JP2015200659A - 局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 - Google Patents
局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 Download PDFInfo
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- JP2015200659A JP2015200659A JP2015094777A JP2015094777A JP2015200659A JP 2015200659 A JP2015200659 A JP 2015200659A JP 2015094777 A JP2015094777 A JP 2015094777A JP 2015094777 A JP2015094777 A JP 2015094777A JP 2015200659 A JP2015200659 A JP 2015200659A
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- botulinum toxin
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- 108030001720 Bontoxilysin Proteins 0.000 title claims abstract description 44
- 229940053031 botulinum toxin Drugs 0.000 title claims abstract description 44
- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000003387 muscular Effects 0.000 title abstract description 20
- 238000000746 purification Methods 0.000 title abstract description 6
- 230000001769 paralizing effect Effects 0.000 title abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 52
- 108010057266 Type A Botulinum Toxins Proteins 0.000 claims abstract description 31
- 239000011780 sodium chloride Substances 0.000 claims abstract description 26
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 16
- 229940094657 botulinum toxin type a Drugs 0.000 claims abstract description 13
- 150000001450 anions Chemical class 0.000 claims abstract description 10
- 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 claims abstract description 9
- 239000003456 ion exchange resin Substances 0.000 claims abstract description 9
- 229920003303 ion-exchange polymer Polymers 0.000 claims abstract description 9
- 238000009472 formulation Methods 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims abstract description 4
- 206010033799 Paralysis Diseases 0.000 claims description 31
- 150000002500 ions Chemical class 0.000 claims description 13
- 210000003141 lower extremity Anatomy 0.000 claims description 13
- 210000003205 muscle Anatomy 0.000 claims description 12
- 239000003053 toxin Substances 0.000 claims description 11
- 231100000765 toxin Toxicity 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 9
- 238000009792 diffusion process Methods 0.000 claims description 7
- 230000004083 survival effect Effects 0.000 claims description 7
- 210000003019 respiratory muscle Anatomy 0.000 claims description 6
- 229910001425 magnesium ion Inorganic materials 0.000 claims description 3
- 230000007423 decrease Effects 0.000 claims description 2
- 231100000111 LD50 Toxicity 0.000 claims 1
- 230000000694 effects Effects 0.000 description 25
- 229940089093 botox Drugs 0.000 description 19
- 239000000872 buffer Substances 0.000 description 13
- 208000021090 palsy Diseases 0.000 description 12
- 241000699666 Mus <mouse, genus> Species 0.000 description 11
- 239000013065 commercial product Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 238000003916 acid precipitation Methods 0.000 description 10
- 241000699670 Mus sp. Species 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 108700012359 toxins Proteins 0.000 description 9
- 238000011282 treatment Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 5
- 239000007927 intramuscular injection Substances 0.000 description 5
- 238000010255 intramuscular injection Methods 0.000 description 4
- 231100000636 lethal dose Toxicity 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 241000193155 Clostridium botulinum Species 0.000 description 3
- 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 3
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000005571 anion exchange chromatography Methods 0.000 description 3
- -1 anion ion Chemical class 0.000 description 3
- 206010008129 cerebral palsy Diseases 0.000 description 3
- 229960004716 idoxuridine Drugs 0.000 description 3
- 230000037303 wrinkles Effects 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 210000003423 ankle Anatomy 0.000 description 2
- 230000003712 anti-aging effect Effects 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000004255 ion exchange chromatography Methods 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007974 sodium acetate buffer Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 101710117542 Botulinum neurotoxin type A Proteins 0.000 description 1
- 101710084578 Short neurotoxin 1 Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 101710182532 Toxin a Proteins 0.000 description 1
- 208000005248 Vocal Cord Paralysis Diseases 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940066189 botox cosmetic Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000001097 facial muscle Anatomy 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000009616 inductively coupled plasma Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004237 neck muscle Anatomy 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 208000026843 stiff neck Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
-
- 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
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/76—Viruses; Subviral particles; Bacteriophages
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P23/00—Anaesthetics
- A61P23/02—Local anaesthetics
-
- 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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/96—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation using ion-exchange
Abstract
【解決手段】非拡散型ボツリヌス毒素の精製方法は、精製されたボツリヌス毒素A型製剤を、pHは4.5ないし6.5の範囲、塩化ナトリウム(NaCl)の濃度を0.02ないし0.2Mに調節して添加した陰イオンイオン交換樹脂クロマトグラフィーを遂行して亜分画を分離する段階;及び上記亜分画のうちA260/A280の値が0.4ないし0.6の水準を維持する非拡散性ボツリヌス毒素分画を収得する段階を含む。
【選択図】図1
Description
Claims (2)
- 精製されたボツリヌス毒素A型製剤を、pHは4.5ないし6.5の範囲、
塩化ナトリウム(NaCl)の濃度を0.02ないし0.2Mに調節して添加した陰イオンイオン交換樹脂クロマトグラフィーを遂行して亜分画を分離する段階;及び、
上記亜分画のうちA260/A280の値が0.4ないし0.6の水準を維持する非拡散性ボツリヌス毒素分画を収得する段階を含む非拡散型ボツリヌス毒素の精製方法によって分離精製されたものであって、
毒素100U/ml当りZnイオンが少なくとも150ppb、Feイオンが少なくとも80ppb、Mgイオンが少なくとも140ppbで含まれることを特徴とする非拡散型ボツリヌス毒素を、拡散型ボツリヌス毒素であればその半数致死量に相当する単位の1.5ないし3倍の投与量でマウスの右下肢に注射し、右下肢の筋肉と呼吸筋の麻痺有無と致死有無を観察し、呼吸筋の麻痺と致死が認められない場合、そのボツリヌス毒素が非拡散型であると確認することを特徴とする非拡散型ボツリヌス毒素を判別する方法。 - 上記半数致死量を1Uとし、2Uの上記毒素を注射後96時間における生存率の低下が認められない場合、そのボツリヌス毒素が非拡散型であると確認することを特徴とする請求項1に記載の非拡散型ボツリヌス毒素を判別する方法。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020100051076A KR101134146B1 (ko) | 2010-05-31 | 2010-05-31 | 국소 근마비 효과를 갖는 비확산형 보툴리눔 독소와 그의 정제방법 |
KR10-2010-0051076 | 2010-05-31 |
Related Parent Applications (1)
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JP2013513102A Division JP5919608B2 (ja) | 2010-05-31 | 2011-05-13 | 局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 |
Publications (2)
Publication Number | Publication Date |
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JP2015200659A true JP2015200659A (ja) | 2015-11-12 |
JP5998419B2 JP5998419B2 (ja) | 2016-09-28 |
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JP2013513102A Expired - Fee Related JP5919608B2 (ja) | 2010-05-31 | 2011-05-13 | 局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 |
JP2015094777A Expired - Fee Related JP5998419B2 (ja) | 2010-05-31 | 2015-05-07 | 局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 |
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JP2013513102A Expired - Fee Related JP5919608B2 (ja) | 2010-05-31 | 2011-05-13 | 局所筋麻痺効果を有する非拡散型ボツリヌス毒素とその精製方法 |
Country Status (8)
Country | Link |
---|---|
US (3) | US9598683B2 (ja) |
EP (1) | EP2578228B1 (ja) |
JP (2) | JP5919608B2 (ja) |
KR (1) | KR101134146B1 (ja) |
CN (1) | CN102985102B (ja) |
AU (1) | AU2011262499B2 (ja) |
ES (1) | ES2659820T3 (ja) |
WO (1) | WO2011152618A2 (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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KR101134146B1 (ko) | 2010-05-31 | 2012-04-19 | 메덱스젠 주식회사 | 국소 근마비 효과를 갖는 비확산형 보툴리눔 독소와 그의 정제방법 |
KR101775682B1 (ko) * | 2015-11-30 | 2017-09-06 | 주식회사 대웅 | 보툴리눔 독소의 제조방법 |
Citations (1)
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WO2003082315A1 (fr) * | 2002-03-29 | 2003-10-09 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Remede contre l'hypermyotonie |
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KR101930962B1 (ko) * | 2010-01-25 | 2018-12-19 | 알러간, 인코포레이티드 | 단일-사슬 단백질의 그의 이-사슬 형태로의 세포내 전환 방법 |
KR101134146B1 (ko) * | 2010-05-31 | 2012-04-19 | 메덱스젠 주식회사 | 국소 근마비 효과를 갖는 비확산형 보툴리눔 독소와 그의 정제방법 |
EP3434346B1 (en) * | 2010-07-30 | 2020-09-02 | Medimmune, LLC | Purified active polypeptides or immunoconjugates |
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WO2003082315A1 (fr) * | 2002-03-29 | 2003-10-09 | Juridical Foundation The Chemo-Sero-Therapeutic Research Institute | Remede contre l'hypermyotonie |
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JPN6016019550; AOKI K R: 'A comparison of the safety margins of botulinum neurotoxin serotypes A, B, and F in mice' Toxicon Vol.39 No.12, 2001, Page.1815-1820 * |
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JPN6016019555; PEARCE L B: 'The median paralysis unit: a more pharmacologically relevant unit of biologic activity for botulinum' Toxicon Vol.33 No.2, 1995, Page.217-227 * |
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JPN6016019560; SCHANTZ E J: 'Properties and Use of Botulinum Toxin and Other Microbial Neurotoxins in Medicine' Microbiol Rev Vol.56 No.1, 1992, Page.80-99 * |
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WO2011152618A9 (ko) | 2012-03-22 |
US20130071331A1 (en) | 2013-03-21 |
ES2659820T3 (es) | 2018-03-19 |
JP2013533856A (ja) | 2013-08-29 |
KR20110131572A (ko) | 2011-12-07 |
US20170143849A1 (en) | 2017-05-25 |
CN102985102A (zh) | 2013-03-20 |
CN102985102B (zh) | 2016-06-08 |
US20170145399A1 (en) | 2017-05-25 |
AU2011262499A1 (en) | 2013-01-24 |
JP5998419B2 (ja) | 2016-09-28 |
EP2578228A4 (en) | 2013-10-02 |
JP5919608B2 (ja) | 2016-05-18 |
WO2011152618A3 (ko) | 2012-05-24 |
WO2011152618A2 (ko) | 2011-12-08 |
AU2011262499B2 (en) | 2015-01-22 |
US9598683B2 (en) | 2017-03-21 |
US10369235B2 (en) | 2019-08-06 |
KR101134146B1 (ko) | 2012-04-19 |
EP2578228A2 (en) | 2013-04-10 |
WO2011152618A4 (ko) | 2012-07-12 |
EP2578228B1 (en) | 2017-11-15 |
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