNIP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940069521 aloe extract Drugs 0.000 description 1
- 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 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000019836 digestive system infectious disease Diseases 0.000 description 1
- GRIXGZQULWMCLU-GDUWRUPCSA-L disodium;(6r,7r)-7-[[(2r)-2-carboxylato-2-(4-hydroxyphenyl)acetyl]amino]-7-methoxy-3-[(1-methyltetrazol-5-yl)sulfanylmethyl]-8-oxo-5-oxa-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].C1([C@@H](C([O-])=O)C(=O)N[C@]2(OC)C(N3C(=C(CSC=4N(N=NN=4)C)CO[C@@H]32)C([O-])=O)=O)=CC=C(O)C=C1 GRIXGZQULWMCLU-GDUWRUPCSA-L 0.000 description 1
- CSVGEMRSDNSWRF-UHFFFAOYSA-L disodium;dihydrogen phosphate Chemical compound [Na+].[Na+].OP(O)([O-])=O.OP(O)([O-])=O CSVGEMRSDNSWRF-UHFFFAOYSA-L 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- DFIWJEVKLWMZBI-UHFFFAOYSA-M sodium;dihydrogen phosphate;phosphoric acid Chemical compound [Na+].OP(O)(O)=O.OP(O)([O-])=O DFIWJEVKLWMZBI-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000002061 vacuum sublimation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to latamoxef sodium freeze-dried powder for injection and a preparation method thereof. The invention adopts aloe polysaccharide and mannitol as the auxiliary agents for freeze-drying latamoxef sodium, which can effectively inhibit the generation of free water and reduce the hydrolysis of latamoxef sodium caused by the free water, thereby reducing the impurity content of latamoxef sodium freeze-dried powder and improving the stability thereof. Furthermore, the invention optimizes the buffer solution aiming at the novel auxiliary agent, and finds that the acetic acid-ammonium acetate buffer has obvious advantages compared with other buffers, thereby obtaining the latamoxef sodium freeze-dried powder with low impurities and high stability.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to latamoxef sodium freeze-dried powder for injection and a preparation method thereof.
Background
Latamoxef sodium, a semisynthetic beta-lactam antibiotic developed by Nippon salt Yeyi company, was first marketed in Germany in 1981, and its antibacterial property is similar to that of the third-generation cephalosporin, and has good antibacterial effect on various gram-negative bacteria. The preparation is clinically used for various infections caused by sensitive bacteria, such as septicemia, meningitis, digestive system infection, intraperitoneal infection and the like.
At present, latamoxef sodium on the market at home is freeze-dried powder injection, and freeze-drying technology is adopted to obtain powder for injection. The whole process of freeze-drying comprises the following steps: pre-freezing the product, drying in the first stage, heating the product, and drying in the second stage.
Prefreezing is to fix the product for vacuum sublimation under vacuum conditions. If the frozen product is not frozen firmly during pre-freezing, the product can emerge from the bottle during vacuum pumping and has no certain shape; if the cold is too low, not only is energy and time wasted, but for some products the survival rate may be reduced. Therefore three data should be determined before pre-freezing: pre-freezing rate, pre-freezing temperature, pre-freezing time.
First-stage drying: when the pressure in the chamber falls below 10Pa (depending on the product characteristics), the product is heated to provide energy for sublimation of the product, the rate of sublimation of the product being determined by the heating capacity and the water capturing capacity of the condenser.
A temperature rising stage: when the first stage of drying of the article is complete, the temperature in the oven is raised, typically at a rate not too fast, before the second stage of drying, to a maximum temperature that can not exceed the maximum temperature that the sample can withstand.
And (3) second-stage drying: the temperature of the product can be raised to below its maximum allowable temperature and maintained for a certain period of time to reach a predetermined residual moisture content, and the freeze-drying can be finished.
The freeze-drying curve is determined flexibly according to the properties of the product and the protective agent, and needs to be repeatedly searched. However, no specific debugging and record exists in the freeze drying process of latamoxef sodium at present.
In addition, there are various stresses throughout the lyophilization process of lyophilized products, typically including low temperature stress, freezing stress (including dendritic ice crystal formation, increase in ionic strength, change in pH, phase separation, etc.), drying stress (removal of a monolayer of water molecules from the surface of the drug), etc., which are often factors that directly or indirectly contribute to drug instability. Latamoxef sodium is unstable in chemical structure and is susceptible to hydrolysis and ring opening of latamoxef acid beta-lactam ring due to moisture. Therefore, some protective/shaping agent needs to be added during the lyophilization process when performing the lyophilization.
How to obtain stable freeze-dried latamoxef sodium powder is of great importance to select proper protective agent. At present, the latamoxef sodium freeze-dried powder for injection has the problems of long freeze-drying time, high drying temperature, high energy consumption, low finished product clarity and solution color qualification rate, high water content and impurities of latamoxef sodium for injection obtained by a freeze-drying process, unstable quality and the like because the auxiliary material used in production is single mannitol. Obviously, mannitol, as a single freeze-drying protective agent, cannot well inhibit ring-opening hydrolysis of latamoxef sodium during freeze-drying, so that it is difficult to obtain latamoxef sodium freeze-dried powder with low impurity content and good stability.
The existing research has proved that the existence form of the water in the latamoxef sodium freeze-dried powder is 3, namely free water, absorbed water and bonded water, and the water content is the sum of the free water, the absorbed water and the bonded water in the sample. However, the adsorbed water and the bonded water have no hydration, and only free water can perform hydration reaction, which is a main factor influencing the stability of latamoxef sodium. Therefore, it is necessary to select a protecting agent more suitable for use in the freeze-drying process of latamoxef sodium and to adjust the corresponding freeze-drying process.
CN 106176625B discloses a pharmaceutical composition of latamoxef sodium for injection, which adopts alkyl cyanoacrylate as a carrier, mannitol, trehalose, lactose, xylitol, sorbitol and glucose as excipients, and is further assisted with a certain surface stabilizer. Although the latamoxef sodium can be protected to a certain extent in the form of a carrier matched with a protective agent, the stability of the latamoxef sodium can be maintained. However, it has a low drug loading, the amount and quality of the adjuvant used, and a slow release rate of moxalactam, which are very disadvantageous for injectable formulations.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides latamoxef sodium freeze-dried powder for injection and a preparation method thereof.
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10-11 parts of latamoxef sodium, 2-3 parts of freeze-drying auxiliary agent, 30-40 parts of water for injection and 0.5-1 part of buffer solution.
The buffer solution is an acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5-7; preferably, the pH value of the acetic acid-ammonium acetate buffer solution is 5-6; further preferably, the pH value of the acetic acid-ammonium acetate buffer solution is 5.3-5.8.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps: cleaning and sterilizing, preparing, filling, freeze-drying, capping, inspecting by a lamp and packaging.
Preferably, the preparation method of the latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310-330 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300-320 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121-131 deg.C for 20-30min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121-130 deg.C for 15-20min;
(2) Mixing latamoxef sodium and water for injection, adjusting pH value to 6.0-7.0 with buffer solution, adding freeze-drying auxiliary agent, and dissolving to obtain latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas washing step (1) comprises the following steps of: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The preparation method of the freeze-drying auxiliary agent in the step (2) comprises the following steps:
n1, mixing aloe powder and water according to a mass ratio (100-200): 2000 mixing, stirring at 100-200r/min for 10-20min to obtain aloe water solution, standing for 12-24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, regulating the pH value of the filtrate obtained in the step N1 to 6.3-6.5 by hydrochloric acid, heating to 115-118 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, regulating the pH value of the sterile filtrate obtained in the step N2 to 4.2-4.5 by using hydrochloric acid, and performing ultrafiltration by using an ultrafiltration membrane to obtain an aloe polysaccharide solution;
n4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain aloe polysaccharide freeze-dried powder;
n5, mixing the aloe polysaccharide freeze-dried powder and mannitol according to the mass ratio (5-6): (1.5-1.6) to obtain a freeze-drying auxiliary agent.
And the aperture of the ultrafiltration membrane in the step N3 is 10000-12000Da.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled semi-tamponade penicillin bottle is sent into a freeze drying box to be pre-frozen at minus 45- (-50) DEG C for 1-2h under normal pressure, then the temperature is raised to minus 10- (-20) DEG C, the vial is pre-frozen for 4-5h under normal pressure, then the temperature is lowered to minus 35- (-40) DEG C, and the vial is pre-frozen for 2.5-4h under normal pressure, so that pre-freezing is completed;
s2, primary drying: heating to 0- (-5) DEG C, vacuumizing the freeze drying oven with the vacuum degree of 10-12Pa, and drying for 24-30h to finish primary drying;
s3, secondary drying: heating to 40-50 deg.C, and drying under 7-9Pa for 3-5 hr; then adjusting the air pressure to 3-4Pa, and drying for 5-7h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 300-500mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Aiming at the problems of long freeze-drying time, high impurity content, instability and the like in the production process of the conventional latamoxef sodium freeze-dried powder for injection because the auxiliary material used in the production process is single mannitol. The stability of latamoxef sodium is improved by adopting a mode that aloe polysaccharide and mannitol are matched as auxiliary agents. Firstly, the aloe polysaccharide is prepared by directly sterilizing and drying the aloe extract, the obtained aloe polysaccharide has larger polysaccharide molecules and stronger water retention capacity, and the obtained latamoxef sodium powder contains higher water after freeze-drying, so that the free water content is higher, the latamoxef sodium is easy to hydrolyze, and in addition, the content of anthraquinone compounds, proteins and other impurities in the aloe can also cause the increase of the total impurity content. Therefore, in the step N2 of preparing the aloe polysaccharide, hydrochloric acid is added to adjust the pH value of the aloe polysaccharide to weak acidity during high-temperature sterilization, which is beneficial to killing bacteria, and can promote hydrolysis of the aloe polysaccharide to obtain the aloe polysaccharide with smaller molecular weight, so that the water retention capacity of the aloe polysaccharide is reduced, the free water content of the latamoxef sodium powder is reduced, and the stability of the alopolysaccharide is improved. Furthermore, the invention adopts an ultrafiltration membrane to filter the sterilized aloe polysaccharide, which not only can reduce the content of anthraquinone compounds, proteins and other impurities in the aloe and improve the purity of the aloe polysaccharide, but also can further filter unhydrolyzed macromolecular polysaccharide, further reduce the water retention capacity of the aloe polysaccharide and reduce the content of free water, thereby improving the stability of the latamoxef sodium powder.
In addition, mannitol mainly limits the movement of water molecules through hydrogen bonds, and bonds between mannitol and water molecules are weaker, so that the content of free water is larger, aloe polysaccharides can form more stable chemical bonds through adsorption and bonding means to limit the generation of free water, but active groups of the aloe polysaccharides are fewer, and a small amount of mannitol is added to combine the aloe polysaccharides and the mannitol to limit water molecules more and more stably, so that the generation of free water is reduced, and the stability of the latamoxef sodium is improved.
Furthermore, after aloe polysaccharide is added as an auxiliary agent, the selection of the buffer solution can also affect the stability of latamoxef sodium to a certain extent. When mannitol is simply added as an auxiliary agent, the stability of the buffer solution is not greatly influenced, which shows that ammonium ions mainly have certain influence on aloe polysaccharide. The aloe polysaccharide is supposed to be composed of various polysaccharide components such as ethoxylated glucan, glucomannan, arabino-galactan and the like, wherein ammonium ions have certain activation effect on partial polysaccharides, so that the limit capacity of the aloe polysaccharide on water molecules can be improved to a certain extent, the generation of free water is reduced, and the stability of the latamoxef sodium is improved
The invention has the beneficial effects that:
the invention adopts aloe polysaccharide and mannitol as the auxiliary agents for freeze-drying latamoxef sodium, which can effectively inhibit the generation of free water and reduce the hydrolysis of latamoxef sodium caused by the free water, thereby reducing the impurity content of latamoxef sodium freeze-dried powder and improving the stability thereof. Furthermore, the invention optimizes the buffer solution aiming at the novel auxiliary agent, and finds that the acetic acid-ammonium acetate buffer has obvious advantages compared with other buffers, thereby obtaining the latamoxef sodium freeze-dried powder with low impurities and high stability.
Detailed Description
Latamoxef sodium, CAS:64953-12-4.
Aloe powder, cargo number: ANDY, west ampere hanyuan biochemical technologies, ltd.
Example 1
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10.3 parts of latamoxef sodium, 2.4 parts of freeze-drying auxiliary agent, 36.7 parts of water for injection and 0.7 part of buffer solution.
The buffer solution is acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5.6.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121 deg.C for 20min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121 deg.C for 15min;
(2) Mixing latamoxef sodium with water for injection, adjusting the pH value to 5.6 by using a buffer solution, adding a freeze-drying auxiliary agent, and dissolving to obtain a latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas washing step (1) comprises the following steps of: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The preparation method of the freeze-drying auxiliary agent in the step (2) comprises the following steps:
n1, mixing aloe powder and water according to a mass ratio of 100:2000 mixing, stirring at 120r/min for 15min to obtain aloe water solution, standing for 24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, heating the filtrate obtained in the step N1 to 115 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, adjusting the pH value of the sterile filtrate obtained in the step N2 to 4.3 by using hydrochloric acid to obtain an aloe polysaccharide solution;
n4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain aloe polysaccharide freeze-dried powder;
n5, mixing aloe polysaccharide freeze-dried powder and mannitol according to a mass ratio of 5:1.5, obtaining the freeze-drying auxiliary agent.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled penicillin bottles are sent into a freeze drying box to be pre-frozen for 2 hours at minus 45 ℃ under normal pressure, then the temperature is increased to minus 18 ℃ and pre-frozen for 4.25 hours under normal pressure, then the temperature is decreased to minus 35 ℃ and pre-frozen for 3 hours under normal pressure, and pre-freezing is completed to obtain pre-frozen latamoxef sodium solution;
s2, primary drying: heating to 0 ℃, vacuumizing the freeze drying box to a vacuum degree of 11Pa, and drying for 30h to finish primary drying;
s3, secondary drying: heating to 45 ℃, and drying for 4 hours under the pressure of 8 Pa; then adjusting the air pressure to 4Pa, and drying for 6h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 400mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Example 2
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10.3 parts of latamoxef sodium, 2.4 parts of freeze-drying auxiliary agent, 36.7 parts of water for injection and 0.7 part of buffer solution.
The buffer solution is acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5.6.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121 deg.C for 20min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121 deg.C for 15min;
(2) Mixing latamoxef sodium and water for injection, adjusting the pH value to 5.6 by using a buffer solution, adding a freeze-drying auxiliary agent, and dissolving to obtain a latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas washing step (1) comprises the following steps of: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The preparation method of the freeze-drying auxiliary agent in the step (2) comprises the following steps:
n1, mixing aloe powder and water according to a mass ratio of 100:2000 mixing, stirring at 120r/min for 15min to obtain aloe water solution, standing for 24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, regulating the pH value of the filtrate obtained in the step N1 to 6.4 by using hydrochloric acid, heating to 115 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, adjusting the pH value of the sterile filtrate obtained in the step N2 to 4.3 by using hydrochloric acid to obtain an aloe polysaccharide solution;
n4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain aloe polysaccharide freeze-dried powder;
n5, mixing aloe polysaccharide freeze-dried powder and mannitol according to a mass ratio of 5:1.5, obtaining the freeze-drying auxiliary agent.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled penicillin bottles are sent into a freeze drying box to be pre-frozen for 2 hours at minus 45 ℃ under normal pressure, then the temperature is increased to minus 18 ℃ and pre-frozen for 4.25 hours under normal pressure, then the temperature is decreased to minus 35 ℃ and pre-frozen for 3 hours under normal pressure, and pre-freezing is completed to obtain pre-frozen latamoxef sodium solution;
s2, primary drying: heating to 0 ℃, vacuumizing the freeze drying box to a vacuum degree of 11Pa, and drying for 30h to finish primary drying;
s3, secondary drying: heating to 45 ℃, and drying for 4 hours under the pressure of 8 Pa; then adjusting the air pressure to 4Pa, and drying for 6h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 400mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Example 3
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10.3 parts of latamoxef sodium, 2.4 parts of freeze-drying auxiliary agent, 36.7 parts of water for injection and 0.7 part of buffer solution.
The buffer solution is acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5.6.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121 deg.C for 20min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121 deg.C for 15min;
(2) Mixing latamoxef sodium and water for injection, adjusting the pH value to 5.6 by using a buffer solution, adding a freeze-drying auxiliary agent, and dissolving to obtain a latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas washing step (1) comprises the following steps of: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The preparation method of the freeze-drying auxiliary agent in the step (2) comprises the following steps:
n1, mixing aloe powder and water according to a mass ratio of 100:2000 mixing, stirring at 120r/min for 15min to obtain aloe water solution, standing for 24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, regulating the pH value of the filtrate obtained in the step N1 to 6.4 by using hydrochloric acid, heating to 115 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, regulating the pH value of the sterile filtrate obtained in the step N2 to 4.3 by using hydrochloric acid, and performing ultrafiltration by using an ultrafiltration membrane to obtain an aloe polysaccharide solution;
n4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain aloe polysaccharide freeze-dried powder;
n5, mixing aloe polysaccharide freeze-dried powder and mannitol according to the mass ratio of 5:1.5, obtaining the freeze-drying auxiliary agent.
And the aperture of the ultrafiltration membrane in the step N3 is 10000Da.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled penicillin bottles are sent into a freeze drying oven, pre-frozen for 2 hours at minus 45 ℃ under normal pressure, then pre-frozen for 4.25 hours at minus 18 ℃ under normal pressure, and then pre-frozen for 3 hours at minus 35 ℃ under normal pressure to finish pre-freezing, so as to obtain pre-frozen latamoxef sodium solution;
s2, primary drying: heating to 0 ℃, vacuumizing the freeze drying box to a vacuum degree of 11Pa, and drying for 30h to finish primary drying;
s3, secondary drying: heating to 45 ℃, and drying for 4 hours under the pressure of 8 Pa; then adjusting the air pressure to 4Pa, and drying for 6h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 400mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Example 4
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10.3 parts of latamoxef sodium, 2.4 parts of freeze-drying auxiliary agent, 36.7 parts of water for injection and 0.7 part of buffer solution.
The buffer solution is acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5.6.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121 deg.C for 20min; cleaning the aluminum plastic cover with water for injection, and sterilizing at 121 deg.C for 15min;
(2) Mixing latamoxef sodium and water for injection, adjusting the pH value to 5.6 by using a buffer solution, adding a freeze-drying auxiliary agent, and dissolving to obtain a latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas washing step (1) comprises the following steps of: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The preparation method of the freeze-drying auxiliary agent in the step (2) comprises the following steps:
n1, mixing aloe powder and water according to a mass ratio of 100:2000 mixing, stirring at 120r/min for 15min to obtain aloe water solution, standing for 24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, regulating the pH value of the filtrate obtained in the step N1 to 6.4 by using hydrochloric acid, heating to 115 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, regulating the pH value of the sterile filtrate obtained in the step N2 to 4.3 by using hydrochloric acid, and performing ultrafiltration by using an ultrafiltration membrane to obtain an aloe polysaccharide solution;
and N4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain the freeze-drying auxiliary agent.
And the aperture of the ultrafiltration membrane in the step N3 is 10000Da.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled penicillin bottles are sent into a freeze drying box to be pre-frozen for 2 hours at minus 45 ℃ under normal pressure, then the temperature is increased to minus 18 ℃ and pre-frozen for 4.25 hours under normal pressure, then the temperature is decreased to minus 35 ℃ and pre-frozen for 3 hours under normal pressure, and pre-freezing is completed to obtain pre-frozen latamoxef sodium solution;
s2, primary drying: heating to 0 ℃, vacuumizing the freeze drying oven with the vacuum degree of 11Pa, and drying for 30 hours to complete primary drying;
s3, secondary drying: heating to 45 ℃, and drying for 4 hours under the pressure of 8 Pa; then adjusting the air pressure to 4Pa, and drying for 6h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 400mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Example 5
The latamoxef sodium freeze-dried powder for injection comprises the following components in parts by mass: 10.3 parts of latamoxef sodium, 2.4 parts of freeze-drying auxiliary agent, 36.7 parts of water for injection and 0.7 part of buffer solution.
The buffer solution is acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5.6.
The freeze-drying auxiliary agent is mannitol.
A preparation method of latamoxef sodium freeze-dried powder for injection comprises the following steps:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121 deg.C for 20min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121 deg.C for 15min;
(2) Mixing latamoxef sodium and water for injection, adjusting the pH value to 5.6 by using a buffer solution, adding a freeze-drying auxiliary agent, and dissolving to obtain a latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
The three-water two-gas cleaning in the step (1) comprises the following steps in cleaning sequence: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
The freeze drying in the step (3) comprises the following specific steps:
s1, pre-freezing: the filled penicillin bottles are sent into a freeze drying box to be pre-frozen for 2 hours at minus 45 ℃ under normal pressure, then the temperature is increased to minus 18 ℃ and pre-frozen for 4.25 hours under normal pressure, then the temperature is decreased to minus 35 ℃ and pre-frozen for 3 hours under normal pressure, and pre-freezing is completed to obtain pre-frozen latamoxef sodium solution;
s2, primary drying: heating to 0 ℃, vacuumizing the freeze drying box to a vacuum degree of 11Pa, and drying for 30h to finish primary drying;
s3, secondary drying: heating to 45 ℃, and drying for 4 hours under the air pressure of 8 Pa; then adjusting the air pressure to 4Pa, and drying for 6h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 400mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Comparative example 1
The difference from example 3 is that: the buffer solution is acetic acid-sodium acetate buffer solution.
Comparative example 2
The difference from example 3 is that: the buffer solution is a phosphoric acid-sodium hydrogen phosphate buffer solution.
Comparative example 3
The differences from example 5 are: the buffer solution is acetic acid-sodium acetate buffer solution.
Test example 1
Stability test
The latamoxef sodium freeze-dried powder for injection prepared in the embodiment and the comparative example is placed for 10 days at 60 ℃ under the illumination of 4500Lx, and the content change of impurities of the latamoxef sodium freeze-dried powder before and after the placement is measured.
Table 1: results of stability test
As can be seen from Table 1, the freeze-dried powder of latamoxef sodium for injection prepared in example 1 of the present invention has the highest impurity content and the lowest stability. The method for preparing aloe polysaccharides is considered to be that polysaccharide molecules contained in the method for preparing aloe polysaccharides are large, the water retention capacity of the aloe polysaccharides is high, and the obtained latamoxef sodium powder after freeze-drying contains high water, so that the free water content of the latamoxef sodium is high, hydrolysis of latamoxef sodium is easy to cause, and in addition, the total impurity content of anthraquinone compounds, proteins and other impurities contained in aloe can also be increased. The content of impurities in the latamoxef sodium freeze-dried powder for injection prepared in example 2 is slightly reduced compared with that in example 1, and the stability is improved. The hydrochloric acid is added to adjust the pH value of the aloe polysaccharide to weak acidity during high-temperature sterilization in the step N2 for preparing the aloe polysaccharide, so that the aloe polysaccharide is beneficial to killing bacteria, and can promote hydrolysis of the aloe polysaccharide to obtain the aloe polysaccharide with smaller molecular weight, so that the water retention capacity of the aloe polysaccharide is reduced, the free water content of the latamoxef sodium powder is reduced, and the stability of the latamoxef sodium powder is improved. Embodiment 3 further adopts the milipore filter to filter the aloe polysaccharide after the sterilization, not only can reduce the content of anthraquinone compounds, proteins and other impurities contained in the aloe, improve the purity of the aloe polysaccharide, but also can further filter the unhydrolyzed macromolecular polysaccharide, further reduce the water-retaining capacity of the aloe, reduce the content of free water, thereby improving the stability of the latamoxef sodium powder. As can be seen from the comparison of example 4, example 5 and example 3, the stability of mannitol is very poor when mannitol is used alone, and the stability of aloe polysaccharide is greatly improved when mannitol is used alone, but the effect of using aloe polysaccharide and mannitol in combination is slightly poor when mannitol is used in comparison with example 3. The invention supposes that the mannitol mainly limits the movement of water molecules through hydrogen bonds, and the bond energy between the mannitol and the water molecules is weaker, so that the content of free water is larger, while the aloe polysaccharide can form more stable chemical bonds through adsorption and bonding means to limit the generation of the free water, but the aloe polysaccharide has fewer active groups, and is assisted with a small amount of mannitol, so that the combination of the mannitol and the aloe polysaccharide has larger and more stable limit on the water molecules, so that the generation of the free water is reduced, and the stability of the latamoxef sodium is improved.
From the comparison of comparative example 1, comparative example 2 and example 3, it was found that the selection of the buffer solution also has an influence on the stability of latamoxef sodium to some extent after addition of aloe polysaccharide as adjuvant, and from experimental data, the acetate-ammonium acetate buffer is clearly superior to the acetate-sodium acetate buffer and the phosphate-sodium hydrogen phosphate buffer, which is considered by the present invention to be due to the effect of ammonium radical on the adjuvant. As can be seen from the comparison of comparative example 3 and example 5, the buffer solution had little effect on the stability of the aloe polysaccharide when mannitol was simply added as an adjuvant, indicating that ammonium ions mainly have some effect on aloe polysaccharides. According to the invention, the aloe polysaccharide is formed by various polysaccharide components such as ethoxylated glucan, glucomannan, arabino-galactan and the like, wherein ammonium ions have a certain activation effect on part of polysaccharides, so that the limiting capacity of the aloe polysaccharide on water molecules can be improved to a certain extent, the generation of free water is reduced, and the stability of latamoxef sodium is improved.
Test example 2
The water activity (Aw) values of the latamoxef sodium freeze-dried powder for injection prepared in the embodiment and the comparative example, namely the content of free water, are respectively measured by a temperature-controlled water activity meter according to a mirror dew point condensation method. Before the test, the instrument is calibrated by using an activity standard solution prepared by a water activity meter, each sample is measured for 5 times, the average value is taken, and the measurement temperature is 25 ℃. The results are shown in Table 2.
Table 2: water Activity Aw
| Aw | |
| Example 1 | 0.1323 |
| Example 2 | 0.1282 |
| Example 3 | 0.0999 |
| Example 4 | 0.1011 |
| Example 5 | 0.1619 |
| Comparative example 1 | 0.1223 |
| Comparative example 2 | 0.1155 |
| Comparative example 3 | 0.1621 |
It can be seen from test example 2 that the water activity of the latamoxef sodium freeze-dried powder prepared in examples 1-5 and comparative examples 1-3 corresponds to that of test example 1, which indicates that the use of aloe polysaccharides and mannitol in combination can greatly reduce the content of free water in the latamoxef sodium freeze-dried powder, thereby inhibiting the hydrolysis of latamoxef sodium and improving the stability thereof.
Claims (8)
1. The latamoxef sodium freeze-dried powder for injection is characterized by comprising the following raw materials: latamoxef sodium, freeze-drying adjuvant, water for injection and buffer solution.
2. The latamoxef sodium freeze-dried powder for injection as claimed in claim 1, wherein the buffer solution is an acetic acid-ammonium acetate buffer solution, and the pH value of the acetic acid-ammonium acetate buffer solution is 5-7.
3. A method for preparing latamoxef sodium freeze-dried powder for injection, which is characterized in that the raw material of latamoxef sodium freeze-dried powder for injection as claimed in claim 1 is adopted.
4. The process for the preparation of freeze-dried powder of latamoxef sodium for injection as claimed in claim 3, comprising the steps of:
(1) After being cleaned by three water and two gases, the penicillin bottle enters a tunnel oven, wherein the sterilization temperature of a 10ml penicillin bottle tunnel oven is 310-330 ℃, and the sterilization temperature of a 5ml penicillin bottle tunnel oven is 300-320 ℃; cleaning the rubber plug with purified water and water for injection, and sterilizing at 121-131 deg.C for 20-30min; cleaning the aluminum-plastic cover with water for injection, and sterilizing at 121-130 deg.C for 15-20min;
(2) Mixing latamoxef sodium and water for injection, adjusting pH value to 6.0-7.0 with buffer solution, adding freeze-drying auxiliary agent, and dissolving to obtain latamoxef sodium solution;
(3) Filling the latamoxef sodium solution prepared in the step (2) into a penicillin bottle, and freeze-drying to obtain latamoxef sodium freeze-dried powder;
(4) And (4) obtaining the latamoxef sodium freeze-dried powder for injection through capping, light inspection and packaging.
5. The process for the preparation of freeze-dried powder of latamoxef sodium for injection as claimed in claim 4, wherein the three water and two gas in step (1) are in the order of washing: purified water ultrasonic wave, purified water, compressed air, water for injection, and compressed air.
6. The process for preparing freeze-dried powder of latamoxef sodium for injection as claimed in claim 4, wherein the process for preparing the freeze-dried adjuvant in step (2) comprises the steps of:
n1, mixing aloe powder and water according to a mass ratio (100-200): 2000 mixing, stirring at 100-200r/min for 10-20min to obtain aloe water solution, standing for 12-24 hr, collecting supernatant, and filtering to obtain filtrate;
n2, regulating the pH value of the filtrate obtained in the step N1 to 6.3-6.5 by hydrochloric acid, heating to 115-118 ℃, sterilizing for 30min, and then cooling to room temperature to obtain sterile filtrate;
n3, regulating the pH value of the sterile filtrate obtained in the step N2 to 4.2-4.5 by using hydrochloric acid, and performing ultrafiltration by using an ultrafiltration membrane to obtain an aloe polysaccharide solution;
n4, freeze-drying the aloe polysaccharide solution prepared in the step N3 to obtain aloe polysaccharide freeze-dried powder;
n5, mixing the aloe polysaccharide freeze-dried powder and mannitol according to the mass ratio (5-6): (1.5-1.6) to obtain a freeze-drying auxiliary agent.
7. The process for preparing freeze-dried powder of latamoxef sodium for injection as claimed in claim 6, wherein the pore size of the ultrafiltration membrane of step N3 is 10000-12000Da.
8. The process for preparing freeze-dried powder of latamoxef sodium for injection as claimed in claim 4, wherein the freeze-drying of step (3) is specifically:
s1, pre-freezing: the filled semi-tamponade penicillin bottle is sent into a freeze drying box to be pre-frozen at minus 45- (-50) DEG C for 1-2h under normal pressure, then the temperature is raised to minus 10- (-20) DEG C, the vial is pre-frozen for 4-5h under normal pressure, then the temperature is lowered to minus 35- (-40) DEG C, and the vial is pre-frozen for 2.5-4h under normal pressure, so that pre-freezing is completed;
s2, primary drying: heating to 0- (-5) DEG C, vacuumizing the freeze drying oven with the vacuum degree of 10-12Pa, and drying for 24-30h to complete primary drying;
s3, secondary drying: heating to 40-50 deg.C, and drying under 7-9Pa for 3-5 hr; then adjusting the air pressure to 3-4Pa, and drying for 5-7h;
and S4, finally, introducing nitrogen subjected to sterilization and filtration into the freeze-drying box to 300-500mbar, and finishing freeze-drying to obtain the latamoxef sodium freeze-dried powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN202211533054.5A CN115737573B (en) | 2022-11-30 | 2022-11-30 | Cephalosporium oxydanum freeze-dried powder for injection and preparation method thereof |
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| CN202211533054.5A CN115737573B (en) | 2022-11-30 | 2022-11-30 | Cephalosporium oxydanum freeze-dried powder for injection and preparation method thereof |
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| US20050250704A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder comprising new compositions of oligosaccharides and methods for their preparation |
| US20050250705A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh Co. Kg | Spray-dried powder comprising at least one 1,4 O-linked saccharose-derivative and methods for their preparation |
| US20080096858A1 (en) * | 2004-04-22 | 2008-04-24 | University Of Connecticut | Method of Stabilizing Disordered Cefovecin Sodium Salt |
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| CN107802604A (en) * | 2017-11-06 | 2018-03-16 | 刘兴付 | A kind of double auxiliary material latamoxef sodium for injection freeze drying powder injections |
| CN112843003A (en) * | 2021-03-25 | 2021-05-28 | 海南海灵化学制药有限公司 | Lyophilized powder of latamoxef sodium for injection and its lyophilization process |
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| US20080096858A1 (en) * | 2004-04-22 | 2008-04-24 | University Of Connecticut | Method of Stabilizing Disordered Cefovecin Sodium Salt |
| US20050250704A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder comprising new compositions of oligosaccharides and methods for their preparation |
| US20050250705A1 (en) * | 2004-05-10 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh Co. Kg | Spray-dried powder comprising at least one 1,4 O-linked saccharose-derivative and methods for their preparation |
| CN106176625A (en) * | 2015-04-29 | 2016-12-07 | 重庆福安药业(集团)股份有限公司 | The pharmaceutical composition of latamoxef sodium for injection |
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| CN107802604A (en) * | 2017-11-06 | 2018-03-16 | 刘兴付 | A kind of double auxiliary material latamoxef sodium for injection freeze drying powder injections |
| CN112843003A (en) * | 2021-03-25 | 2021-05-28 | 海南海灵化学制药有限公司 | Lyophilized powder of latamoxef sodium for injection and its lyophilization process |
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| CN115737573B (en) | 2024-02-20 |
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