CN108606955B - Medicinal composition of cultivated hippocampus japonicus peptide and preparation method thereof - Google Patents
Medicinal composition of cultivated hippocampus japonicus peptide and preparation method thereof Download PDFInfo
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 65
- 239000000203 mixture Substances 0.000 title claims abstract description 14
- 241001478425 Hippocampus japonicus Species 0.000 title claims description 11
- 210000001320 hippocampus Anatomy 0.000 claims abstract description 29
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 29
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 229940124531 pharmaceutical excipient Drugs 0.000 claims abstract 2
- 238000001035 drying Methods 0.000 claims description 43
- 238000004108 freeze drying Methods 0.000 claims description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 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 20
- 229930195725 Mannitol Natural products 0.000 claims description 20
- 239000000594 mannitol Substances 0.000 claims description 20
- 235000010355 mannitol Nutrition 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 13
- 239000008101 lactose Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 238000004321 preservation Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 238000005303 weighing Methods 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 9
- 208000007502 anemia Diseases 0.000 claims description 9
- 239000010452 phosphate Substances 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical group OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- 238000007710 freezing Methods 0.000 claims description 5
- 230000008014 freezing Effects 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 230000002950 deficient Effects 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims description 4
- 208000014951 hematologic disease Diseases 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 208000032467 Aplastic anaemia Diseases 0.000 claims description 3
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 3
- 206010058116 Nephrogenic anaemia Diseases 0.000 claims description 3
- 208000037581 Persistent Infection Diseases 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 3
- 208000037976 chronic inflammation Diseases 0.000 claims description 3
- 230000006020 chronic inflammation Effects 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 208000034737 hemoglobinopathy Diseases 0.000 claims description 3
- 208000007056 sickle cell anemia Diseases 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 208000005980 beta thalassemia Diseases 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000010437 erythropoiesis Effects 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000008215 water for injection Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 9
- 230000000971 hippocampal effect Effects 0.000 claims 5
- 241000517325 Pediculus Species 0.000 claims 2
- IUKLSMSEHKDIIP-BZMYINFQSA-N Verticine Chemical compound C([C@@H]1[C@@H](O)C[C@H]2[C@@H]3CC[C@@H]4[C@]5(C)O)[C@@H](O)CC[C@]1(C)[C@H]2C[C@H]3[C@@H]4CN1[C@H]5CC[C@H](C)C1 IUKLSMSEHKDIIP-BZMYINFQSA-N 0.000 claims 2
- 238000011534 incubation Methods 0.000 claims 2
- 238000012792 lyophilization process Methods 0.000 claims 2
- IUKLSMSEHKDIIP-UHFFFAOYSA-N petine Natural products CC1(O)C2CCC3C4CC(O)C5CC(O)CCC5(C)C4CC3C2CN2C1CCC(C)C2 IUKLSMSEHKDIIP-UHFFFAOYSA-N 0.000 claims 2
- 206010002068 Anaemia neonatal Diseases 0.000 claims 1
- 208000019838 Blood disease Diseases 0.000 claims 1
- 201000000975 anemia of prematurity Diseases 0.000 claims 1
- 239000001963 growth medium Substances 0.000 claims 1
- 208000018706 hematopoietic system disease Diseases 0.000 claims 1
- 239000003381 stabilizer Substances 0.000 abstract description 3
- 239000008194 pharmaceutical composition Substances 0.000 abstract 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000002994 raw material Substances 0.000 description 18
- 239000002033 PVDF binder Substances 0.000 description 10
- 239000002510 pyrogen Substances 0.000 description 10
- 239000008227 sterile water for injection Substances 0.000 description 10
- 229940079593 drug Drugs 0.000 description 9
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 9
- 235000019799 monosodium phosphate Nutrition 0.000 description 9
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 9
- 239000011521 glass Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 210000003743 erythrocyte Anatomy 0.000 description 6
- 239000001632 sodium acetate Substances 0.000 description 6
- 235000017281 sodium acetate Nutrition 0.000 description 6
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 4
- 229960001380 cimetidine Drugs 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 3
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 3
- 229930064664 L-arginine Natural products 0.000 description 3
- 235000014852 L-arginine Nutrition 0.000 description 3
- 201000011152 Pemphigus Diseases 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 201000001976 pemphigus vulgaris Diseases 0.000 description 3
- 229920001993 poloxamer 188 Polymers 0.000 description 3
- 229940044519 poloxamer 188 Drugs 0.000 description 3
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 3
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 102100031939 Erythropoietin Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000244268 Peucedanum japonicum Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- HQMLIDZJXVVKCW-UHFFFAOYSA-N 2-aminopropanamide Chemical compound CC(N)C(N)=O HQMLIDZJXVVKCW-UHFFFAOYSA-N 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 102000003951 Erythropoietin Human genes 0.000 description 1
- 108090000394 Erythropoietin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 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
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 206010034277 Pemphigoid Diseases 0.000 description 1
- 241000721454 Pemphigus Species 0.000 description 1
- 208000018020 Sickle cell-beta-thalassemia disease syndrome Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043391 Thalassaemia beta Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000000337 buffer salt Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003013 erythroid precursor cell Anatomy 0.000 description 1
- 229940105423 erythropoietin Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- 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
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a pharmaceutical composition of Pedized hippocampus peptide and a preparation method thereof, and particularly relates to a pharmaceutical composition taking Pedized hippocampus peptide as an active ingredient, which comprises the active ingredient and pharmaceutically acceptable pharmaceutical excipients, wherein the excipients are selected from excipients and pH regulators, and optionally comprise isotonic regulators. The medicinal composition provided by the invention does not need to add a stabilizer, and has better stability than the existing preparation.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a preparation of a Pedized Simima peptide preparation and a preparation method of the preparation.
Background
The chemical structure of the cultivated hippocampus peptide is as follows:
chinese culture name: n, N-bis { 2' -acetyl [ epsilon "-amino- (acetyl-glycyl-L-threonyl-L-conosyl-L-seryl-L-cysteinyl-L-histidyl-L-phenylalanyl-glycyl-L-alanyl-L-leucyl-L-threonyl-L-tryptophanyl-L-valyl-L-cysteinyl-L-arginyl-L-prolyl-L-glutaminyl-L-arginyl-glycyl-beta-alanyl-L-lysyl ring 6 → 15 disulfide) ] } -3-polyethylene glycol aminopropionamide.
The cultivated western hippocampus peptide is an erythropoietin mimetic peptide derivative modified by polyethylene glycol, wherein EPO acts on bone marrow hematopoietic cells, stimulates mitosis and differentiation of erythrocyte precursor cells, promotes proliferation and differentiation of erythroid stem cells, and finally matures into endocrine hormone. Since EPO, which is essential in the process of red blood cell formation, promotes the proliferation of red blood cells, increases the total amount of hemoglobin (Hb) in the body, and improves the oxygen-carrying capacity of the body, it has been widely used in the diagnosis and treatment of blood diseases in which the formation of red blood cells is insufficient or the production of red blood cells is deficient. In addition, it can be used for autologous blood transfusion before surgery and recovery of anemia after surgery, myelodysplastic syndrome anemia, hemoglobinopathy sickle cell anemia and beta-thalassemia, premature infant anemia, anemia due to chronic inflammation or infection, spinal cord injury, renal anemia, aplastic anemia, etc.
The cultivated hippocampus japonicus peptide is easy to degrade under the conditions of illumination, high humidity and oxidation, and is easy to degrade under the conditions of peracid and over-alkali, and the problems are beset on the application of the cultivated hippocampus japonicus peptide in pharmacy. Patent CN 201210245744.0 discloses a Pedized hippocampus peptide injection prepared by taking poloxamer 188, L-arginine, mannitol, potassium dihydrogen phosphate and the like as auxiliary materials, but the preparation contains a plurality of components and is not suitable for injection application, so that the field urgently needs a Pedized hippocampus peptide injection preparation with simple prescription and good stability.
Disclosure of Invention
The invention aims to provide a preparation of the bacitracin which has simple components and good stability and is applied to medicaments well.
In order to achieve the purpose, the invention adopts the following scheme:
a preparation of Peucedanum japonicum comprises an active ingredient and an auxiliary material, wherein the active ingredient is Peucedanum japonicum, and the auxiliary material comprises an excipient and a pH regulator.
According to the preparation of the pemphigus peptide, the excipient is selected from one or more of mannitol, lactose, sorbitol, xylitol, glucose or dextran, or is selected from one or two of mannitol or lactose.
The pemphigoid preparation according to the present invention, the pH adjusting agent is selected from acetic acid, hydrochloric acid, citric acid, phosphoric acid, tartaric acid, citric acid, glutamic acid, histidine, sodium hydroxide and/or buffer salts thereof, such as acetic acid/acetate, phosphate or phosphate/alkali metal hydroxide, the phosphate is further selected from dihydrogen phosphate, and alkali metal is selected from lithium, sodium or potassium. For example, one or more of acetic acid/acetate, dihydrogen phosphate or alkali metal hydroxide, further for example, one or more of acetic acid/sodium acetate, dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydroxide or potassium hydroxide.
According to the preparation of the Pachylomycete, the isoosmotic adjusting agent is selected from sodium chloride, glycerol or polyethylene glycol.
According to the cultured hippocampus japonicus peptide preparation, the final product of the cultured hippocampus japonicus peptide preparation is a freeze-dried preparation, the moisture of the freeze-dried preparation is less than or equal to 3%, or 0.5-3%, and further 0.8-2.5%, and other non-terminal processes such as preparation process, filling and the like are not included.
According to the preparation method of the cultured hippocampus japonicus peptide preparation, the pH value of the cultured hippocampus peptide preparation is adjusted to be within the range of 3.0-7.0 or within the range of 5.0-7.0 by the pH adjusting agent in the preparation process.
According to the cultured hippocampus japonicus peptide preparation, the weight ratio of the cultured hippocampus japonicus peptide to the excipient is 1: 2-20, or can be 1: 2.5-10, or can be 1: 2.5-5.
According to the preparation of the pemphigus vulgaris peptide, the preparation is a freeze-dried preparation, and the moisture of the freeze-dried preparation is 0.8% -2.5%. The method comprises the steps of adjusting the pH to 5.0-7.0 by using a pH regulator, wherein the pH regulator is one or more of acetic acid, sodium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium hydroxide, the weight ratio of the cultivated hippocampus peptide to an excipient is 1:2.5, or 1:3.75, or 1:5, or 1:10, and the excipient is mannitol or lactose.
The preparation of the pilified cimetidine is a freeze-dried preparation, the moisture of the freeze-dried preparation is less than or equal to 3%, the preparation comprises the pilified cimetidine, an excipient and a pH regulator, the pH regulator is used for regulating the pH to 3.0-7.0, preferably 5.0-7.0, the pH regulator is acetic acid/acetate, phosphate or phosphate/alkali metal hydroxide, the phosphate is further selected from dihydrogen phosphate and dihydrogen phosphate, the alkali metal hydroxide is selected from sodium hydroxide and potassium hydroxide, and the weight percentage of the pilified cimetidine and the excipient is as follows:
cultivating the Xihaima peptide: 5 to 35 percent
Excipient: 65 to 95 percent.
According to the preparation of the pemphigus vulgaris peptide, the preparation is a freeze-dried preparation, and the moisture of the freeze-dried preparation is 0.8% -2.5%. The composition comprises the cultured hippocampus japonicus peptide, mannitol and a pH regulator, wherein the pH regulator is used for regulating the pH to 5.0-7.0, the pH regulator is one or more of acetic acid, sodium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium hydroxide, and the cultured hippocampus peptide and an excipient are as follows in percentage by weight:
cultivating the Xihaima peptide: 15 to 30 percent
Mannitol: 70 to 85 percent.
According to the preparation of the pemphigus vulgaris peptide, the preparation is a freeze-dried preparation, and the moisture of the freeze-dried preparation is 0.8% -2.5%. The composition comprises the cultured hippocampus peptide, lactose and a pH regulator, wherein the pH is regulated to 5.0-7.0 by the pH regulator, the pH regulator is one or more of acetic acid, sodium acetate, sodium dihydrogen phosphate, disodium hydrogen phosphate and sodium hydroxide, and the weight percentage of the cultured hippocampus peptide and an excipient is as follows:
cultivating the Xihaima peptide: 15 to 30 percent
Lactose: 70 to 85 percent.
The second purpose of the invention is to provide a preparation method of a peiminate hippocampus peptide preparation. The technical scheme is as follows:
A) weighing a prescription amount of excipient, dissolving the excipient in water for injection, adding an active component to culture the Xihaima peptide, and dissolving and uniformly mixing;
B) using pH regulator to regulate the volume;
C) filtering, filling, and freeze drying to obtain the final product.
Specifically, the method comprises the following steps:
A) weighing excipient according to the formula, dissolving in sterile water for injection, ultrafiltering to remove pyrogen, adding active components according to the formula, dissolving, and mixing;
B) adjusting the pH to 3-7, preferably 5-7, by using a pH regulator, and fixing the volume to a specified volume;
C) filtering with PVDF, packaging, freeze drying under aseptic condition, pre-freezing at-30 deg.C to-70 deg.C for 2-5 hr, and freeze vacuum drying; drying at 0-10 deg.C for 10-30 hr for the first time, drying at 25-35 deg.C for 2-15 hr for the second time, and drying at 30-35 deg.C for 2-10 hr at the stage of heat preservation to make the water content of lyophilized product less than or equal to 3% to obtain the final product.
According to the preparation process of the culture cimetidine, the freeze-drying process of freeze drying is that pre-freezing is carried out for 2-5 hours at-30 ℃ to-50 ℃, primary drying is carried out for 10-30 hours at 0 ℃ to 10 ℃, secondary drying is carried out for 5-15 hours at 25 ℃ to 35 ℃, and drying is carried out for 2-10 hours at 30 ℃ to 35 ℃ in a heat preservation stage.
According to the preparation process of the culture Simima peptide, the freeze drying is performed for 3-5 hours at the temperature of minus 30 ℃ to minus 40 ℃, the primary drying time is performed for 15-25 hours at the temperature of 5 +/-2 ℃, the secondary drying is performed for 10-15 hours at the temperature of 25 +/-2 ℃, and the drying is performed for 5-8 hours at the temperature of 30 +/-2 ℃ in the heat preservation stage.
The research of the invention finds that mannitol or lactose is determined to be used as an excipient through prescription screening, the stability of the preparation of the Pezima Pezidanum can be greatly improved through further optimization without adding a stabilizer, and the drug effect period is greatly prolonged under the same condition.
The invention also relates to a preparation method of the Pachylomycete preparation, and application of the Pachylomycete preparation in preparing medicines for treating blood diseases with insufficient erythropoiesis or deficient erythrocyte production, such as myelodysplastic syndrome anemia, sickle cell anemia of hemoglobinopathy and beta-thalassemia, anemia of premature infants, anemia caused by chronic inflammation or infection, spinal cord injury, renal anemia or aplastic anemia.
Detailed Description
Example 1:
weighing lactose 15g, dissolving in sterile water for injection, ultrafiltering to remove pyrogen, adding raw materials 4g according to the formula, dissolving, mixing, adjusting pH to 4.0 with acetic acid and sodium acetate, diluting to 1000ml, filtering with 0.22 micrometer PVDF, bottling 4mg raw materials in each bottle, freeze drying under sterile condition,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; the primary drying time is 20 hours at 5 ℃, the secondary drying time is 10 hours at 25 ℃, and the heat preservation stage is 5 hours at 30 ℃.
Example 2:
weighing 10g of lactose, dissolving the lactose in sterile water for injection, ultrafiltering to remove pyrogen, adding 4g of the raw material medicines according to the formula, dissolving and mixing uniformly, adjusting the pH value to 5.0 by using acetic acid and sodium acetate, fixing the volume to 1000ml, filtering by PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of the raw material medicines in each bottle into glass bottles, freeze-drying under the sterile condition,
freeze-drying at-40 deg.C for 5 hr, and freeze-drying; the primary drying time is 25 hours at 5 ℃, the secondary drying time is 10 hours at 25 ℃, and the heat preservation stage is 5 hours at 30 ℃.
Example 3:
weighing lactose 15g, dissolving in sterile water for injection, ultrafiltering to remove pyrogen, adding 4mg of raw materials according to the formula, dissolving, mixing, adjusting pH to 5.0 with sodium dihydrogen phosphate and sodium hydroxide, diluting to 1000ml, filtering with 0.22 micrometer PVDF, bottling 4mg of raw materials in each bottle, freeze drying under sterile condition,
freeze-drying at-36 deg.C for 3 hr, and freeze-drying; drying at 5 deg.C for 20 hr for the first time, drying at 25 deg.C for 10 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 4:
weighing 15g of mannitol, dissolving the mannitol in sterile water for injection, ultrafiltering to remove pyrogen, adding 4mg of raw material medicine according to a formula, dissolving and uniformly mixing, adjusting the pH value to 5.0 by using sodium dihydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of raw material medicine in each bottle into glass bottles, freeze-drying under the sterile condition,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; drying at 5 deg.C for 20 hr for the first time, drying at 25 deg.C for 10 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 5:
weighing 15g of mannitol, dissolving the mannitol in sterile water for injection, ultrafiltering to remove pyrogen, adding 20g of raw material medicine according to a formula, dissolving and uniformly mixing, adjusting the pH value to 6.0 by using sodium dihydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by using PVDF (polyvinylidene fluoride) with the diameter of 0.22 micron, subpackaging 4mg of raw material medicine in each bottle into a glass bottle, freeze-drying under the sterile condition,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; drying at 5 deg.C for 20 hr for the first time, drying at 25 deg.C for 15 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 6:
weighing 15g of lactose, dissolving the lactose in sterile water for injection, ultrafiltering to remove pyrogen, adding a certain amount of raw material medicines according to a formula, dissolving and uniformly mixing, adjusting the pH value to 7.0 by using disodium hydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by using PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of raw material medicines in each bottle into glass bottles, freeze-drying under sterile conditions,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; drying at 5 deg.C for 20 hr for the first time, drying at 25 deg.C for 10 hr for the second time, and drying at 30 deg.C for 7 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 7:
weighing 15g of mannitol, dissolving the mannitol in sterile water for injection, ultrafiltering to remove pyrogen, adding a certain amount of raw material medicines according to a formula, dissolving and uniformly mixing, adjusting the pH value to 5.0 by using sodium dihydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by using PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of raw material medicines in each bottle into a glass bottle, freeze-drying under the sterile condition,
freeze-drying at-20 deg.C for 5 hr, and freeze-drying; drying at-5 deg.C for 5 hr for the first time, drying at 35 deg.C for 10 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 8
Weighing 15g of mannitol, dissolving the mannitol in sterile water for injection, ultrafiltering to remove pyrogen, adding a certain amount of raw material medicines according to a formula, dissolving and uniformly mixing, adjusting the pH value to 5.0 by using sodium dihydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by using PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of raw material medicines in each bottle into a glass bottle, freeze-drying under the sterile condition,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; drying at 5 deg.C for 35 hr for the first time, drying at 25 deg.C for 20 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Example 9:
weighing 40g of mannitol, dissolving the mannitol in sterile water for injection, ultrafiltering to remove pyrogen, adding 4mg of raw material medicine according to a formula, dissolving and uniformly mixing, adjusting the pH value to 5.0 by using sodium dihydrogen phosphate and sodium hydroxide, fixing the volume to 1000ml, filtering by PVDF (polyvinylidene fluoride) of 0.22 micron, subpackaging 4mg of raw material medicine in each bottle into glass bottles, freeze-drying under the sterile condition,
freeze-drying at-36 deg.C for 5 hr, and freeze-drying; drying at 5 deg.C for 20 hr for the first time, drying at 25 deg.C for 10 hr for the second time, and drying at 30 deg.C for 5 hr for the heat preservation stage to obtain injectable Hippocampus Pekinensis peptide.
Comparative example 1
The preparation of a peidide cimetide peptide injection according to the method of example 1 of patent CN 103536900:
8g of Pezima peptide
Poloxamer 188, 15g
L-arginine, 15g
Mannitol, 42g
20g of monopotassium phosphate.
Comparative example 2
Removing stabilizer L-arginine, and preparing a Pedized Xihaima peptide injection according to the method of patent CN103536900 example 1:
8g of Pezima peptide
Poloxamer 188, 20g
Mannitol, 50g
20g of monopotassium phosphate.
Claims (14)
1. A Pediculus hippocampus peptide preparation comprises an active ingredient and pharmaceutically acceptable pharmaceutical excipients, wherein the active ingredient is Pediculus hippocampus peptide, the excipients are selected from excipient and pH regulator, the excipient is selected from one or two of mannitol or lactose, the pH regulator is selected from acetic acid/acetate, phosphate or phosphate/alkali metal hydroxide, the phosphate is selected from dihydrogen phosphate and dihydrogen phosphate, and the alkali metal is selected from lithium, sodium or potassium, and the preparation optionally comprises an isotonic regulator; the preparation method comprises the following steps of (1) preparing a culture hippocampus japonicus peptide preparation, wherein the water content of the culture hippocampus peptide preparation is less than or equal to 3%, the pH value of the culture hippocampus peptide preparation is 3.0-7.0, and the weight ratio of the culture hippocampus peptide to an excipient is 1: 2-20; in the method for preparing the peiminized hippocampus peptide preparation, the freeze-drying process of freeze drying is that pre-freezing is carried out for 2-5 hours at the temperature of minus 30 ℃ to minus 70 ℃, primary drying is carried out for 10-30 hours at the temperature of 0 ℃ to 10 ℃, secondary drying is carried out for 2-15 hours at the temperature of 25 ℃ to 35 ℃, and drying is carried out for 2-10 hours at the temperature of 30 ℃ to 35 ℃ in a heat preservation stage.
2. The peidized hippocampal peptide formulation of claim 1, wherein the isotonicity adjusting agent is selected from sodium chloride, glycerol, or polyethylene glycol.
3. The peichthey japonicus peptide preparation as claimed in claim 1, wherein the water content of the lyophilized preparation is 0.5-3%.
4. The peichthey japonicus peptide preparation as claimed in claim 1, wherein the water content of the lyophilized preparation is 0.8-2.5%.
5. The hippocampal peptide formulation of claim 1, wherein the pH of said formulation is 5.0-7.0.
6. The peichimde hippocampus peptide formulation of claim 1, wherein the weight ratio of the peichimde hippocampus peptide to the excipient is 1: 2.5-10.
7. The peichimde hippocampus peptide formulation of claim 6, wherein the weight ratio of the peichimde hippocampus peptide to the excipient is 1: 2.5-5.
8. The peichimde hippocampal peptide formulation of claim 1, wherein the weight percentage of the peichimde hippocampi peptide to excipient is:
cultivating the Xihaima peptide: 5 to 35 percent
Excipient: 65 to 95 percent.
9. The peichimde hippocampal peptide formulation of claim 1, wherein the weight percentage of the peichimde hippocampi peptide to excipient is:
cultivating the Xihaima peptide: 15 to 30 percent
Excipient: 70 to 85 percent.
10. A method of preparing the pezidohippocampus peptide formulation of claim 1, comprising the steps of:
A) weighing excipient with prescription amount, dissolving in water for injection, adding active component to culture Simima peptide,
dissolving and uniformly mixing;
B) adjusting the pH value by using a pH regulator, and fixing the volume;
C) filtering, filling, and freeze drying to obtain the final product.
11. The method of claim 10, wherein the lyophilization process of the culture medium comprises pre-freezing at-30 ℃ to-50 ℃ for 2-5 hours, drying at 0 ℃ to 10 ℃ for 10-30 hours for the first time, drying at 25 ℃ to 35 ℃ for 5-15 hours for the second time, and drying at 30 ℃ to 35 ℃ for 2-10 hours for the incubation period.
12. The method for preparing a hippocampal peptide formulation of claim 10, wherein the lyophilization process of the freeze-drying comprises pre-freezing at-30 ℃ to-40 ℃ for 3-5 hours, drying at 5 ± 2 ℃ for 15-25 hours for the first time, drying at 25 ± 2 ℃ for 10-15 hours for the second time, and drying at 30 ± 2 ℃ for 5-8 hours for the incubation period.
13. Use of a peimine peptide preparation according to any one of claims 1 to 9 or a peimine peptide preparation prepared by the method according to any one of claims 10 to 12 for the preparation of a medicament for the treatment of a hematological disorder in which erythropoiesis is deficient or defective.
14. The use according to claim 13, wherein the blood disorder is selected from myelodysplastic syndrome anemia, sickle cell anemia of hemoglobinopathy and β -thalassemia, anemia of prematurity, anemia arising from chronic inflammation or infection, spinal cord injury, renal anemia, or aplastic anemia.
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