IL104152A - Stabilized pharmaceutical preparation comprising growth hormone and histidine - Google Patents

Stabilized pharmaceutical preparation comprising growth hormone and histidine

Info

Publication number: IL104152A
Authority: IL; Israel
Prior art keywords: growth hormone; histidine; hgh; crystals; pharmaceutical preparation
Prior art date: 1991-12-20

Application number

IL104152A

Other languages

English (en)

Other versions

IL104152A0 (en

Original Assignee

Novo Nordisk As

Priority date (The priority date 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 date listed.)

1991-12-20

Filing date

1992-12-18

Publication date

1998-06-15

1991-12-20 Priority claimed from DK204691A external-priority patent/DK204691D0/da

1992-11-10 Priority claimed from DK136492A external-priority patent/DK136492D0/da

1992-12-18 Application filed by Novo Nordisk As filed Critical Novo Nordisk As

1993-05-13 Publication of IL104152A0 publication Critical patent/IL104152A0/xx

1998-06-15 Publication of IL104152A publication Critical patent/IL104152A/en

Links

HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 title claims abstract description 90
239000000122 growth hormone Substances 0.000 title claims abstract description 89
102000018997 Growth Hormone Human genes 0.000 title claims abstract description 76
108010051696 Growth Hormone Proteins 0.000 title claims abstract description 76
239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 21
HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims abstract description 70
239000013078 crystal Substances 0.000 claims abstract description 59
238000000034 method Methods 0.000 claims abstract description 15
150000002411 histidines Chemical class 0.000 claims abstract 5
239000000872 buffer Substances 0.000 claims description 33
239000000203 mixture Substances 0.000 claims description 31
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 21
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
229930195725 Mannitol Natural products 0.000 claims description 21
239000000594 mannitol Substances 0.000 claims description 21
235000010355 mannitol Nutrition 0.000 claims description 21
229930006000 Sucrose Natural products 0.000 claims description 18
239000005720 sucrose Substances 0.000 claims description 18
150000002016 disaccharides Chemical class 0.000 claims description 9
229940121366 growth hormone derivative Drugs 0.000 claims description 8
239000002904 solvent Substances 0.000 claims description 8
239000003111 growth hormone derivative Substances 0.000 claims description 7
150000005846 sugar alcohols Chemical class 0.000 claims description 6
HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 5
HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 5
150000001767 cationic compounds Chemical class 0.000 claims description 5
229910001411 inorganic cation Inorganic materials 0.000 claims description 5
150000002892 organic cations Chemical class 0.000 claims description 3
125000002723 alicyclic group Chemical group 0.000 claims description 2
125000001931 aliphatic group Chemical group 0.000 claims description 2
239000007900 aqueous suspension Substances 0.000 claims description 2
-1 aromatic alcohols Chemical class 0.000 claims description 2
150000002576 ketones Chemical class 0.000 claims description 2
230000000063 preceeding effect Effects 0.000 claims 2
125000000185 sucrose group Chemical group 0.000 claims 1
238000002360 preparation method Methods 0.000 abstract description 70
238000002425 crystallisation Methods 0.000 abstract description 14
230000008025 crystallization Effects 0.000 abstract description 13
230000006240 deamidation Effects 0.000 abstract description 12
239000000654 additive Substances 0.000 abstract description 8
230000003647 oxidation Effects 0.000 abstract description 6
238000007254 oxidation reaction Methods 0.000 abstract description 6
230000000996 additive effect Effects 0.000 abstract description 4
238000003776 cleavage reaction Methods 0.000 abstract description 3
230000007017 scission Effects 0.000 abstract description 3
239000006172 buffering agent Substances 0.000 abstract description 2
108010000521 Human Growth Hormone Proteins 0.000 description 89
102000002265 Human Growth Hormone Human genes 0.000 description 89
239000000854 Human Growth Hormone Substances 0.000 description 89
229960002885 histidine Drugs 0.000 description 60
235000014304 histidine Nutrition 0.000 description 59
WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 36
239000000243 solution Substances 0.000 description 25
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
230000015572 biosynthetic process Effects 0.000 description 19
CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 17
238000009472 formulation Methods 0.000 description 17
239000008363 phosphate buffer Substances 0.000 description 13
235000019445 benzyl alcohol Nutrition 0.000 description 12
238000004108 freeze drying Methods 0.000 description 11
150000003462 sulfoxides Chemical class 0.000 description 11
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
150000001768 cations Chemical class 0.000 description 9
230000002829 reductive effect Effects 0.000 description 9
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
239000000539 dimer Substances 0.000 description 8
150000002410 histidine derivatives Chemical class 0.000 description 8
RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 8
239000003960 organic solvent Substances 0.000 description 8
230000009467 reduction Effects 0.000 description 8
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
239000011701 zinc Substances 0.000 description 8
229910019142 PO4 Inorganic materials 0.000 description 7
229940024606 amino acid Drugs 0.000 description 7
235000001014 amino acid Nutrition 0.000 description 7
150000001413 amino acids Chemical class 0.000 description 7
238000006731 degradation reaction Methods 0.000 description 7
239000010452 phosphate Substances 0.000 description 7
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
229920005862 polyol Polymers 0.000 description 7
150000003077 polyols Chemical class 0.000 description 7
230000008569 process Effects 0.000 description 7
150000003839 salts Chemical class 0.000 description 7
NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
241001465754 Metazoa Species 0.000 description 6
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
230000000694 effects Effects 0.000 description 6
229920000642 polymer Polymers 0.000 description 6
239000004471 Glycine Substances 0.000 description 5
241000282414 Homo sapiens Species 0.000 description 5
238000007112 amidation reaction Methods 0.000 description 5
238000004458 analytical method Methods 0.000 description 5
230000015556 catabolic process Effects 0.000 description 5
229960002449 glycine Drugs 0.000 description 5
230000012010 growth Effects 0.000 description 5
238000004519 manufacturing process Methods 0.000 description 5
239000003381 stabilizer Substances 0.000 description 5
239000000725 suspension Substances 0.000 description 5
RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
FRJIAZKQGSCKPQ-FSPLSTOPSA-N His-Ala Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H](N)CC1=CN=CN1 FRJIAZKQGSCKPQ-FSPLSTOPSA-N 0.000 description 4
LYCVKHSJGDMDLM-LURJTMIESA-N His-Gly Chemical compound OC(=O)CNC(=O)[C@@H](N)CC1=CN=CN1 LYCVKHSJGDMDLM-LURJTMIESA-N 0.000 description 4
KRBMQYPTDYSENE-BQBZGAKWSA-N His-Ser Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CNC=N1 KRBMQYPTDYSENE-BQBZGAKWSA-N 0.000 description 4
XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
108010040030 histidinoalanine Proteins 0.000 description 4
108010036413 histidylglycine Proteins 0.000 description 4
108010018006 histidylserine Proteins 0.000 description 4
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
239000000047 product Substances 0.000 description 4
108090000623 proteins and genes Proteins 0.000 description 4
239000011780 sodium chloride Substances 0.000 description 4
QZNNVYOVQUKYSC-JEDNCBNOSA-N (2s)-2-amino-3-(1h-imidazol-5-yl)propanoic acid;hydron;chloride Chemical compound Cl.OC(=O)[C@@H](N)CC1=CN=CN1 QZNNVYOVQUKYSC-JEDNCBNOSA-N 0.000 description 3
241000283690 Bos taurus Species 0.000 description 3
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
MMFKFJORZBJVNF-UWVGGRQHSA-N His-Leu Chemical compound CC(C)C[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 MMFKFJORZBJVNF-UWVGGRQHSA-N 0.000 description 3
CZVQSYNVUHAILZ-UWVGGRQHSA-N His-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CC1=CN=CN1 CZVQSYNVUHAILZ-UWVGGRQHSA-N 0.000 description 3
XMAUFHMAAVTODF-STQMWFEESA-N His-Phe Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CN=CN1 XMAUFHMAAVTODF-STQMWFEESA-N 0.000 description 3
206010062767 Hypophysitis Diseases 0.000 description 3
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
ZQISRDCJNBUVMM-UHFFFAOYSA-N L-Histidinol Natural products OCC(N)CC1=CN=CN1 ZQISRDCJNBUVMM-UHFFFAOYSA-N 0.000 description 3
CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
ZQISRDCJNBUVMM-YFKPBYRVSA-N L-histidinol Chemical compound OC[C@@H](N)CC1=CNC=N1 ZQISRDCJNBUVMM-YFKPBYRVSA-N 0.000 description 3
229910000147 aluminium phosphate Inorganic materials 0.000 description 3
125000000539 amino acid group Chemical group 0.000 description 3
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
239000004067 bulking agent Substances 0.000 description 3
238000005119 centrifugation Methods 0.000 description 3
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
150000001875 compounds Chemical class 0.000 description 3
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BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
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239000012153 distilled water Substances 0.000 description 3
238000005516 engineering process Methods 0.000 description 3
229960001340 histamine Drugs 0.000 description 3
108010025306 histidylleucine Proteins 0.000 description 3
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125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
238000004255 ion exchange chromatography Methods 0.000 description 3
239000000463 material Substances 0.000 description 3
BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
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238000004007 reversed phase HPLC Methods 0.000 description 3
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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 2
108010016626 Dipeptides Proteins 0.000 description 2
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206010056438 Growth hormone deficiency Diseases 0.000 description 2
102000004877 Insulin Human genes 0.000 description 2
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BXRMEWOQUXOLDH-LURJTMIESA-N L-Histidine methyl ester Chemical compound COC(=O)[C@@H](N)CC1=CN=CN1 BXRMEWOQUXOLDH-LURJTMIESA-N 0.000 description 2
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 2
108010013127 Met-human growth hormone Proteins 0.000 description 2
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238000006460 hydrolysis reaction Methods 0.000 description 2
PRJKNHOMHKJCEJ-UHFFFAOYSA-N imidazol-4-ylacetic acid Chemical compound OC(=O)CC1=CN=CN1 PRJKNHOMHKJCEJ-UHFFFAOYSA-N 0.000 description 2
229940125396 insulin Drugs 0.000 description 2
239000008101 lactose Substances 0.000 description 2
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125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 2
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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
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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
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WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
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229940043230 sarcosine Drugs 0.000 description 1
238000007391 self-medication Methods 0.000 description 1
210000002356 skeleton Anatomy 0.000 description 1
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HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
235000011083 sodium citrates Nutrition 0.000 description 1
229910000162 sodium phosphate Inorganic materials 0.000 description 1
239000001433 sodium tartrate Substances 0.000 description 1
229960002167 sodium tartrate Drugs 0.000 description 1
235000011004 sodium tartrates Nutrition 0.000 description 1
230000009576 somatic growth Effects 0.000 description 1
239000000600 sorbitol Substances 0.000 description 1
230000006641 stabilisation Effects 0.000 description 1
238000011105 stabilization Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
229960002317 succinimide Drugs 0.000 description 1
150000008163 sugars Chemical class 0.000 description 1
238000013268 sustained release Methods 0.000 description 1
239000012730 sustained-release form Substances 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
RULSWEULPANCDV-PIXUTMIVSA-N turanose Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](C(=O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RULSWEULPANCDV-PIXUTMIVSA-N 0.000 description 1
210000001835 viscera Anatomy 0.000 description 1
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239000008215 water for injection Substances 0.000 description 1
230000029663 wound healing Effects 0.000 description 1
239000000811 xylitol Substances 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
235000010447 xylitol Nutrition 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000004246 zinc acetate Substances 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 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
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/61—Growth hormone [GH], i.e. somatotropin
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Landscapes

Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Endocrinology (AREA)
Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
General Health & Medical Sciences (AREA)
Medicinal Chemistry (AREA)
Bioinformatics & Cheminformatics (AREA)
Veterinary Medicine (AREA)
Engineering & Computer Science (AREA)
Pharmacology & Pharmacy (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Zoology (AREA)
Animal Behavior & Ethology (AREA)
Gastroenterology & Hepatology (AREA)
Public Health (AREA)
Biochemistry (AREA)
Diabetes (AREA)
Immunology (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
Molecular Biology (AREA)
Epidemiology (AREA)
Toxicology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Medicinal Preparation (AREA)
Peptides Or Proteins (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

IL104152A 1991-12-20 1992-12-18 Stabilized pharmaceutical preparation comprising growth hormone and histidine IL104152A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
DK204691A DK204691D0 (da)	1991-12-20	1991-12-20	Hidtil ukendt farmaceutisk praeparat
DK136492A DK136492D0 (da)	1992-11-10	1992-11-10	A pharmaceutical formulation

Publications (2)

Publication Number	Publication Date
IL104152A0 IL104152A0 (en)	1993-05-13
IL104152A true IL104152A (en)	1998-06-15

Family

ID=26065653

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL104152A IL104152A (en)	1991-12-20	1992-12-18	Stabilized pharmaceutical preparation comprising growth hormone and histidine

Country Status (24)

Country	Link
EP (2)	EP0618807B1 (da)
JP (2)	JP2950617B2 (da)
KR (1)	KR100266502B1 (da)
AT (2)	ATE368472T1 (da)
AU (1)	AU667503B2 (da)
BG (1)	BG63075B1 (da)
CA (1)	CA2125855C (da)
CZ (1)	CZ283361B6 (da)
DE (3)	DE69233704T2 (da)
DK (1)	DK0618807T3 (da)
ES (2)	ES2185625T3 (da)
FI (1)	FI115116B (da)
HU (1)	HUT69402A (da)
IL (1)	IL104152A (da)
MX (1)	MX9207374A (da)
NL (1)	NL300126I1 (da)
NO (1)	NO942300L (da)
NZ (1)	NZ246556A (da)
PT (1)	PT618807E (da)
RO (1)	RO111990B1 (da)
RU (1)	RU2122426C1 (da)
SK (1)	SK279641B6 (da)
UA (1)	UA41502C2 (da)
WO (1)	WO1993012812A1 (da)

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US5849700A (en) *	1991-12-20	1998-12-15	Novo Nordisk A/S	Pharmaceutical formulation
US6022858A (en) *	1991-12-20	2000-02-08	Novo Nordisk A/S	Pharmaceutical formulation of human-growth hormone pretreated with zinc salt
DK204791D0 (da) *	1991-12-20	1991-12-20	Novo Nordisk As	Hidtil ukendt farmaceutisk praeparat
US5849704A (en) *	1991-12-20	1998-12-15	Novo Nordisk A/S	Pharmaceutical formulation
US6288030B1 (en) *	1993-12-22	2001-09-11	Amgen Inc.	Stem cell factor formulations and methods
ES2139081T3 (es) *	1994-06-17	2000-02-01	Applied Res Systems Ars Holding N V	Composiciones farmaceuticas que contienen la hormona humana del crecimiento.
TW426737B (en) *	1994-06-27	2001-03-21	Hayashibara Biochem Lab	Saccharide composition with reduced reducibility, and preparation and uses thereof
US5547696A (en) *	1994-10-13	1996-08-20	Novo Nordisk A/S	Pharmaceutical formulation
IL115592A (en) *	1994-10-13	2000-07-26	Novo Nordisk As	Stabilized pharmaceutical formulation comprising a growth hormone and leucine
US5631225A (en) *	1994-10-13	1997-05-20	Novo Nordisk A/S	Pharmaceutical formulation
US5654278A (en) *	1994-10-13	1997-08-05	Novo Nordisk A/S	Composition and method comprising growth hormone and leucine
JPH10511964A (ja) *	1995-01-13	1998-11-17	ノボノルディスクアクティーゼルスカブ	成長ホルモン及びＸ−Ｌｙｓを含む安定化医薬製剤
ZA96122B (en) *	1995-01-13	1996-07-24	Novo Nordisk As	A pharmaceutical formulation
US5705482A (en) *	1995-01-13	1998-01-06	Novo Nordisk A/S	Pharmaceutical formulation
US5552385A (en) *	1995-06-05	1996-09-03	Novo Nordisk A/S	Pharmaceutical formulation
US6936289B2 (en)	1995-06-07	2005-08-30	Danisco A/S	Method of improving the properties of a flour dough, a flour dough improving composition and improved food products
ZA965367B (en) *	1995-07-12	1997-01-23	Novo Nordisk As	A pharmaceutical formulation
US6267958B1 (en)	1995-07-27	2001-07-31	Genentech, Inc.	Protein formulation
KR100236393B1 (ko) *	1996-02-02	1999-12-15	나까니시 히로유끼	사람성장호르몬을 함유하는 의약제제
US20070179096A1 (en)	1996-04-24	2007-08-02	Novo Nordisk A/S	Pharmaceutical Formulation
US20020077461A1 (en) *	1996-04-24	2002-06-20	Soren Bjorn	Pharmaceutical formulation
ES2350891T3 (es)	1997-04-09	2011-01-28	Danisco A/S	Lipasa y utilización de la misma para mejorar las masas y los productos horneados.
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1992
- 1992-12-16 DE DE69233704T patent/DE69233704T2/de not_active Expired - Lifetime
- 1992-12-16 CA CA002125855A patent/CA2125855C/en not_active Expired - Lifetime
- 1992-12-16 RO RO94-01056A patent/RO111990B1/ro unknown
- 1992-12-16 EP EP93902089A patent/EP0618807B1/en not_active Expired - Lifetime
- 1992-12-16 RU RU94045932A patent/RU2122426C1/ru active
- 1992-12-16 ES ES93902089T patent/ES2185625T3/es not_active Expired - Lifetime
- 1992-12-16 CZ CZ941507A patent/CZ283361B6/cs not_active IP Right Cessation
- 1992-12-16 HU HU9401832A patent/HUT69402A/hu unknown
- 1992-12-16 UA UA94005308A patent/UA41502C2/uk unknown
- 1992-12-16 KR KR1019940702139A patent/KR100266502B1/ko not_active Expired - Lifetime
- 1992-12-16 JP JP5511361A patent/JP2950617B2/ja not_active Expired - Lifetime
- 1992-12-16 NZ NZ246556A patent/NZ246556A/en unknown
- 1992-12-16 DE DE69232847T patent/DE69232847T2/de not_active Expired - Lifetime
- 1992-12-16 SK SK754-94A patent/SK279641B6/sk not_active IP Right Cessation
- 1992-12-16 AU AU33446/93A patent/AU667503B2/en not_active Ceased
- 1992-12-16 WO PCT/DK1992/000379 patent/WO1993012812A1/en not_active Ceased
- 1992-12-16 EP EP01128974A patent/EP1197222B1/en not_active Expired - Lifetime
- 1992-12-16 DK DK93902089T patent/DK0618807T3/da active
- 1992-12-16 AT AT01128974T patent/ATE368472T1/de not_active IP Right Cessation
- 1992-12-16 ES ES01128974T patent/ES2291264T3/es not_active Expired - Lifetime
- 1992-12-16 AT AT93902089T patent/ATE227583T1/de active
- 1992-12-16 PT PT93902089T patent/PT618807E/pt unknown
- 1992-12-16 DE DE10399015C patent/DE10399015I1/de active Granted
- 1992-12-17 MX MX9207374A patent/MX9207374A/es active IP Right Grant
- 1992-12-18 IL IL104152A patent/IL104152A/en not_active IP Right Cessation
1994
- 1994-05-30 BG BG98806A patent/BG63075B1/bg unknown
- 1994-06-17 NO NO942300A patent/NO942300L/no not_active Application Discontinuation
- 1994-06-17 FI FI942906A patent/FI115116B/fi not_active IP Right Cessation
1999
- 1999-02-03 JP JP11026405A patent/JPH11315031A/ja active Pending
2003
- 2003-05-01 NL NL300126C patent/NL300126I1/nl unknown

Also Published As

Publication number	Publication date
UA41502C2 (uk)	2001-09-17
IL104152A0 (en)	1993-05-13
DE69233704D1 (de)	2007-09-13
EP0618807A1 (en)	1994-10-12
ATE368472T1 (de)	2007-08-15
AU3344693A (en)	1993-07-28
ES2185625T3 (es)	2003-05-01
DK0618807T3 (da)	2003-03-03
HU9401832D0 (en)	1994-09-28
CZ283361B6 (cs)	1998-03-18
RU2122426C1 (ru)	1998-11-27
RO111990B1 (ro)	1997-04-30
EP0618807B1 (en)	2002-11-13
SK279641B6 (sk)	1999-01-11
NO942300D0 (no)	1994-06-17
DE69232847D1 (de)	2002-12-19
DE10399015I1 (de)	2012-05-03
SK75494A3 (en)	1995-03-08
HUT69402A (en)	1995-09-28
KR100266502B1 (ko)	2000-09-15
AU667503B2 (en)	1996-03-28
DE69232847T2 (de)	2003-09-11
DE69233704T2 (de)	2008-05-21
BG63075B1 (bg)	2001-03-30
EP1197222A3 (en)	2004-02-04
FI942906A0 (fi)	1994-06-17
CZ150794A3 (en)	1995-01-18
JPH11315031A (ja)	1999-11-16
NL300126I1 (nl)	2003-07-01
NO942300L (no)	1994-08-19
CA2125855A1 (en)	1993-07-08
WO1993012812A1 (en)	1993-07-08
FI115116B (fi)	2005-03-15
BG98806A (bg)	1995-02-28
CA2125855C (en)	2008-05-13
DE10399015I2 (de)	2008-08-07
PT618807E (pt)	2003-03-31
MX9207374A (es)	1993-07-01
ATE227583T1 (de)	2002-11-15
FI942906L (fi)	1994-06-17
JPH07502516A (ja)	1995-03-16
EP1197222B1 (en)	2007-08-01
NZ246556A (en)	1996-03-26
EP1197222A2 (en)	2002-04-17
JP2950617B2 (ja)	1999-09-20
RU94045932A (ru)	1997-04-20
ES2291264T3 (es)	2008-03-01

Legal Events

Date	Code	Title
1998-11-26	FF	Patent granted
1999-04-11	KB	Patent renewed
1999-06-20	KB	Patent renewed
2003-02-12	KB	Patent renewed
2007-02-12	KB	Patent renewed
2010-12-30	KB	Patent renewed
2013-07-31	EXP	Patent expired

Publication	Publication Date	Title
AU667503B2 (en)	1996-03-28	A stabilized pharmaceutical formulation comprising growth hormone and histidine
US5849700A (en)	1998-12-15	Pharmaceutical formulation
US5849704A (en)	1998-12-15	Pharmaceutical formulation
US5977069A (en)	1999-11-02	Pharmaceutical formulation
US5705482A (en)	1998-01-06	Pharmaceutical formulation
WO1997003692A1 (en)	1997-02-06	A stabilized pharmaceutical formulation comprising a growth hormone pre-treated with zinc and optionally lysine or calcium ions
US5654278A (en)	1997-08-05	Composition and method comprising growth hormone and leucine
US5631225A (en)	1997-05-20	Pharmaceutical formulation
US5547696A (en)	1996-08-20	Pharmaceutical formulation
EP0785797B1 (en)	2002-03-06	A pharmaceutical formulation comprising a growth hormone and leucine
US6022858A (en)	2000-02-08	Pharmaceutical formulation of human-growth hormone pretreated with zinc salt
CA2226553A1 (en)	1997-01-30	A stabilized pharmaceutical formulation comprising a growth hormone and a peptide comprising at least, one basic amino acid residue and at least one acid amino acid residue
EP0804224A1 (en)	1997-11-05	A stabilized pharmaceutical formulation comprising a growth hormone and lys-x
PL171356B1 (pl)	1997-04-30	Sposób wytwarzania kryształów hormonu wzrostu lub pochodnych hormonu wzrostu i histydyny lub pochodnej histydyny