HRP930700A2 - Process for the purification of chymopapain, purified chymopapain and preparations containing the same - Google Patents
Process for the purification of chymopapain, purified chymopapain and preparations containing the same Download PDFInfo
- Publication number
- HRP930700A2 HRP930700A2 HR930700A HRP930700A HRP930700A2 HR P930700 A2 HRP930700 A2 HR P930700A2 HR 930700 A HR930700 A HR 930700A HR P930700 A HRP930700 A HR P930700A HR P930700 A2 HRP930700 A2 HR P930700A2
- Authority
- HR
- Croatia
- Prior art keywords
- chymopapain
- solution
- added
- minutes
- mixture
- Prior art date
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- 108090001069 Chymopapain Proteins 0.000 title claims abstract description 210
- 229960002976 chymopapain Drugs 0.000 title claims abstract description 203
- ISWQCIVKKSOKNN-UHFFFAOYSA-L Tiron Chemical compound [Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ISWQCIVKKSOKNN-UHFFFAOYSA-L 0.000 title claims abstract description 202
- 238000000034 method Methods 0.000 title claims description 55
- 238000002360 preparation method Methods 0.000 title claims description 42
- 238000000746 purification Methods 0.000 title claims description 33
- 230000008569 process Effects 0.000 title claims description 10
- 239000000203 mixture Substances 0.000 claims abstract description 105
- 230000000694 effects Effects 0.000 claims abstract description 80
- 108010092515 glycyl endopeptidase Proteins 0.000 claims abstract description 64
- 108090000391 Caricain Proteins 0.000 claims abstract description 27
- 108090000526 Papain Proteins 0.000 claims abstract description 18
- 239000004365 Protease Substances 0.000 claims abstract description 18
- 235000019834 papain Nutrition 0.000 claims abstract description 18
- 229940055729 papain Drugs 0.000 claims abstract description 18
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 14
- 239000000243 solution Substances 0.000 claims description 141
- 239000011159 matrix material Substances 0.000 claims description 39
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 34
- 235000018102 proteins Nutrition 0.000 claims description 31
- 102000004169 proteins and genes Human genes 0.000 claims description 31
- 108090000623 proteins and genes Proteins 0.000 claims description 31
- 102000004190 Enzymes Human genes 0.000 claims description 28
- 108090000790 Enzymes Proteins 0.000 claims description 28
- 238000001042 affinity chromatography Methods 0.000 claims description 28
- 239000007864 aqueous solution Substances 0.000 claims description 28
- 229940088598 enzyme Drugs 0.000 claims description 28
- 239000003480 eluent Substances 0.000 claims description 19
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 16
- 108010041102 azocasein Proteins 0.000 claims description 14
- 238000011534 incubation Methods 0.000 claims description 14
- 108050004038 cystatin Proteins 0.000 claims description 13
- 238000003916 acid precipitation Methods 0.000 claims description 10
- 238000005277 cation exchange chromatography Methods 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 8
- 230000002441 reversible effect Effects 0.000 claims description 7
- 238000004587 chromatography analysis Methods 0.000 claims description 5
- 238000003776 cleavage reaction Methods 0.000 claims description 5
- 230000007017 scission Effects 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 238000011033 desalting Methods 0.000 claims description 3
- 230000008021 deposition Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 102100028007 Cystatin-SA Human genes 0.000 claims 1
- 101710144510 Cysteine proteinase inhibitor Proteins 0.000 claims 1
- 239000002852 cysteine proteinase inhibitor Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 68
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 66
- DEOKFPFLXFNAON-UHFFFAOYSA-N N-α-Benzoyl-DL-arginine 4-nitroanilide hydrochloride Chemical compound Cl.C=1C=C([N+]([O-])=O)C=CC=1NC(=O)C(CCCN=C(N)N)NC(=O)C1=CC=CC=C1 DEOKFPFLXFNAON-UHFFFAOYSA-N 0.000 description 62
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- 238000003756 stirring Methods 0.000 description 42
- 239000000872 buffer Substances 0.000 description 41
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 40
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 34
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000002904 solvent Substances 0.000 description 31
- 238000001914 filtration Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 26
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 25
- 239000004816 latex Substances 0.000 description 23
- 229920000126 latex Polymers 0.000 description 23
- 235000009467 Carica papaya Nutrition 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 229960002433 cysteine Drugs 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 229920002684 Sepharose Polymers 0.000 description 18
- 239000000499 gel Substances 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 17
- 235000018417 cysteine Nutrition 0.000 description 17
- -1 for example Chemical class 0.000 description 17
- 108010005843 Cysteine Proteases Proteins 0.000 description 16
- 102000005927 Cysteine Proteases Human genes 0.000 description 16
- 102000036639 antigens Human genes 0.000 description 16
- 108091007433 antigens Proteins 0.000 description 16
- 239000011736 potassium bicarbonate Substances 0.000 description 16
- 235000015497 potassium bicarbonate Nutrition 0.000 description 16
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 16
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 16
- 239000000758 substrate Substances 0.000 description 16
- 239000000427 antigen Substances 0.000 description 15
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 15
- 235000017281 sodium acetate Nutrition 0.000 description 15
- 229910000162 sodium phosphate Inorganic materials 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 229910052799 carbon Inorganic materials 0.000 description 14
- 238000010828 elution Methods 0.000 description 14
- 239000006228 supernatant Substances 0.000 description 14
- 241000219173 Carica Species 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- RNAMYOYQYRYFQY-UHFFFAOYSA-N 2-(4,4-difluoropiperidin-1-yl)-6-methoxy-n-(1-propan-2-ylpiperidin-4-yl)-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound N1=C(N2CCC(F)(F)CC2)N=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC1CCN(C(C)C)CC1 RNAMYOYQYRYFQY-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 150000003839 salts Chemical class 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 11
- 229940105325 3-dimethylaminopropylamine Drugs 0.000 description 11
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 11
- 239000011928 denatured alcohol Substances 0.000 description 11
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 239000001632 sodium acetate Substances 0.000 description 11
- 238000010998 test method Methods 0.000 description 11
- 102000035195 Peptidases Human genes 0.000 description 10
- 108091005804 Peptidases Proteins 0.000 description 10
- 230000000951 immunodiffusion Effects 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 235000019833 protease Nutrition 0.000 description 10
- 150000007659 semicarbazones Chemical class 0.000 description 10
- 238000004448 titration Methods 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 9
- 240000006432 Carica papaya Species 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 238000005119 centrifugation Methods 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000012153 distilled water Substances 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 229910052739 hydrogen Inorganic materials 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 239000008188 pellet Substances 0.000 description 9
- 239000001509 sodium citrate Substances 0.000 description 9
- 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 9
- 239000001488 sodium phosphate Substances 0.000 description 9
- 235000011008 sodium phosphates Nutrition 0.000 description 9
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 9
- XXAXVMUWHZHZMJ-UHFFFAOYSA-N Chymopapain Chemical compound OC1=CC(S(O)(=O)=O)=CC(S(O)(=O)=O)=C1O XXAXVMUWHZHZMJ-UHFFFAOYSA-N 0.000 description 8
- 108010016626 Dipeptides Proteins 0.000 description 8
- 102000004196 processed proteins & peptides Human genes 0.000 description 8
- 210000002966 serum Anatomy 0.000 description 8
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 7
- 150000001413 amino acids Chemical group 0.000 description 7
- 239000000356 contaminant Substances 0.000 description 7
- 238000000502 dialysis Methods 0.000 description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 7
- 235000019800 disodium phosphate Nutrition 0.000 description 7
- 229910000397 disodium phosphate Inorganic materials 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 7
- 239000012160 loading buffer Substances 0.000 description 7
- 229910052753 mercury Inorganic materials 0.000 description 7
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical class Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 7
- 238000001556 precipitation Methods 0.000 description 7
- DUIOPKIIICUYRZ-UHFFFAOYSA-N semicarbazide Chemical compound NNC(N)=O DUIOPKIIICUYRZ-UHFFFAOYSA-N 0.000 description 7
- 235000015096 spirit Nutrition 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 238000005341 cation exchange Methods 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
- 239000008367 deionised water Substances 0.000 description 6
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 6
- 239000002198 insoluble material Substances 0.000 description 6
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 6
- 235000019799 monosodium phosphate Nutrition 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 6
- TVSCFMXJYNZEER-UHFFFAOYSA-N 7-methoxy-11a-methyl-1,9b,10,11-tetrahydronaphtho[1,2-g]indole Chemical compound C1CC2(C)CC=NC2=C2C=CC3=CC(OC)=CC=C3C21 TVSCFMXJYNZEER-UHFFFAOYSA-N 0.000 description 5
- 238000002965 ELISA Methods 0.000 description 5
- HQRSUIDICNOLPX-UHFFFAOYSA-M Mersalyl acid Chemical group O[Hg]CC(OC)CNC(=O)C1=CC=CC=C1OCC(O)=O HQRSUIDICNOLPX-UHFFFAOYSA-M 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000012149 elution buffer Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 230000002779 inactivation Effects 0.000 description 5
- 150000002923 oximes Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- KYNFOMQIXZUKRK-UHFFFAOYSA-N 2,2'-dithiodiethanol Chemical compound OCCSSCCO KYNFOMQIXZUKRK-UHFFFAOYSA-N 0.000 description 4
- BDKLKNJTMLIAFE-UHFFFAOYSA-N 2-(3-fluorophenyl)-1,3-oxazole-4-carbaldehyde Chemical compound FC1=CC=CC(C=2OC=C(C=O)N=2)=C1 BDKLKNJTMLIAFE-UHFFFAOYSA-N 0.000 description 4
- VLQBSKLZRSUMTJ-UHFFFAOYSA-N 2-methylsulfanylpyridine Chemical compound CSC1=CC=CC=N1 VLQBSKLZRSUMTJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 206010020751 Hypersensitivity Diseases 0.000 description 4
- 239000004201 L-cysteine Substances 0.000 description 4
- 235000013878 L-cysteine Nutrition 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- 206010052428 Wound Diseases 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 230000002159 abnormal effect Effects 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 238000012512 characterization method Methods 0.000 description 4
- 230000037029 cross reaction Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
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- 229940087562 sodium acetate trihydrate Drugs 0.000 description 4
- HAEPBEMBOAIUPN-UHFFFAOYSA-L sodium tetrathionate Chemical class O.O.[Na+].[Na+].[O-]S(=O)(=O)SSS([O-])(=O)=O HAEPBEMBOAIUPN-UHFFFAOYSA-L 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
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- HAXFWIACAGNFHA-UHFFFAOYSA-N aldrithiol Chemical compound C=1C=CC=NC=1SSC1=CC=CC=N1 HAXFWIACAGNFHA-UHFFFAOYSA-N 0.000 description 3
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 3
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 3
- 235000011130 ammonium sulphate Nutrition 0.000 description 3
- 239000012062 aqueous buffer Substances 0.000 description 3
- OHDRQQURAXLVGJ-HLVWOLMTSA-N azane;(2e)-3-ethyl-2-[(e)-(3-ethyl-6-sulfo-1,3-benzothiazol-2-ylidene)hydrazinylidene]-1,3-benzothiazole-6-sulfonic acid Chemical compound [NH4+].[NH4+].S/1C2=CC(S([O-])(=O)=O)=CC=C2N(CC)C\1=N/N=C1/SC2=CC(S([O-])(=O)=O)=CC=C2N1CC OHDRQQURAXLVGJ-HLVWOLMTSA-N 0.000 description 3
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- 238000000576 coating method Methods 0.000 description 3
- 238000011109 contamination Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
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- 238000005859 coupling reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 150000002019 disulfides Chemical class 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
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- 229910001385 heavy metal Inorganic materials 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960002523 mercuric chloride Drugs 0.000 description 3
- 229960000224 mersalyl Drugs 0.000 description 3
- KRKPYFLIYNGWTE-UHFFFAOYSA-N n,o-dimethylhydroxylamine Chemical compound CNOC KRKPYFLIYNGWTE-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
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- 239000011148 porous material Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011002 quantification Methods 0.000 description 3
- 239000013037 reversible inhibitor Substances 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012064 sodium phosphate buffer Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Landscapes
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- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB898909836A GB8909836D0 (en) | 1989-04-28 | 1989-04-28 | Therapeutic agent |
| YU87090A YU87090A (sh) | 1989-04-28 | 1990-05-04 | Postupak za prečišćavanje himopapaina |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP930700A2 true HRP930700A2 (en) | 1995-06-30 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HR930700A HRP930700A2 (en) | 1989-04-28 | 1993-04-02 | Process for the purification of chymopapain, purified chymopapain and preparations containing the same |
Country Status (34)
| Country | Link |
|---|---|
| US (2) | US5380656A (de) |
| EP (1) | EP0470136B1 (de) |
| JP (1) | JPH04506003A (de) |
| KR (1) | KR920701241A (de) |
| CN (1) | CN1047340A (de) |
| AT (1) | ATE107660T1 (de) |
| AU (1) | AU631641B2 (de) |
| BG (1) | BG60916B1 (de) |
| CA (1) | CA2056402C (de) |
| DD (1) | DD296960A5 (de) |
| DE (1) | DE69010199T2 (de) |
| DK (1) | DK0470136T3 (de) |
| EG (1) | EG19583A (de) |
| ES (1) | ES2055427T3 (de) |
| FI (1) | FI914995A0 (de) |
| GB (1) | GB8909836D0 (de) |
| GR (1) | GR1001011B (de) |
| HR (1) | HRP930700A2 (de) |
| HU (2) | HUT58345A (de) |
| IE (1) | IE64351B1 (de) |
| IL (1) | IL94227A (de) |
| IN (2) | IN170683B (de) |
| LT (1) | LT3827B (de) |
| LV (1) | LV10200B (de) |
| MX (1) | MX20503A (de) |
| NO (1) | NO914206L (de) |
| NZ (1) | NZ233475A (de) |
| PL (1) | PL166810B1 (de) |
| PT (1) | PT93921B (de) |
| RO (1) | RO112032B1 (de) |
| RU (1) | RU2074891C1 (de) |
| WO (1) | WO1990013561A1 (de) |
| YU (1) | YU87090A (de) |
| ZA (1) | ZA903228B (de) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8909836D0 (en) * | 1989-04-28 | 1989-06-14 | Boots Co Plc | Therapeutic agent |
| EP0572547A1 (de) * | 1991-02-22 | 1993-12-08 | The Du Pont Merck Pharmaceutical Company | Substituierte alpha-amino aldehyde und derivate |
| CA2061861A1 (en) * | 1991-03-04 | 1992-09-05 | Jonathan Duvick | Plant polypeptides with inhibitory activity towards pathogenic microorganisms |
| CN1060519C (zh) * | 1991-05-09 | 2001-01-10 | 广西亚热带作物研究所 | 桄榔植物蛋白酶的提取方法 |
| ES2112333T3 (es) * | 1991-10-14 | 1998-04-01 | Cash Eng Res | Combinacion de control de admision para un sistema compresor. |
| US6753006B1 (en) | 1993-02-22 | 2004-06-22 | American Bioscience, Inc. | Paclitaxel-containing formulations |
| WO1994028012A1 (en) * | 1993-05-28 | 1994-12-08 | Warner-Lambert Company | Hydroxamate inhibitors of endothelin converting enzyme |
| JP2002538151A (ja) | 1999-03-02 | 2002-11-12 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | カテプシンの可逆的インヒビターとして有用な化合物 |
| KR100688740B1 (ko) * | 1999-03-15 | 2007-02-28 | 액시스 파마슈티컬스 인코포레이티드 | 프로테아제 억제제로서의 ｎ-시아노메틸 아미드 |
| US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
| US6703040B2 (en) | 2000-01-11 | 2004-03-09 | Intralytix, Inc. | Polymer blends as biodegradable matrices for preparing biocomposites |
| AU2003292755A1 (en) | 2002-12-25 | 2004-07-22 | Hirotaka Haro | Remedy for degenerative intervertebral discs |
| US7169405B2 (en) * | 2003-08-06 | 2007-01-30 | Warsaw Orthopedic, Inc. | Methods and devices for the treatment of intervertebral discs |
| US20080069907A1 (en) * | 2004-07-06 | 2008-03-20 | Chikao Morimoto | Compositions for Cancer Prevention, Treatment, or Amelioration Comprising Papaya Extract |
| CN1320111C (zh) * | 2004-08-09 | 2007-06-06 | 王美岭 | 一种制备木瓜凝乳酶的方法 |
| US20060241566A1 (en) * | 2005-04-11 | 2006-10-26 | Orthox, Llc | Nucleus Extraction from Spine Intervertebral Disc |
| US7879027B2 (en) * | 2006-04-24 | 2011-02-01 | Warsaw Orthopedic, Inc. | Controlled release devices for fusion of osteal structures |
| US7771414B2 (en) * | 2006-04-24 | 2010-08-10 | Warsaw Orthopedic, Inc. | Controlled release devices for therapeutic treatments of spinal discs |
| US8642059B2 (en) | 2006-04-24 | 2014-02-04 | Warsaw Orthopedic, Inc. | Controlled release systems and methods for intervertebral discs |
| US8642060B2 (en) * | 2006-04-24 | 2014-02-04 | Warsaw Orthopedic, Inc. | Controlled release systems and methods for osteal growth |
| US20070265633A1 (en) * | 2006-05-11 | 2007-11-15 | Moon Jon K | Implement and method to extract nucleus from spine intervertebral disc |
| US8257938B2 (en) * | 2009-02-27 | 2012-09-04 | Medical Diagnostic Laboratories, Llc | Hemolysin and its protein fragments in sero-detection of Anaplasma phagocytophilum |
| WO2013038936A1 (ja) * | 2011-09-13 | 2013-03-21 | タカラバイオ株式会社 | ペルオキシダーゼ反応の停止方法及び反応停止剤 |
| WO2014004512A1 (en) | 2012-06-25 | 2014-01-03 | Surmodics, Inc. | Bioerodable poly(etheresteramides) and medical article uses |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE270723C (de) * | ||||
| US2313875A (en) * | 1940-12-17 | 1943-03-16 | Eugene F Jansen | Proteolytic enzyme process |
| US3320131A (en) * | 1964-10-23 | 1967-05-16 | Baxter Laboratories Inc | Method for the treatment of herniation of intervertebral discs |
| US3558433A (en) * | 1967-11-07 | 1971-01-26 | Baxter Laboratories Inc | Process for purification of chymopapain |
| YU40433B (en) * | 1975-02-20 | 1986-02-28 | Lek Tovarna Farmacevtskih | Process for obtaining pure, proteolytically active anzymes |
| DE3212846A1 (de) | 1981-04-13 | 1982-11-04 | Sintokogio, Ltd., Nagoya, Aichi | Apparat und verfahren zum herstellen eines kerns |
| EP0065395B1 (de) * | 1981-05-13 | 1988-08-24 | BOOTS-FLINT, INC. (a Delaware corp.) | Chymopapain und Verfahren zu seiner Herstellung und Verwendung |
| US4439423A (en) * | 1981-05-13 | 1984-03-27 | Smith Laboratories, Inc. | Chymopapain and method for its use |
| US4374926A (en) * | 1981-05-13 | 1983-02-22 | Smith Laboratories, Inc. | Method for the production of improved chymopapain |
| US4719108A (en) * | 1981-05-13 | 1988-01-12 | Smith Laboratories, Inc. | Chymopapain composition and method for its use |
| GB2124233B (en) * | 1982-07-19 | 1985-09-18 | Nat Res Dev | Synthetic peptides and their preparation |
| GB2156821A (en) * | 1984-04-03 | 1985-10-16 | Simmons James W | Process for purifying chymopapain |
| HU196624B (en) * | 1986-12-08 | 1988-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing chymopapain with high specific activity |
| GB8909836D0 (en) * | 1989-04-28 | 1989-06-14 | Boots Co Plc | Therapeutic agent |
-
1989
- 1989-04-28 GB GB898909836A patent/GB8909836D0/en active Pending
-
1990
- 1990-04-26 IN IN327/MAS/90A patent/IN170683B/en unknown
- 1990-04-26 GR GR900100315A patent/GR1001011B/el unknown
- 1990-04-27 DE DE69010199T patent/DE69010199T2/de not_active Expired - Fee Related
- 1990-04-27 WO PCT/EP1990/000647 patent/WO1990013561A1/en active IP Right Grant
- 1990-04-27 IL IL9422790A patent/IL94227A/en not_active IP Right Cessation
- 1990-04-27 MX MX2050390A patent/MX20503A/es unknown
- 1990-04-27 IE IE153890A patent/IE64351B1/en not_active IP Right Cessation
- 1990-04-27 RO RO148615A patent/RO112032B1/ro unknown
- 1990-04-27 AT AT90906939T patent/ATE107660T1/de not_active IP Right Cessation
- 1990-04-27 RU SU905010237A patent/RU2074891C1/ru active
- 1990-04-27 DD DD90340234A patent/DD296960A5/de not_active IP Right Cessation
- 1990-04-27 NZ NZ233475A patent/NZ233475A/xx unknown
- 1990-04-27 HU HU903342A patent/HUT58345A/hu unknown
- 1990-04-27 CA CA002056402A patent/CA2056402C/en not_active Expired - Fee Related
- 1990-04-27 EP EP90906939A patent/EP0470136B1/de not_active Expired - Lifetime
- 1990-04-27 JP JP2506560A patent/JPH04506003A/ja active Pending
- 1990-04-27 AU AU55472/90A patent/AU631641B2/en not_active Ceased
- 1990-04-27 ES ES90906939T patent/ES2055427T3/es not_active Expired - Lifetime
- 1990-04-27 DK DK90906939.5T patent/DK0470136T3/da active
- 1990-04-27 CN CN90103907A patent/CN1047340A/zh active Pending
- 1990-04-27 PL PL90284970A patent/PL166810B1/pl unknown
- 1990-04-27 ZA ZA903228A patent/ZA903228B/xx unknown
- 1990-04-27 KR KR1019910701462A patent/KR920701241A/ko not_active Application Discontinuation
- 1990-04-27 US US07/768,325 patent/US5380656A/en not_active Expired - Fee Related
- 1990-04-27 PT PT93921A patent/PT93921B/pt not_active IP Right Cessation
- 1990-04-29 EG EG24990A patent/EG19583A/xx active
- 1990-05-04 YU YU87090A patent/YU87090A/sh unknown
-
1991
- 1991-10-23 FI FI914995A patent/FI914995A0/fi unknown
- 1991-10-24 BG BG95362A patent/BG60916B1/bg unknown
- 1991-10-25 NO NO91914206A patent/NO914206L/no unknown
- 1991-11-25 IN IN873MA1991 patent/IN173230B/en unknown
-
1993
- 1993-04-02 HR HR930700A patent/HRP930700A2/hr not_active Application Discontinuation
- 1993-06-19 LV LVP-93-624A patent/LV10200B/xx unknown
- 1993-12-21 LT LTIP1645A patent/LT3827B/lt not_active IP Right Cessation
-
1994
- 1994-09-08 US US08/302,369 patent/US5468480A/en not_active Expired - Fee Related
-
1995
- 1995-06-30 HU HU95P/P00687P patent/HU211746A9/hu unknown
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