WO2005014009A1 - グリチルリチン高濃度製剤 - Google Patents
グリチルリチン高濃度製剤 Download PDFInfo
- Publication number
- WO2005014009A1 WO2005014009A1 PCT/JP2004/011462 JP2004011462W WO2005014009A1 WO 2005014009 A1 WO2005014009 A1 WO 2005014009A1 JP 2004011462 W JP2004011462 W JP 2004011462W WO 2005014009 A1 WO2005014009 A1 WO 2005014009A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- glycyrrhizin
- cysteine
- concentration
- aminoacetic acid
- active ingredient
- Prior art date
Links
- 235000019410 glycyrrhizin Nutrition 0.000 title claims abstract description 33
- 239000004378 Glycyrrhizin Substances 0.000 title claims abstract description 32
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960004949 glycyrrhizic acid Drugs 0.000 title claims abstract description 32
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 title claims abstract description 32
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title abstract description 14
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 30
- 235000018417 cysteine Nutrition 0.000 claims abstract description 21
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960002449 glycine Drugs 0.000 claims abstract description 15
- 235000013905 glycine and its sodium salt Nutrition 0.000 claims abstract description 15
- 239000000654 additive Substances 0.000 claims abstract description 3
- 229960002433 cysteine Drugs 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical group O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 claims description 11
- 229960001305 cysteine hydrochloride Drugs 0.000 claims description 11
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 4
- 229940074774 glycyrrhizinate Drugs 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 abstract description 13
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical class OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 239000003381 stabilizer Substances 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000000203 mixture Substances 0.000 abstract description 4
- LPLVUJXQOOQHMX-MOGLOQIBSA-N (2s,3s,4s,5r,6r)-6-[(2r,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxy-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-trihydroxyoxane-2-c Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-MOGLOQIBSA-N 0.000 abstract description 2
- 230000000996 additive effect Effects 0.000 abstract description 2
- 229940000425 combination drug Drugs 0.000 abstract description 2
- 238000013329 compounding Methods 0.000 abstract description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 27
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 19
- 235000010265 sodium sulphite Nutrition 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000009471 action Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- -1 for example Chemical class 0.000 description 4
- 208000019423 liver disease Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical group N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RRBZUCWNYQUCTR-UHFFFAOYSA-N 2-(aminoazaniumyl)acetate Chemical compound NNCC(O)=O RRBZUCWNYQUCTR-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical compound NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 description 2
- 229960003067 cystine Drugs 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000013373 food additive Nutrition 0.000 description 2
- 239000002778 food additive Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- WBJOKIMCMNCILB-ZICUSWQYSA-N (2r,4as,6ar,6as,6br,10s,12as,14bs)-10-hydroxy-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1h-picene-2-carboxylic acid;2-aminoacetic acid;(2r)-2-amino-3-sulfanylpropanoic acid Chemical compound NCC(O)=O.SC[C@H](N)C(O)=O.C([C@@H]1C2=CC(=O)[C@H]34)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CCC1[C@]3(C)CC[C@H](O)C1(C)C WBJOKIMCMNCILB-ZICUSWQYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- 240000004670 Glycyrrhiza echinata Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- BIVBRWYINDPWKA-VLQRKCJKSA-L Glycyrrhizinate dipotassium Chemical compound [K+].[K+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O BIVBRWYINDPWKA-VLQRKCJKSA-L 0.000 description 1
- 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 description 1
- 239000004201 L-cysteine Substances 0.000 description 1
- 235000013878 L-cysteine Nutrition 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- KPQJOKRSYYJJEL-VLQRKCJKSA-K [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O Chemical compound [Na+].[Na+].CC1(C)[C@H](CC[C@@]2(C)[C@H]1CC[C@]1(C)[C@@H]2C(=O)C=C2[C@@H]3C[C@](C)(CC[C@]3(C)CC[C@@]12C)C([O-])=O)O[C@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O[C@@H]1O[C@@H]([C@@H](O)[C@H](O)[C@H]1O)C([O-])=O)C([O-])=O KPQJOKRSYYJJEL-VLQRKCJKSA-K 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 229940101029 dipotassium glycyrrhizinate Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000020932 food allergy Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 201000004335 respiratory allergy Diseases 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- CCXAYLQLOLXXKE-DWJAGBRCSA-K trisodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4s,5s,6s)-2-[[(3s,4ar,6ar,6bs,8as,11s,12ar,14ar,14bs)-11-carboxylato-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1h-picen-3-yl]oxy]-6-carboxylato-4,5-dihydroxyoxan-3-yl]oxy-3,4,5-t Chemical compound [Na+].[Na+].[Na+].O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C([O-])=O)C([O-])=O)[C@@H]1O[C@H](C([O-])=O)[C@@H](O)[C@H](O)[C@H]1O CCXAYLQLOLXXKE-DWJAGBRCSA-K 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
Definitions
- the present invention relates to a pharmaceutical composition containing glycyrrhizin, cysteine, and aminoacetic acid (glycine) at high concentrations, which is useful as a drug for liver disease or allergy.
- glycyrrhizins have various pharmacological actions such as anti-cortisone action, decholesterolism action, anti-allergic action, anti-inflammatory action, detoxification action, gastric ulcer repair action, and their safety. Therefore, glycyrrhizin preparations containing this as an active ingredient are widely used as therapeutic agents for various diseases. In recent years, the effectiveness of glycyrrhizin preparations has been reviewed by the report of the efficacy of intravenous glycyrrhizin for chronic liver disease.
- Glycyrrhizin 'Aminoacetic acid ⁇ Cystine combination agent (trade name: Strong Neominophagency) currently available on the market is monoammonium glycyrrhizinate 2.65 mg / mL (2 mg / mL as glycyrrhizin), lmgZmL cysteine hydrochloride (0.77 mgZmL as cysteine) This is an injection based on the combination ratio of aminoaminoacetic acid 20mgZmL, which may be adjusted according to age and symptoms as appropriate, but for chronic liver disease 40 to 60mL once a day (can be increased to 100mL) by intravenous injection or infusion It is to be injected intravenously.
- Patent Document 1 Japanese Unexamined Patent Application Publication No. 2002-65808, page 2, paragraph 0004
- Non-Patent Document 1 “Strong Neo-Minophagen C” Package Insert (Prepared by MinoPharma Co., Ltd.)
- Non-patent document 2 Tatsuo Sakamoto: Food additives and asthma (mainly sulfite) Airway allergy '96 Medicano Review: pl 51, 1996
- Non-Patent Document 3 Yoichi Kono: Basics and Clinic of Food Allergy ⁇ Allergenicity of Food> Area of Noregi: 4 (6), p741-745, 1997
- Non-patent document 4 Masataka Michibata: Self-management of steroids My contrivances Clinical and drug treatment: 16 (3), p226-230, 1997
- An object of the present invention is to provide a glycyrrhizin / amino acetic acid / cysteine combination agent which contains an active ingredient at a higher concentration than existing products and is excellent in stability and safety. Simply increasing the concentration of the ingredients in the existing product caused decomposition and precipitation of the active ingredient, and did not provide sufficient stability. In addition, there was a problem of safety due to the contained sulfite.
- the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, the active ingredient was blended at a high concentration without adding sodium sulfite used as a stabilizer in existing products.
- the present inventors have found that a glycyrrhizin 'aminoacetic acid' cysteine combination preparation containing an active ingredient at a higher concentration than the existing preparations and having excellent safety can be obtained, and the present invention has been completed.
- the invention's effect [0008]
- the pharmaceutical composition of the present invention does not contain the sulfite used as a stabilizer in the existing product, whereby precipitation of glycyrrhizin incorporated at a high concentration does not occur, and cysteine is not added.
- the stability was also improved with less decrease in content.
- the present invention provides a glycyrrhizin preparation containing glycyrrhizin or a pharmacologically acceptable salt thereof as an active ingredient, which comprises cysteine and aminoacetic acid in addition to the above components, and does not contain sulfites. It relates to a high concentration of glycyrrhizin'aminoacetic acid / cysteine combination.
- Glycyrrhizin which is an active ingredient of the pharmaceutical composition of the present invention, can be obtained by extracting from licorice, or a commercially available product may be used. Glycyrrhizin is also referred to as glycinolleritic acid, and the present invention includes pharmacologically acceptable salts of glycyrrhizin.
- salts include salts with acids or bases, for example, ammonium salts such as monoammonium glycyrrhizinate, and alkali metal salts such as disodium glycyrrhizinate, trisodium glycyrrhizinate, and dipotassium glycyrrhizinate.
- ammonium salts such as monoammonium glycyrrhizinate
- alkali metal salts such as disodium glycyrrhizinate, trisodium glycyrrhizinate, and dipotassium glycyrrhizinate.
- the cysteine and aminoacetic acid (glycine) of the present invention include pharmaceutically acceptable salts thereof, for example, acid addition salts with hydrochloric acid, malic acid and the like, and alkali metals and alkaline earths such as sodium. Both salts of base addition salts with metals, ammonium, nitrogen-containing organic bases and the like are included, and preferred salts of cysteine include hydrochloride. Further, hydrates of cystine, aminoacetic acid or a salt thereof, for example, cysteine hydrochloride monohydrate sodium aminoacetate hydrate and the like are also included as the cysteine and aminoacetic acid of the present invention. Regarding the cysteine, the force in which the optically active substance exists S, L-form or racemic form, preferably L-cysteine can be used.
- the desirable compounding amount of the pharmaceutical composition of the present invention is 4 to 8 times the active ingredient content of the above-mentioned existing preparations, that is, glycyrrhizin 8 to 16 mg / mL, cysteine hydrochloride 4 to 8 mg / mL (3 as cysteine). To 6 mg / mL) and 80 to 160 mg / mL of aminoacetic acid. Particularly preferably, a preparation containing the highest concentration of the active ingredient, that is, a pharmaceutical composition containing glycyrrhizin 16 mg / mL, cysteine hydrochloride 8 mg / mL, and aminoacetic acid 160 mg / mL It is.
- the numerical values of each of the above concentrations are indicated in accordance with the standard values of the Japanese Pharmacopoeia, 14th Edition, and are rounded off to the first decimal place.
- the pharmaceutical composition of the present invention can be combined with a suitable pharmaceutical carrier or diluent to obtain a final drug, and can be formulated by any ordinary method.
- injections should be aqueous or non-aqueous solvents such as distilled water for injection, physiological saline, Ringer's solution, vegetable oil, synthetic fatty acid glyceride, higher fatty acid ester, propylene glycol, etc. Can be.
- the composition may be combined with other pharmaceutically active ingredients.
- Glycyrrhizinate monoammonium 16 mg / mL (as glycyrrhizin), cysteine hydrochloride 8 mg / mL, and aminoacetic acid 160 mg / mL Dissolve in water with low dissolved oxygen to achieve the mixing ratio, and add sodium hydroxide to pH 7.2-7.5.
- sodium sulfite was added as a stabilizing agent to a concentration of 0, 2.4, 4. Omg / mL, respectively, and dissolved oxygen was removed with nitrogen. After sterilization by filtration, the ampoule was filled with nitrogen.
- the concentrated glycyrrhizin preparation of the present invention has a higher concentration of the active ingredient than the conventional preparations, and is excellent in stability and safety, and its usefulness as a pharmaceutical is extremely high.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Molecular Biology (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
【課題】 有効成分を高濃度で含有し、かつ安定性及び安全性に優れたグリチルリチン・アミノ酢酸・システイン配合剤を提供する。
【解決手段】 既存製品において安定化剤として使用していた亜硫酸塩類を添加しないことで、有効成分を高濃度に配合した場合の安定性が改善された。本発明グリチルリチン濃縮製剤は、グリチルリチン８乃至１６ｍｇ／ｍＬ、システイン３乃至６ｍｇ／ｍＬ及びアミノ酢酸８０乃至１６０ｍｇ／ｍＬを含有し、かつ添加剤として亜硫酸塩類を含有しない医薬組成物である。
Description
明 細 書
グリチルリチン高濃度製剤
技術分野
[0001] 本発明は、肝臓疾患用あるいはアレルギー用薬剤等として有用なグリチルリチン、 システィン及びアミノ酢酸 (グリシン)を高濃度で含有する医薬組成物に関する。
背景技術
[0002] 従来より、グリチルリチン類は抗コルチゾン作用、脱コレステロール作用、抗アレル ギー作用、抗炎症作用、解毒作用、胃潰瘍修復作用等各種の薬理作用を有すること が知られており、またその安全性が確認されていることから、これを有効成分として含 有するグリチルリチン製剤は、各種疾患の治療薬として広く用いられている。そして近 年では、慢性肝疾患に対するグリチルリチンの静脈注射による大量投与の有効性が 報告されたことにより、グリチルリチン製剤の有用性が見直されている。
[0003] 一般に、肝疾患治療用の医薬品は、比較的長期にわたって薬剤を連続投与するこ とが多い。現在市販されているグリチルリチン 'ァミノ酢酸 ·システィン配合剤（商品名 ：強力ネオミノファーゲンシー）は、グリチルリチン酸モノアンモニゥム 2. 65mg/mL ( グリチルリチンとして 2mg/mL)、システィン塩酸塩 lmgZmL (システィンとして 0.7 7mgZmL)、ァミノ酢酸 20mgZmLの配合比による注射剤であり、年齢、症状により 適宜増減するが、慢性肝疾患に対しては 1日 1回 40乃至 60mL (100mLまで増量可 能）を静脈内に注射または点滴静注するものである。このような大量投与は、投与時 に患者に苦痛を与えるば力、りでなぐ連日の長時間にわたる投与は注射部位の組織 に肥厚を生じさせるという問題も生じる。また、本製剤の配合成分であるグリチルリチ ンは沈殿を生じたり、またシスティン塩酸塩は分解し易く不安定であるという問題があ り（特許文献 1参照）、既存の注射用製剤においては安定化剤として亜硫酸塩 (亜硫 酸ナトリウム： 0. 8mg/mL)が添加されている（非特許文献 1参照）。しかし亜硫酸塩 類は、喘息発作の誘引物質であるとの報告があり（非特許文献 2参照）、またアレルギ 一を引き起こす食品添加物として報告されていることから (非特許文献 3及び 4参照） 、これを高濃度で含む製剤は安全性に問題がある。
[0004] 特許文献 1 :特開 2002 - 65808公報 第 2頁 0004段落
非特許文献 1：「強力ネオミノファーゲンシー」医薬品添付文書 (株式会社ミノファーゲ ン製薬作成）
非特許文献 2：坂本龍雄：食品添加物と喘息〈亜硫酸塩を中心に〉 気道アレルギー ' 96メディカノレビュー社： pl 51 , 1996
非特許文献 3：河野陽一：食物アレルギーの基礎と臨床〈食物のアレルゲン性〉 ァレ ノレギ一の領域： 4 (6)， p741-745, 1997
非特許文献 4 :道端正孝:ステロイドの自己管理 私の工夫 臨床と薬物治療： 16 (3) , p226-230, 1997
発明の開示
発明が解決しょうとする課題
[0005] 上述のように、グリチルリチン'アミノ酢酸'システィン配合剤の投与に関して、静脈 注射等による大量投与時の疼痛及び注射部位の組織肥厚などの患者への負担を少 しでも軽減することが望まれていることから、本発明者らは少量投与で薬効が期待で き、かつ安定性及び安全性に優れた高濃度製剤について鋭意研究を行ってきた。
[0006] 本発明における課題は、既存品より有効成分を高濃度で配合し、かつ安定性及び 安全性に優れたグリチルリチン ·ァミノ酢酸 ·システィン配合剤を提供することである。 単に既存品の配合成分を高濃度にしただけでは、有効成分の分解や沈殿等が生じ てしまい、十分な安定性が得られなかった。また、含有された亜硫酸塩による安全性 の問題が生じた。
課題を解決するための手段
[0007] 本発明者は、上記課題を解決するために鋭意研究を行った結果、既存製品におい て安定化剤として使用していた亜硫酸ナトリウムを添加しないことで、有効成分を高 濃度に配合した場合の安定性が改善され、既存製剤より有効成分を高濃度で含有し 、かつ安全性に優れたグリチルリチン'ァミノ酢酸'システィン配合剤が得られることを 見出し本発明を完成するに至った。 発明の効果
[0008] 本発明医薬組成物は、既存品で安定化剤として使用していた亜硫酸塩を添加しな いものであり、これによつて高濃度で配合したグリチルリチンの沈殿も生じず、またシ スティン含量の減少も低ぐ安定性が向上した。
発明を実施するための最良の形態
[0009] 本発明は、グリチルリチン又はその薬理学上許容される塩を有効成分とするグリチ ルリチン製剤において、上記成分の他にシスティン及びアミノ酢酸を含有し、亜硫酸 塩類を含有しないことを特徴とする高濃度のグリチルリチン'ァミノ酢酸 ·システィン配 合剤に関する。
[0010] 本発明医薬組成物の有効成分であるグリチルリチンは、甘草から抽出することによ り得ることができ、また市販されているものを使用してもよい。グリチルリチンはグリチ ノレリチン酸とも呼ばれており、本発明ではグリチルリチンの薬理学上許容される塩を 包含する。薬学上許容される塩としては、酸または塩基との塩、例えば、グリチルリチ ン酸モノアンモニゥム等のアンモニゥム塩や、グリチルリチン酸ニナトリウム、グリチル リチン酸三ナトリウム、グリチルリチン酸二カリウム等のアルカリ金属塩などを挙げるこ とができる。
[0011] また、本発明のシスティン及びアミノ酢酸 (グリシン）はそれらの薬学的に許容される 塩を包含し、例えば塩酸、リンゴ酸等との酸付加塩及びナトリウム等のアルカリ金属 やアルカリ土類金属、アンモニゥム、含窒素有機塩基等との塩基付加塩の両種の塩 が包含され、システィンの好ましい塩として塩酸塩を挙げることができる。さらに、シス ティン、ァミノ酢酸又はそれらの塩の水和物、例えばシスティン塩酸塩一水和物ゃァ ミノ酢酸ナトリウム水和物等も、本発明のシスティン及びアミノ酢酸として包含される。 システィンについては光学活性体が存在する力 S、 L体又はラセミ体のいずれであって もよぐ好ましくは L一システィンを用いることができる。
[0012] 本発明医薬組成物の望ましい配合量は、上記既存製剤の 4乃至 8倍の有効成分含 有量、即ち、グリチルリチン 8乃至 16mg/mL、システィン塩酸塩 4乃至 8mg/mL ( システィンとして 3乃至 6mg/mL)及びアミノ酢酸 80乃至 160mg/mLである。特に 好ましくは、有効成分を最も高濃度で含有する製剤、即ち、グリチルリチン 16mg/m L、システィン塩酸塩 8mg/mL及びアミノ酢酸 160mg/mLを含有する医薬組成物
である。なお、上記各濃度 (mg/mL)の数値は、第十四改正日本薬局方の通則 18 の規格値の規定に従った表示であり、小数点第一位を四捨五入した値である。
[0013] また、本発明医薬組成物は、適当な医薬用の担体若しくは希釈剤と組み合わせて 最終的な医薬とすることができ、通常の如何なる方法によっても製剤化できる。例え ば、注射剤としては水性溶剤又は非水性溶剤、例えば注射用蒸溜水、生理食塩水、 リンゲル液、植物油、合成脂肪酸グリセリド、高級脂肪酸エステル、プロピレングリコ ール等の溶液若しくは懸濁液とすることができる。処方にあたっては、他の医薬活性 成分との配合剤としてもよい。
実施例 1
[0014] 亜硫酸ナトリウム添加による影響（1)
グリチルリチン酸モノアンモニゥム 16mg/mL (グリチルリチンとして）、システィン塩 酸塩 8mg/mL、ァミノ酢酸 160mg/mLの配合比になるように溶存酸素の少ない水 に溶かし、水酸化ナトリウムで pH7. 2-7. 5に調整した。さらに、安定化剤として亜 硫酸ナトリウムを各々 0、 2. 4、 4. Omg/mLの濃度となるように添加した後、窒素で 溶存酸素を除去し、濾過滅菌後、アンプルに窒素充填した。これらのアンプルを 25 °C4年間保存しグリチルリチンの沈殿の状況を観察し、また、これとは別に 40°C4ヶ月 間及び 60°C14日間保存した後、システィンを HPLCで定量した。このようにして本発 明医薬組成物の亜硫酸ナトリウム添加量の差による安定性を測定した結果の一例を 表 1に示す。
[0015] [表 1]
亜硫酸ナトリウム添加量（mg/mL)
0 2. 4 4. 0 製造時 pH 7. 22 7. 49 7. 29 ゲリチルリチン
25。C4年後 一 + + 沈濂の有無
未滅菌時 97. 3 101 . 6 98. 9 滅'纏後 94. 4 95. 2 91 . 1
3曰後 89. 7 87. 8 81 . 4 シス亍イン
60°C 7曰後 81 . 2 71 . 3 64. 2 含量 (％)
14曰後 77. 8 66. 5 53. 9
2ヶ月後 89. 4 86. 0
40°C
4ヶ月後 83. 6 77. 7 68. 5 実施例 2
[0016] 亜硫酸ナトリウム添カ卩による影響（2)
上記実施例 1と同様に、グリチルリチン酸モノアンモニゥム 16mg/mL (ダリチルリ チンとして）、システィン塩酸塩 8mgZmL、ァミノ酢酸 160mg/mLの配合比になる ように溶存酸素の少ない水に溶かし、水酸化ナトリウムで pH7. 2-7. 5に調整した。 さらに、安定化剤として亜硫酸ナトリウムを 6. 4mg/mLとなるよう添カ卩したものと無添
！卜 加のものを作製し、また、これらの配合から、システィン塩酸塩の濃度が 6m ogZmL及
O C
び4 mg/mLとなるように希釈したものも作製した。各々について、窒素で溶存酸素 を除去し、濾過滅菌後、アンプノレに窒素充填した。これらのアンプルを 60。C14日間 保存し、開始時、 4日後、 7日後、 14日後にシスティンを HPLCで定量した。このよう にして本発明医薬組成物のシスティン塩酸塩の安定性に対する亜硫酸ナトリウム添 加による影響を測定した結果の一例を表 2に示す。
[0017] [表 2]
シス亍イン塩酸塩配合量 (mg mL) 8 6 4
開始 100.0 100.0 100.0
4曰 93.5 97.5 94.3 無添加
7曰 89.5
14曰
88.7 開始 100.0 100.0 100.0 亜硫酸 Na 4曰 73.6 84.4
添加 7曰 53. 1 70.4 77. 1
14曰 40.4 52.2 59.8 産業上の利用の可能性
上記表 1及び表 2に示した結果から明らかなように、亜硫酸ナトリウムの濃度が高い ほど、システィン含量の経時的減少が著しかった。また、亜硫酸ナトリウムを添加した ものでは、グリチルリチンの沈殿が生じたが、添加しない場合には、高濃度で配合し たグリチルリチンの沈殿も生じず、またシスティン含量の減少も低ぐ安定性が向上し た。このように、本発明グリチルリチン濃縮製剤は、従来製剤より有効成分含量が高 濃度で、かつ安定性及び安全性に優れており、医薬品としてその有用性0 0は非常に高 いものである。 o o
Claims
[1] グリチルリチン 8乃至 16mg/mL、システィン 3乃至 6mg/mL及びアミノ酢酸 80乃 至 160mgZmLを含有する医薬組成物。
[2] 亜硫酸塩類を含有しない請求項 1記載の医薬組成物。
[3] グリチルリチンがグリチルリチン酸モノアンモニゥムである請求項 1又は 2記載の医薬 組成物。
[4] システィンがシスティン塩酸塩である請求項 1乃至 3のいずれかに記載の医薬組成 物。
[5] グリチルリチン 16mg/mL、システィン塩酸塩 8mg/mL及びアミノ酢酸 160mg/ mLを含有し、添加物として亜硫酸塩類を含有しない医薬組成物。
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2005512629A JP4463206B2 (ja) | 2003-08-12 | 2004-08-10 | グリチルリチン高濃度製剤 |
| EP04771449A EP1676580A4 (en) | 2003-08-12 | 2004-08-10 | PREPARATION HAVING A HIGH CONCENTRATION OF GLYCYRRHIZINE |
| AU2004263036A AU2004263036B2 (en) | 2003-08-12 | 2004-08-10 | Glycyrrhizin high-concentration preparation |
| US10/566,588 US20060160754A1 (en) | 2003-08-12 | 2004-08-10 | Glycyrrhizin high-concentration preparation |
| CA2534259A CA2534259C (en) | 2003-08-12 | 2004-08-10 | Glycyrrhizin high-concentration preparation |
| US14/010,141 US20130345160A1 (en) | 2003-08-12 | 2013-08-26 | Glycyrrhizin high-concentration preparation |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2003-292135 | 2003-08-12 | ||
| JP2003292135 | 2003-08-12 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US14/010,141 Continuation-In-Part US20130345160A1 (en) | 2003-08-12 | 2013-08-26 | Glycyrrhizin high-concentration preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2005014009A1 true WO2005014009A1 (ja) | 2005-02-17 |
Family
ID=34131698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/JP2004/011462 WO2005014009A1 (ja) | 2003-08-12 | 2004-08-10 | グリチルリチン高濃度製剤 |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US20060160754A1 (ja) |
| EP (1) | EP1676580A4 (ja) |
| JP (1) | JP4463206B2 (ja) |
| KR (1) | KR101153250B1 (ja) |
| CN (2) | CN101773509A (ja) |
| AU (1) | AU2004263036B2 (ja) |
| CA (1) | CA2534259C (ja) |
| TW (1) | TWI316403B (ja) |
| WO (1) | WO2005014009A1 (ja) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1818053A4 (en) * | 2004-11-02 | 2008-02-27 | Ajinomoto Kk | MEDICINE FOR THE TREATMENT / PROPHYLAXIS OF ALLERGIC DISEASES |
| AU2007328210B2 (en) * | 2006-12-06 | 2012-11-22 | Cornell Research Foundation, Inc. | Intermediate duration neuromuscular blocking agents and antagonists thereof |
| WO2010107488A1 (en) | 2009-03-17 | 2010-09-23 | Cornell University | Reversible nondepolarizing neuromuscular blockade agents and methods for their use |
| WO2011022491A1 (en) * | 2009-08-19 | 2011-02-24 | Cornell University | Cysteine for physiological injection |
| CN102871958A (zh) * | 2012-09-24 | 2013-01-16 | 罗诚 | 一种含甘草酸单铵化合物药物组合物及其制备方法 |
| CN105143428B (zh) | 2013-04-29 | 2017-08-25 | 哈沙·奇古鲁帕蒂 | 酒精饮料中降低的毒性 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6333332A (ja) * | 1986-07-26 | 1988-02-13 | Minofuaagen Seiyaku Honpo:Goushi | エイズ・ウイルス増殖抑制剤 |
| JPH05271097A (ja) * | 1991-10-07 | 1993-10-19 | Asahi Chem Ind Co Ltd | アクレアシン類の可溶化剤および医薬組成物 |
| JPH06135836A (ja) * | 1992-10-28 | 1994-05-17 | Minofuaagen Seiyaku Honpo:Goushi | コントラサプレッサー細胞の誘導剤 |
| JPH06172187A (ja) * | 1992-12-04 | 1994-06-21 | Minofuaagen Seiyaku Honpo:Goushi | 筋ジストロフィー症治療薬 |
| JP2002065808A (ja) * | 2000-08-30 | 2002-03-05 | Nisshin Seiyaku Kk | アミノ酸含有薬液入りプラスチック容器の安定な保存用包装体 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4150744A (en) * | 1976-02-27 | 1979-04-24 | Smith & Nephew Pharmaceuticals Ltd. | Packaging |
| JPS5849310A (ja) * | 1981-09-17 | 1983-03-23 | Minofuaagen Seiyaku Honpo:Goushi | 有用なるグリチルリチン溶液の調製法 |
| US5030645A (en) * | 1990-10-15 | 1991-07-09 | Merck & Co., Inc. | Method of treating asthma using (S)-α-fluoromethyl-histidine and esters thereof |
| JP3435405B2 (ja) * | 2000-11-24 | 2003-08-11 | 株式会社ティーセル研究所 | 家畜の乳房炎治療剤及びこれを用いた乳房炎の治療方法 |
| WO2002074238A2 (en) * | 2001-02-16 | 2002-09-26 | Lavipharm Laboratories Inc. | Water soluble and palatable complexes |
-
2004
- 2004-08-10 JP JP2005512629A patent/JP4463206B2/ja not_active Expired - Fee Related
- 2004-08-10 CN CN201010134563A patent/CN101773509A/zh active Pending
- 2004-08-10 AU AU2004263036A patent/AU2004263036B2/en not_active Ceased
- 2004-08-10 KR KR1020067002767A patent/KR101153250B1/ko not_active IP Right Cessation
- 2004-08-10 WO PCT/JP2004/011462 patent/WO2005014009A1/ja active Application Filing
- 2004-08-10 CA CA2534259A patent/CA2534259C/en not_active Expired - Fee Related
- 2004-08-10 US US10/566,588 patent/US20060160754A1/en not_active Abandoned
- 2004-08-10 CN CNA200480022998XA patent/CN1835758A/zh active Pending
- 2004-08-10 EP EP04771449A patent/EP1676580A4/en not_active Withdrawn
- 2004-08-11 TW TW093124048A patent/TWI316403B/zh not_active IP Right Cessation
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6333332A (ja) * | 1986-07-26 | 1988-02-13 | Minofuaagen Seiyaku Honpo:Goushi | エイズ・ウイルス増殖抑制剤 |
| JPH05271097A (ja) * | 1991-10-07 | 1993-10-19 | Asahi Chem Ind Co Ltd | アクレアシン類の可溶化剤および医薬組成物 |
| JPH06135836A (ja) * | 1992-10-28 | 1994-05-17 | Minofuaagen Seiyaku Honpo:Goushi | コントラサプレッサー細胞の誘導剤 |
| JPH06172187A (ja) * | 1992-12-04 | 1994-06-21 | Minofuaagen Seiyaku Honpo:Goushi | 筋ジストロフィー症治療薬 |
| JP2002065808A (ja) * | 2000-08-30 | 2002-03-05 | Nisshin Seiyaku Kk | アミノ酸含有薬液入りプラスチック容器の安定な保存用包装体 |
Non-Patent Citations (1)
| Title |
|---|
| See also references of EP1676580A4 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1676580A1 (en) | 2006-07-05 |
| AU2004263036A1 (en) | 2005-02-17 |
| TW200505469A (en) | 2005-02-16 |
| CA2534259A1 (en) | 2005-02-17 |
| US20060160754A1 (en) | 2006-07-20 |
| EP1676580A4 (en) | 2010-07-28 |
| KR101153250B1 (ko) | 2012-06-05 |
| CN101773509A (zh) | 2010-07-14 |
| CA2534259C (en) | 2012-04-24 |
| TWI316403B (en) | 2009-11-01 |
| JPWO2005014009A1 (ja) | 2006-09-28 |
| KR20060061351A (ko) | 2006-06-07 |
| CN1835758A (zh) | 2006-09-20 |
| AU2004263036B2 (en) | 2010-06-03 |
| JP4463206B2 (ja) | 2010-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2260429C9 (ru) | Составы моксифлоксацина, содержащие поваренную соль | |
| JP5185488B2 (ja) | ２−（４−イソブチルフェニル）プロピオン酸の医薬組成物 | |
| AU2011281035B2 (en) | Acetycysteine compositions and methods of use thereof | |
| KR101202649B1 (ko) | 소듐 디클로페낙 및 β-시클로덱스트린을 포함하는 주사용약학 조성물 | |
| JP7042531B2 (ja) | デオキシコール酸を含む医薬組成物 | |
| JP6353577B2 (ja) | 組み合わせ組成物 | |
| US6727286B2 (en) | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid | |
| AU2002224475A1 (en) | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid | |
| EA035079B1 (ru) | Композиция диклофенака | |
| JP6818019B2 (ja) | レファムリンの注射可能医薬組成物 | |
| CN101123957B (zh) | 双氯芬酸及其药学上可接受盐的注射剂 | |
| US20040132823A1 (en) | Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid | |
| WO2005014009A1 (ja) | グリチルリチン高濃度製剤 | |
| KR20190141871A (ko) | 안정성을 개선한 이부프로펜 약학 조성물 | |
| JP2007045788A (ja) | グリチルリチン酸高濃度水溶液の調製法 | |
| WO2020025986A1 (en) | Injectable combination of diclofenac sodium and thiocolchicoside | |
| JP2003171273A (ja) | 安定な液状製剤 | |
| CN115518035A (zh) | 一种酮咯酸液体组合物、其制备方法及应用 | |
| US20130345160A1 (en) | Glycyrrhizin high-concentration preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WWE | Wipo information: entry into national phase |
Ref document number: 200480022998.X Country of ref document: CN |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2005512629 Country of ref document: JP |
|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| ENP | Entry into the national phase |
Ref document number: 2534259 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2004263036 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 1020067002767 Country of ref document: KR |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 2004771449 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 2004263036 Country of ref document: AU Date of ref document: 20040810 Kind code of ref document: A |
|
| WWP | Wipo information: published in national office |
Ref document number: 2004263036 Country of ref document: AU |
|
| ENP | Entry into the national phase |
Ref document number: 2006160754 Country of ref document: US Kind code of ref document: A1 |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 10566588 Country of ref document: US |
|
| WWP | Wipo information: published in national office |
Ref document number: 1020067002767 Country of ref document: KR |
|
| WWP | Wipo information: published in national office |
Ref document number: 2004771449 Country of ref document: EP |
|
| WWP | Wipo information: published in national office |
Ref document number: 10566588 Country of ref document: US |