CN110917166A - Cefteram pivoxil tablet and preparation method thereof - Google Patents
Cefteram pivoxil tablet and preparation method thereof Download PDFInfo
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- CN110917166A CN110917166A CN201911414130.9A CN201911414130A CN110917166A CN 110917166 A CN110917166 A CN 110917166A CN 201911414130 A CN201911414130 A CN 201911414130A CN 110917166 A CN110917166 A CN 110917166A
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- China
- Prior art keywords
- cefteram pivoxil
- cefteram
- pivoxil
- acrylic resin
- tablets
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- 229950002506 cefteram pivoxil Drugs 0.000 title claims abstract description 62
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- UIYAXIPXULMHAI-JLGRZTKVSA-N Cefteram pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 UIYAXIPXULMHAI-JLGRZTKVSA-N 0.000 title claims abstract 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 26
- 229920002472 Starch Polymers 0.000 claims abstract description 22
- 239000008107 starch Substances 0.000 claims abstract description 22
- 235000019698 starch Nutrition 0.000 claims abstract description 22
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 21
- 239000011734 sodium Substances 0.000 claims abstract description 21
- AFZFFLVORLEPPO-UVYJNCLZSA-N cefditoren pivoxil Chemical compound S([C@@H]1[C@@H](C(N1C=1C(=O)OCOC(=O)C(C)(C)C)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1\C=C/C=1SC=NC=1C AFZFFLVORLEPPO-UVYJNCLZSA-N 0.000 claims abstract description 15
- 229960002142 cefditoren pivoxil Drugs 0.000 claims abstract description 15
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 15
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 15
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims abstract description 7
- 239000011248 coating agent Substances 0.000 claims description 23
- 238000000576 coating method Methods 0.000 claims description 23
- 239000004925 Acrylic resin Substances 0.000 claims description 18
- 229920000178 Acrylic resin Polymers 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 238000007873 sieving Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 235000019438 castor oil Nutrition 0.000 claims description 9
- 239000004359 castor oil Substances 0.000 claims description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 9
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 7
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 7
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 7
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 238000000227 grinding Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000011812 mixed powder Substances 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 238000005507 spraying Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims 1
- 235000012222 talc Nutrition 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 23
- 238000004090 dissolution Methods 0.000 abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000012738 dissolution medium Substances 0.000 abstract description 5
- 239000002904 solvent Substances 0.000 abstract description 3
- 231100000252 nontoxic Toxicity 0.000 abstract description 2
- 230000003000 nontoxic effect Effects 0.000 abstract description 2
- 229910021426 porous silicon Inorganic materials 0.000 abstract description 2
- 239000000741 silica gel Substances 0.000 abstract description 2
- 229910002027 silica gel Inorganic materials 0.000 abstract description 2
- XSPUSVIQHBDITA-RKYNPMAHSA-N cefteram Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CN1N=NC(C)=N1 XSPUSVIQHBDITA-RKYNPMAHSA-N 0.000 description 59
- 239000000243 solution Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 12
- 229950000679 cefteram Drugs 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- -1 2-amino-4-thiazolyl Chemical group 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000006184 cosolvent Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 238000001879 gelation Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 229950009297 pivoxil Drugs 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000008351 acetate buffer Substances 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- JXKPEJDQGNYQSM-UHFFFAOYSA-M sodium propionate Chemical compound [Na+].CCC([O-])=O JXKPEJDQGNYQSM-UHFFFAOYSA-M 0.000 description 2
- 239000004324 sodium propionate Substances 0.000 description 2
- 229960003212 sodium propionate Drugs 0.000 description 2
- 235000010334 sodium propionate Nutrition 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- UKRMLMLMUQODDB-UHFFFAOYSA-N 2,2-dimethylpropanoyloxymethyl 2-methyloct-2-enoate Chemical compound CCCCCC=C(C)C(=O)OCOC(=O)C(C)(C)C UKRMLMLMUQODDB-UHFFFAOYSA-N 0.000 description 1
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588923 Citrobacter Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588748 Klebsiella Species 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010037596 Pyelonephritis Diseases 0.000 description 1
- 206010039587 Scarlet Fever Diseases 0.000 description 1
- 241000607720 Serratia Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 206010006451 bronchitis Diseases 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
- 201000001352 cholecystitis Diseases 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 201000003146 cystitis Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 208000020426 gonococcal urethritis Diseases 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229940087562 sodium acetate trihydrate Drugs 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 206010044008 tonsillitis Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a cefteram pivoxil tablet and a preparation method thereof. Mixing the cefditoren pivoxil and the sodium carboxymethyl starch, dissolving the mixture in a nontoxic solvent polyethylene glycol 400 which can be mixed and dissolved with water, adsorbing the mixture by using a porous silicon dioxide carrier, and finally preparing the mixture into tablets. Since the drug is adsorbed on the silica gel in a molecular state, the drug is easily dissolved when contacting the dissolution medium, and the dissolution rate of the drug is increased.
Description
The technical field is as follows:
the invention belongs to the field of pharmaceutical preparations, and particularly relates to a cefteram pivoxil tablet and a preparation method thereof.
Background art:
cefteram pivoxil, chemical name (6R, 7R) -7- [ (Z) -2- (2-amino-4-thiazolyl) -2- (methoxyimino) acetamido ] -3- [2- (5-methyl-2H-tetrazol-2-yl) methyl ] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid pivaloyloxymethyl ester. The cefteram pivoxil belongs to oral third-generation cephalosporin, is a prodrug of the cefteram modified by an ester group structure, has weaker self activity, and generates active cefteram by esterase hydrolysis after oral absorption to generate antibacterial activity. Has spectrum antibacterial effect on gram negative and positive bacteria such as Citrobacter, Serratia and Enterobacter. The medicine is mainly used for treating infections caused by streptococcus, pneumococcus, escherichia coli, klebsiella, proteus and haemophilus influenzae, such as sphagitis, tonsillitis, bronchitis, pneumonia, pyelonephritis, cystitis, gonococcal urethritis, cholecystitis, otitis media, scarlet fever and the like.
The cefteram pivoxil has poor water solubility, almost is insoluble in water, has good fat solubility, is easily soluble in solvents such as methanol and the like, has better photo-thermal stability in a solid state, is not stable in a solution, and is easily decomposed when meeting acid and alkali. Therefore, the existing cefteram pivalol preparation has slow dissolution, absorption and distribution in vivo and relatively low bioavailability.
Patent CN108113972A discloses a pharmaceutical composition containing cefteram pivoxil, wherein sodium propionate is added into the composition as a gel inhibitor, so as to effectively inhibit the solid preparation from gelling in an aqueous solution, effectively improve the dissolution performance of the solid preparation, and further improve the bioavailability. And the problem of bitter taste of the granular preparation is solved by utilizing the synergistic flavoring effect of the sodium propionate and the aspartame.
Patent CN103919744A discloses a cefteram pivoxil tablet, which comprises the following components in parts by weight: 80-120 parts of cefteram pivoxil; 80-100 parts of starch; 5-15 parts of lactose; 5-15 parts by weight of microcrystalline cellulose; 15-30 parts by weight of croscarmellose sodium; 0.5-2 parts by weight of magnesium stearate; and (4) a proper amount of adhesive. The tablet adopts the croscarmellose sodium to match with the microcrystalline cellulose, so that the disintegration time limit and the release effect of the tablet are unexpectedly improved, the drug effect is more obvious, but the impurity content is higher, and the stability of the preparation needs to be improved.
Patent CN1709262A discloses a cefteram composition for injection, which comprises the following components: cefteram or a pharmaceutically acceptable salt thereof as an active ingredient and a cosolvent as a cosolvent ingredient; the cosolvent is basic amino acid, or inorganic acid salt of alkali metal, or organic acid salt of alkali metal, or inorganic acid salt of alkaline earth metal, or organic acid salt of alkaline earth metal; the proportion of the cefteram or the medicinal salt thereof to the cosolvent is 1: 0.05-20 in parts by weight. Due to the addition of a proper amount of cosolvent, the cefteram composition becomes a soluble medicament, has good water solubility, can fully exert the antibacterial action of the active cefteram when used as an injection medicament, and overcomes the defect of the existing cefteram ester oral preparation and can be used for all indications of the cefteram ester.
Patent CN100998595A provides a pharmaceutical composition of a cyclodextrin inclusion compound of cefteram pivoxil, which comprises the following basic components: A) cefteram pivoxil, and B) a pharmaceutically acceptable cyclodextrin; the cyclodextrin is selected from B-cyclodextrin or one or more of derivatives thereof. The clathrate compound of the invention obviously increases the solubility and stability of the drug, and simultaneously has lower hemolysis stimulation and high activity.
The method adopts a method of adding a pharmaceutical adjuvant to improve the solubility and stability of the cefditoren pivoxil.
Patent CN102351886A discloses a cefteram pivoxil crystal and a composition tablet of the crystal, starting from a cefteram pivoxil raw material drug, a cefteram pivoxil crystal with a small particle size is prepared by an ultrasonic method, and the obtained cefteram pivoxil crystal is added with pharmaceutically acceptable auxiliary materials to prepare the cefteram pivoxil composition tablet.
Patent CN108143723A discloses a cefoperan pivoxil tablet, which is mainly composed of cefoperan pivoxil micropowder with the particle size of 35-50 μm, and is assisted by ultrafine powder with the particle size of 3-6 μm, so that the cefoperan pivoxil tablet has a good space scale effect, and meanwhile, mannitol with poor fluidity and microcrystalline cellulose with good fluidity are matched according to a certain proportion to be used as a disintegrating agent.
Patent CN102091039A discloses a solid preparation of cefteram pivoxil liposome, which is prepared from the following raw and auxiliary materials in parts by weight: 1 part of cefteram pivoxil, 4-25 parts of soybean lecithin, 1-12 parts of cholesterol, 0.5-20 parts of tween 80, 1-4 parts of soyasterol and 5-40 parts of a pharmaceutically acceptable carrier. The liposome solid preparation has high entrapment rate, uniform particle size and long retention time of the drug in blood circulation, but the production control requirement of the liposome solid preparation is higher, so that the clinical application is greatly limited.
Summarizing the preparation of the cefteram pivoxil in the prior art, the tablet is a common preparation form, and a wetting agent water or alcohol is required to be added in the wet granulation process, so that gelation is easy to cause, and the bonding phenomenon is serious; although the dry granulation can avoid the problem of gelation, the problem of dissolution reduction caused by gelation when meeting water in the medication process still exists; the direct tabletting effect of the powder is poor, so a large amount of filler is generally required to be added, and the requirement on the filler is high, so that the preparation cost is greatly increased, and the medicine is not dissolved well.
The invention content is as follows:
in order to overcome the defects in the prior art, the invention provides a cefteram pivoxil tablet and a preparation method thereof.
The invention provides a cefteram pivoxil tablet which is prepared from the following raw and auxiliary materials:
wherein, the coating material comprises acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and 85% ethanol, and the mass ratio is that acrylic resin No. 2: acrylic resin No. 3: castor oil: talc powder: 15% ethanol: 5:3:2: 25.
the preparation method of the cefteram pivoxil tablet provided by the invention comprises the following steps:
(1) mixing and grinding the cefditoren pivoxil and the sodium carboxymethyl starch, sieving the mixture with a 200-mesh sieve, and sieving the silicon dioxide with a 100-mesh sieve
(2) Adding polyethylene glycol 400 into the mixed powder of the cefteram pivoxil and the sodium carboxymethyl starch, stirring and dissolving,
(3) the dissolved cefditoren pivoxil and sodium carboxymethyl starch are slowly sprayed on the silicon dioxide in a fluidized bed, so that the solution is completely absorbed.
(4) Tabletting
(5) Adding acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and croscarmellose sodium into 85% ethanol, heating and stirring for 8 hours to form a coating solution;
(6) and (4) putting the plain tablets obtained in the step (4) into a coating pan, atomizing the coating solution into small liquid drops through a spray gun, attaching the small liquid drops to the surface of the plain tablets for coating, and drying to obtain the cefteram pivoxil tablets.
Compared with the prior art, the invention has the following beneficial technical effects:
(1) the hydrophobic cefditoren pivoxil and a large amount of water-soluble sodium carboxymethyl starch are ground together to prepare a mixture, the particle sizes of the medicine and the auxiliary materials can be reduced to be very small, a large amount of water-soluble auxiliary material particles are adsorbed around the fine medicine particles, the mutual aggregation of the fine medicine particles is prevented, the fine medicine particles exist in the mixture stably, and when the water-soluble auxiliary materials are dissolved, the fine medicine particles are directly exposed in a dissolving medium, so the dissolution/dissolution is accelerated.
(2) Mixing the cefditoren pivoxil and the sodium carboxymethyl starch, dissolving the mixture in a nontoxic solvent polyethylene glycol 400 which can be mixed and dissolved with water, adsorbing the mixture by using a porous silicon dioxide carrier, and finally preparing the mixture into tablets. Since the drug is adsorbed on the silica gel in a molecular state, the drug is easily dissolved when contacting the dissolution medium, and the dissolution rate of the drug is increased.
(3) Through the determination of a plurality of dissolution curves, compared with the prior art, the prepared cefteram pivoxil tablet can ensure higher dissolution in solutions with different pH values and is more suitable for the dissolution environment of the medicine in vivo.
The specific implementation mode is as follows:
example 1
The cefteram pivoxil tablet is prepared into 1000 tablets by the following raw and auxiliary materials:
the preparation method comprises the following steps:
(1) mixing and grinding the cefteram pivoxil and the sodium carboxymethyl starch, sieving the mixture with a 200-mesh sieve, and sieving the silicon dioxide with a 120-mesh sieve for later use;
(2) adding the mixed powder of the cefteram pivoxil and the sodium carboxymethyl starch into polyethylene glycol 400, and stirring for dissolving;
(3) slowly spraying the dissolved cefteram pivoxil and the sodium carboxymethyl starch on silicon dioxide in a fluidized bed to ensure that the solution is completely absorbed;
(4) tabletting the silicon dioxide absorbed with the cefteram pivoxil and the sodium carboxymethyl starch;
(5) adding acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and croscarmellose sodium into 85% ethanol, heating to 35 ℃, and stirring for 8 hours to form a coating solution;
(6) and (4) putting the plain tablets obtained in the step (4) into a coating pan, atomizing the coating solution into small liquid drops through a spray gun, attaching the small liquid drops to the surface of the plain tablets for coating, and drying to obtain the cefteram pivoxil tablets.
Example 2
The cefteram pivoxil tablet is prepared into 1000 tablets by the following raw and auxiliary materials:
the preparation method comprises the following steps:
(1) mixing and grinding the cefteram pivoxil and the sodium carboxymethyl starch, sieving the mixture with a 200-mesh sieve, and sieving the silicon dioxide with a 120-mesh sieve for later use;
(2) adding the mixed powder of the cefteram pivoxil and the sodium carboxymethyl starch into polyethylene glycol 400, and stirring for dissolving;
(3) slowly spraying the dissolved cefteram pivoxil and the sodium carboxymethyl starch on silicon dioxide in a fluidized bed to ensure that the solution is completely absorbed;
(4) tabletting the silicon dioxide absorbed with the cefteram pivoxil and the sodium carboxymethyl starch;
(5) adding acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and croscarmellose sodium into 85% ethanol, heating to 40 ℃, and stirring for 8 hours to form a coating solution;
(6) and (4) putting the plain tablets obtained in the step (4) into a coating pan, atomizing the coating solution into small liquid drops through a spray gun, attaching the small liquid drops to the surface of the plain tablets for coating, and drying to obtain the cefteram pivoxil tablets.
Example 3
The cefteram pivoxil tablet is prepared into 1000 tablets by the following raw and auxiliary materials:
the preparation method comprises the following steps:
(1) mixing and grinding the cefteram pivoxil and the sodium carboxymethyl starch, sieving the mixture with a 200-mesh sieve, and sieving the silicon dioxide with a 120-mesh sieve for later use;
(2) adding the mixed powder of the cefteram pivoxil and the sodium carboxymethyl starch into polyethylene glycol 400, and stirring for dissolving;
(3) slowly spraying the dissolved cefteram pivoxil and the sodium carboxymethyl starch on silicon dioxide in a fluidized bed to ensure that the solution is completely absorbed;
(4) tabletting the silicon dioxide absorbed with the cefteram pivoxil and the sodium carboxymethyl starch;
(5) adding acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and croscarmellose sodium into 85% ethanol, heating to 45 ℃, and stirring for 8 hours to form a coating solution;
(6) and (4) putting the plain tablets obtained in the step (4) into a coating pan, atomizing the coating solution into small liquid drops through a spray gun, attaching the small liquid drops to the surface of the plain tablets for coating, and drying to obtain the cefteram pivoxil tablets.
Experimental example 1 dissolution measurement
According to the dissolution determination method under the item of the cefditoren pivoxil tablet in the 17 th edition of the Japanese medicine office, according to the paddle method, hydrochloric acid solution with pH value of 1.0, acetate buffer solution with pH value of 4.5, phosphate buffer solution with pH value of 6.8 and 900mL of purified water are respectively used as dissolution media, the rotating speed is 75 revolutions per minute, the operation is carried out according to the method, after 30 minutes, a proper amount of solution is taken, filtered, a proper amount of subsequent filtrate is taken precisely, the solution containing about 20 mu g of cefditoren pivoxil in each 1mL is prepared by quantitative dilution with the dissolution media, the absorbance is measured at the wavelength of 300nm, a proper amount of cefditoren pivoxil reference substance is weighed precisely, the solution containing about 20 mu g of cefditoren pivoxil in each 1mL is prepared by dissolving and quantitative dilution with the dissolution media, and the determination is carried out by the same method. The amount of elution was calculated for each tablet.
Hydrochloric acid solution at pH 1.0: precisely measuring 9.0ml of concentrated hydrochloric acid, adding water to dilute the concentrated hydrochloric acid to 1000ml, and shaking up to obtain the product.
Acetate buffer at pH 4.5: taking 2.99g of sodium acetate trihydrate and 14.0mL of 2mol/L acetic acid (120.0 g of glacial acetic acid is taken, water is added for dilution to 1000mL, and the mixture is shaken up) and adding water for dissolution and dilution to 1000mL, and the mixture is shaken up to obtain the sodium acetate.
phosphate buffer at pH 6.8: precisely weighing 6.80g of potassium dihydrogen phosphate, adding 112.0mL of 0.2mol/L sodium hydroxide solution (obtained by dissolving 8.0g of sodium hydroxide in water and diluting to 1000 mL), adding water to dissolve and dilute to 1000mL, and shaking up to obtain the potassium dihydrogen phosphate.
Reference formulation 1: a tablet of cefteram pivoxil prepared according to patent CN102351886 formulation example 1.
Reference formulation 2: cefditoren pivoxil tablets prepared according to patent CN103919744, example 1.
Reference formulation 3: cefditoren pivoxil tablets prepared according to patent CN108113972, example 1.
Reference formulation 4: cefditoren pivoxil tablets prepared according to patent CN108143723, example 1.
The samples of examples 1 to 3 of the present invention and reference preparations 1 to 4 were taken for testing, respectively, and the results were as follows:
experimental example 2 stability test
And (4) investigating items: properties, dissolution rate, content, related substances and water. The test is carried out according to the guiding principle of 9001 raw material medicaments and preparation stability test in the fourth pharmacopoeia 2015 edition.
(1) Test for influencing factor
High-temperature test: taking the cefditoren pivoxil tablet obtained in the embodiment 1 of the invention, placing the tablet at the temperature of 60 ℃ for 10 days, sampling on the 5 th day and the 10 th day, and detecting according to a stability focus examination item.
High humidity test: taking the cefteram pivoxil tablet obtained in the embodiment 1 of the invention, placing the cefteram pivoxil tablet in a constant-humidity closed container, placing the cefteram pivoxil tablet in a condition of 90% +/-5% relative humidity for 10 days at 25 ℃, sampling on the 5 th day and the 10 th day, and detecting according to the requirements of key stability investigation projects.
Strong light irradiation test: the cefteram pivoxil tablet obtained in the embodiment 1 of the invention is put in a lighting box provided with a fluorescent lamp, is placed for 10 days under the condition that the illumination intensity is 4500lx +/-500 lx, and is sampled on the 5 th day and the 10 th day, and is detected according to the key stability investigation items.
The effect test results are shown in the following table:
(2) accelerated test
The cefteram pivoxil tablets obtained in the embodiment 1 of the invention are packaged according to the market and placed for 6 months under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75% +/-5%. Samples were taken at the end of 1 month, 2 months, 3 months and 6 months during the test period, and were tested according to stability focus test items.
The results of the accelerated testing are shown in the following table:
(3) long term test
Taking the cefteram pivoxil tablets obtained in the embodiment 1 of the invention, packaging the cefteram pivoxil tablets according to the market, placing the cefteram pivoxil tablets for 12 months under the conditions of 25 ℃ plus or minus 2 ℃ and 60 percent plus or minus 10 percent of relative humidity, sampling every 3 months, sampling for 0 month, 3 months, 6 months, 9 months and 12 months respectively, and detecting according to the stability key examination item.
Claims (6)
1. The cefteram pivoxil tablet is characterized by being prepared from the following raw and auxiliary materials:
2. the cefteram pivoxil tablet according to claim 1, which is characterized by being prepared from the following raw and auxiliary materials:
3. the cefteram pivoxil tablet according to any one of claims 1 or 2, characterized in that the coating material consists of acrylic resin No. 2, acrylic resin No. 3, castor oil, talc, 85% ethanol.
4. The cefteram pivoxil tablet according to claim 3, characterized in that the mass ratio of the auxiliary materials composing the coating material is acrylic resin No. 2: acrylic resin No. 3: castor oil: talc powder: 85% ethanol-15: 5:3:2: 25.
5. The process for the preparation of the cefteram pivoxil tablet according to claim 4, characterized by comprising the steps of:
(1) mixing and grinding the cefditoren pivoxil and the sodium carboxymethyl starch, sieving the mixture with a 200-mesh sieve, sieving the silicon dioxide with a 100-mesh sieve,
(2) adding polyethylene glycol 400 into the mixed powder of the cefteram pivoxil and the sodium carboxymethyl starch, stirring and dissolving,
(3) slowly spraying the dissolved cefteram pivoxil and the sodium carboxymethyl starch on silicon dioxide in a fluidized bed to ensure that the solution is completely absorbed,
(4) tabletting is carried out, and the mixture is pressed into tablets,
(5) adding acrylic resin No. 2, acrylic resin No. 3, castor oil, talcum powder and croscarmellose sodium into 85% ethanol, heating and stirring for 8 hours to form a coating solution;
(6) and (4) putting the plain tablets obtained in the step (4) into a coating pan, atomizing the coating solution into small liquid drops through a spray gun, attaching the small liquid drops to the surface of the plain tablets for coating, and drying to obtain the cefteram pivoxil tablets.
6. The method for preparing cefteram pivoxil according to claim 5, wherein the mixing temperature in the step (5) is 35-45 ℃.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103965A (en) * | 2006-05-02 | 2008-01-16 | 兰贝克赛实验室有限公司 | Stable solid preparation containing amorphous cefditoren pivoxil and preparation method thereof |
| CN103919744A (en) * | 2014-04-25 | 2014-07-16 | 优胜美特制药有限公司 | Cefteram pivoxil tablet and preparation process thereof |
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2019
- 2019-12-31 CN CN201911414130.9A patent/CN110917166A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101103965A (en) * | 2006-05-02 | 2008-01-16 | 兰贝克赛实验室有限公司 | Stable solid preparation containing amorphous cefditoren pivoxil and preparation method thereof |
| CN103919744A (en) * | 2014-04-25 | 2014-07-16 | 优胜美特制药有限公司 | Cefteram pivoxil tablet and preparation process thereof |
Non-Patent Citations (1)
| Title |
|---|
| 缪立德主编: "《药剂学》", 31 May 1999, 中国医药科技出版社 * |
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