DK2920199T3 - Process for the preparation of botulinum toxin - Google Patents
Process for the preparation of botulinum toxin Download PDFInfo
- Publication number
- DK2920199T3 DK2920199T3 DK14832966.7T DK14832966T DK2920199T3 DK 2920199 T3 DK2920199 T3 DK 2920199T3 DK 14832966 T DK14832966 T DK 14832966T DK 2920199 T3 DK2920199 T3 DK 2920199T3
- Authority
- DK
- Denmark
- Prior art keywords
- botulinum toxin
- toxin
- botulinum
- precipitate
- anion exchange
- Prior art date
Links
- 108030001720 Bontoxilysin Proteins 0.000 title claims abstract description 168
- 229940053031 botulinum toxin Drugs 0.000 title claims abstract description 159
- 238000000034 method Methods 0.000 title claims abstract description 68
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title description 3
- 238000005571 anion exchange chromatography Methods 0.000 claims abstract description 40
- 239000002244 precipitate Substances 0.000 claims abstract description 27
- 239000000872 buffer Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 16
- 101710163270 Nuclease Proteins 0.000 claims abstract description 9
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 claims abstract description 9
- 239000000137 peptide hydrolase inhibitor Substances 0.000 claims abstract description 9
- 108700012359 toxins Proteins 0.000 claims description 54
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 42
- 231100000765 toxin Toxicity 0.000 claims description 36
- 239000003053 toxin Substances 0.000 claims description 36
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 24
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 16
- 238000000746 purification Methods 0.000 claims description 16
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 15
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 15
- 238000001556 precipitation Methods 0.000 claims description 15
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 5
- 102000016911 Deoxyribonucleases Human genes 0.000 claims description 4
- 108010053770 Deoxyribonucleases Proteins 0.000 claims description 4
- 102000006382 Ribonucleases Human genes 0.000 claims description 4
- 108010083644 Ribonucleases Proteins 0.000 claims description 4
- 241000193403 Clostridium Species 0.000 claims description 2
- LZCZIHQBSCVGRD-UHFFFAOYSA-N benzenecarboximidamide;hydron;chloride Chemical compound [Cl-].NC(=[NH2+])C1=CC=CC=C1 LZCZIHQBSCVGRD-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 206010008129 cerebral palsy Diseases 0.000 abstract description 5
- 230000002829 reductive effect Effects 0.000 abstract description 5
- 230000001839 systemic circulation Effects 0.000 abstract description 5
- 206010019468 Hemiplegia Diseases 0.000 abstract description 4
- 208000018360 neuromuscular disease Diseases 0.000 abstract description 4
- 201000007770 spastic cerebral palsy Diseases 0.000 abstract description 4
- 201000008417 spastic hemiplegia Diseases 0.000 abstract description 4
- 230000037303 wrinkles Effects 0.000 abstract description 4
- 108010048262 DWP450 Proteins 0.000 description 39
- 210000003205 muscle Anatomy 0.000 description 32
- 102000004169 proteins and genes Human genes 0.000 description 22
- 108090000623 proteins and genes Proteins 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 21
- 235000018102 proteins Nutrition 0.000 description 21
- 101710117542 Botulinum neurotoxin type A Proteins 0.000 description 16
- 229940089093 botox Drugs 0.000 description 16
- 241000193155 Clostridium botulinum Species 0.000 description 15
- 239000012535 impurity Substances 0.000 description 15
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 14
- 229960004716 idoxuridine Drugs 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000003957 anion exchange resin Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000003916 acid precipitation Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 238000007792 addition Methods 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000001769 paralizing effect Effects 0.000 description 7
- 238000011218 seed culture Methods 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 239000002581 neurotoxin Substances 0.000 description 6
- 231100000618 neurotoxin Toxicity 0.000 description 6
- 102000008100 Human Serum Albumin Human genes 0.000 description 5
- 108091006905 Human Serum Albumin Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000894006 Bacteria Species 0.000 description 4
- 101710154606 Hemagglutinin Proteins 0.000 description 4
- 101710138657 Neurotoxin Proteins 0.000 description 4
- 101710093908 Outer capsid protein VP4 Proteins 0.000 description 4
- 101710135467 Outer capsid protein sigma-1 Proteins 0.000 description 4
- 101710176177 Protein A56 Proteins 0.000 description 4
- 206010040954 Skin wrinkling Diseases 0.000 description 4
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 4
- 230000036982 action potential Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 231100000062 no-observed-adverse-effect level Toxicity 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 238000012453 sprague-dawley rat model Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 102100028188 Cystatin-F Human genes 0.000 description 3
- 101710169749 Cystatin-F Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 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
- 108091005804 Peptidases Proteins 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 238000000502 dialysis Methods 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- 238000012869 ethanol precipitation Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000004255 ion exchange chromatography Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000001542 size-exclusion chromatography Methods 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 3
- 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
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000193464 Clostridium sp. Species 0.000 description 2
- 208000014094 Dystonic disease Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000008454 Hyperhidrosis Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010010469 Qa-SNARE Proteins Proteins 0.000 description 2
- 108010005730 R-SNARE Proteins Proteins 0.000 description 2
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 102000002215 Synaptobrevin Human genes 0.000 description 2
- 102000050389 Syntaxin Human genes 0.000 description 2
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 2
- 231100001103 botulinum neurotoxin Toxicity 0.000 description 2
- 229940041514 candida albicans extract Drugs 0.000 description 2
- 239000013622 capto Q Substances 0.000 description 2
- 108010079058 casein hydrolysate Proteins 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000012149 elution buffer Substances 0.000 description 2
- 230000028023 exocytosis Effects 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000000185 hemagglutinin Substances 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 239000012138 yeast extract Substances 0.000 description 2
- 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 description 1
- UPXRTVAIJMUAQR-UHFFFAOYSA-N 4-(9h-fluoren-9-ylmethoxycarbonylamino)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound C1C(C(O)=O)N(C(=O)OC(C)(C)C)CC1NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 UPXRTVAIJMUAQR-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 241000270728 Alligator Species 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
- 206010002153 Anal fissure Diseases 0.000 description 1
- 206010059237 Auriculotemporal syndrome Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 206010064888 Cervicogenic headache Diseases 0.000 description 1
- 241001112695 Clostridiales Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000000289 Esophageal Achalasia Diseases 0.000 description 1
- 206010063006 Facial spasm Diseases 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000004041 Gustatory Sweating Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 208000004095 Hemifacial Spasm Diseases 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020853 Hypertonic bladder Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 206010062575 Muscle contracture Diseases 0.000 description 1
- 206010028391 Musculoskeletal Pain Diseases 0.000 description 1
- 208000002033 Myoclonus Diseases 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 1
- 206010030136 Oesophageal achalasia Diseases 0.000 description 1
- 208000009722 Overactive Urinary Bladder Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 206010034650 Peritoneal adhesions Diseases 0.000 description 1
- 206010036313 Post-traumatic headache Diseases 0.000 description 1
- 239000012564 Q sepharose fast flow resin Substances 0.000 description 1
- 208000003782 Raynaud disease Diseases 0.000 description 1
- 208000012322 Raynaud phenomenon Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 206010040744 Sinus headache Diseases 0.000 description 1
- 206010040925 Skin striae Diseases 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010067672 Spasmodic dysphonia Diseases 0.000 description 1
- 208000004350 Strabismus Diseases 0.000 description 1
- 208000031439 Striae Distensae Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010043269 Tension headache Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 206010044074 Torticollis Diseases 0.000 description 1
- 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 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010046555 Urinary retention Diseases 0.000 description 1
- 241000700647 Variola virus Species 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 208000013142 Writer cramp Diseases 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 108010079650 abobotulinumtoxinA Proteins 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 201000000621 achalasia Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 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 description 1
- 238000000540 analysis of variance Methods 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000036617 axillary hyperhidrosis Effects 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 206010005159 blepharospasm Diseases 0.000 description 1
- 230000000744 blepharospasm Effects 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 150000001768 cations Chemical group 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000002866 cervical dystonia Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 201000003892 detrusor sphincter dyssynergia Diseases 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940098753 dysport Drugs 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 201000002904 focal dystonia Diseases 0.000 description 1
- 201000002865 focal hand dystonia Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001641 gel filtration chromatography Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 210000000527 greater trochanter Anatomy 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 230000001660 hyperkinetic effect Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 229960004184 ketamine hydrochloride Drugs 0.000 description 1
- 210000004717 laryngeal muscle Anatomy 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000013028 medium composition Substances 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 210000000715 neuromuscular junction Anatomy 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
- 230000037392 palmar hyperhidrosis Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000036563 plantar hyperhidrosis Effects 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940074404 sodium succinate Drugs 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L sodium succinate (anhydrous) Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 201000002849 spasmodic dystonia Diseases 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-M thioglycolate(1-) Chemical compound [O-]C(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-M 0.000 description 1
- 210000002303 tibia Anatomy 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- 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)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/18—Ion-exchange chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/30—Extraction; Separation; Purification by precipitation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P21/00—Preparation of peptides or proteins
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Wood Science & Technology (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Analytical Chemistry (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Peptides Or Proteins (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020130092024A KR101339349B1 (ko) | 2013-08-02 | 2013-08-02 | 보툴리눔 독소의 제조방법 |
| PCT/KR2014/004003 WO2015016462A1 (en) | 2013-08-02 | 2014-05-07 | Method for production of botulinum toxin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2920199T3 true DK2920199T3 (en) | 2018-05-28 |
Family
ID=49987856
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK14832966.7T DK2920199T3 (en) | 2013-08-02 | 2014-05-07 | Process for the preparation of botulinum toxin |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US9512418B2 (en:Method) |
| EP (1) | EP2920199B1 (en:Method) |
| JP (2) | JP6307150B2 (en:Method) |
| KR (1) | KR101339349B1 (en:Method) |
| CN (1) | CN105392795B (en:Method) |
| AR (1) | AR096541A1 (en:Method) |
| AU (1) | AU2014297167B2 (en:Method) |
| BR (1) | BR112015029973B1 (en:Method) |
| CA (1) | CA2912553C (en:Method) |
| CY (1) | CY1120410T1 (en:Method) |
| DK (1) | DK2920199T3 (en:Method) |
| ES (1) | ES2665288T3 (en:Method) |
| HR (1) | HRP20180679T1 (en:Method) |
| HU (1) | HUE036840T2 (en:Method) |
| LT (1) | LT2920199T (en:Method) |
| MX (1) | MX362821B (en:Method) |
| NO (1) | NO2920199T3 (en:Method) |
| PH (1) | PH12015501855A1 (en:Method) |
| PL (1) | PL2920199T3 (en:Method) |
| PT (1) | PT2920199T (en:Method) |
| RU (1) | RU2627159C2 (en:Method) |
| SA (1) | SA515370208B1 (en:Method) |
| SG (1) | SG11201509486VA (en:Method) |
| SI (1) | SI2920199T1 (en:Method) |
| WO (1) | WO2015016462A1 (en:Method) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8129139B2 (en) | 2009-07-13 | 2012-03-06 | Allergan, Inc. | Process for obtaining botulinum neurotoxin |
| KR101339349B1 (ko) * | 2013-08-02 | 2013-12-09 | 주식회사 대웅 | 보툴리눔 독소의 제조방법 |
| KR101723167B1 (ko) | 2015-04-28 | 2017-04-05 | 주식회사 대웅 | 보툴리눔 독소의 제조를 위한 배지 조성물 |
| KR101729251B1 (ko) | 2015-04-28 | 2017-04-21 | 주식회사 대웅 | 보툴리눔 독소의 제조를 위한 배지 조성물 |
| KR101723168B1 (ko) | 2015-04-28 | 2017-04-05 | 주식회사 대웅 | 보툴리눔 독소의 제조를 위한 배지 조성물 |
| KR101853463B1 (ko) * | 2015-09-09 | 2018-06-20 | 휴젤(주) | 보툴리눔 독소의 정제 방법 |
| KR101775682B1 (ko) | 2015-11-30 | 2017-09-06 | 주식회사 대웅 | 보툴리눔 독소의 제조방법 |
| CN109641941B (zh) * | 2016-05-16 | 2023-06-16 | 哈佛大学校长及研究员协会 | 用于纯化和激活肉毒杆菌神经毒素的方法 |
| KR102463881B1 (ko) | 2016-10-04 | 2022-11-07 | (주)메디톡스 | 보툴리눔 독소 함유 용액으로부터 보툴리눔 독소를 분리하는 방법 |
| KR101744900B1 (ko) | 2017-01-20 | 2017-06-08 | 주식회사 대웅 | 보툴리눔 독소를 포함하는 안정한 액상 조성물 |
| CN109646673A (zh) * | 2017-10-12 | 2019-04-19 | 秀杰股份公司 | 肉毒杆菌毒素的微结构制剂技术 |
| CA3124535A1 (en) | 2018-12-21 | 2020-06-25 | The Research Foundation For Microbial Diseases Of Osaka University | Botulinum toxin producing method |
| KR102516204B1 (ko) * | 2019-04-15 | 2023-03-30 | (주)제테마 | 보툴리눔 독소의 정제방법 |
| KR102516203B1 (ko) * | 2019-04-15 | 2023-03-30 | (주)제테마 | 보툴리눔 독소의 제조방법 |
| TWI854077B (zh) * | 2019-12-20 | 2024-09-01 | 瑞士商葛德瑪控股公司 | 生產肉毒桿菌毒素的方法 |
| TW202136286A (zh) * | 2019-12-20 | 2021-10-01 | 瑞士商葛德瑪控股公司 | 純化肉毒桿菌毒素的方法 |
| KR102724651B1 (ko) * | 2021-07-08 | 2024-11-01 | 주식회사 파마리서치바이오 | 비-독소 단백질이 제거된 클로스트리디움 보툴리눔 신경독소 단백질의 정제방법 |
| TWI852454B (zh) * | 2022-04-01 | 2024-08-11 | 大陸商重慶譽顏製藥有限公司 | 一種肉毒毒素蛋白組合物、製備方法及其應用 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20030060150A (ko) * | 2002-01-07 | 2003-07-16 | (주)메디톡스 | 클로스트리디움 보툴리눔 ａ형 독소를 정제하는 방법 |
| RU2206337C1 (ru) * | 2002-10-29 | 2003-06-20 | Общество с ограниченной ответственностью "Токсины и сопутствующие продукты" | Лекарственный препарат для лечения мышечных дистоний и способ его получения |
| US7452697B2 (en) * | 2003-09-25 | 2008-11-18 | Allergan, Inc. | Chromatographic method and system for purifying a botulinum toxin |
| US7879341B2 (en) * | 2004-07-26 | 2011-02-01 | Merz Pharma Gmbh & Co. Kgaa | Therapeutic composition with a botulinum neurotoxin |
| AU2005327458B2 (en) * | 2005-03-03 | 2011-12-15 | Allergan, Inc. | Animal product free system and process for purifying a botulinum toxin |
| KR101025617B1 (ko) * | 2008-02-25 | 2011-03-30 | 메덱스젠 주식회사 | 클로스트리디움 보툴리눔으로부터 보툴리눔 독소를정제하는 방법 |
| US8129139B2 (en) * | 2009-07-13 | 2012-03-06 | Allergan, Inc. | Process for obtaining botulinum neurotoxin |
| HRP20181869T1 (hr) * | 2009-10-21 | 2019-01-11 | Revance Therapeutics, Inc. | Metode i sustavi za pročišćavanje nekompleksiranog botulinskog neurotoksina |
| KR101434558B1 (ko) * | 2011-07-21 | 2014-08-27 | (주)메디톡스 | 식물 유래 성분 함유 배지 및 가요성 폐쇄 용기를 이용하여 클로스트리디움 보툴리눔 독소를 생산하는 방법 |
| KR101339349B1 (ko) * | 2013-08-02 | 2013-12-09 | 주식회사 대웅 | 보툴리눔 독소의 제조방법 |
-
2013
- 2013-08-02 KR KR1020130092024A patent/KR101339349B1/ko active Active
-
2014
- 2014-05-07 US US14/654,819 patent/US9512418B2/en active Active
- 2014-05-07 PT PT148329667T patent/PT2920199T/pt unknown
- 2014-05-07 JP JP2016506267A patent/JP6307150B2/ja active Active
- 2014-05-07 HU HUE14832966A patent/HUE036840T2/hu unknown
- 2014-05-07 EP EP14832966.7A patent/EP2920199B1/en active Active
- 2014-05-07 MX MX2015016481A patent/MX362821B/es active IP Right Grant
- 2014-05-07 BR BR112015029973-3A patent/BR112015029973B1/pt active IP Right Grant
- 2014-05-07 RU RU2015151186A patent/RU2627159C2/ru active
- 2014-05-07 HR HRP20180679TT patent/HRP20180679T1/hr unknown
- 2014-05-07 PL PL14832966T patent/PL2920199T3/pl unknown
- 2014-05-07 ES ES14832966.7T patent/ES2665288T3/es active Active
- 2014-05-07 CA CA2912553A patent/CA2912553C/en active Active
- 2014-05-07 NO NO14832966A patent/NO2920199T3/no unknown
- 2014-05-07 CN CN201480012202.6A patent/CN105392795B/zh active Active
- 2014-05-07 SI SI201430702T patent/SI2920199T1/en unknown
- 2014-05-07 WO PCT/KR2014/004003 patent/WO2015016462A1/en not_active Ceased
- 2014-05-07 DK DK14832966.7T patent/DK2920199T3/en active
- 2014-05-07 LT LTEP14832966.7T patent/LT2920199T/lt unknown
- 2014-05-07 AU AU2014297167A patent/AU2014297167B2/en active Active
- 2014-05-07 SG SG11201509486VA patent/SG11201509486VA/en unknown
- 2014-06-06 AR ARP140102204A patent/AR096541A1/es active IP Right Grant
-
2015
- 2015-08-24 PH PH12015501855A patent/PH12015501855A1/en unknown
- 2015-11-29 SA SA515370208A patent/SA515370208B1/ar unknown
-
2017
- 2017-03-06 JP JP2017041239A patent/JP2017141237A/ja active Pending
-
2018
- 2018-04-26 CY CY20181100439T patent/CY1120410T1/el unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK2920199T3 (en) | Process for the preparation of botulinum toxin | |
| US8895713B2 (en) | Clostridial neurotoxins with altered persistency | |
| ES2420430T3 (es) | Sistema libre de productos de origen animal y procedimiento de purificación de una toxina botulínica | |
| ES2688065T5 (es) | Métodos y sistemas para purificar la neurotoxina botulínica no complejada | |
| KR101025617B1 (ko) | 클로스트리디움 보툴리눔으로부터 보툴리눔 독소를정제하는 방법 | |
| HK1215715B (zh) | 生产肉毒杆菌毒素的方法 | |
| US20100112005A1 (en) | Compositions of activated botulinum toxin type B | |
| US20100034854A1 (en) | Compositions of activated botulinum holotoxin type B (150 KD) | |
| US20100112006A1 (en) | Compositions of activated botulinum holotoxin type B (150 kD) | |
| KR20050074806A (ko) | 결정형 보툴리늄 독소의 제조방법 | |
| CN118215734A (zh) | 肉毒毒素制剂的干燥方法 |