CN106580891B - A kind of Aescinate B injection and preparation method thereof - Google Patents
A kind of Aescinate B injection and preparation method thereof Download PDFInfo
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- CN106580891B CN106580891B CN201611022549.6A CN201611022549A CN106580891B CN 106580891 B CN106580891 B CN 106580891B CN 201611022549 A CN201611022549 A CN 201611022549A CN 106580891 B CN106580891 B CN 106580891B
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- aescinate
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- 238000002347 injection Methods 0.000 title claims abstract description 24
- 239000007924 injection Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000011259 mixed solution Substances 0.000 claims description 15
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical group CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 14
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 11
- 229930195725 Mannitol Natural products 0.000 claims description 11
- 238000004108 freeze drying Methods 0.000 claims description 11
- 235000010355 mannitol Nutrition 0.000 claims description 11
- 239000000594 mannitol Substances 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 9
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 7
- 235000014655 lactic acid Nutrition 0.000 claims description 7
- 239000004310 lactic acid Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- 239000003002 pH adjusting agent Substances 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 230000003247 decreasing effect Effects 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 238000011017 operating method Methods 0.000 claims 1
- 210000004185 liver Anatomy 0.000 abstract description 11
- 150000001413 amino acids Chemical class 0.000 abstract description 10
- 230000007794 irritation Effects 0.000 abstract description 9
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 8
- 210000004204 blood vessel Anatomy 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 231100000417 nephrotoxicity Toxicity 0.000 abstract description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 14
- 239000002504 physiological saline solution Substances 0.000 description 11
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 10
- 235000003704 aspartic acid Nutrition 0.000 description 10
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 10
- 235000018977 lysine Nutrition 0.000 description 10
- 239000004471 Glycine Substances 0.000 description 9
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 9
- 239000004472 Lysine Substances 0.000 description 9
- 230000001575 pathological effect Effects 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 239000013641 positive control Substances 0.000 description 8
- 235000002374 tyrosine Nutrition 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 235000018417 cysteine Nutrition 0.000 description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 6
- 210000003734 kidney Anatomy 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 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 5
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 5
- 230000005856 abnormality Effects 0.000 description 5
- 238000004925 denaturation Methods 0.000 description 5
- 230000036425 denaturation Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000017074 necrotic cell death Effects 0.000 description 5
- 235000013930 proline Nutrition 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 238000005374 membrane filtration Methods 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 230000002792 vascular Effects 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 238000012449 Kunming mouse Methods 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 210000000683 abdominal cavity Anatomy 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 235000015177 dried meat Nutrition 0.000 description 2
- 210000005069 ears Anatomy 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 210000003292 kidney cell Anatomy 0.000 description 2
- 210000005229 liver cell Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- YFESOSRPNPYODN-RSMWSHJLSA-N (2s,3s,4s,5r,6r)-6-[[(4s,6ar,6bs,8r,8ar,9r,10r,14br)-9-acetyloxy-8-hydroxy-4,8a-bis(hydroxymethyl)-4,6a,6b,11,11,14b-hexamethyl-10-[(z)-2-methylbut-2-enoyl]oxy-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-4-hydroxy-3,5-bis[[(2s,3r,4s, Chemical compound O([C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)OC1CC[C@]2(C)C3CC=C4[C@@]([C@@]3(CCC2[C@]1(CO)C)C)(C)C[C@@H](O)[C@@]1(CO)[C@@H](OC(C)=O)[C@@H](C(CC14)(C)C)OC(=O)C(\C)=C/C)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.O([C@@H]1[C@H](O[C@H]([C@@H]([C@H]1O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)OC1CC[C@]2(C)C3CC=C4[C@@]([C@@]3(CCC2[C@]1(CO)C)C)(C)C[C@@H](O)[C@@]1(CO)[C@@H](OC(C)=O)[C@@H](C(CC14)(C)C)OC(=O)C(/C)=C/C)C(O)=O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YFESOSRPNPYODN-RSMWSHJLSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- AXNVHPCVMSNXNP-GKTCLTPXSA-N Aescin Natural products O=C(O[C@H]1[C@@H](OC(=O)C)[C@]2(CO)[C@@H](O)C[C@@]3(C)[C@@]4(C)[C@@H]([C@]5(C)[C@H]([C@](CO)(C)[C@@H](O[C@@H]6[C@@H](O[C@H]7[C@@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O7)[C@@H](O)[C@H](O[C@H]7[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O7)[C@@H](C(=O)O)O6)CC5)CC4)CC=C3[C@@H]2CC1(C)C)/C(=C/C)/C AXNVHPCVMSNXNP-GKTCLTPXSA-N 0.000 description 1
- 241000157282 Aesculus Species 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241001143502 Hippocastanaceae Species 0.000 description 1
- 206010048469 Kidney enlargement Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 229930189092 Notoginsenoside Natural products 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 108090000992 Transferases Proteins 0.000 description 1
- 102000004357 Transferases Human genes 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 108010065394 aminopherase Proteins 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003150 biochemical marker Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical class OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 235000010181 horse chestnut Nutrition 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003325 tomography Methods 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a kind of Aescinate B injection, it contains Aescinate B and amino acid, and the weight ratio of the Aescinate B and amino acid is 10~50: 1~10, and the invention also discloses the preparation methods of injection.Compared with prior art, the present invention has stronger anti-inflammatory, impervious activity out and lower blood vessel irritation and liver renal toxicity.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of Aescinate B injection, the invention further relates to preparation sides
Method.
Background technique
Otoginsenoside is the total saposins extracted from Hippocastanaceae buckeye seed, the water dissolution of otoginsenoside
It spends poor, to increase its solubility, is often made into sodium salt.Otoginsenoside mainly contains 4 kinds of ingredients, and China's national standard presses liquid
Before and after phase chromatography appearance, it is successively named as Aescinate A, Aescinate B, otoginsenoside C and otoginsenoside D.
Sodium Aescinate has the multiple efficacies such as anti-inflammatory, antioedematous, can be used for the treatment of the diseases such as brain edema, wound, mesh
Before mostly use the administration mode of intravenous injection.CN 102836133A discloses a kind of notoginsenoside sodium freezing-dried powder needle and its preparation
Method, it is made of Sodium Aescinate, the freeze drying protectant tert-butyl alcohol and water for injection, but due to Sodium Aescinate have compared with
Strong blood vessel irritation also has stronger renal toxicity, Yi Yinqi acute renal failure, to limit its clinical application.
CN 1491657A discloses a kind of pharmaceutical composition being made of Sodium Aescinate and diclofenac salt, and double chlorine are fragrant
The addition substantially reduced irritation of aescin for injection and the caused pain of hydrochlorate.CN 1931176A discloses one
The pharmaceutical composition of kind otoginsenoside, it is made of seven leaf total saposins with pharmaceutical carriers such as lysines, and the two combination has significant
Synergistic function, and reduce otoginsenoside to the irritation of blood vessel and muscle, but not can be reduced renal toxicity.Has examination
Test the anti-inflammatory activity and otoginsenoside that show otoginsenoside purity be positively correlated, i.e., Aescinate A, B, C, D total purity get over
Height, related content of material is fewer, and activity is stronger, and the blood vessel irritation of otoginsenoside is exactly the opposite, i.e. Aescinate A, B, C, D
Total purity it is higher, related content of material is fewer, and irritation is bigger.
Summary of the invention
The purpose of the present invention is in view of the deficiencies in the prior art, providing a kind of Aescinate B injection, not only have
There is stronger therapeutic activity, while also can be reduced vascular stimulation and renal toxicity, to better meet clinical treatment.
Aescinate B injection provided by the present invention, containing Aescinate B and amino acid, the Aescinate B and ammonia
The weight ratio of base acid is 10~50: 1~10.
Preferably, the amino acid is glycine, in lysine, proline, aspartic acid, tyrosine, cysteine
One or more any combination.
Preferably, the weight ratio of the Aescinate B and amino acid is 30~40: 2~6.
Preferably, the Aescinate B injection also contains acceptable auxiliary element on medicament.
Preferably, the injection is freeze-dried powder, and the auxiliary element is pH adjusting agent and mannitol.
Preparation method provided by the present invention the following steps are included:
1) Aescinate B, amino acid, mannitol are dissolved in water for injection and mixed solution is made, it is sweet in the mixed solution
The concentration for revealing alcohol is 10~20g/100ml, and the concentration of Aescinate B is 0.5~2g/100ml；
It 2) is 4.5~6.5 with the pH value that pH adjusting agent adjusts mixed solution；
3) by the solution filter membrane or filter element filtering after adjusting pH value；
4) after filling freeze-drying to get.
Preferably, the pH adjusting agent is lactic acid.Aescinate B property is unstable, and being adjusted with acid pH can be improved stabilization
Property, wherein the stability of lactic acid is best, and lactic acid can also reduce irritation.
Preferably, the freeze-drying includes pre-freeze, primary distillation and re-dry three phases, the operation step in each stage
It is rapid as follows:
Pre-freeze: being first rapidly decreased to -25~-20 DEG C for temperature of charge, is kept for 0.5~1 hour, then again delays temperature of charge
Slowly -40~-35 DEG C are down to, keeps the temperature 2~5 hours；
Primary distillation: control vacuum degree is in 20 pas hereinafter, temperature of charge is increased to -15~-5 DEG C and to keep the temperature 3~5 small
When；
Re-dry: temperature of charge is raised to 30~40 DEG C, keeps the temperature 10~15 hours.
The quality of the pharmaceutical preparations and stability can be improved using the above lyophilized technique.
The beneficial effects of the present invention are:
1) compared with prior art, the present invention has stronger anti-inflammatory, impervious activity out.Animal experiment shows that mouse is quiet
Arteries and veins injects 0.125mg/Kg, can reach 60% or more, up to 70% or more to swelling inhibiting rate；Mouse mainline
1mg/Kg can reach 40% or more, up to 58% to the inhibiting rate of exudation.
2) injection site has no that obvious stimulation is reacted, and pathology section examination has no that blood vessel and its peripheral cell have denaturation, bad
Dead and obvious pathological abnormalities, show vascular irritation of the present invention.
3) every biochemical indicator and liver, Kidney coefficients are compared with physiological saline group without significant difference, pathological section
Observation is substantially similar to physiological saline group, has no that liver and kidney cells have denaturation, necrosis and obvious pathological abnormalities, shows liver of the invention
Renal toxicity is very low.
4) freeze-dried powder appearance provided by the invention is full, no atrophy, collapse, tomography phenomena such as, solubility and quality are steady
Qualitative good, storage period was up to 1 year.
Specific embodiment
The present invention is described in detail by the following examples.Raw material Aescinate B used in following embodiment
The purity that is obtained from otoginsenoside using chromatography separating method up to 98% or more sterling.
Embodiment 1
1) 30g Aescinate B, 2g glycine, 200g mannitol are dissolved in 2000ml water for injection and mixed solution, institute is made
The concentration for stating mannitol in mixed solution is 10g/100ml, and the concentration of Aescinate B is 1.5g/100ml, the concentration of glycine
For 0.1g/100ml；
It 2) is 6.5 with the pH value that lactic acid adjusts mixed solution；
3) 0.22 μm of the membrane filtration of solution after pH value will be adjusted；
4) filling rear freeze-drying.
The program of freeze-drying is as follows:
Pre-freeze: being first rapidly decreased to -20 DEG C for temperature of charge, is kept for 1 hour, temperature of charge is then slowly dropped to -40 again
DEG C, keep the temperature 4 hours；
Primary distillation: control vacuum degree is in 20 pas hereinafter, temperature of charge is increased to -10 DEG C and keeps the temperature 4 hours；
Re-dry: temperature of charge is raised to 35 DEG C, keeps the temperature 12 hours.
Embodiment 2
1) 40g Aescinate B, 6g lysine, 800g mannitol are dissolved in 4000ml water for injection and mixed solution, institute is made
The concentration for stating mannitol in mixed solution is 20g/100ml, and the concentration of Aescinate B is 1g/100ml, and the concentration of lysine is
0.15g/100ml；
It 2) is 4.5 with the pH value that lactic acid adjusts mixed solution；
3) 0.22 μm of the membrane filtration of solution after pH value will be adjusted；
4) filling rear freeze-drying.
The program of freeze-drying is as follows:
Pre-freeze: being first rapidly decreased to -25 DEG C for temperature of charge, is kept for 0.5 hour, be then again slowly dropped to temperature of charge -
35 DEG C, keep the temperature 5 hours；
Primary distillation: control vacuum degree is in 20 pas hereinafter, temperature of charge is increased to -5 DEG C and keeps the temperature 3 hours；
Re-dry: temperature of charge is raised to 40 DEG C, keeps the temperature 10 hours.
Embodiment 3
1) 25g Aescinate B, 5g aspartic acid, 150g mannitol are dissolved in 1250ml water for injection and mixed solution are made,
The concentration of mannitol is 12g/100ml in the mixed solution, and the concentration of Aescinate B is 2g/100ml, aspartic acid it is dense
Degree is 0.4g/100ml；
It 2) is 5.5 with the pH value that lactic acid adjusts mixed solution；
3) 0.22 μm of the membrane filtration of solution after pH value will be adjusted；
4) filling rear freeze-drying.
The program of freeze-drying is as follows:
Pre-freeze: being first rapidly decreased to -22 DEG C for temperature of charge, is kept for 0.5 hour, be then again slowly dropped to temperature of charge -
38 DEG C, keep the temperature 3 hours；
Primary distillation: control vacuum degree is in 20 pas hereinafter, temperature of charge is increased to -15 DEG C and keeps the temperature 5 hours；
Re-dry: temperature of charge is raised to 30 DEG C, keeps the temperature 15 hours.
Test example
1. anti-inflammatory activity is tested
Trial drug: by Aescinate B respectively with glycine, lysine, proline, aspartic acid, tyrosine, half Guang ammonia
Acid, tryptophan, glutamic acid are mixed by 15: 1 weight ratio, and freeze-dried powder are made according to a conventional method, while being frozen with Aescinate B
Dry powder needle is positive control.
Healthy male mouse of kunming 100 of 25~30g of weight are taken, are divided into 10 big groups, every group of 10 mouse are injected intravenously
0.125mg/Kg (in terms of Aescinate B), blank control injecting normal saline, after 30 minutes, every mouse auris dextra smears dimethylbenzene
0.06ml put to death mouse after 2 hours, laid ears disk with punch, and weighing calculates the swelling of each mouse, in detail side
Method reference literature CN1931176A.Test result is shown in Table 1.
The anti-inflammatory activity of 1 Aescinate B injection of table
| Grouping | Trial drug | Number of animals (n) | Swelling value (x ± s.mg) | Inhibiting rate (%) |
| 1 | Aescinate B+glycine | 10 | 6.06 | 67.3 |
| 2 | Aescinate B+lysine | 10 | 7.54 | 59.4 |
| 3 | Aescinate B+proline | 10 | 7.89 | 57.5 |
| 4 | Aescinate B+aspartic acid | 10 | 6.46 | 65.2 |
| 5 | Aescinate B+tyrosine | 10 | 5.33 | 71.3 |
| 6 | Aescinate B+cysteine | 10 | 8.63 | 53.5 |
| 7 | Aescinate B+tryptophan | 10 | 10.17 | 45.2 |
| 8 | Aescinate B+glutamic acid | 10 | 9.86 | 46.9 |
| 9 | Aescinate B (positive control) | 10 | 11.12 | 40.1 |
| 10 | Physiological saline (blank control) | 10 | 18.56 | —— |
As can be seen from the above tests: compared with blank control, Aescinate B and its amino acid composition are all had obviously
Anti-inflammatory activity.Compared with Aescinate B positive control, the 1st~6 group of swelling suppression for all having significant difference, especially the 5th group
Rate processed has reached 70% or more, and the 7th, 8 group of notable difference no compared with positive control, illustrates glycine, lysine, dried meat ammonia
Acid, aspartic acid, tyrosine, cysteine can be further improved the anti-inflammatory activity of Aescinate B.
2. impervious activity test out
Trial drug is the same as test example 1.
The method of reference literature CN 1931176A test example 6, takes healthy kunming mice 100, is divided into 10 groups, every group 10
Only, it is injected intravenously 1mg/Kg (in terms of Aescinate B), blank control injecting normal saline after 1 hour, is injected intravenously 1% Yi Wen
Think blue physiological saline, while 1% acetum 0.2ml of peritoneal injection, puts to death mouse after twenty minutes, cut off abdominal cavity, use physiology salt
Water 6ml washs abdominal cavity by several times, cleaning solution is merged, and adds physiological saline 10ml, is centrifuged 300rpm × 20 minute, takes supernatant,
Absorbance value is measured at 590nm, the results are shown in Table 2.
The impervious activity out of 2 Aescinate B injection of table
| Grouping | Trial drug | Number of animals (n) | Absorbance | Inhibiting rate (%) |
| 1 | Aescinate B+glycine | 10 | 0.1865 | 50.5 |
| 2 | Aescinate B+lysine | 10 | 0.1888 | 49.9 |
| 3 | Aescinate B+proline | 10 | 0.2080 | 44.8 |
| 4 | Aescinate B+aspartic acid | 10 | 0.2197 | 41.7 |
| 5 | Aescinate B+tyrosine | 10 | 0.1575 | 58.2 |
| 6 | Aescinate B+cysteine | 10 | 0.1937 | 48.6 |
| 7 | Aescinate B+tryptophan | 10 | 0.2536 | 32.7 |
| 8 | Aescinate B+glutamic acid | 10 | 0.2656 | 29.5 |
| 9 | Aescinate B (positive control) | 10 | 0.2759 | 26.8 |
| 10 | Physiological saline (blank control) | 10 | 0.3768 | —— |
As can be seen from the above tests: compared with blank control, Aescinate B and its amino acid composition are all had obviously
It is impervious go out activity.Compared with Aescinate B positive control, the 1st~6 group of exudation for all having significant difference, especially the 5th group
Inhibiting rate has reached 55% or more, and the 7th, 8 group of notable difference no compared with positive control, illustrates glycine, lysine, dried meat
Propylhomoserin, aspartic acid, tyrosine, cysteine can be further improved the impervious activity out of Aescinate B.
3. vascular stimulation tests
Trial drug is same as Example 1.
The method of bibliography CN 1931176A test example 3, taking weight is that the rabbit 30 of 2Kg is only divided into 10 groups, every group 3
Only, group technology is identical as test example 1.Each trial drug is in terms of contained Aescinate B, every rabbit daily 1ml: 5mg, blank control
Injecting normal saline is injected from same auricular vein, the 4th day execution animal for three days on end, is cut administration ear edge, is observed drug pair
The stimulation of vein, and make check pathological section, it is as a result as follows:
1st~8 group is showed no obvious stimulation reaction, and pathology section examination is substantially similar to physiological saline group, has no blood vessel
And its peripheral cell has denaturation, necrosis and obvious pathological abnormalities；The 9th group of serious congestion and edema of appearance, most of injection site are aobvious
Puce, pathological section show there is serious degenerative, necrosis and thrombosis；The ear of 10th group of animal has no that obvious stimulation is anti-
It answers, pathological section no abnormality seen.
The above result shows that: amino acid can significantly reduce the blood vessel irritation of Aescinate B.
4. liver renal toxicity test
Healthy kunming mice 100 is taken, is divided into 10 groups, every group 10, is injected intravenously 5mg/Kg (in terms of Aescinate B),
Successive administration 7d weighs and records, fasting 12h before putting to death, weighing before control group intravenous injection physiological saline administration.15% crow
Smooth intraperitoneal injection of anesthesia is drawn, abdominal aorta blood sampling separates serum, measures each group rat blood serum histidine amino group transferase (ALT), day
Four aspartic acid aminopherase (AST), urea nitrogen (BUN), creatinine (Cr) biochemical indicators.Rat is put to death, liver, kidney measurement are taken
Organ coefficient (dirty/body ratio)=Organ weight/weight × 100%, takes the tissue of liver and kidney, respectively with 4% first
Aldehyde solution is fixed, conventional to be dehydrated, paraffin embedding, slice, HE dyeing, the microstructure of light microscopic observation liver and renal tissue.
Test result is shown in Table 3, table 4.
Influence of the 3 Aescinate B injection of table to mouse biochemical marker level
Influence of the 4 Aescinate B injection of table to mouse liver, Kidney coefficients
| Grouping | Trial drug | Number of animals (n) | Liver coefficient | Kidney coefficients |
| 1 | Aescinate B+glycine | 10 | 6.828±0.549 | 1.788±0.254 |
| 2 | Aescinate B+lysine | 10 | 6.855±0.582 | 1.786±0.269 |
| 3 | Aescinate B+proline | 10 | 6.811±0.643 | 1.793±0.258 |
| 4 | Aescinate B+aspartic acid | 10 | 6.836±0.594 | 1.795±0.268 |
| 5 | Aescinate B+tyrosine | 10 | 6.894±0.567 | 1.769±0.289 |
| 6 | Aescinate B+cysteine | 10 | 6.821±0.467 | 1.803±0.371 |
| 7 | Aescinate B+tryptophan | 10 | 6.923±0.633 | 1.801±0.225 |
| 8 | Aescinate B+glutamic acid | 10 | 6.845±0.612 | 1.826±0.345 |
| 9 | Aescinate B (positive control) | 10 | 8.668±0.862 | 2.955±0.342 |
| 10 | Physiological saline (blank control) | 10 | 6.821±0.768 | 1.742±0.237 |
It can be seen that the 1st~8 group of every biochemical indicator and liver, Kidney coefficients from the test result of table 3 and table 4
Without significant difference compared with physiological saline group, pathology section examination is substantially similar to physiological saline group, has no that liver and kidney cells have
Denaturation, necrosis and obvious pathological abnormalities；The 9th group of serious liver kidney enlargement of appearance, every biochemical indicator significantly increase, pathological section table
It is bright to have the pathological changes such as severe haemorrhage, denaturation, necrosis.The above result shows that: amino acid can significantly reduce the liver of Aescinate B
Renal toxicity.
Claims (6)
1. a kind of Aescinate B injection, it is characterised in that: containing Aescinate B and tyrosine, the Aescinate B and junket
The weight ratio of propylhomoserin is 15: 1.
2. Aescinate B injection as described in claim 1, it is characterised in that: also containing auxiliary acceptable on medicament at
Point.
3. Aescinate B injection as claimed in claim 2, it is characterised in that: the injection is freeze-dried powder, described auxiliary
Furtherance is divided into pH adjusting agent and mannitol.
4. a kind of method for preparing Aescinate B injection described in claim 3, it is characterised in that the following steps are included:
1) Aescinate B, tyrosine, mannitol are dissolved in water for injection and mixed solution, mannitol in the mixed solution is made
Concentration be 10~20g/100ml, the concentration of Aescinate B is 0.5~2g/100ml；
It 2) is 4.5~6.5 with the pH value that pH adjusting agent adjusts mixed solution；
3) by the solution filter membrane or filter element filtering after adjusting pH value；
4) after filling freeze-drying to get.
5. the preparation method of Aescinate B injection as claimed in claim 4, it is characterised in that: the pH adjusting agent is lactic acid.
6. the preparation method of Aescinate B injection as claimed in claim 5, it is characterised in that: the freeze-drying includes pre-
Freeze, once distillation and re-dry three phases, the operating procedure in each stage are as follows:
Pre-freeze: being first rapidly decreased to -25~-20 DEG C for temperature of charge, is kept for 0.5~1 hour, then again slowly drops temperature of charge
To -40~-35 DEG C, 2~5 hours are kept the temperature；
Primary distillation: control vacuum degree is in 20 pas hereinafter, temperature of charge is increased to -15~-5 DEG C and keeps the temperature 3~5 hours；
Re-dry: temperature of charge is raised to 30~40 DEG C, keeps the temperature 10~15 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1931176A (en) * | 2005-07-15 | 2007-03-21 | 武汉爱民制药有限公司 | Aescin medicine composition and its prepn process and use |
| CN101134042A (en) * | 2005-07-15 | 2008-03-05 | 武汉爱民制药有限公司 | Notoginsenoside pharmaceutical composition and method for preparing the same and use thereof |
| CN102755297A (en) * | 2011-04-29 | 2012-10-31 | 天津药物研究院 | Escin B freeze-dried powder injection and preparation method and application thereof |
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| CN100357312C (en) * | 2005-07-15 | 2007-12-26 | 武汉爱民制药有限公司 | Lysine aescin saponin, its preparation and use |
| CN104873469B (en) * | 2015-06-04 | 2017-08-25 | 武汉爱民制药股份有限公司 | A kind of preparation method of aescin for injection freeze-dried emulsion |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1931176A (en) * | 2005-07-15 | 2007-03-21 | 武汉爱民制药有限公司 | Aescin medicine composition and its prepn process and use |
| CN101134042A (en) * | 2005-07-15 | 2008-03-05 | 武汉爱民制药有限公司 | Notoginsenoside pharmaceutical composition and method for preparing the same and use thereof |
| CN102755297A (en) * | 2011-04-29 | 2012-10-31 | 天津药物研究院 | Escin B freeze-dried powder injection and preparation method and application thereof |
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