CN108659104A - A kind of preparation method and its pharmaceutical composition of terlipressin - Google Patents
A kind of preparation method and its pharmaceutical composition of terlipressin Download PDFInfo
- Publication number
- CN108659104A CN108659104A CN201810707079.XA CN201810707079A CN108659104A CN 108659104 A CN108659104 A CN 108659104A CN 201810707079 A CN201810707079 A CN 201810707079A CN 108659104 A CN108659104 A CN 108659104A
- Authority
- CN
- China
- Prior art keywords
- terlipressin
- acetic acid
- preparation
- solution
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108010010056 Terlipressin Proteins 0.000 title claims abstract description 96
- 229960003813 terlipressin Drugs 0.000 title claims abstract description 96
- BENFXAYNYRLAIU-QSVFAHTRSA-N terlipressin Chemical group NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)CN)CSSC1 BENFXAYNYRLAIU-QSVFAHTRSA-N 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000004108 freeze drying Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 17
- 239000000843 powder Substances 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 92
- 239000000243 solution Substances 0.000 claims description 73
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 229960000583 acetic acid Drugs 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 24
- 239000007788 liquid Substances 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 20
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 19
- 239000007974 sodium acetate buffer Substances 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003480 eluent Substances 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 13
- 229930195725 Mannitol Natural products 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 13
- 239000000594 mannitol Substances 0.000 claims description 13
- 235000010355 mannitol Nutrition 0.000 claims description 13
- 239000001509 sodium citrate Substances 0.000 claims description 13
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 239000008215 water for injection Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 10
- 239000005695 Ammonium acetate Substances 0.000 claims description 10
- 230000005526 G1 to G0 transition Effects 0.000 claims description 10
- 229940043376 ammonium acetate Drugs 0.000 claims description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims description 10
- 238000011068 loading method Methods 0.000 claims description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 9
- 239000001632 sodium acetate Substances 0.000 claims description 9
- 235000017281 sodium acetate Nutrition 0.000 claims description 9
- 229940038773 trisodium citrate Drugs 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000010790 dilution Methods 0.000 claims description 6
- 239000012895 dilution Substances 0.000 claims description 6
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 6
- 150000001343 alkyl silanes Chemical group 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 5
- 239000000499 gel Substances 0.000 claims description 5
- 238000005374 membrane filtration Methods 0.000 claims description 5
- 239000008363 phosphate buffer Substances 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 2
- 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 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims 1
- 239000000872 buffer Substances 0.000 claims 1
- 239000011574 phosphorus Substances 0.000 claims 1
- 229910052698 phosphorus Inorganic materials 0.000 claims 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 239000007924 injection Substances 0.000 abstract description 20
- 238000002347 injection Methods 0.000 abstract description 20
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000007791 liquid phase Substances 0.000 abstract 1
- 238000012360 testing method Methods 0.000 description 16
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000007853 buffer solution Substances 0.000 description 12
- 235000019263 trisodium citrate Nutrition 0.000 description 11
- 239000004471 Glycine Substances 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 239000012982 microporous membrane Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 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 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 3
- 239000003643 water by type Substances 0.000 description 3
- BJFIDCADFRDPIO-DZCXQCEKSA-N (2S)-N-[(2S)-6-amino-1-[(2-amino-2-oxoethyl)amino]-1-oxohexan-2-yl]-1-[[(4R,7S,10S,13S,16S,19R)-19-amino-7-(2-amino-2-oxoethyl)-10-(3-amino-3-oxopropyl)-16-[(4-hydroxyphenyl)methyl]-6,9,12,15,18-pentaoxo-13-(phenylmethyl)-1,2-dithia-5,8,11,14,17-pentazacycloeicos-4-yl]-oxomethyl]-2-pyrrolidinecarboxamide Chemical compound NCCCC[C@@H](C(=O)NCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H]1NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](N)CSSC1 BJFIDCADFRDPIO-DZCXQCEKSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010048179 Lypressin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 239000000356 contaminant Substances 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- CBMPTFJVXNIWHP-UHFFFAOYSA-L disodium;hydrogen phosphate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].OP([O-])([O-])=O.OC(=O)CC(O)(C(O)=O)CC(O)=O CBMPTFJVXNIWHP-UHFFFAOYSA-L 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 2
- 201000011200 hepatorenal syndrome Diseases 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229960003837 lypressin Drugs 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000007981 phosphate-citrate buffer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 2
- 230000009278 visceral effect Effects 0.000 description 2
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 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 description 1
- 102000004400 Aminopeptidases Human genes 0.000 description 1
- 108090000915 Aminopeptidases Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010030210 Oesophageal varices haemorrhage Diseases 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 102400000800 Thymosin alpha-1 Human genes 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 231100000836 acute liver failure Toxicity 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012537 formulation buffer Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940072644 pitressin Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- -1 sorbierite Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000012905 visible particle Substances 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/16—Oxytocins; Vasopressins; Related peptides
-
- 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
- A61K47/26—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
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to biomedicine technical fields, and in particular to a kind of preparation method and its pharmaceutical composition of terlipressin；The preparation method obtains terlipressin using the different preparation liquid phase of two steps；Operation is simple for purifying terlipressin method provided by the invention, and the terlipressin purity of acquisition is up to 99.7% or more, yield up to 60% or more.Freeze drying powder injection dissolubility made from composition of the present invention is good, stability is good, solubility is good；The freeze drying powder injection made from the composition is easy to use, is conducive to storing, preparation method is simple, is easy to industrialized production, and production cost is low.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to the preparation method of terlipressin and pressurize containing special profit
The pharmaceutical composition of element.
Background technology
Terlipressin (Terlipressin, also known as acetic acid thymosin α1), the entitled N- α-three glycyl -8- of chemistry rely ammonia
Acid-pitressin, structural formula is as follows, molecular formula C52H74N16O15S2, relative molecular mass 1227.37 is white powder.
Terlipressin is a kind of novel artificial synthesized long-acting vasopressing preparation, belongs to a kind of pro-drug,
Itself is inactive, is acted in vivo through aminopeptidase, and after 3 glycinyl residues for sloughing its N-terminal, slow " release " goes out to have work
The lypressin of property.Exactly this " slow release " mechanism, makes it smooth muscle contraction can be maintained to be up to after single administration
10 hours, and the same dose of vasopressings, activity can only maintain 20-40 minutes.On the other hand since enzymolysis speed is slow
Slowly, toxic level is not achieved in the lypressin in cycle, and therefore, the use of terlipressin is safer.
The pharmacological action of terlipressin is to shrink visceral vessel smooth muscle, reduction visceral blood flow (such as reduction mesenterium,
The blood flow in spleen, uterus etc.), to reduce portal venous flow, reduce portal venous pressure, on the other hand it is dense can also to reduce plasma renin for it
The effect of degree improves renal function, increases urine volume to increase the renal blood flow of patients with hepatorenal syndrome.Terlipressin is mesh
The preceding only drug that can improve esophageal varices hemorrhage survival is mainly used for treating variceal bleeding,
Existing clinic is widely used in hepatorenal syndrome, cirrhotic ascites, infectious shock, burn, acute liver failure, heart arrest etc.
Treatment.Compared with vasopressing, its persistent does not cause dangerous complication, including promotees fibrinolysis and the heart
Severe complication in terms of vascular system, and application method is simple (can use intravenous injection), more suitable for suffering to Severe acute disease
The rescue and treatment of person.
Terlipressin is a kind of polypeptide, and degradation, and system at present are easy under acid, alkali, illumination, oxidation, hot conditions
The purity and yield of the standby terlipressin obtained are all relatively low, cannot meet the needs of industrialized production, can not especially advise greatly
Mould purifies terlipressin, constrains the application of terlipressin.Therefore it provides a kind of method of purifying terlipressin has
Significance.
Invention content
For solve it is above-mentioned the problems of in the prior art, We conducted a large amount of experimental explorations, find a kind of new
Terlipressin purification process, the Terlipressin purity higher that the present invention obtains.The present invention another
It is designed to provide a kind of Terlipressin pharmaceutical composition and preparation method thereof, the preparation which obtains has
More excellent product quality.
What the present invention was achieved through the following technical solutions：
A kind of preparation method of terlipressin, preparation method include the following steps：
Step 1 dissolves Terlipressin crude product with the aqueous acetic acid of mass concentration 1~5%, and filter is collected by filtration
Liquid, then with water by the acetic acid dilution proportion in terlipressin crude product solution to 0.5% or less mass concentration；
Step 2, using octadecylsilane as stationary phase, after step 1 gained terlipressin crude product solution loading, to contain matter
The phosphate buffer for measuring a concentration of 35~45% methanol is A phases, with mass concentration be 80~95% methanol aqueous solutions is B phases,
Linear gradient elution collects characteristic peak eluent and eluent membrane filtration is concentrated into 25 DEG C of relative density 1.05-1.08；
Step 3, using eight alkyl silane bonded silica gels as stationary phase, after step 2 gained concentrate loading, first use mass concentration
80% methanol aqueous solution for 0.5~1.6% ammonium acetate rinses 30~45min, and it is 0.05~0.1% then to use mass concentration
Ammonium acetate the elution of 70% acetonitrile solution, collect characteristic peak eluent, be concentrated and dried up to Terlipressin.
The step 1 is per 100g Te Lijia with the aqueous acetic acid dissolving terlipressin crude product of mass concentration 1~5%
The aqueous acetic acid of 1L mass concentrations 1~5% is added in the plain crude product of pressure.
The pH value of phosphate buffer in the step 2 is 5.0~7.0.
4, a kind of pharmaceutical composition containing terlipressin, including Terlipressin, excipient, sodium acetate, ice
Acetic acid, feature is in the mixture that the excipient is dextrosan, mannitol, trisodium citrate composition.
The composition includes the ingredient of following parts by weight：0.8~1 parts by weight acetic acid terlipressin, 30~50 weight
Part excipient, sodium acetate, glacial acetic acid.
Dextrosan is to be spray-dried poly- dextrosan in the excipient.
Dextrosan in the excipient：Mannitol：The weight ratio of trisodium citrate is (3~5)：1：(0.1~0.3).
The pH value of the composition is 4.5~6.0.
A method of the pharmaceutical composition containing terlipressin prepares freeze-dried powder, and this approach includes the following steps：
1) it takes excipient to be dissolved in the water for injection of 2/3 recipe quantity, stirs evenly；
2) glacial acetic acid and sodium acetate is used to configure Acetic acid-sodium acetate buffer solution, it is spare；
3) it waits for that above-mentioned preparation liquid is cooled to room temperature, Terlipressin is added, survey pH value, buffered with Acetic acid-sodium acetate
Liquid adjusts pH to 4.5~6.0, water for injection is added to full dose, with 0.22 μm of miillpore filter refined filtration, freeze-drying obtains freeze-dried powder.
Compared with the prior art, the present invention has the following advantages and good effect：
1, operation is simple for purifying terlipressin method provided by the invention, and the terlipressin purity of acquisition is reachable
99.7% or more, yield is up to 60% or more.
2, the freeze drying powder injection made from the composition has good stability, and solubility is good；It is lyophilized made from the composition
Powder-injection is easy to use, is conducive to storing, preparation method is simple, is easy to industrialized production, and production cost is low.
Specific implementation mode
The following describes the present invention further through the description of specific embodiments, but this is not the limit to the present invention
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Terlipressin crude product is purchased from Shenzhen City Jianyuan Pharmaceutical Technology Co., Ltd, its HPLC purity is after testing
92.02%.
Acetic acid-sodium acetate buffer solution configuration method：According to formula pH=4.75+lg [C(NaAc)/C(HAc)](C(HAc)Refer to acetic acid
Concentration, C(NaAc)Refer to the concentration of sodium acetate) acetic acid and sodium acetate dosage are calculated, then by the sodium acetate weighed and glacial acetic acid
It is added in 1000mL water and dissolves, stirs evenly.For example, being pre-configured the buffer solution of pH=5.5, is then substituted into, can be obtained
C(NaAc)/C(HAc)=5.6.Such as C(HAc)=0.1mol/L, then C(NaAc)It is 82* that=0.56mol/L, which weighs sodium acetate solid masses,
0.56=46 grams, measurement glacial acetic acid volume is 0.1*1000/17.5=5.7mL.
Embodiment 1
Step 1：Terlipressin crude product 1000g is dissolved with the aqueous acetic acid 10L of mass concentration 5%, filtering is received
Collect filtrate, then with water by the acetic acid dilution proportion in crude product solution to mass concentration 0.45%；
Step 2：Using octadecylsilane as stationary phase, after step 1 gained crude product solution loading, it is to contain mass concentration
Disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution (pH6.9) of 35% methanol is A phases, with mass concentration for 60% methanol aqueous solution
For B phases, flow velocity 105ml/min elutes 350min, and gradient is 40%B → 70%B, collects purity and is eluted more than 95% or more
0.22 μm of membrane filtration of eluent is concentrated into 25 DEG C of relative density 1.05-1.08 by liquid；
Step 3：Using eight alkyl silane bonded silica gels as stationary phase, after step 2 acquired solution loading, it is with mass concentration first
80% methanol aqueous solution of 1% ammonium acetate rinses 45min, and it is 70% acetonitrile of 0.1% ammonium acetate then to use mass concentration
Aqueous solution elutes, and collects purity and is more than 99% or more eluent, is concentrated and dried, and obtains the special profit pressurization of acetic acid that purity is 99.93%
Plain 643.2g, purifying total recovery are 64.32%.
Embodiment 2
Step 1：Terlipressin peak crude product 100g is dissolved with the aqueous acetic acid 1000ml of mass concentration 3%, filtering is received
Collect filtrate, then with water by the acetic acid dilution proportion in crude product solution to mass concentration 0.45%；
Step 2：Using octadecylsilane as stationary phase, after step 1 gained crude product solution loading, it is to contain mass concentration
Disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution (pH5.5) of 40% methanol is A phases, with mass concentration for 90% methanol aqueous solution
For B phases, flow velocity 90ml/min elutes 40min, and gradient is 40%B → 70%B, collects purity and is more than 95% or more eluent,
By 0.22 μm of membrane filtration of eluent, it is concentrated into 25 DEG C of relative density 1.05-1.08；
Step 3：Using eight alkyl silane bonded silica gels as stationary phase, after step 2 acquired solution loading, it is with mass concentration first
80% methanol aqueous solution of 1.6% ammonium acetate rinses 30min, and it is 70% second of 0.05% ammonium acetate then to use mass concentration
Nitrile aqueous solution elutes, and collects purity and is more than 99% or more eluent, is concentrated and dried, and obtains the acetic acid Te Lijia that purity is 99.81%
It is 63.21% to press element 63.21g, purifying total recovery.
Embodiment 3
Step 1：Terlipressin crude product 50g is dissolved with the aqueous acetic acid 500ml of mass concentration 1%, filtering is received
Collect filtrate, then with water by the acetic acid dilution proportion in crude product solution to mass concentration 0.5%；
Step 2：Using octadecylsilane as stationary phase, after step 1 gained crude product solution loading, it is to contain mass concentration
Disodium hydrogen phosphate-phosphate sodium dihydrogen buffer solution (pH6.5) of 45% methanol is A phases, with mass concentration for 80% methanol aqueous solution
For B phases, flow velocity 75ml/min elutes 25min, and gradient is 40%B → 70%B, collects purity and is more than 95% or more eluent,
By 0.22 μm of membrane filtration of eluent, concentration；
Step 3：Using eight alkyl silane bonded silica gels as stationary phase, after step 2 acquired solution loading, it is with mass concentration first
80% methanol aqueous solution of 1.6% ammonium acetate rinses 30min, and it is 70% second of 0.05% ammonium acetate then to use mass concentration
Nitrile aqueous solution elutes, and collects purity and is more than 99% or more eluent, is concentrated and dried, and obtains the acetic acid Te Lijia that purity is 99.81%
It is 69.04% to press element 34.52g, purifying total recovery.
Above-described embodiment method is chromatography, Detection wavelength 220nm.
Test case 1：
Related substance takes this product appropriate, uses water that solution in every 1ml containing about 0.2mg is made as test solution；It is accurate
1ml is measured, sets in 100ml measuring bottles, is diluted with water to scale, shake up, as a contrast solution.Precision measures contrast solution 1ml, sets
In 50ml measuring bottles, it is diluted to scale with mobile phase, is shaken up, as sensitivity solution.According to the chromatographic condition under assay item, take
20 μ l of sensitivity solution inject liquid chromatograph, and the signal-to-noise ratio at terlipressin peak should be greater than 10.Precision measures test solution
With each 20 μ l of contrast solution, it is injected separately into liquid chromatograph, records chromatogram.
Assay is measured according to high performance liquid chromatography (Chinese Pharmacopoeia version in 2015).Chromatographic condition is tried with system suitability
It is filler to test with octadecylsilane chemically bonded silica；Mobile phase A be 0.067mol/L sodium dihydrogen phosphates (extremely with phosphoric acid tune pH value
3.5), Mobile phase B is acetonitrile, and gradient elution is carried out by table 1；Detection wavelength is 210nm；28 DEG C of column temperature.Take the special profit pressurization of acetic acid
Plain reference substance with go glycine terlipressin reference substance appropriate, be made in every 1ml with water containing terlipressin and removing glycine
The mixed solution of each about 0.1mg of terlipressin takes 20 μ l injection liquid chromatographs, theoretical plate as system suitability solution
Number is calculated by terlipressin peak is not less than 2000, terlipressin peak and goes the separating degree at glycine terlipressin peak should not
Less than 1.0.
Measuring method takes this product appropriate, accurately weighed, and being dissolved in water and diluting is made in every 1ml containing about terlipressin
The solution of 0.2mg, precision measure 20 μ l and inject liquid chromatograph, record chromatogram；It is another to take Terlipressin reference substance suitable
Amount, is measured in the same method.By external standard method with calculated by peak area to get.As a result table 2.
1 gradient elution of table
| Time (minute) | Mobile phase A | Mobile phase B (%) |
| 0 | 92 | 8 |
| 4 | 92 | 8 |
| 18 | 85 | 15 |
| 30 | 80 | 20 |
| 30.1 | 92 | 8 |
| 40 | 92 | 8 |
2 sample impurity of table compares
| Sample | Total related substance (%) | Single maximum contaminant (%) | Impurity number |
| Embodiment 1 | 0.07 | 0.03 | 3 |
| Embodiment 2 | 0.08 | 0.03 | 3 |
| Embodiment 3 | 0.09 | 0.04 | 4 |
| Raw material | 6.45 | 0.98 | 14 |
Conclusion：The above results show that total related substance of Terlipressin prepared by the present invention is respectively less than 0.1%, list
A maximum contaminant is less than 0.05%, is superior to raw material.
Embodiment 4
Under conditions of cleaning, by 41g dextrosans, 8.2g mannitol, 0.82g trisodium citrates input liquid dispenser tool
In, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature, 1g Terlipressins are added and (press
1 the method for embodiment is made), pH value is surveyed, pH to 5.2 is adjusted with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), is added
Water for injection obtains Terlipressin filtrate to full dose through 0.22 μm of filtering with microporous membrane.3ml is dispensed in ampere bottle,
Aseptic freeze-dried powder-injection is made in 72 hours in freeze-drying.
Embodiment 5
Under conditions of cleaning, 34.8g dextrosans and 11.6g mannitol, 3.48g trisodium citrates are put into liquid dispenser
In tool, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature, 1g Terlipressins are added
(being made by 3 the method for embodiment), surveys pH value, and pH to 5.1 is adjusted with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5),
Water for injection is added and obtains Terlipressin filtrate through 0.22 μm of filtering with microporous membrane to full dose.3ml is dispensed in ampere
In bottle, aseptic freeze-dried powder-injection is made in 72 hours in freeze-drying.
Embodiment 6
Under conditions of cleaning, 30.8g dextrosans and 7.7g mannitol, 1.54g trisodium citrates are put into liquid dispenser
In tool, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature, 1g Terlipressins are added
(being made by 2 the method for embodiment), surveys pH value, and with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5) to 5.0, note is added
It penetrates and obtains Terlipressin filtrate through 0.22 μm of filtering with microporous membrane with water to full dose.3ml is dispensed in ampere bottle, it is cold
It is lyophilized dry 72 hours and aseptic freeze-dried powder-injection is made.
Embodiment 7
Under conditions of cleaning, 28.5g dextrosans and 7.5g mannitol, 1.50g trisodium citrates are put into liquid dispenser
In tool, stirring and dissolving in water for injection 700ml is added, waits for that above-mentioned preparation liquid is cooled to room temperature, the special profit pressurization of 1.0g acetic acid is added
Element (by 1 the method for embodiment be made), survey pH value, with Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5) adjust pH to
4.9, water for injection is added and obtains Terlipressin filtrate through 0.22 μm of filtering with microporous membrane to full dose.Dispense 3ml in
In ampere bottle, aseptic freeze-dried powder-injection is made in 72 hours in freeze-drying.
Prescription screening is tested
1, the screening of formulation buffer system
Prepare Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), citric acid-sodium citrate buffer solution (0.1M, pH=
4.8), disodium hydrogen phosphate-citrate buffer solution (0.1M, pH=7.0).Measure dissolving of the terlipressin in each buffer solution
Degree, specially：Appropriate amount of sample is weighed, in 25 DEG C of ± 1 DEG C of a certain amount of solution, every strength oscillation in 5 minutes 30 seconds, observation 30
Dissolving situation in minute is considered as dissolving when without visual visible particles of solute, selects water, acetonitrile, DMSO, physiological saline conduct
Solvent.Test result is shown in Table 3, judges from solubility angle, the preferred Acetic acid-sodium acetate buffer solution of preparation solution.
Solubility of 3 Terlipressin of table in buffer solution
| Buffer solution | Solubility (mg/ml) |
| Acetic acid-sodium acetate buffer solution | ＞ 50 |
| Citric acid-sodium citrate buffer solution | ~0 |
| Disodium hydrogen phosphate-citrate buffer solution | ~10 |
2, the stability analysis in Acetic acid-sodium acetate buffer solution
Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5) is prepared, a certain amount of Terlipressin is weighed and dissolves in wherein,
A concentration of 1mg/ml solution is formed, 37 DEG C of incubators is positioned over and incubates bath, it is pure to wherein terlipressin in 0,1,2,4,8,12 hour
Degree carries out HPLC detections, and test result is shown in Table 4.Judge from stability angle, the preferred Acetic acid-sodium acetate buffer solution of preparation solution is made
For buffer solution.
Purity (%) of 4 terlipressin of table in buffer solution
| Time point (hour) | Acetic acid-sodium acetate buffer solution |
| 0 | 99.82 |
| 1 | 99.82 |
| 2 | 99.76 |
| 4 | 99.68 |
| 8 | 99.67 |
| 12 | 99.63 |
3, in preparation solution excipients screening (one)
Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5) is prepared, Terlipressin 1mg/ml is contained.And contain respectively
There are the mannitol, dextrosan and glycine (weight ratio 1 of 4% (W/V):1) composition, sorbierite, lactose are as excipients.
It is positioned over 37 DEG C of incubators and incubates bath, detect the stability of Terlipressin in each time point solution.And (freeze-drying journey is lyophilized
Sequence is：- 40 DEG C of pre-freezes 4 hours；It is evacuated to 300mT；1 DEG C/min of temperature program is set, rises to -20 DEG C；It is small to be lyophilized 12
When；1 DEG C/min of temperature program is set, rises to 30 DEG C；It is 4 hours dry；Tamponade simultaneously rolls lid.), observe its lyophilized form preparation
Appearance, test result such as table 5.Judge from stability and freeze-drying appearance angle, the preferred mannitol of preparation solution or dextrosan with
The composition of glycine is as excipients.
5 terlipressin of table is containing the purity (%) and freeze-drying appearance in excipient formulation solution buffer solution
4, in preparation solution excipients screening (two)
Prepare Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), containing Terlipressin 0,0.1,0.25,0.5,
1.0,1.6,3.2 or 6.0mg/ml.And contain the glycine, the composition of dextrosan and mannitol, mountain of 4% (W/V) respectively
Pears alcohol, lactose are as excipients.The preparation solution without containing excipients is prepared simultaneously.Vial is taken, it is above-mentioned by 1ml/ bottles of packing
Preparation solution, freeze-drying.The pharmaceutical preparation for investigating lyophilized form redissolves situation.Test result such as table 6.
Lyophilized preparation when containing different excipients in 6 preparation solution of table, the clarity of preparation after redissolution
Note：<1, which refers to turbidity, is less than No. 1 titer；>1, which refers to turbidity, is more than No. 1 titer
This test result is shown, introduces the solute molecules such as glycine or the excipients such as dextrosan or sorbierite, only will
The concentration range for preparing Terlipressin in the pharmaceutical preparation solution that can dissolve lyophilized preparation is increased to by 0~0.1mg/ml
0~0.25mg/ml can redissolve Terlipressin concentration in pharmaceutical preparation after slightly increasing freeze-drying；Some excipients
It is little to the influence that can redissolve terlipressin concentration in pharmaceutical preparation after raising freeze-drying to be introduced into (such as lactose).
5, in preparation solution excipients screening (two)
Formulated solution, wherein Acetic acid-sodium acetate buffer solution (0.1M, pH=4.5), different weight than dextrosan with
Glycine, trisodium citrate composition, Terlipressin 1mg/ml, are allocated with water.It is (beautiful using PB-10 types pH meter
Sartorius companies of state), according to《Pharmacopoeia of People's Republic of China 2015 editions》The requirement of related pH value detection is detected.Inspection
Survey the solubility of terlipressin in preparation solution.Preparation solution is packed into 2ml glass, bottle is lyophilized, 1ml/ bottles, moves into low temperature cold
Lyophilizer (Supermodulyo types, 0.4m2, E-CApparatus companies) product bin is lyophilized.It is redissolved and is frozen with 1ml waters for injection
Dry preparation, the pharmaceutical preparation for investigating lyophilized form redissolve situation.The preparation of freeze-drying is put into 37 DEG C of incubators, incubates after bathing 8 weeks every bottle
It is redissolved with 1ml waters for injection, detects the purity of Terlipressin in preparation solution.Different weight than dextrosan with it is sweet
The appearance and redissolution situation and lyophilized form of lyophilized form preparation after dew alcohol, the preparation solution pH value of trisodium citrate, freeze-drying
Preparation placed 8 weeks at 37 DEG C after Terlipressin purity it is as shown in table 7, acetic acid Te Lijia after the freeze-drying of each preparation solution
The purity detecting of pressure element is 99.86%.Stability by preparation solution pH, lyophilized form preparation shape and lyophilized preparation is comprehensive
It closes and judges, preferably poly- dextrosan and mannitol, trisodium citrate weight ratio are (3~5)：1：(0.1~0.3).Lyophilized form
The available 1ml of pharmaceutical preparation redissolved to 5ml waters for injection, liquid pharmaceutical formulation is made again.Containing not in 7 preparation solution of table
With under trisodium citrate concentration pH, freeze-drying appearance, weight molten time and
8 peripheral stabilities
Note：<1, which refers to turbidity, is less than No. 1 titer；>1, which refers to turbidity, is more than No. 1 titer
Conclusion (of pressure testing)：Experiments have shown that, made using a certain proportion of dextrosan, mannitol, trisodium citrate by above-mentioned
For excipient, terlipressin lyophilized preparation has more excellent product quality.
Injection terlipressin test example
1, instrument and drug
High performance liquid chromatograph (HP1100 types, hewlette-packard), DAD detectors, AgilentChemstation colors
Compose work station：YB-2 type clarity test instrument (Precision Instrument Factory, Tianjin Univ.)；DU640 types UV detector (U.S. shellfish
Gram Mann)；PHS-3C types digital ph (Shanghai Lei Ci instrument plants)；WS/08-0l types temperature and humidity regulator (Hangzhou blue sky instrument
Device production Co., Ltd)；METYLER.AE200 type analysis balance (Switzerland)；Injection terlipressin is (according to 5 institute of embodiment
State the sample of preparation).
2, method
Acidity takes this product 5, and every bottle plus water 3ml makes dissolving, mixing measure (Chinese Pharmacopoeia 2015) in accordance with the law, and pH value is answered
It is 4.5~6.0.
Related substance takes this product, and being dissolved in water and diluting is made in every 1ml containing about the solution of terlipressin 0.4mg, makees
For test solution；Precision measures 1ml, sets in 100ml measuring bottles, is diluted with water to scale, shakes up solution as a contrast；Precision amount
Contrast solution 1ml is taken, is set in 100ml measuring bottles, uses mobile phase to be diluted to scale and shakes up as sensitive solution.According under assay item
Chromatographic condition, take 10 μ l injection liquid chromatograph of sensitivity solution, the signal-to-noise ratio at terlipressin peak to should be greater than 10.Precision amount
Contrast solution and each 10 μ l of test solution are taken, liquid chromatograph is injected separately into, records chromatogram.
Assay takes 10 bottles of this product, every bottle of precision that water 2ml, shaking is added to make contents melting, as test solution, essence
10 μ l of close measurement, according to the method under Terlipressin assay item；It separately takes Terlipressin reference substance appropriate, adds
Water dissolution simultaneously quantifies dilution and is made in every 1ml containing about the solution of terlipressin 0.4mg, is measured in the same method, finds out 10 bottles and be averaged
Content to get.
2.3 influence factors are tested
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160505,160507,160601) are existed
Investigated 5,10 days under high temperature (60 DEG C), strong light (4500lx), super-humid conditions, to the indexs such as its acidity, content and related substance into
Row is investigated, and indices meet regulation.Measurement result is shown in Table 8.
8 influence factor test result of table
A, B, C represent three batches of samples of embodiment 5, the sample of lot number 160505,160507,160601.
2.6 Acceleration study
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160505,160507,160601) are existed
It stores under the conditions of temperature (40 ± 2) DEG C, 75% soil 5% of relative humidity, is sampled respectively at 0,1,2,3,6 the end of month, measured every
Index.Each batch of sample property is white loose block.Acidity the results are shown in Table 9 in relation to substance and assay.
2.7 long-term experiment
Under marketed products terms of packing, three batches of 5 samples of embodiment (lot number 160505,160507,160601) are existed
It stores under the conditions of temperature (25 ± 2) DEG C, relative humidity 60% ± 10%, is sampled respectively at 0,3,6,12,18,24 the end of month, surveyed
Determine indices.Each batch of sample property is white loose block, and acidity the results are shown in Table 9 in relation to substance and assay.
9 accelerated test of table and long term test investigate result
A, B, C represent three batches of samples of embodiment 5, the sample of lot number 160505,160507,160601.
Conclusion：Influence factor experiment, accelerated test the results show that injection terlipressin items testing index without apparent
Variation, has good stability；24 months every quality index of the special profit pressurization of injection are placed under the conditions of long-term room-temperature without significant change,
Product stability is good.
Stability Determination after injection terlipressin redissolves is tested
After 160505,160507,160601 sample is redissolved with water for injection 250ml, it is placed in 4 DEG C of refrigerators, daily
Primary, METHOD FOR CONTINUOUS DETERMINATION 14 days is measured, linear regression analysis is carried out to the time (X) with measured value (Y).The results are shown in Table 10.
Stability after the redissolution of 10 injection terlipressin of table
P>0.05 illustrates that the concentration of terlipressin is basicly stable within the time measured.
Conclusion：As known from Table 10, for METHOD FOR CONTINUOUS DETERMINATION after 14 days, terlipressin keeps content after three batches of products of the present invention redissolve
Stablize.Property is stablized after illustrating injection terlipressin redissolution prepared by method shown in the present invention.
Claims (9)
1. a kind of preparation method of terlipressin, the feature preparation method includes the following steps：
Step 1 dissolves Terlipressin crude product with the aqueous acetic acid of mass concentration 1~5%, filtrate is collected by filtration, so
Afterwards with water by the acetic acid dilution proportion in terlipressin crude product solution to 0.5% or less mass concentration；
Step 2, using octadecylsilane as stationary phase, it is dense to contain quality after step 1 gained terlipressin crude product solution loading
Degree is that the phosphate buffer of 35~45% methanol is A phases, with mass concentration be 80~95% methanol aqueous solutions is B phases, linearly
Gradient elution collects characteristic peak eluent and eluent membrane filtration is concentrated into 25 DEG C of relative density 1.05-1.08；
Step 3, using eight alkyl silane bonded silica gels as stationary phase, after step 2 gained concentrate loading, be with mass concentration first
80% methanol aqueous solution of 0.5~1.6% ammonium acetate rinses 30~45min, and it is 0.05~0.1% then to use mass concentration
70% acetonitrile solution of ammonium acetate elutes, and collects characteristic peak eluent, is concentrated and dried up to Terlipressin.
2. a kind of preparation method of terlipressin according to claim 1, which is characterized in that the step 1 is with quality
The aqueous acetic acid dissolving terlipressin crude product of concentration 1~5% is that 1L mass concentrations 1 are added per 100g terlipressin crude products
~5% aqueous acetic acid.
3. a kind of preparation method of terlipressin according to claim 1, which is characterized in that the phosphorus in the step 2
The pH value of phthalate buffer is 5.0~7.0.
4. a kind of pharmaceutical composition containing terlipressin, which is characterized in that include Terlipressin, excipient, vinegar
Sour sodium, glacial acetic acid, feature is in the mixture that the excipient is dextrosan, mannitol, trisodium citrate composition.
5. pharmaceutical composition according to claim 4, which is characterized in that the composition include following parts by weight at
Point：0.8~1 parts by weight acetic acid terlipressin, 30~50 parts by weight excipient, sodium acetate, glacial acetic acid.
6. according to the pharmaceutical composition described in claim 4,5, which is characterized in that dextrosan is that spraying is dry in the excipient
Dry dextrosan.
7. according to the pharmaceutical composition described in claim 4,5, which is characterized in that dextrosan in the excipient：Mannitol：
The weight ratio of trisodium citrate is (3~5)：1：(0.1~0.3).
8. pharmaceutical composition according to claim 4, which is characterized in that the pH value of the composition is 4.5~6.0.
9. a kind of method that the pharmaceutical composition containing terlipressin prepares freeze-dried powder, it is characterised in that this method include with
Lower step：
1) it takes excipient to be dissolved in the water for injection of 2/3 recipe quantity, stirs evenly；
2) glacial acetic acid and sodium acetate is used to configure Acetic acid-sodium acetate buffer solution, it is spare；
3) it waits for that above-mentioned preparation liquid is cooled to room temperature, Terlipressin is added, pH value is surveyed, with Acetic acid-sodium acetate buffer solution tune
PH to 4.5~6.0 is saved, water for injection is added to full dose, with 0.22 μm of miillpore filter refined filtration, freeze-drying obtains freeze-dried powder.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110585170A (en) * | 2019-09-17 | 2019-12-20 | 南京赛弗斯医药科技有限公司 | Sustained-release microsphere prepared by 3D printing and used for injection of terlipressin acetate and preparation method thereof |
| CN112675128A (en) * | 2021-01-08 | 2021-04-20 | 南京羚诺生物医药技术研究院有限公司 | Terlipressin injection and preparation method thereof |
| CN113453661A (en) * | 2018-12-21 | 2021-09-28 | 艾瑞克有限公司 | New composition |
| CN114096267A (en) * | 2019-05-22 | 2022-02-25 | 柏欧韦股份有限公司 | Terlipressin formulations |
| CN114177147A (en) * | 2021-12-15 | 2022-03-15 | 福建省闽东力捷迅药业股份有限公司 | Preparation method of terlipressin for injection and prepared terlipressin for injection |
| US20240156895A1 (en) * | 2022-10-28 | 2024-05-16 | Mallinckrodt Pharmaceuticals Ireland Limited | Compositions for improving kidney function in patients with hepatorenal syndrome |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068685A (en) * | 2010-04-09 | 2011-05-25 | 深圳翰宇药业股份有限公司 | Terlipressin preparation and preparations method thereof |
| CN102584953A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
| CN102731625A (en) * | 2012-06-27 | 2012-10-17 | 深圳翰宇药业股份有限公司 | Method for purifying terli |
-
2018
- 2018-07-03 CN CN201810707079.XA patent/CN108659104B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102068685A (en) * | 2010-04-09 | 2011-05-25 | 深圳翰宇药业股份有限公司 | Terlipressin preparation and preparations method thereof |
| CN102584953A (en) * | 2012-02-09 | 2012-07-18 | 深圳翰宇药业股份有限公司 | Purification method for atosiban |
| CN102731625A (en) * | 2012-06-27 | 2012-10-17 | 深圳翰宇药业股份有限公司 | Method for purifying terli |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113453661A (en) * | 2018-12-21 | 2021-09-28 | 艾瑞克有限公司 | New composition |
| CN114096267A (en) * | 2019-05-22 | 2022-02-25 | 柏欧韦股份有限公司 | Terlipressin formulations |
| CN110585170A (en) * | 2019-09-17 | 2019-12-20 | 南京赛弗斯医药科技有限公司 | Sustained-release microsphere prepared by 3D printing and used for injection of terlipressin acetate and preparation method thereof |
| CN112675128A (en) * | 2021-01-08 | 2021-04-20 | 南京羚诺生物医药技术研究院有限公司 | Terlipressin injection and preparation method thereof |
| CN114177147A (en) * | 2021-12-15 | 2022-03-15 | 福建省闽东力捷迅药业股份有限公司 | Preparation method of terlipressin for injection and prepared terlipressin for injection |
| US20240156895A1 (en) * | 2022-10-28 | 2024-05-16 | Mallinckrodt Pharmaceuticals Ireland Limited | Compositions for improving kidney function in patients with hepatorenal syndrome |
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