CN1861064A - Medicine composition contg. sodium azulene sulfonate and L-glutamine water-soluble precursor - Google Patents
Medicine composition contg. sodium azulene sulfonate and L-glutamine water-soluble precursor Download PDFInfo
- Publication number
- CN1861064A CN1861064A CNA2006100872513A CN200610087251A CN1861064A CN 1861064 A CN1861064 A CN 1861064A CN A2006100872513 A CNA2006100872513 A CN A2006100872513A CN 200610087251 A CN200610087251 A CN 200610087251A CN 1861064 A CN1861064 A CN 1861064A
- Authority
- CN
- China
- Prior art keywords
- glutamine
- sodium azulenesulfonate
- glycyl
- water
- alanyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- GEYJUFBPCGDENK-UHFFFAOYSA-M sodium;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 GEYJUFBPCGDENK-UHFFFAOYSA-M 0.000 title claims abstract description 111
- 239000000203 mixture Substances 0.000 title claims abstract description 86
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 title claims abstract description 52
- 229930182816 L-glutamine Natural products 0.000 title abstract 2
- 239000002243 precursor Substances 0.000 title abstract 2
- 239000003814 drug Substances 0.000 title description 22
- 229940079593 drug Drugs 0.000 title description 16
- 229960002648 alanylglutamine Drugs 0.000 claims abstract description 57
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 claims abstract description 55
- 108010010147 glycylglutamine Proteins 0.000 claims abstract description 53
- PNMUAGGSDZXTHX-BYPYZUCNSA-N Gly-Gln Chemical compound NCC(=O)N[C@H](C(O)=O)CCC(N)=O PNMUAGGSDZXTHX-BYPYZUCNSA-N 0.000 claims abstract description 49
- 210000001156 gastric mucosa Anatomy 0.000 claims abstract description 17
- 239000008187 granular material Substances 0.000 claims description 50
- 239000007788 liquid Substances 0.000 claims description 19
- 239000000651 prodrug Substances 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 19
- 239000003826 tablet Substances 0.000 claims description 16
- 239000002552 dosage form Substances 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 208000007882 Gastritis Diseases 0.000 abstract description 13
- 208000000718 duodenal ulcer Diseases 0.000 abstract description 11
- 208000007107 Stomach Ulcer Diseases 0.000 abstract description 6
- 230000001154 acute effect Effects 0.000 abstract description 6
- 208000023652 chronic gastritis Diseases 0.000 abstract description 6
- 201000005917 gastric ulcer Diseases 0.000 abstract description 6
- 239000003223 protective agent Substances 0.000 abstract 1
- 229920002472 Starch Polymers 0.000 description 62
- 239000008107 starch Substances 0.000 description 62
- 235000019698 starch Nutrition 0.000 description 62
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 150000001875 compounds Chemical class 0.000 description 31
- 238000002360 preparation method Methods 0.000 description 31
- FPKFWYUHWUOPGP-RJXKWAGSSA-M sodium;(2s)-2,5-diamino-5-oxopentanoic acid;3,8-dimethyl-5-propan-2-ylazulene-1-sulfonate Chemical compound [Na+].OC(=O)[C@@H](N)CCC(N)=O.CC(C)C1=CC=C(C)C2=C(S([O-])(=O)=O)C=C(C)C2=C1 FPKFWYUHWUOPGP-RJXKWAGSSA-M 0.000 description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 20
- 230000006378 damage Effects 0.000 description 20
- 208000025865 Ulcer Diseases 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 231100000397 ulcer Toxicity 0.000 description 19
- 241000700159 Rattus Species 0.000 description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 18
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 18
- 239000000463 material Substances 0.000 description 18
- 238000012856 packing Methods 0.000 description 18
- 238000005303 weighing Methods 0.000 description 16
- 208000027418 Wounds and injury Diseases 0.000 description 15
- 208000014674 injury Diseases 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 239000000796 flavoring agent Substances 0.000 description 13
- 206010013786 Dry skin Diseases 0.000 description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 12
- 238000010009 beating Methods 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 235000019634 flavors Nutrition 0.000 description 12
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 12
- 239000008108 microcrystalline cellulose Substances 0.000 description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 description 12
- 239000002002 slurry Substances 0.000 description 12
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 12
- 239000004299 sodium benzoate Substances 0.000 description 12
- 235000010234 sodium benzoate Nutrition 0.000 description 12
- 239000007779 soft material Substances 0.000 description 12
- 230000000857 drug effect Effects 0.000 description 11
- 230000002496 gastric effect Effects 0.000 description 11
- 210000002784 stomach Anatomy 0.000 description 11
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- PNMUAGGSDZXTHX-UHFFFAOYSA-N glycyl-glutamine Chemical compound NCC(=O)NC(C(O)=O)CCC(N)=O PNMUAGGSDZXTHX-UHFFFAOYSA-N 0.000 description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 10
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- -1 maloyl imines Chemical class 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 229940032147 starch Drugs 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- 229930006000 Sucrose Natural products 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000004570 mortar (masonry) Substances 0.000 description 6
- 238000007789 sealing Methods 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 230000008961 swelling Effects 0.000 description 6
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 5
- 208000018522 Gastrointestinal disease Diseases 0.000 description 5
- QNAYBMKLOCPYGJ-UWTATZPHSA-N L-Alanine Natural products C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 5
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 206010042220 Stress ulcer Diseases 0.000 description 5
- 229960003767 alanine Drugs 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000011049 filling Methods 0.000 description 5
- 239000007902 hard capsule Substances 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 229960004889 salicylic acid Drugs 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 238000005498 polishing Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 235000013599 spices Nutrition 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- FWKQNCXZGNBPFD-UHFFFAOYSA-N Guaiazulene Chemical compound CC(C)C1=CC=C(C)C2=CC=C(C)C2=C1 FWKQNCXZGNBPFD-UHFFFAOYSA-N 0.000 description 3
- CJUMAFVKTCBCJK-UHFFFAOYSA-N N-benzyloxycarbonylglycine Chemical compound OC(=O)CNC(=O)OCC1=CC=CC=C1 CJUMAFVKTCBCJK-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960002350 guaiazulen Drugs 0.000 description 3
- 230000035876 healing Effects 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- 230000017423 tissue regeneration Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000002467 anti-pepsin effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 239000000706 filtrate Substances 0.000 description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N 2-Amino-2-Deoxy-Hexose Chemical compound NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000628997 Flos Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 125000000729 N-terminal amino-acid group Chemical group 0.000 description 1
- 101710138657 Neurotoxin Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 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 description 1
- 230000009471 action Effects 0.000 description 1
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- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940069428 antacid Drugs 0.000 description 1
- 239000003159 antacid agent Substances 0.000 description 1
- 230000001458 anti-acid effect Effects 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000002318 cardia Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
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- 238000007654 immersion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
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- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000008881 mucosal defense Effects 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 231100000618 neurotoxin Toxicity 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
A composition used as gastric mucosa protecting agent for treating acute or chronic gastritis, gastric ulcer, duodenal ulcer, etc is prepared from the water-soluble precursors including sodium azulenesulfonate and L-glutamine or glycyl-L-glutamine or L-alanyl-L-glutamine through proportioning and conventional steps.
Description
Technical field
The present invention relates to a kind of stable and novel safely and effectively gastric mucosal protection compositions, particularly a kind of compositions that contains Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug, both weight ratio scopes are 1: 2.5～1: 1000.
Background technology
The oral formulations that contains Sodium Azulenesulfonate and L-glutaminate is as gastric mucosa protectant; be widely used in gastrointestinal disorders treatment of diseases such as acute or chronic gastritis, gastric ulcer, duodenal ulcer, as " Marzulene-S " granule and home-made " the compound glutamine granules agent " of Japan.Sodium Azulenesulfonate is the effective ingredient of anthemidis flos, has antiinflammatory, antipepsin, prevention histamine release and promotes granulation new life, epitheliogenic effect.L-glutaminate is a kind of crucial condition essential amino acids, can promote defense factor hexosamine, mucopolysaccharide and the mucinous biosynthesis of gastric mucosa, strengthens the defensive enginery of gastric mucosa, participates in tissue repair and accelerates ulcer healing.Sodium Azulenesulfonate and L-glutaminate compatibility use has the synergism of tangible promotion ulcer healing, and not influenced by gastric acidity, is therapeutic agent for ulcer applied widely, and its application is subject to people's attention day by day.
Yet L-glutaminate dissolubility in water is low, and dissolubility is 35 grams per liters in 20 ℃ of L-glutaminate water; There is the report L-glutaminate to observe gastric after oral 4 hours and still have glutamine monomer crystal to separate out, shows relatively poor absorbability, cause bioavailability low, so need be than (663.3mg/ unit dose) competence exertion drug effect under the heavy dose; In addition, L-glutaminate is unstable in liquid environment, easily resolves into deleterious burnt glutamine of body (the intravital neurotoxin of rodent) and ammonia, and its degradation speed depends on temperature, pH and ion concentration.Have report L-glutaminate solution to preserve 24 hours for 28 ℃, when burnt glutamine is preparation 10 times cause the product active constituent content to reduce.As seen the unstability of L-glutaminate makes the oral formulations that contains Sodium Azulenesulfonate and L-glutaminate have the potential unfavorable factor of victimization body health, is unfavorable for the storage of product simultaneously, influences the usefulness of product.
The present invention is through research; adopted the L-glutaminate water-soluble prodrug to substitute L-glutaminate and Sodium Azulenesulfonate compatibility; make the compound medicinal formulation that Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug are formed; said preparation has not only strengthened stability of drug greatly; improved bioavailability; reduce untoward reaction, and had the effect of slow release, long-acting, collaborative performance gastric mucosal protection drug effect.
Summary of the invention
In order to overcome the deficiencies in the prior art, researcher of the present invention is found to use the L-glutaminate water-soluble prodrug and is substituted L-glutaminate and Sodium Azulenesulfonate compatibility, and more traditional compound recipe Sodium Azulenesulfonate/the L-glutaminate preparation is more stable, safer, more effective.
The L-glutaminate water-soluble prodrug of discovered in recent years (as glycyl-L-glutamine or L-alanyl-L-glutamine), stable in properties (room temperature liquid condition following 2 years still keep stable) not only, (dissolubility of 20 ℃ of glycyl-L-glutamines and L-alanyl-L-glutamine is respectively 150 grams per liters and 586 grams per liters to good water solubility, be L-glutaminate 4-17 doubly) and in vivo easily enzymolysis discharge L-glutaminate and be absorbed into performance tissue repair effect cell in, one of main component of infusing mainly as the outer full nutrition of intestinal clinically at present.Studies show that, the human plasma half-life behind glycyl-L-glutamine and the L-alanyl-L-glutamine intravenously administrable is respectively 7.79 ± 0.58min and 2.44 ± 0.23min, and both in vivo the metabolism hydrolysis become corresponding aminoacid (glycine or L-alanine), wherein the L-alanyl-L-glutamine is than glycyl-L-glutamine facile hydrolysis more; Zoopery is the result also show, in the L-glutaminate water-soluble prodrug of different n terminal amino acid residues, the plasma half-life of glycyl-L-glutamine is the longest, and its reason may facile hydrolysis be not relevant with hydrolytic enzyme due to glycine is too little.In addition, studies show that no matter glutamine is derived from blood or intestinal, intestinal is consistent to its utilization rate, use all can the raise concentration of glutamine in the blood of glycyl-L-glutamine (or L-alanyl-L-glutamine) and glutamine, increase the picked-up of internal organs to glutamine, physiological action does not have marked difference between them.So oral L-glutaminate water-soluble prodrug good absorbing; the pharmacokinetics feature similar to the intravenous route administration will be shown; fully can be safely, effectively, slow release provides L-glutaminate, is used for gastrointestinal disorders treatment of diseases such as acute or chronic gastritis, gastric ulcer, duodenal ulcer as gastric mucosa protectant thereby substitute L-glutaminate.
The object of the present invention is to provide a kind of stable and novel safely and effectively gastric mucosal protection compositions, it is characterized in that containing Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug.The said composition physicochemical property is stable, the bioavailability height, and have multiple characteristics such as long-acting, slow release, collaborative performance gastric mucosal protection drug effect concurrently.Can bring into play its antiinflammatory, antipepsin, prevention histamine release after one side Sodium Azulenesulfonate component is oral rapidly and promote effects such as granulation new life, epithelium formation; L-glutaminate water-soluble prodrug component can be gone out L-glutaminate by the enzymatic hydrolysis slow release in vivo on the other hand, bring into play its biosynthesis that promotes the gastric mucosal defense factor, strengthen gastric mucosa defensive enginery, participate in tissue repair and accelerate effect such as ulcer healing.Therefore; compositions provided by the invention can be used as novel gastric mucosa protectant; be widely used in gastrointestinal disorders treatment of diseases such as acute or chronic gastritis, gastric ulcer, duodenal ulcer; obviously be better than traditional compound recipe Sodium Azulenesulfonate/L-glutaminate preparation, not seeing so far to have has identical research report both at home and abroad.
Compositions of the present invention contains Sodium Azulenesulfonate and at least a L-glutaminate water-soluble prodrug.Wherein the weight ratio scope of Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug is 1: 2.5～1: 1000, preferably 1: 25～1: 500, is more preferably 1: 100～1: 350.
Compositions of the present invention, wherein said L-glutaminate water-soluble prodrug includes but not limited to glycyl-L-glutamine or L-alanyl-L-glutamine.As previously mentioned, the plasma half-life of glycyl-L-glutamine is the longest in the L-glutaminate water-soluble prodrug, and the glycine of enzymolysis can be used as antacid in the body, uses treatment digestive tract ulcer better efficacy, therefore preferred glycyl-L-glutamine with the glutamine compatibility.
Compositions of the present invention, wherein said Sodium Azulenesulfonate can utilize well-known conventional chemical synthesizing mean preparation, for example be that raw material prepares the Sodium Azulenesulfonate raw material through sulfonation, two step of salify synthetic reaction, also comprise and buy the raw material that meets standards of pharmacopoeia from the market with the Kessazulen.
Compositions of the present invention; wherein said glycyl-L-glutamine can utilize well-known conventional chemical synthesizing mean preparation; be initiation material for example with the carbobenzoxy glycine; after making corresponding maloyl imines active ester; with the L-glutaminate condensation; remove three step such as protecting group synthetic reactions through hydrogenolysis and prepare the glycyl-L-glutamine raw material, also comprise and buy the raw material that meets standards of pharmacopoeia from the market.
Compositions of the present invention; wherein said L-alanyl-L-glutamine can utilize well-known conventional chemical synthesizing mean preparation; be initiation material for example with the L-alanine; behind the benzyloxycarbonyl group protection amino; make corresponding maloyl imines active ester; then with the L-glutaminate condensation, remove four step synthetic reactions such as protecting group through hydrogenolysis and prepare L-alanyl-L-glutamine raw material, also comprise and buy the raw material that meets standards of pharmacopoeia from the market.
Compositions of the present invention can be used as novel gastric mucosa protectant, is used to prepare the oral therapeutic drug of gastrointestinal disorders diseases such as acute or chronic gastritis, gastric ulcer, duodenal ulcer.
The dosage form of compositions of the present invention can be any pharmaceutical dosage forms, peroral dosage form preferably, include but not limited to following dosage form: tablet, can select conventional tablet, dispersible tablet, oral cavity disintegration tablet, buccal tablet, chewable tablet, double-layer tablet, slow releasing tablet, controlled release tablet etc.; Capsule can be selected hard capsule, soft capsule, self-emulsification soft capsules, enteric coated capsule, long-acting slow-release capsule etc.; Granule; Oral liquid can be selected common oral liquid, emulsion, nano-emulsion, self-emulsifying microemulsion liquid etc.
The present invention can add when making preparation and be fit to medicinal any pharmaceutically acceptable auxiliaries, and what can exemplify is adhesive, disintegrating agent, lubricant, surfactant, antiseptic, sweeting agent, flavouring agent, coloring agent etc.Compositions of the present invention is according to the preparation of galenic pharmacy routine techniques, and its preparation method comprises active component and the blended step of pharmaceutic adjuvant, makes the oral formulations that tablet, capsule, granule, oral liquid etc. are fit to take then.
Compositions of the present invention is a unit dosage form, and these unit dosage forms can be pharmaceutical preparation unit dosage forms commonly used, as the tablet of unit dose, capsule, granule, oral liquid etc.For tablet, unit dose is meant every; For capsule, unit dose is meant every; For granule, unit dose is meant every bag (bag); For oral liquid, unit dose is meant every (bottle).
Compositions of the present invention contains Sodium Azulenesulfonate 1～20mg in the unit dose of described preparation, glycyl-L-glutamine 50～20000mg; Preferred Sodium Azulenesulfonate 1～5mg, glycyl-L-glutamine 50～1000mg; More preferably Sodium Azulenesulfonate 1～4mg, glycyl-L-glutamine 50～700mg; Sodium Azulenesulfonate 2～3mg most preferably, glycyl-L-glutamine 200～500mg.Other are the medicine acceptable carrier.
Compositions of the present invention contains Sodium Azulenesulfonate 1～20mg in the unit dose of described preparation, L-alanyl-L-glutamine 50～20000mg; Preferred Sodium Azulenesulfonate 1～5mg, L-alanyl-L-glutamine 50～1000mg; More preferably Sodium Azulenesulfonate 1～4mg, L-alanyl-L-glutamine 50～700mg; Sodium Azulenesulfonate 2～3mg most preferably, L-alanyl-L-glutamine 200～500mg.Other are the medicine acceptable carrier.
Following data declaration beneficial effect of the present invention by experiment:
Tried thing
Compositions 1 is (light blue, water solublity is better, 2 parts of Sodium Azulenesulfonate and 663.3 parts of glycyl-L-glutamine uniform mixing), compositions 2 (light blue, water solublity is better, 2 parts of Sodium Azulenesulfonate and 663.3 parts of L-alanyl-L-glutamine uniform mixing), the positive control drug Marzulene-S Granules is (light blue, water solublity is relatively poor, contains Sodium Azulenesulfonate 2mg, L-glutaminate 663.3mg in every bag).Face with preceding and all be mixed with desired concn with 1% sodium carboxymethyl cellulose.
The experiment grouping
110 of SD rats, male and female half and half, be divided into 11 groups at random by the sex body weight, it is normal group, model group, positive controls heavy dose of 1000mg/kg, middle dosage 600mg/kg and low dose of 200mg/kg (be equivalent to respectively clinical consumption 25 times, 15 times and 5 times), compositions 1 heavy dose of 1000mg/kg, middle dosage 600mg/kg and low dose of 200mg/kg, compositions 2 heavy dose of 1000mg/kg, middle dosage 600mg/kg and low dose of 200mg/kg.
Experimental technique
1. rat water logging stress ulcer model
Each group is irritated stomach 1 time by design dosage every day, and medicine liquid volume is 1ml/100g, continuous 5 days.Except that normal group, each organizes rat in administration beginning on the 4th fasting, freely drinks water, animal was fixed on the iron railings in the 5th, vertically immerses in 23 ± 0.5 ℃ of water, the flat xiphoid-process level of immersion depth, take out after 14 hours, open the abdominal cavity under the etherization, ligation stomach cardia and pylorus, and through coat of the stomach injects 1% formalin 8ml in gastral cavity after, stomach is taken out, immerse in 10% formalin and fix 30 minutes, cut off stomach, observe the gastric mucosa injury situation along greater gastric curvature.
2. ethanol causes the rat pipe film injury model
Each group is irritated stomach 1 time by design dosage every day, and medicine liquid volume is 1ml/100g, continuous 5 days.Except that normal group, each organizes rat in administration beginning on the 3rd fasting, freely drinks water, and 1 hour every Mus filling stomach 80% ethanol 1ml after the last administration on the 5th got stomach after 1 hour, observed the gastric mucosa injury situation after the formaldehyde fixed, and the operation step, preface was with 1.
3. ethanol adds salicylic acid and causes the rat pipe film injury model
Except that normal group, each organize rat all after 48 hours every Mus irritate stomach 40% ethanol and add 1% salicylic acid mixed liquor 1.5ml/100g and set up the acute gastritis model.Each group is irritated stomach 2 times by design dosage every day after 24 hours, and medicine liquid volume is 1ml/100g, continuous 10 days.Administration finishes next day, dissects and gets stomach, observes the gastric mucosa injury situation after the formaldehyde fixed, and the operation step, preface was with 1.
Observation index and efficacy assessment standard
Curative effect of medication mainly suppresses percentage rate with gastric mucosa injury degree (ulcer index) and ulcer and estimates.Method is with the streak damaged length of vernier caliper measurement gastric mucosa under the magnifier, and it is (as follows with reference to the score of the gastric mucosa injury standard of index, damage width＞2mm, the index score doubles), keep the score and add up to the ulcer index of this animal, relatively can further calculate with T check carrying out significance between group according to ulcer index:
| The mucosa injury degree | Normally | The point-like damage | Sick damage＞1mm | Sick damage＞1-2mm | Sick damage＞2-3mm | Analogize |
| The score number | 0 | 1 | 2 | 3 | 4 |
Concrete test:
Compositions is to the protective effect of rat water logging stress ulcer
Compare with model group, the administration group all can suppress the generation of rat water logging stress ulcer in various degree, and ulcer index all significantly reduces (p＜0.05～0.001), and drug effect is certain dose-dependence.Compositions 1 is approaching with the effect of compositions 2; and gastric mucosal protective effect all obviously is better than Marzulene-S Granules with dosage group (p＜0.05); the drug effect of low dose group (200mg/kg) and Marzulene-S Granules (600mg/kg; this dosage is 15 times of clinical consumption) act on quite, the clinical consumption of prediction group compound is lower than Marzulene-S Granules (table 1) thus.
Table 1 compositions 1-2 is to the preventive effect of rat water logging stress ulcer
(x ± s,
*P＜0.05
* *P＜0.001 vs model group; #P＜0.05 vs Marzulene-S is with the dosage group)
| Group | Dosage (mgkg -1) | Number of animals (only) | Ulcer index | Ulcer suppresses percentage rate (%) |
| Normal group | 10 | 0 | ||
| Model group | 10 | 45.60±9.73 | ||
| Compositions 1 | 1000 | 10 | 6.79±8.29 ***# | 85.10 |
| Compositions 1 | 600 | 10 | 10.73±7.15 ***# | 76.48 |
| Compositions 1 | 200 | 10 | 20.25±8.16 *** | 55.60 |
| Compositions 2 | 1000 | 10 | 8.51±9.15 ***# | 81.34 |
| Compositions 2 | 600 | 10 | 12.80±8.03 ***# | 71.92 |
| Compositions 2 | 200 | 10 | 22.45±10.10 *** | 50.76 |
| Marzulene-S | 1000 | 10 | 19.40±11.85 *** | 57.46 |
| Marzulene-S | 600 | 10 | 22.90±12.77 *** | 49.78 |
| Marzulene-S | 200 | 10 | 29.90±15.11 * | 34.43 |
Compositions causes the protective effect of rat pipe film injury model to ethanol
The result shows that the administration group all can alleviate ethanol in various degree and cause rat pipe film injury, and the ulcer index of comparing the administration group with model group all significantly reduces (p＜0.05～0.001), and drug effect is certain dose-dependence.Compositions 1 is approaching with the effect of compositions 2; and gastric mucosal protective effect all obviously is better than Marzulene-S Granules with dosage group (p＜0.05); the drug effect of low dose group (200mg/kg) and Marzulene-S Granules (600mg/kg; this dosage is 15 times of clinical consumption) act on quite, the clinical consumption of prediction group compound is lower than Marzulene-S Granules (table 2) thus.
Table 2 compositions 1-2 is to the preventive effect of rat ethanol gastric mucosa injury
(x ± s,
*P＜0.05
* *P＜0.001 vs model group; #P＜0.05 vs Marzulene-S is with the dosage group)
| Group | Dosage (mgkg -1) | Number of animals (only) | Ulcer index | Ulcer suppresses percentage rate (%) |
| Normal group | 10 | 0 | ||
| Model group | 10 | 52.80±7.74 | ||
| Compositions 1 | 1000 | 10 | 8.71±7.29 ***# | 83.50 |
| Compositions 1 | 600 | 10 | 15.67±9.65 ***# | 70.33 |
| Compositions 1 | 200 | 10 | 26.29±12.16 ***# | 50.21 |
| Compositions 2 | 1000 | 10 | 10.64±7.23 ***# | 79.83 |
| Compositions 2 | 600 | 10 | 19.50±10.81 ***# | 63.20 |
| Compositions 2 | 200 | 10 | 26.58±11.09 ***# | 49.65 |
| Marzulene-S | 1000 | 10 | 21.50±13.12 *** | 59.28 |
| Marzulene-S | 600 | 10 | 30.20±15.72 *** | 42.80 |
| Marzulene-S | 200 | 10 | 39.80±12.90 * | 24.62 |
Compositions adds the therapeutical effect that salicylic acid causes rat pipe film injury to ethanol
The result shows that compositions 1-2 administration group all can treat ethanol in various degree and add sodium salicylate and cause rat pipe film injury, and the ulcer index of comparing the administration group with model group all significantly reduces (p＜0.05), and drug effect is certain dose-dependence.Compositions 1 is approaching with the effect of compositions 2; and gastric mucosal protective effect all is better than Marzulene-S Granules with the dosage group; the drug effect of low dose group (200mg/kg) and Marzulene-S Granules (600mg/kg; this dosage is 15 times of clinical consumption) act on quite, the clinical consumption of prediction group compound is lower than Marzulene-S Granules thus.Marzulene-S Granules (200mg/kg) therapeutical effect is remarkable (table 3) not.
Table 3 compositions 1-2 adds the therapeutical effect that salicylic acid causes rat pipe film injury to ethanol
(x ± s,
*P＜0.05
*P＜0.01 vs model group)
| Group | Dosage (mgkg -1) | Number of animals (only) | Ulcer index | Ulcer suppresses percentage rate (%) |
| Normal group | 8 | 0 | ||
| Model group | 8 | 35.75±20.87 | ||
| Compositions 1 | 1000 | 8 | 6.84±6.29 ** | 80.88 |
| Compositions 1 | 600 | 8 | 10.83±9.65 ** | 69.72 |
| Compositions 1 | 200 | 8 | 16.74±11.84 * | 53.17 |
| Compositions 2 | 1000 | 8 | 9.52±6.32 ** | 73.38 |
| Compositions 2 | 600 | 8 | 11.74±6.84 ** | 67.17 |
| Compositions 2 | 200 | 8 | 17.91±9.09 * | 49.88 |
| Marzulene-S | 1000 | 8 | 15.25±14.82 * | 57.34 |
| Marzulene-S | 600 | 8 | 17.15±9.25 * | 52.08 |
| Marzulene-S | 200 | 8 | 28.00±17.95 | 21.68 |
In sum, Sodium Azulenesulfonate adds to rat water logging stress ulcer, ethanol and ethanol with the compositions of glycyl-L-glutamine and L-alanyl-L-glutamine respectively that rat pipe film injury all has obvious prevention and therapeutical effect due to the salicylic acid, its act on try that a certain amount of effect relationship is arranged in 200～1000mg/kg scope, and the drug effect of low dose group (200mg/kg) and Marzulene-S Granules (600mg/kg, this dosage is 15 times of clinical consumption) act on quite, the clinical consumption of prediction group compound is lower than Marzulene-S Granules thus.Confirm that thus compositions of the present invention has obvious therapeutic action to digestive tract ulcer; the drug effect dosage of more traditional compound recipe Sodium Azulenesulfonate/L-glutaminate is littler; curative effect is stronger, and therefore can be used as gastric mucosa protectant is used for gastrointestinal disorders treatment of diseases such as acute or chronic gastritis, gastric ulcer, duodenal ulcer.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment, but be not any limitation of the invention.
Embodiment 1
The preparation method of Sodium Azulenesulfonate
Kessazulen 40.0g (0.20mol) is dissolved in the 200ml acetic anhydride, and the external cryosel is bathed cooling and stirred down, in dripping concentrated sulphuric acid 76.0mL (0.18mol) below 5 ℃, adds in 1 hour.Remove ice bath, continue to be stirred to room temperature.In stirring at room 2 hours, sulfonating reaction was finished.With reactant impouring 500mL frozen water slowly, (60～90 ℃, 3 * 200mL) extract water layers to remove unreacted Kessazulen to petroleum ether.Water layer adds in 25% sodium hydroxide and pH value to 8, separates out the Sodium Azulenesulfonate crude product, filters, till 200mL water is taken out fast and is washed till washing liquid and is bluish violet.Suitable quantity of water recrystallization 1 time gets Sodium Azulenesulfonate elaboration 31.7g, yield 79.3%.
Embodiment 2
The preparation method of glycyl-L-glutamine
In the exsiccant 2L reaction bulb; add 46.0g (0.22mol) carbobenzoxy glycine, 26.5g (0.23mol) maloyl imines and 1300mL ethyl acetate successively; ice bath is cooled to below 5 ℃ after the stirring and dissolving; add 49.4g (0.24mol) dicyclohexylcarbodiimide, stirred 8 hours in room temperature (25 ± 5 ℃).Reaction finishes after-filtration and removes the 1,3-Dicyclohexylurea that dereaction generates, and obtains the ethyl acetate solution I (standby) of active ester.
In the 3L reaction bulb, add 36.5g L-glutaminate and 400mL 10% sodium bicarbonate aqueous solution, frozen water is cooled to 10～15 ℃ of room temperatures, stirs the ethyl acetate solution I that dropwise adds active ester down, adds in about 1 hour.When adding about 2/3 volume activity ester solution, in reaction bulb, add 200mL 10% sodium bicarbonate aqueous solution again.After adding active ester, continue to stir 8 hours in 15～25 ℃.Reaction finishes the back standing demix, discards ethyl acetate layer, and (2 * 200mL) extract 2 times water layer with ethyl acetate.Water layer cools off with frozen water, adds about 280mL 3N hydrochloric acid adjust pH to 2 under the vigorous stirring.The ice bath cool overnight is separated out the carbobenzoxy glycyl-L-glutamine fully.Filter, porphyrize, inorganic impurities such as NaCl are removed in washing, dry carbobenzoxy glycyl-L-glutamine 56.3g, the yield 76% of getting.
Add 33.7g (0.1mol) carbobenzoxy glycyl-L-glutamine and 50% alcoholic solution 1500mL in the 3L reaction bulb successively, add 1.0g 5% palladium charcoal after the stirring and dissolving.Oil pump is taken out a bottle interior air, nitrogen replacement 3 times, and the back of finding time feeds hydrogen, and the normal pressure hydrogenolysis needs reaction in 8～10 hours to finish to no longer inhaling hydrogen approximately.Remove by filter palladium charcoal (recovery set with), concentrating under reduced pressure filtrate to 50～60mL adds 750mL ethanol while hot, and the ice bath cooling is placed more than 4 hours down, filter the glycyl-L-glutamine crude product.Crude product gets glycyl-L-glutamine elaboration 16.5g, 200～204 ℃ of fusing points (decomposition), yield 75% (in the carbobenzoxy glycine, yield 57%) 1～2 time with the alcohol-water recrystallization.HPLC measures glycyl-L-glutamine content＞99%.
Embodiment 3
The preparation method of L-alanyl-L-glutamine
Add 1000mL ethyl acetate and dry 48.0g (0.54mol) L-alanine fine powder in the 2L reaction bulb successively, after the half an hour of refluxing under stirring, (82.0mL, 0.57mol) carbobenzoxy chloride continue stirring and refluxing 12h to add 97.0g from the condensing tube upper end.The reactant liquor cooled and filtered is removed L-alanine hydrochlorate and a small amount of unreacted L-alanine; concentrating under reduced pressure (ethyl acetate is recyclable applies mechanically) back residue adds the 500mL petroleum ether and soaks; filter and with a little petroleum ether (petroleum ether distillation back recovery set with); get carbobenzoxy-L-alanine 48.4g after the oven dry; 80～84 ℃ of fusing points, yield 80%.
In the exsiccant 2L reaction bulb; add 48.4g (0.22mol) carbobenzoxy-L-alanine, 28.0g (0.24mol) maloyl imines and 1500mL ethyl acetate successively; ice bath is cooled to below 5 ℃ after the stirring and dissolving; add 52.0g (0.25mol) dicyclohexylcarbodiimide, stirred 8 hours in room temperature (25 ± 5 ℃).Reaction finishes after-filtration and removes the 1,3-Dicyclohexylurea that dereaction generates, and obtains the ethyl acetate solution II (standby) of active ester.
In the 3L reaction bulb, add 36.0g L-glutaminate and 400mL 10% sodium bicarbonate aqueous solution, frozen water is cooled to 10～15 ℃ of room temperatures, stirs the ethyl acetate solution II that dropwise adds active ester down, adds in about 1 hour.When adding about 2/3 volume activity ester solution, in reaction bulb, add 200mL 10% sodium bicarbonate aqueous solution again.After adding active ester, continue to stir 8 hours in 15～25 ℃.Reaction finishes the back standing demix, discards ethyl acetate layer, and (2 * 200mL) extract 2 times water layer with ethyl acetate.Water layer cools off with frozen water, adds about 280mL 3N hydrochloric acid adjust pH to 2 under the vigorous stirring.The ice bath cool overnight is separated out carbobenzoxy-L-alanyl-L-glutamine fully.Filter, porphyrize, inorganic impurities such as NaCl are removed in washing, dry carbobenzoxy glycyl-L-glutamine 56.8g, the yield 75% of getting.
Add 35.1g (0.1mol) carbobenzoxy-L-alanyl-L-glutamine and 70% alcoholic solution 1500mL in the 3L reaction bulb successively, add 1.0g 5% palladium charcoal after the stirring and dissolving.Oil pump is taken out a bottle interior air, nitrogen replacement 3 times, and the back of finding time feeds hydrogen, and the normal pressure hydrogenolysis needs reaction in 8～10 hours to finish to no longer inhaling hydrogen approximately.Remove by filter palladium charcoal (recovery set with), concentrating under reduced pressure filtrate to 50～60mL adds 750mL ethanol while hot, and the ice bath cooling is placed more than 4 hours down, filter L-alanyl-L-glutamine crude product.Crude product gets L-alanyl-L-glutamine elaboration 15.6g, 212～216 ℃ of fusing points (decomposition), yield 72% (in carbobenzoxy-L-alanine, yield 54%) 1～2 time with the alcohol-water recrystallization.HPLC measures L-alanyl-L-glutamine content＞99%.
Embodiment 4
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
Glycyl-L-glutamine 663.3g
Starch 12g
Microcrystalline Cellulose 5g
Making beating starch (8%) 8g
Magnesium stearate 1.5g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (10g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, and tabletting promptly.
Embodiment 5
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
Glycyl-L-glutamine 442.2g
Starch 22g
Microcrystalline Cellulose 5g
Making beating starch (8%) 10g
Magnesium stearate 2g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (20g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, and tabletting promptly.
Embodiment 6
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
Glycyl-L-glutamine 221.1g
Starch 32g
Microcrystalline Cellulose 5g
Making beating starch (8%) 15g
Magnesium stearate 3g
Preparation method: raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (30g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, and tabletting promptly.
Embodiment 7
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
L-alanyl-L-glutamine 663.3g
Starch 12g
Microcrystalline Cellulose 5g
Making beating starch (8%) 8g
Magnesium stearate 1.5g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (10g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, and tabletting promptly.
Embodiment 8
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
L-alanyl-L-glutamine 442.2g
Starch 22g
Microcrystalline Cellulose 5g
Making beating starch (8%) 10g
Magnesium stearate 2g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (20g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, tabletting.
Embodiment 9
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine tablet
Prescription (1000)
Sodium Azulenesulfonate 2.01g
L-alanyl-L-glutamine 221.1g
Starch 32g
Microcrystalline Cellulose 5g
Making beating starch (8%) 15g
Magnesium stearate 3g
Preparation method: earlier raw and auxiliary material is crossed 100 sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch (2g) more respectively, after adopting equivalent to pass the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule and starch (30g), microcrystalline Cellulose, magnesium stearate are always mixed, and cross 14 mesh sieve granulate, survey drug content, the calculating slice is heavy, and tabletting promptly.
Embodiment 10
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine capsule
Prescription (1000)
Sodium Azulenesulfonate 2.01g
Glycyl-L-glutamine 442.2g
Starch 20g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, select No. 0 hard capsule case, the filling spice covers joint, flattens polishing promptly.
Embodiment 11
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine capsule
Prescription (1000)
Sodium Azulenesulfonate 2.01g
Glycyl-L-glutamine 221.1g
Starch 20g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, select No. 2 hard capsule case, the filling spice covers joint, flattens polishing promptly.
Embodiment 12
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine capsule
Prescription (1000)
Sodium Azulenesulfonate 2.01g
L-alanyl-L-glutamine 442.2g
Starch 20g
Preparation method: earlier raw and auxiliary material is crossed 100 sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, select No. 0 hard capsule case, the filling spice covers joint, flattens polishing promptly.
Embodiment 13
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine capsule
Prescription (1000)
Sodium Azulenesulfonate 2.01g
L-alanyl-L-glutamine 221.1g
Starch 20g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, select No. 2 hard capsule case, the filling spice covers joint, flattens polishing promptly.
Embodiment 14
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 2.01g
L-glycyl-L-glutamine 663.3g
Sucrose 50g
Starch 250g
Making beating starch (10%) 30g
Edible essence 4.69g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, behind 14 sieve series grains, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 15
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 2.01g
L-glycyl-L-glutamine 442.2g
Sucrose 50g
Starch 250g
Making beating starch (10%) 20g
Edible essence 4.79g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 mesh sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 16
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 2.01g
L-glycyl-L-glutamine 221.1g
Sucrose 50g
Starch 250g
Making beating starch (10%) 15g
Edible essence 4.89g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, glycyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 mesh sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 17
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 5.01g
L-alanyl-L-glutamine 50.3g
Sucrose 50g
Starch 250g
Making beating starch (10%) 30g
Edible essence 4.69g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 mesh sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 18
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 20.01g
L-alanyl-L-glutamine 50.2g
Sucrose 50g
Starch 250g
Making beating starch (10%) 20g
Edible essence 4.79g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 mesh sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 19
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine granule
Prescription (1000 bags)
Sodium Azulenesulfonate 1.01g
L-glycyl-L-glutamine 1000.1g
Sucrose 50g
Starch 250g
Making beating starch (10%) 15g
Edible essence 4.89g
Preparation method: earlier raw and auxiliary material is crossed 100 mesh sieves respectively, take by weighing recipe quantity Sodium Azulenesulfonate, L-alanyl-L-glutamine, starch more respectively, after employing equivalent is passed the interpretation of the law mix homogeneously, add starch slurry and make soft material, after granulating with 14 mesh sieves, wet granular is in putting 50～60 ℃ of dryings, dried granule is after 14 mesh sieve granulate, under slowly stirring, spray into edible essence, and vexed 30min, drug content surveyed, calculate the every bag of grain amount that should adorn, packing then, sealing, packing is promptly.
Embodiment 20
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 1.01g
L-glycyl-L-glutamine 50.3g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-glycyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Embodiment 21
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 4.01g
L-glycyl-L-glutamine 700.2g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-glycyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Embodiment 22
Compound recipe Sodium Azulenesulfonate/glycyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 3.01g
L-glycyl-L-glutamine 500.1g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-glycyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Embodiment 23
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 5.01g
L-alanyl-L-glutamine 1000.3g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-alanyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Embodiment 21
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 20.01g
L-alanyl-L-glutamine 20000.2g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-alanyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Embodiment 22
Compound recipe Sodium Azulenesulfonate/L-alanyl-L-glutamine oral liquid
Prescription (1000,20ml/ props up)
Sodium Azulenesulfonate 1.01g
L-alanyl-L-glutamine 50.1g
Hydroxypropyl methylcellulose 100g
Sodium benzoate 60g
Fruity flavor 60g
Deionized water 20000ml
The 100g hydroxypropyl methylcellulose is heated abundant swelling with appropriate amount of deionized water, standby; Recipe quantity Sodium Azulenesulfonate and L-alanyl-L-glutamine, fruity flavor and sodium benzoate were pulverized 100 orders put in the mortar, it is even slowly to add hydroxypropyl methylcellulose aqueous solution ground and mixed, adds an amount of distilled water at last to the full dose mixing, and packing is sterilized promptly.
Claims (10)
1. a pharmaceutical composition of protecting gastric mucosa is characterized in that, described compositions contains Sodium Azulenesulfonate and at least a L-glutaminate water-soluble prodrug.
2. according to the described compositions of claim 1, it is characterized in that: the weight ratio of Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug is 1: 2.5～1: 1000.
3. according to the described compositions of claim 1, it is characterized in that: the weight ratio of Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug is 1: 25～1: 500.
4. according to the described compositions of claim 1, it is characterized in that: the weight ratio of Sodium Azulenesulfonate and L-glutaminate water-soluble prodrug is 1: 100～1: 350.
5. according to the described compositions of claim 1, it is characterized in that: the L-glutaminate water-soluble prodrug is selected from glycyl-L-glutamine, the L-alanyl-L-glutamine.
6. according to the described compositions of claim 1, it is characterized in that, is the oral Pharmaceutical dosage forms that is fit to take.
7. according to the described compositions of claim 1, it is characterized in that described oral Pharmaceutical dosage forms is selected from tablet, capsule, granule, oral liquid etc.
8. according to the described compositions of claim 1, it is characterized in that: be unit dosage form, contain Sodium Azulenesulfonate 1～20mg in the per unit dosage, glycyl-L-glutamine 50～20000mg; Or Sodium Azulenesulfonate 1～20mg, L-alanyl-L-glutamine 50～20000mg.
9. according to the described compositions of claim 1, it is characterized in that: be unit dosage form, contain Sodium Azulenesulfonate 1～5mg in the per unit dosage, glycyl-L-glutamine 50～1000mg; Or Sodium Azulenesulfonate 1～5mg, L-alanyl-L-glutamine 50～1000mg.
10. according to the described compositions of claim 1, it is characterized in that: be unit dosage form, contain Sodium Azulenesulfonate 2～3mg in the per unit dosage, glycyl-L-glutamine 200～500mg; Or Sodium Azulenesulfonate 2～3mg, L-alanyl-L-glutamine 200～500mg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610087251A CN100584325C (en) | 2006-06-15 | 2006-06-15 | Medicine composition containing sodium azulene sulfonate and L-glutamine water-soluble precursor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610087251A CN100584325C (en) | 2006-06-15 | 2006-06-15 | Medicine composition containing sodium azulene sulfonate and L-glutamine water-soluble precursor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1861064A true CN1861064A (en) | 2006-11-15 |
| CN100584325C CN100584325C (en) | 2010-01-27 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405747A (en) * | 2013-08-27 | 2013-11-27 | 重庆市第三人民医院 | Preparation method for alanyl-glutamine biological adhesive preparation as well as product and application of preparation |
| CN103512976A (en) * | 2013-09-18 | 2014-01-15 | 河北凯盛医药科技有限公司 | Analysis and detection method of azulene sulfonate isomer and salt thereof |
| CN108310389A (en) * | 2018-01-12 | 2018-07-24 | 佛山科学技术学院 | One kind pro-drug of sodium sulfonate containing Kessazulen and preparation method thereof |
| CN115452994A (en) * | 2022-09-19 | 2022-12-09 | 地奥集团成都药业股份有限公司 | Method for detecting content of L-glutamine in compound glutamine enteric-coated capsule |
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2006
- 2006-06-15 CN CN200610087251A patent/CN100584325C/en not_active Expired - Fee Related
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103405747A (en) * | 2013-08-27 | 2013-11-27 | 重庆市第三人民医院 | Preparation method for alanyl-glutamine biological adhesive preparation as well as product and application of preparation |
| CN103405747B (en) * | 2013-08-27 | 2015-06-17 | 重庆市人民医院 | Preparation method for alanyl-glutamine biological adhesive preparation as well as product and application of preparation |
| CN105561288A (en) * | 2013-08-27 | 2016-05-11 | 重庆市人民医院 | Alanyl-glutamine-containing bioadhesive hydrogel and membrane |
| CN105561289A (en) * | 2013-08-27 | 2016-05-11 | 重庆市人民医院 | Pharmaceutic preparation for treating oral ulcer |
| CN105561288B (en) * | 2013-08-27 | 2019-05-07 | 重庆市人民医院 | A kind of bioadhesive hydrogel and film containing alanyl glutamine |
| CN105561289B (en) * | 2013-08-27 | 2019-05-07 | 重庆市人民医院 | It is a kind of for treating the pharmaceutical preparation of canker sore |
| CN103512976A (en) * | 2013-09-18 | 2014-01-15 | 河北凯盛医药科技有限公司 | Analysis and detection method of azulene sulfonate isomer and salt thereof |
| CN103512976B (en) * | 2013-09-18 | 2017-08-25 | 河北凯盛医药科技有限公司 | A kind of analyzing detecting method of Azulene sulfonic acid isomers and its salt |
| CN108310389A (en) * | 2018-01-12 | 2018-07-24 | 佛山科学技术学院 | One kind pro-drug of sodium sulfonate containing Kessazulen and preparation method thereof |
| CN115452994A (en) * | 2022-09-19 | 2022-12-09 | 地奥集团成都药业股份有限公司 | Method for detecting content of L-glutamine in compound glutamine enteric-coated capsule |
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|---|---|
| CN100584325C (en) | 2010-01-27 |
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Denomination of invention: Medicine composition contg. sodium azulene sulfonate and L-glutamine water-soluble precursor Effective date of registration: 20150929 Granted publication date: 20100127 Pledgee: Shaanxi Qin Nong rural commercial bank Limited by Share Ltd. Pledgor: XI'AN LIJUN PHARMACEUTICAL Co.,Ltd. Registration number: 2015990000836 |
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