CN104876947B - Cefetamet Pivoxil Hydrochloride hydrate crystal and its dispersible tablet - Google Patents
Cefetamet Pivoxil Hydrochloride hydrate crystal and its dispersible tablet Download PDFInfo
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- CN104876947B CN104876947B CN201510227083.2A CN201510227083A CN104876947B CN 104876947 B CN104876947 B CN 104876947B CN 201510227083 A CN201510227083 A CN 201510227083A CN 104876947 B CN104876947 B CN 104876947B
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- China
- Prior art keywords
- cefetamet pivoxil
- pivoxil hydrochloride
- hydrochloride hydrate
- cefetamet
- ethanol
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- 229950000726 cefetamet pivoxil Drugs 0.000 title claims description 111
- DASYMCLQENWCJG-XUKDPADISA-N cefetamet pivoxil Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 DASYMCLQENWCJG-XUKDPADISA-N 0.000 title claims description 109
- 239000013078 crystal Substances 0.000 title claims description 29
- 239000007919 dispersible tablet Substances 0.000 title description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 89
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 64
- 238000003756 stirring Methods 0.000 claims description 33
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- 238000002156 mixing Methods 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 229920002472 Starch Polymers 0.000 claims description 20
- 239000008107 starch Substances 0.000 claims description 20
- 229940032147 starch Drugs 0.000 claims description 20
- 235000019698 starch Nutrition 0.000 claims description 20
- 239000000047 product Substances 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 15
- 239000011780 sodium chloride Substances 0.000 claims description 15
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 14
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 14
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 14
- 239000012047 saturated solution Substances 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 229960004041 cefetamet Drugs 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 238000004806 packaging method and process Methods 0.000 claims description 12
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 10
- 229960004998 acesulfame potassium Drugs 0.000 claims description 10
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 10
- 239000000619 acesulfame-K Substances 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 10
- 239000011734 sodium Substances 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 9
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 9
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000000843 powder Substances 0.000 claims description 8
- 239000012153 distilled water Substances 0.000 claims description 7
- 239000002245 particle Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000002994 raw material Substances 0.000 claims description 7
- 238000007789 sealing Methods 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 238000010792 warming Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 5
- 238000005453 pelletization Methods 0.000 claims description 5
- 235000020985 whole grains Nutrition 0.000 claims description 5
- -1 hydroxypropyl Chemical group 0.000 claims description 4
- 238000002347 injection Methods 0.000 claims description 4
- 239000007924 injection Substances 0.000 claims description 4
- 101100008046 Caenorhabditis elegans cut-2 gene Proteins 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910017488 Cu K Inorganic materials 0.000 claims description 2
- 229910017541 Cu-K Inorganic materials 0.000 claims description 2
- 230000005260 alpha ray Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000005259 measurement Methods 0.000 claims description 2
- 229940080313 sodium starch Drugs 0.000 claims description 2
- 229940057948 magnesium stearate Drugs 0.000 claims 1
- 238000005303 weighing Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 description 21
- 229940079593 drug Drugs 0.000 description 11
- 238000012360 testing method Methods 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 8
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 7
- 239000006166 lysate Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 235000012907 honey Nutrition 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000013049 sediment Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 108090000204 Dipeptidase 1 Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 241000193830 Bacillus <bacterium> Species 0.000 description 2
- 241001478240 Coccus Species 0.000 description 2
- 108090000371 Esterases Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229960002588 cefradine Drugs 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 229940106164 cephalexin Drugs 0.000 description 2
- RDLPVSKMFDYCOR-UEKVPHQBSA-N cephradine Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CCC=CC1 RDLPVSKMFDYCOR-UEKVPHQBSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000013401 experimental design Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 238000002411 thermogravimetry Methods 0.000 description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- ILPBINAXDRFYPL-UHFFFAOYSA-N 2-octene Chemical compound CCCCCC=CC ILPBINAXDRFYPL-UHFFFAOYSA-N 0.000 description 1
- 241000588624 Acinetobacter calcoaceticus Species 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 101100008044 Caenorhabditis elegans cut-1 gene Proteins 0.000 description 1
- 101100008047 Caenorhabditis elegans cut-3 gene Proteins 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000588697 Enterobacter cloacae Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010018612 Gonorrhoea Diseases 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 241001263448 Mycetozoa Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193985 Streptococcus agalactiae Species 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 208000037386 Typhoid Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 235000013361 beverage Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 1
- 229960005361 cefaclor Drugs 0.000 description 1
- CZTQZXZIADLWOZ-CRAIPNDOSA-N cefaloridine Chemical compound O=C([C@@H](NC(=O)CC=1SC=CC=1)[C@H]1SC2)N1C(C(=O)[O-])=C2C[N+]1=CC=CC=C1 CZTQZXZIADLWOZ-CRAIPNDOSA-N 0.000 description 1
- 229960003866 cefaloridine Drugs 0.000 description 1
- MLYYVTUWGNIJIB-BXKDBHETSA-N cefazolin Chemical compound S1C(C)=NN=C1SCC1=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 MLYYVTUWGNIJIB-BXKDBHETSA-N 0.000 description 1
- 229960001139 cefazolin Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012263 liquid product Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- NZQJSIPYDOTDFS-JJHIVTNASA-M sodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C([O-])=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 NZQJSIPYDOTDFS-JJHIVTNASA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 229940030998 streptococcus agalactiae Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic 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; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention provides a kind of Cefetamet Pivoxil Hydrochloride hydrate, and the X ray powder diffractograms that it is obtained using Cu K alpha ray measurements are as shown in Figure 1.Cefetamet Pivoxil Hydrochloride hydrate crystal stability of the present invention is good, is difficult moisture absorption, with good mobility, can uniformly be mixed with other auxiliary materials, and prepared hydrochloric acid cefetamet pivoxil dispersible tablet agent infiltration rate is fast, and bioavilability is high.
Description
Technical field
The invention belongs to field of medicaments, more particularly, to a kind of Cefetamet Pivoxil Hydrochloride hydrate crystal and its dispersible tablet.
Background technology
In the prior art, beta-lactam antibiotic is that Clinical practice amount is maximum, most widely used, kind at most, curative effect most
The good and evaluation class antibiotic of highest one, wherein, cynnematin series of products account for 70%, in various cynnematins, hydrochloric acid
Cefetamet Pivoxil is oral third generation broad-spectrum cephalosporin class antibiotic, the features such as with wide spectrum, efficient, resistance to enzyme, low toxicity, compared with
Have the advantages that antibacterial activity is stronger, dosage is smaller with veriety cefalexin, cefradine etc., overcome pioneer's series of products
The shortcoming unstable to beta-lactamase, is cefalexin, the preferable substitute of cefradine.
Cefetamet Pivoxil Hydrochloride is developed by Roche Holding Ag, and Japanese Takeda Pharmaceutical Company Limited develops, and in 1987 at Japanese group
Knit the research of nationwide scale.Since listing in 1992, applied in countries in the world.As anti-infective oral drugs, this product is most
Unique advantage be it is oral after be the cefetamet with antibacterial activity by esterase hydrolyzed in intestinal wall and liver rapidly in vivo and
Play a role.Its chemical name is:(6R, 7R) -3- methyl -7- ((Z) -2- (2- amino -4- thiazolyls) -2- (methoxy imido
Base)-acetylamino) -8- oxos -5- thia -1- azabicyclos (4,2,0) oct-2-ene -2- formic acid pivaloyl oxygen methyl esters hydrochloric acid
Salt.Every Western Europe country is studied from nineteen eighty-three, starts within 1986 clinical test, 1984-1990 is in many international science
Reported in meeting.Japan proceeds by Section 1 clinical test for 1986, and nationwide clinical test results come from 1989
Year.
Cefetamet Pivoxil in-vitro antibacterial vigor is not weaker, not and its parent compound cefetamet activity is strong.Cefetamet Pivoxil
Greatly improved in intestinal wall and liver is entered by the Viability compound cefetamet of esterase hydrolyzed, its antibacterial activity.Cefetamet
Effect of the ester to pneumococcus is most strong, to staphylococcus aureus, table Portugal coccus, streptococcus pyogenes, Streptococcusagalactiae, tetrads etc.
There is certain antibacterial action.To the EHEC in gram-negative bacteria, proteus, Klebsiella Pneumoniae, typhoid bacillus, dysentery
Bacillus has stronger antibacterial activity, and curative effect is substantially better than cefaloridine, cephazoline, 2~64 times of Cefaclor.To gonorrhoea how
The antibody-resistant bacterium that plucked instrument coccus includes producing beta-lactamase is also very effective (MIC≤0.125mg/L).To mycetozoan, Providian
This bacterium, YE, acinetobacter calcoaceticus, bacillus cloacae, Hough Buddhist nun bacterium also have certain antibacterial activity.And to 80%
Produce beta-lactamase bacterial strain still sensitive.The main pathogenic fungi such as pneumonia streptococcus of his the U.S. free acid of active body to respiratory tract infection
Bacterium, haemophilus influenzae, streptococcus pyogenes, mucositis Branhamella, Klebsiella Pneumoniae have fabulous antibacterial action.It is right
The effective percentage of chronic bronchitis and bacterial pneumonia is 72.7%.
CN101550146A discloses a kind of cefetamet pivoxil hydrochloride compound and its preparation method, salt prepared by prior art
Sour Cefetamet Pivoxil crude product prepares relatively pure cefetamet pivoxil hydrochloride compound by following steps.By hydrochloric acid cephalo he
U.S. ester crude product is dissolved in methanol or ethanol, is added sodium hydroxide or potassium hydroxide solution, stirring reaction, is hydrolyzed to obtain Ro 15-8074/001
Or sylvite；Plus charcoal absorption, filtering, then add iodo-ester, organic solvent presence under conditions of react, obtain cephalo he
U.S. ester, Cefetamet Pivoxil is dissolved in isopropanol, and hydrochloric acid is added dropwise, and is added hexamethylene stirring, is separated out crystallization, filter, wash, dries,
Obtain Cefetamet Pivoxil Hydrochloride.
Cefetamet Pivoxil Hydrochloride stability and poor fluidity, the easy moisture absorption is rotten and content uniformity occurs.In view of this,
Spy proposes the present invention.
The content of the invention
It is an object of the invention to provide a kind of Cefetamet Pivoxil Hydrochloride hydrate crystal.
A kind of Cefetamet Pivoxil Hydrochloride hydrate, it is characterised in that each Cefetamet Pivoxil Hydrochloride hydrate contains 1 knot
Brilliant water, and its X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurements is as shown in Figure 1.
Researcher of the present invention be surprised to find that under study for action when Cefetamet Pivoxil Hydrochloride formation 1 hydrate crystal when, its
Stability is dramatically increased and with good mobility.
The Cefetamet Pivoxil Hydrochloride hydrate crystal is determined with powder x-ray diffraction determination method, with 2 θ ± 0.2 ° diffraction
The X-ray powder diffraction pattern that angle is represented 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °,
Characteristic diffraction peak is shown at 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 °.
Described Cefetamet Pivoxil Hydrochloride hydrate is analyzed by heat differential-thermogravimetric TG-DTA, is lost in the range of 80-150 DEG C
Weight 3.1wt%-3.4wt%.
A kind of preparation method of described Cefetamet Pivoxil Hydrochloride hydrate, methods described comprises the following steps：
(1) by Cefetamet Pivoxil Hydrochloride dissolving crude product into 5-10 DEG C of ethanol, the volume of the ethanol is hydrochloric acid cephalo
3-8 times of his U.S. ester crude product quality；
(2) Cefetamet Pivoxil Hydrochloride crude product quality 0.02-0.1 activated carbon decolorizing is added 20-30 minutes, filtering, Shao Liangyi
Alcohol lysate is washed, and obtains Cefetamet Pivoxil Hydrochloride ethanol solution；
(3) Cefetamet Pivoxil Hydrochloride ethanol solution is warming up to 20-30 DEG C, to Cefetamet Pivoxil Hydrochloride under conditions of stirring
- 15 DEG C -5 DEG C of sodium chloride saturated solution is added dropwise in ethanol solution, the volume of sodium chloride saturated solution is Cefetamet Pivoxil Hydrochloride
At the uniform velocity completion of dropping in 5-8 times of volumes of aqueous ethanol, 0.5h, the stir speed (S.S.) is 20-25rmp；
(4) -15 DEG C -5 DEG C are cooled to after being added dropwise to complete to continue to stir 0.5-2h under 10-15rmp stir speed (S.S.), are stood
2-4h separates out light yellow crystal, filtering；
(5) vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal after being washed successively with distilled water, ethyl acetate.
Sodium chloride saturation in the step (3) to the dropwise addition of Cefetamet Pivoxil Hydrochloride ethanol solution under conditions of stirring is molten
Liquid product is 7 times of Cefetamet Pivoxil Hydrochloride volumes of aqueous ethanol；Add sodium chloride saturated solution when the stir speed (S.S.) be
23rmp。
The temperature of sodium chloride saturated solution described in the step (3) is -10 DEG C.
- 10 DEG C are cooled to after being added dropwise to complete in the step (4) to continue to stir 1h under 12rmp stir speed (S.S.).
A kind of pharmaceutical composition containing described Cefetamet Pivoxil Hydrochloride hydrate, described pharmaceutical composition is dispersible tablet
Agent, tablet, capsule, freeze drying powder injection, sterile powder injection.
Disket component containing described Cefetamet Pivoxil Hydrochloride hydrate includes：
A kind of preparation method of the Cefetamet Pivoxil Hydrochloride hydrate Disket, it is characterised in that the preparation side
Method includes：By raw material Cefetamet Pivoxil Hydrochloride hydrate and supplementary product starch, microcrystalline cellulose, hydroxypropylcellulose, acesulfame potassium and carboxylic
First sodium starch is crushed, sieved respectively, wet granular processed, dry particl processed, tabletting and packaging, described wet granular processed is weighs recipe quantity
Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and hydroxypropylcellulose, insert mixed at high speed granulation
In machine, sealing high speed is dry-mixed 5-15 minutes, then adds appropriate amount of ethanol wet mixing 1-5 minutes, after wet mixing, and wet mixing is cut 1-3 minutes,
Particle is released, wet granular is obtained.
The preparation method of the Cefetamet Pivoxil Hydrochloride hydrate Disket comprises the following steps：
1) get the raw materials ready
Cefetamet Pivoxil Hydrochloride hydrate is crushed, 100 mesh sieves are crossed, by starch, microcrystalline cellulose, hydroxypropylcellulose, peace
Match honey and carboxyrnethyl starch sodium are crushed respectively, are crossed 120 mesh sieves, are obtained standby original, auxiliary material；
2) wet granular processed
Weigh above-mentioned standby Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and the hydroxyl of recipe quantity
Third cellulose, is inserted in high-speed mixing granulating machine, and sealing high speed is dry-mixed 5-15 minutes, then adds 1-3 points of appropriate amount of ethanol wet mixing
Clock, after wet mixing, wet mixing is cut 2 minutes, is released particle, is obtained wet granular；
3) dry particl processed
Wet granular made from upper step is transferred in ebullated dryer, temperature control is dried 17-20 minutes at 60-70 DEG C, shut down,
Clear filter bag, blowing obtains dry particl；
4) tabletting, packaging
Dry particl obtained by upper step is added into pelletizing machine, start button carries out whole grain, and the carboxylic first for adding recipe quantity is formed sediment
Powder sodium and appropriate magnesium stearate, add three-dimensional mixer with suction feeding and mix, tabletting, packaging produces hydrochloric acid cefetamet
Ester dispersible tablet.
The present invention has the advantages and positive effects of：Cefetamet Pivoxil Hydrochloride hydrate crystal stability of the present invention is good,
Moisture absorption is difficult, with good mobility, can uniformly be mixed with other auxiliary materials, prepared hydrochloric acid cefetamet pivoxil dispersible tablet
Agent infiltration rate is fast, and bioavilability is high.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction spectrogram of Cefetamet Pivoxil Hydrochloride hydrate of the present invention
Fig. 2 is the thermogravimetric analysis figure of Cefetamet Pivoxil Hydrochloride hydrate of the present invention
Embodiment
Technical scheme is described in detail with embodiment below, it will help to the technical side of the present invention
Advantage, the effect of case, which have, further to be understood, and embodiment does not limit protection scope of the present invention, protection scope of the present invention by
Claim is determined.
Embodiment 1
Take Cefetamet Pivoxil Hydrochloride crude material medicine 10g to be dissolved into during 30ml temperature is 5 DEG C of ethanol, plus hydrochloric acid cephalo he
The activated carbon decolorizing of U.S. ester crude product quality 0.1 20-30 minutes, filtering, a small amount of ethanol lysate washing obtains hydrochloric acid cefetamet
Ester ethanol solution activated carbon decolorizing 20 minutes, filtering, a small amount of ethanol lysate washing obtains Cefetamet Pivoxil Hydrochloride ethanol molten
Liquid, 20 DEG C are warming up to by Cefetamet Pivoxil Hydrochloride ethanol solution, and stir speed (S.S.) is to Cefetamet Pivoxil Hydrochloride under conditions of 20rmp
At the uniform velocity completion of dropping is at the uniform velocity added dropwise in the sodium chloride saturated solution that 200ml temperature is -15 DEG C, 0.5h in ethanol solution, drips
- 15 DEG C are cooled to after to continue to stir 0.5h under 10rmp stir speed (S.S.), are stood 4h and are separated out light yellow crystal, filtering, with steaming
Vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal 9.78g after distilled water, ethyl acetate are washed successively.
Determined, existed with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented with powder x-ray diffraction determination method
7.4°、9.9°、12.8°、13.2°、17.3°、19.6°、20.8°、23.8°、24.4°、26.3°、29.0°、33.5°、36.6°、
Characteristic diffraction peak is shown at 39.0 °.
Elementary analysis：
Measured value：C 42.48%, H 5.03%, N 12.32%, O 22.68%, S11.41%, Cl 6.22%
Theoretical value：C 42.43%, H 4.99%, N 12.38%, O 22.61%, S11.33%, Cl 6.26%.
Elementary analysis result and theoretical value are basically identical.
Use Cattell aquametry to determine moisture for 3.4wt%, coincide substantially with theoretical value.
Determined, as a result as shown in Fig. 2 crystal water content is 3.2wt%, coincide substantially with theoretical value using thermogravimetric analysis.
Embodiment 2
Cefetamet Pivoxil Hydrochloride crude material medicine 10g is taken to be dissolved into the ethanol that 50ml temperature is 10 DEG C, plus hydrochloric acid cephalo
His activated carbon decolorizing of U.S. ester crude product quality 0.02 30 minutes, filtering, a small amount of ethanol lysate washing obtains hydrochloric acid cefetamet
Ester ethanol solution, 30 DEG C are warming up to by Cefetamet Pivoxil Hydrochloride ethanol solution, and stir speed (S.S.) is to hydrochloric acid head under conditions of 23rmp
At the uniform velocity it is added dropwise in the sodium chloride saturated solution that 350ml temperature is -10 DEG C, 0.5h and at the uniform velocity drips in his U.S. ester ethanol solution of spore
Finish, -10 DEG C are cooled to after being added dropwise to complete and continues to stir 1h under 12rmp stir speed (S.S.), 2h is stood and separates out light yellow crystal, mistake
Filter, vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal 9.89g after being washed successively with distilled water, ethyl acetate.
Determined, existed with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented with powder x-ray diffraction determination method
7.4°、9.9°、12.8°、13.2°、17.3°、19.6°、20.8°、23.8°、24.4°、26.3°、29.0°、33.5°、36.6°、
Characteristic diffraction peak is shown at 39.0 °.
Elementary analysis result and embodiment 1 are basically identical.
Moisture is determined using Cattell aquametry and embodiment 1 is basically identical.
Embodiment 3
Take Cefetamet Pivoxil Hydrochloride crude material medicine 10g to be dissolved into during 80ml temperature is 8 DEG C of ethanol, plus hydrochloric acid cephalo he
The activated carbon decolorizing of U.S. ester crude product quality 0.1 25 minutes, filtering, a small amount of ethanol lysate washing obtains Cefetamet Pivoxil Hydrochloride
Ethanol solution, 25 DEG C are warming up to by Cefetamet Pivoxil Hydrochloride ethanol solution, and stir speed (S.S.) is to hydrochloric acid cephalo under conditions of 25rmp
At the uniform velocity completion of dropping, drop are at the uniform velocity added dropwise in the sodium chloride saturated solution that 500ml temperature is -5 DEG C, 0.5h in his U.S. ester ethanol solution
Plus after the completion of be cooled to -10 DEG C under 15rmp stir speed (S.S.) continue stir 2h, stand 4h separate out light yellow crystal, filter, use
Vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal 9.83g after distilled water, ethyl acetate are washed successively.
Determined, existed with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented with powder x-ray diffraction determination method
7.4°、9.9°、12.8°、13.2°、17.3°、19.6°、20.8°、23.8°、24.4°、26.3°、29.0°、33.5°、36.6°、
Characteristic diffraction peak is shown at 39.0 °.
Elementary analysis result and embodiment 1 are basically identical.
Moisture is determined using Cattell aquametry and embodiment 1 is basically identical.
Embodiment 4
Take Cefetamet Pivoxil Hydrochloride crude material medicine 10g to be dissolved into during 50ml temperature is 5 DEG C of ethanol, plus hydrochloric acid cephalo he
The activated carbon decolorizing of U.S. ester crude product quality 0.05 30 minutes, filtering, a small amount of ethanol lysate washing obtains Cefetamet Pivoxil Hydrochloride
Ethanol solution, 25 DEG C are warming up to by Cefetamet Pivoxil Hydrochloride ethanol solution, and stir speed (S.S.) is to hydrochloric acid cephalo under conditions of 23rmp
At the uniform velocity completion of dropping, drop are at the uniform velocity added dropwise in the sodium chloride saturated solution that 300ml temperature is -5 DEG C, 0.5h in his U.S. ester ethanol solution
Plus after the completion of be cooled to -5 DEG C under 12rmp stir speed (S.S.) continue stir 1h, stand 3h separate out light yellow crystal, filter, use
Vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal 9.96g after distilled water, ethyl acetate are washed successively.
Determined, existed with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented with powder x-ray diffraction determination method
7.4°、9.9°、12.8°、13.2°、17.3°、19.6°、20.8°、23.8°、24.4°、26.3°、29.0°、33.5°、36.6°、
39.0 characteristic diffraction peak is shown at °.
Elementary analysis result and embodiment 1 are basically identical.
Moisture is determined using Cattell aquametry and embodiment 1 is basically identical.
Embodiment 5
Take Cefetamet Pivoxil Hydrochloride crude material medicine 10g to be dissolved into during 60ml temperature is 5 DEG C of ethanol, plus hydrochloric acid cephalo he
The activated carbon decolorizing of U.S. ester crude product quality 0.08 30 minutes, filtering, a small amount of ethanol lysate washing obtains Cefetamet Pivoxil Hydrochloride
Ethanol solution, 25 DEG C are warming up to by Cefetamet Pivoxil Hydrochloride ethanol solution, and stir speed (S.S.) is to hydrochloric acid cephalo under conditions of 23rmp
At the uniform velocity completion of dropping is at the uniform velocity added dropwise in the sodium chloride saturated solution that 360ml temperature is -15 DEG C, 0.5h in his U.S. ester ethanol solution,
- 15 DEG C are cooled to after being added dropwise to complete to continue to stir 0.5h under 12rmp stir speed (S.S.), are stood 3h and are separated out light yellow crystal, mistake
Filter, vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal 9.87g after being washed successively with distilled water, ethyl acetate.
Determined, existed with the X-ray powder diffraction pattern that the 2 θ ± 0.2 ° angles of diffraction are represented with powder x-ray diffraction determination method
7.4°、9.9°、12.8°、13.2°、17.3°、19.6°、20.8°、23.8°、24.4°、26.3°、29.0°、33.5°、36.6°、
Characteristic diffraction peak is shown at 39.0 °.
Elementary analysis result and embodiment 1 are basically identical.
Moisture is determined using Cattell aquametry and embodiment 1 is basically identical.
The formula ratio of each raw material into embodiment 10 of embodiment 6 of table 1
Table 1
Embodiment 6
Preparation technology：
1) get the raw materials ready
Cefetamet Pivoxil Hydrochloride hydrate is crushed, 100 mesh sieves are crossed, by starch, microcrystalline cellulose, hydroxypropylcellulose, peace
Match honey and carboxyrnethyl starch sodium are crushed respectively, are crossed 120 mesh sieves, are obtained standby original, auxiliary material；
2) wet granular processed
Weigh above-mentioned standby Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and the hydroxyl of recipe quantity
Third cellulose, is inserted in high-speed mixing granulating machine, dry-mixed 10 minutes of sealing high speed, then adds appropriate amount of ethanol wet mixing 3 minutes, wet
After mixed, wet mixing is cut 2 minutes, is released particle, is obtained wet granular；
3) dry particl processed
Wet granular made from upper step is transferred in ebullated dryer, temperature control is dried 17 minutes at 65 DEG C, shut down, clear filter
Bag, blowing obtains dry particl；
4) tabletting, packaging
Dry particl obtained by upper step is added into pelletizing machine, start button carries out whole grain, and the carboxylic first for adding recipe quantity is formed sediment
Powder sodium and appropriate magnesium stearate, add three-dimensional mixer with suction feeding and mix, tabletting, packaging produces 1000 hydrochloric acid heads
His U.S. ester dispersible tablet of spore.
Embodiment 7
Preparation technology：
1) get the raw materials ready
Cefetamet Pivoxil Hydrochloride hydrate is crushed, 100 mesh sieves are crossed, by starch, microcrystalline cellulose, hydroxypropylcellulose, peace
Match honey and carboxyrnethyl starch sodium are crushed respectively, are crossed 120 mesh sieves, are obtained standby original, auxiliary material；
2) wet granular processed
Weigh above-mentioned standby Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and the hydroxyl of recipe quantity
Third cellulose, is inserted in high-speed mixing granulating machine, dry-mixed 5 minutes of sealing high speed, then adds appropriate amount of ethanol wet mixing 1 minute, wet
After mixed, wet mixing is cut 3 minutes, is released particle, is obtained wet granular；
3) dry particl processed
Wet granular made from upper step is transferred in ebullated dryer, temperature control is dried 17 minutes at 60 DEG C, shut down, clear filter
Bag, blowing obtains dry particl；
4) tabletting, packaging
Dry particl obtained by upper step is added into pelletizing machine, start button carries out whole grain, and the carboxylic first for adding recipe quantity is formed sediment
Powder sodium and appropriate magnesium stearate, add three-dimensional mixer with suction feeding and mix, tabletting, packaging produces 1000 hydrochloric acid heads
His U.S. ester dispersible tablet of spore.
Embodiment 8
Preparation technology：
1) get the raw materials ready
Cefetamet Pivoxil Hydrochloride hydrate is crushed, 100 mesh sieves are crossed, by starch, microcrystalline cellulose, hydroxypropylcellulose, peace
Match honey and carboxyrnethyl starch sodium are crushed respectively, are crossed 120 mesh sieves, are obtained standby original, auxiliary material；
2) wet granular processed
Weigh above-mentioned standby Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and the hydroxyl of recipe quantity
Third cellulose, is inserted in high-speed mixing granulating machine, dry-mixed 15 minutes of sealing high speed, then adds appropriate amount of ethanol wet mixing 5 minutes, wet
After mixed, wet mixing is cut 1 minute, is released particle, is obtained wet granular；
3) dry particl processed
Wet granular made from upper step is transferred in ebullated dryer, temperature control is dried 17 minutes at 70 DEG C, shut down, clear filter
Bag, blowing obtains dry particl；
4) tabletting, packaging
Dry particl obtained by upper step is added into pelletizing machine, start button carries out whole grain, and the carboxylic first for adding recipe quantity is formed sediment
Powder sodium and appropriate magnesium stearate, add three-dimensional mixer with suction feeding and mix, tabletting, packaging produces 1000 hydrochloric acid heads
His U.S. ester dispersible tablet of spore.
Embodiment 9,10
Preparation technology be the same as Example 1.
Present invention also offers following experimental example, to be further illustrated to product of the present invention.
Experimental example 1
This experimental example is examined to the relevant material in the Cefetamet Pivoxil Hydrochloride hydrate crystal prepared by embodiment 1-4
Survey, this experiment is according to the P residual solvents determination method of second annex of Chinese Pharmacopoeia 2010 edition VIII, the F medicine impurity analysis of annex Ⅺ Ⅹ
Guideline is carried out, and it the results are shown in Table 2：
Table 2
About the testing result of material
Experimental example 2
What this experimental example had investigated the Cefetamet Pivoxil Hydrochloride hydrate crystal of the invention provided draws moist, this experiment according to
The J medicine draws moist tests guideline of second annex of Chinese Pharmacopoeia 2010 edition Ⅺ Ⅹ is carried out, and the results are shown in Table 3.
Table 3
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | |
| Draw wet percentage weight increase | 3.8% | 3.6% | 3.9% | 4.2% | 3.8% | 13.5% | 13.2% |
Wherein, sample 1 is the product of embodiment 1；
Sample 2 is the product of embodiment 2；
Sample 3 is the product of embodiment 3；
Sample 4 is the product of embodiment 4；
Sample 5 is the product of embodiment 5；
Sample 6 is the Cefetamet Pivoxil Hydrochloride prepared with reference to patent CN101550146A embodiments 1；
Sample 7 is commercially available Cefetamet Pivoxil Hydrochloride bulk drug, originates from HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory.
As seen from Table 2, compared with the Cefetamet Pivoxil Hydrochloride of prior art, Cefetamet Pivoxil Hydrochloride hydrate of the present invention is brilliant
Body draws that wet percentage weight increase is small, and hygroscopicity is small.
Experimental example 3
This experimental example has investigated the mobility of the Cefetamet Pivoxil Hydrochloride hydrate crystal of the invention provided.
This experimental example evaluates the mobility of sample by the angle of repose of determination sample, and specific method is as follows：Take sample
Grain, flowed into from fixed small funnel circle surface plate in, it is known that obtain highest cone, measure cone height H and
Radius R, calculates angle of repose α by tan α=H/R, the results are shown in Table 3, angle of repose is bigger, mobility is poorer.Refer to table 4.
Table 4
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | |
| H | 2.11cm | 2.18cm | 2.11cm | 2.03cm | 2.10 | 3.21cm | 3.11cm |
| R | 3cm | 3cm | 3cm | 3cm | 3cm | 3cm | 3cm |
| α | 35° | 36° | 35° | 34° | 35° | 47° | 46° |
Wherein, wherein, sample 1 is the product of embodiment 1；
Sample 2 is the product of embodiment 2；
Sample 3 is the product of embodiment 3；
Sample 4 is the product of embodiment 4；
Sample 5 is the product of embodiment 5；
Sample 6 is the Cefetamet Pivoxil Hydrochloride prepared with reference to patent CN101550146A embodiments 1；
Sample 7 is commercially available Cefetamet Pivoxil Hydrochloride bulk drug, originates from HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory.
As seen from Table 4, compared with the Cefetamet Pivoxil Hydrochloride of prior art, Cefetamet Pivoxil Hydrochloride hydrate of the present invention is brilliant
Body has excellent mobility, is conducive to improving the accuracy dispensed, and be easily mixed when mixing with other compositions uniform.
Experimental example 4
This experimental example has investigated the Cefetamet Pivoxil Hydrochloride point prepared by Cefetamet Pivoxil Hydrochloride hydrate crystal of the present invention
Relative bioavailability and bioequivalence of the discrete piece in human body.
1 materials and methods
1.1 medicines and reagent
For test preparation：Hydrochloric acid cefetamet pivoxil dispersible tablet prepared by the embodiment of the present invention 6；
Reference preparation：According to hydrochloric acid cefetamet pivoxil dispersible tablet made from the prescription and preparation method of the embodiment of the present invention 6,
Except that Cefetamet Pivoxil Hydrochloride used is commercially available bulk drug；Acetonitrile, methanol are chromatographically pure, and perchloric acid is analysis
It is pure.
1.2 instrument
Japanese Shimadzu LC-10A type high performance liquid chromatographs, LC-10AD type constant flow pumps, SIL-10AD type automatic samplers,
SPD-10A type UV-detectors.
1.3 study subjects and experimental design
18 subjects are healthy male, age 21-24 Sui, body weight 52-70kg, no habits of smoking and alcohol drinking, through asking before experiment
Ask that medical history, physical examination and laboratory examination are no abnormal, do not take in two weeks it is any may influence this product to absorb, metabolism
Medicine.Tested period unifies bland diet, without using other drugs, does not receive cigarette, wine and the beverage containing coffee.Subject is in examination
Signature informed consent form before testing, experiment is ratified through Ethics Committee of Xiangye No. 2 Hospital of Central South University.
Using itself cross-reference experimental design is intersected at random, subject is divided into two groups, fasting before medication at random
12h, morning 8:00 two groups of difference oral hydrochloride Cefetamet Pivoxils supply test preparation or reference preparation 500mg, uniformly use warm water
200mL takes, medication before and medication after 0.15,0.175,1.10,1.15,2.10,2.15,3.10,3.15,4.10,6.10,
8.10th, 10,12h extracting vein bloods 4mL, the 2nd cycle takes the blood time with the 1st cycle.Blood sample is put in the centrifuge tube containing heparin, immediately
Centrifugation, isolates blood plasma, puts and is preserved in -70 DEG C of refrigerators to measure.
1.4 blood samples are determined
1.4.1 chromatographic condition
Chromatographic column is Phenomenex C18Post (250mm × 46mm, 5 μm), column temperature be 40 DEG C, mobile phase be acetonitrile-
4mmol/L high chloro acid solution (20:80), flow velocity is 0.8mL/min.Detection wavelength is 263nm.
1.4.2 sample treatment
0.5min, 10000r/min centrifugation 5min are shaken after blood plasma unfreezing, then takes 400 μ L blood plasma to insert 1.5mL centrifugations
Guan Zhong, the μ L of perchloric acid solution 400 for plus 6%, vortex mixing 1min, 10000r/min centrifugation 10min, take the μ L of supernatant 100 to enter
The μ L of sample 20 are analyzed.
1.5 data processing
The blood concentration-time data of 18 subjects are subjected to relevant pharmacokinetic parameter and ask calculation, with trapezoidal area
Method calculates lower area of blood concentration-time curve (AUC), to eliminate the straight slope that the phase time is returned to the logarithm of concentration
Calculate half-life period (t1/2), Cmax (Cmax) and peak time (tmax) it is measured value.Single dose administration medicine kinetic parameter
AUC0-12And Cmax, after Logarithm conversion using SPSS statistics program carry out medicine between, week during, individual between 3 factor variances
Analysis, then carry out Doubled haploid population and the calculating of 90% credibility interval.tmaxRank test is carried out using measured value.
2 results
Hydrochloric acid cefetamet main pharmacokinetic parameter is shown in Table 5 in blood plasma after 18 health volunteer's medications.
The pharmacokinetic parameter of 518 health volunteer's single oral dose 500mg hydrochloric acid cefetamet pivoxil dispersible tablets of table
(x ± s, n=18)
As can be seen from Table 5, in the case of prescription and preparation method identical, using the hydrochloric acid cefetamet of the present invention
The highest blood concentration of hydrochloric acid cefetamet pivoxil dispersible tablet made from ester hydrate crystal, which is significantly greater than, uses commercially available hydrochloric acid head
The highest blood concentration of hydrochloric acid cefetamet pivoxil dispersible tablet, illustrates hydrochloric acid cefetamet of the present invention made from his U.S. ester bulk drug of spore
The bioavilability of ester hydrate crystal is higher than the Cefetamet Pivoxil Hydrochloride of prior art；T of the present inventionmaxAlso have with prior art
There is notable difference, illustrate that infiltration rate of the Cefetamet Pivoxil Hydrochloride hydrate crystal of the present invention in human body is faster than prior art
Cefetamet Pivoxil Hydrochloride.
Above-mentioned experiment has also been carried out to hydrochloric acid cefetamet pivoxil dispersible tablet made from other embodiments of the present invention, what it was obtained
As a result it is similar.
Claims (11)
1. a kind of Cefetamet Pivoxil Hydrochloride hydrate, it is characterised in that each Cefetamet Pivoxil Hydrochloride hydrate contains 1 crystallization
Water, and its X-ray powder diffraction spectrogram obtained using Cu-K alpha ray measurements is as shown in Figure 1.
2. Cefetamet Pivoxil Hydrochloride hydrate according to claim 1, it is characterised in that pass through heat differential-thermogravimetric TG-DTA
Analysis, the weightlessness 3.1-3.4wt% in the range of 80-150 DEG C.
3. a kind of preparation method of the Cefetamet Pivoxil Hydrochloride hydrate described in claim 1 or 2, it is characterised in that the side
Method comprises the following steps：
(1) by Cefetamet Pivoxil Hydrochloride dissolving crude product into 5-10 DEG C of ethanol, the volume of the ethanol is hydrochloric acid cefetamet
3-8 times of ester crude product quality；
(2) Cefetamet Pivoxil Hydrochloride crude product quality 0.02-0.1 activated carbon decolorizing is added 20-30 minutes, filtering, a small amount of ethanol is molten
Liquid washing is solved, Cefetamet Pivoxil Hydrochloride ethanol solution is obtained；
(3) Cefetamet Pivoxil Hydrochloride ethanol solution is warming up to 20-30 DEG C, to Cefetamet Pivoxil Hydrochloride ethanol under conditions of stirring
- 15 DEG C -5 DEG C of sodium chloride saturated solution is added dropwise in solution, the volume of sodium chloride saturated solution is Cefetamet Pivoxil Hydrochloride ethanol
At the uniform velocity completion of dropping in 5-8 times of liquor capacity, 0.5h, the stir speed (S.S.) is 20-25rmp；
(4) -15 DEG C -5 DEG C are cooled to after being added dropwise to complete to continue to stir 0.5-2h under 10-15rmp stir speed (S.S.), stand 2-4h
Separate out light yellow crystal, filtering；
(5) vacuum drying obtains Cefetamet Pivoxil Hydrochloride hydrate crystal after being washed successively with distilled water, ethyl acetate.
4. the preparation method of Cefetamet Pivoxil Hydrochloride hydrate according to claim 3, it is characterised in that the step
(3) the sodium chloride saturated solution volume being added dropwise under conditions of stirring to Cefetamet Pivoxil Hydrochloride ethanol solution is hydrochloric acid cephalo
7 times of his U.S. ester volumes of aqueous ethanol；Stir speed (S.S.) when adding sodium chloride saturated solution is 23rmp.
5. the preparation method of Cefetamet Pivoxil Hydrochloride hydrate according to claim 3, it is characterised in that the step
(3) temperature of sodium chloride saturated solution described in is -10 DEG C.
6. the preparation method of Cefetamet Pivoxil Hydrochloride hydrate according to claim 3, it is characterised in that the step
(4) -10 DEG C are cooled to after being added dropwise to complete in continue to stir 1h under 12rmp stir speed (S.S.).
7. a kind of pharmaceutical composition of the Cefetamet Pivoxil Hydrochloride hydrate containing described in claim 1, described pharmaceutical composition
For tablet, capsule, freeze drying powder injection or sterile powder injection.
8. pharmaceutical composition according to claim 7, it is characterised in that：The tablet is Disket.
9. pharmaceutical composition according to claim 8, it is characterised in that：The Disket component includes：
10. a kind of preparation method of claim 9 described pharmaceutical composition, it is characterised in that the preparation method includes：By original
Expect Cefetamet Pivoxil Hydrochloride hydrate and supplementary product starch, microcrystalline cellulose, hydroxypropylcellulose, acesulfame potassium, magnesium stearate and carboxylic first
Sodium starch is crushed, sieved respectively, wet granular processed, dry particl processed, tabletting and packaging, described wet granular processed is to weigh recipe quantity
Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and hydroxypropylcellulose, insert high-speed mixing granulating machine
In, sealing high speed is dry-mixed 5-15 minutes, then adds appropriate amount of ethanol wet mixing 1-5 minutes, after wet mixing, and wet mixing is cut 1-3 minutes, is put
Go out particle, obtain wet granular.
11. preparation method according to claim 10, it is characterised in that described method comprises the following steps：
1) get the raw materials ready
Cefetamet Pivoxil Hydrochloride hydrate is crushed, 100 mesh sieves are crossed, by starch, microcrystalline cellulose, hydroxypropylcellulose, acesulfame potassium
Crushed respectively with carboxyrnethyl starch sodium, cross 120 mesh sieves, obtain standby original, auxiliary material；
2) wet granular processed
Above-mentioned standby Cefetamet Pivoxil Hydrochloride hydrate, starch, microcrystalline cellulose, acesulfame potassium and the hydroxypropyl for weighing recipe quantity are fine
Dimension element, is inserted in high-speed mixing granulating machine, and sealing high speed is dry-mixed 5-15 minutes, then adds appropriate amount of ethanol wet mixing 1-3 minutes, wet
After mixed, wet mixing is cut 2 minutes, is released particle, is obtained wet granular；
3) dry particl processed
Wet granular made from upper step is transferred in ebullated dryer, temperature control is dried 17-20 minutes at 60-70 DEG C, shut down, clear filter
Bag, blowing obtains dry particl；
4) tabletting, packaging
Dry particl obtained by upper step is added into pelletizing machine, start button carries out whole grain, adds the carboxyrnethyl starch sodium of recipe quantity
With appropriate magnesium stearate, add three-dimensional mixer with suction feeding and mix, tabletting, packaging produces Cefetamet Pivoxil Hydrochloride point
Discrete piece.
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| CN105030697A (en) * | 2015-09-15 | 2015-11-11 | 青岛华之草医药科技有限公司 | Anti-infective drug cefetamet pivoxil hydrochloride composite capsule |
| CN105106120A (en) * | 2015-09-17 | 2015-12-02 | 青岛华之草医药科技有限公司 | Antibacterial agents cefetamet pivoxil hydrochloride composition |
| CN105078902A (en) * | 2015-09-24 | 2015-11-25 | 青岛华之草医药科技有限公司 | Cefetamet pivoxil hydrochloride composite granules for treating bacterial infection |
| CN105147698A (en) * | 2015-10-09 | 2015-12-16 | 杨献美 | Drug, namely cefetamet pivoxil hydrochloride composition tablets, for treating infectious diseases |
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| CN101843599A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Oral cephalosporin ester capsule |
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