HRP20100164T1 - Postupak za pripremu smjesa polipeptida uz primjenu pročišćene bromovodične kiseline - Google Patents
Postupak za pripremu smjesa polipeptida uz primjenu pročišćene bromovodične kiseline Download PDFInfo
- Publication number
- HRP20100164T1 HRP20100164T1 HR20100164T HRP20100164T HRP20100164T1 HR P20100164 T1 HRP20100164 T1 HR P20100164T1 HR 20100164 T HR20100164 T HR 20100164T HR P20100164 T HRP20100164 T HR P20100164T HR P20100164 T1 HRP20100164 T1 HR P20100164T1
- Authority
- HR
- Croatia
- Prior art keywords
- glatiramer acetate
- solution
- hydrobromic acid
- acetic acid
- batch
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract 17
- 229920001184 polypeptide Polymers 0.000 title claims abstract 6
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract 6
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract 6
- 239000000203 mixture Substances 0.000 title claims abstract 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 title claims 15
- 150000003668 tyrosines Chemical class 0.000 claims abstract 9
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims abstract 3
- 235000004279 alanine Nutrition 0.000 claims abstract 3
- 239000012535 impurity Substances 0.000 claims abstract 3
- 229910021645 metal ion Inorganic materials 0.000 claims abstract 3
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000001413 amino acids Chemical group 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 39
- 108010072051 Glatiramer Acetate Proteins 0.000 claims 18
- 229960003776 glatiramer acetate Drugs 0.000 claims 18
- FHEAIOHRHQGZPC-KIWGSFCNSA-N acetic acid;(2s)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2s)-2-aminopentanedioic acid;(2s)-2-aminopropanoic acid;(2s)-2,6-diaminohexanoic acid Chemical compound CC(O)=O.C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 FHEAIOHRHQGZPC-KIWGSFCNSA-N 0.000 claims 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 6
- 229910052794 bromium Inorganic materials 0.000 claims 6
- 239000008194 pharmaceutical composition Substances 0.000 claims 6
- -1 trifluoroacetyl glatiramer acetate Chemical compound 0.000 claims 6
- 239000002516 radical scavenger Substances 0.000 claims 4
- RLRYVSYUAHQYLS-QMMMGPOBSA-N (2s)-2-(bromoamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](NBr)CC1=CC=C(O)C=C1 RLRYVSYUAHQYLS-QMMMGPOBSA-N 0.000 claims 2
- KNCHTBNNSQSLRV-YFKPBYRVSA-N (2s)-6-amino-2-[(2,2,2-trifluoroacetyl)amino]hexanoic acid Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)C(F)(F)F KNCHTBNNSQSLRV-YFKPBYRVSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 238000010828 elution Methods 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000012488 sample solution Substances 0.000 claims 2
- 241001550224 Apha Species 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 claims 1
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000005259 measurement Methods 0.000 claims 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 claims 1
- 238000002203 pretreatment Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 241000894007 species Species 0.000 claims 1
- 238000000108 ultra-filtration Methods 0.000 claims 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 abstract 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 abstract 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 abstract 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 abstract 1
- 239000004472 Lysine Substances 0.000 abstract 1
- 235000013922 glutamic acid Nutrition 0.000 abstract 1
- 239000004220 glutamic acid Substances 0.000 abstract 1
- 235000018977 lysine Nutrition 0.000 abstract 1
- 235000002374 tyrosine Nutrition 0.000 abstract 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
-
- 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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4713—Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Rehabilitation Therapy (AREA)
- Rheumatology (AREA)
- Toxicology (AREA)
- Zoology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Transplantation (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Postupak za dobivanje trifluoracetil glatiramer acetata, naznačen time, da se tijekom postupka, sa šarže smjese polipetida, koja se u biti sastoji od alanina, γ-benzil glutamata, tirozina i trifluoracetil lizina, skida zaštita otopinom bromovodične kiseline u octenoj kiselini, kod čega poboljšanje sadrži stupanj predobrade otopine bromovodične kiseline hvatačem broma, da bi se uklonio slobodni brom. Patent sadrži još 16 patentnih zahtjeva.
Claims (17)
1. Postupak za dobivanje trifluoracetil glatiramer acetata, naznačen time, da se tijekom postupka, sa šarže smjese polipetida, koja se u biti sastoji od alanina, γ-benzil glutamata, tirozina i trifluoracetil lizina, skida zaštita otopinom bromovodične kiseline u octenoj kiselini, kod čega poboljšanje sadrži stupanj predobrade otopine bromovodične kiseline hvatačem broma, da bi se uklonio slobodni brom.
2. Postupak za dobivanje farmaceutskog sastava koji sadrži glatiramer acetat, naznačen time, da sadrži
a) polimeriziranje N- karboksianhidrida od tirozina, alanina, γ-benzil glutamata i trifluoracetil lizina da bi se formirao zaštićeni glatiramer acetat;
b) skidanje zaštite sa zaštićenog glatiramer acetata otopinom bromovodične kiseline u octenoj kiselini, koja je otopina prethodno obrađena hvatačem broma radi uklanjanja slobodnog broma, da bi se formirao trifluoracetil glatiramer acetat;
c) dovođenje u reakciju trifluoracetil glatiramer acetata s vodenastim piperidinom, da bi se formirala otopina vodenastog glatiramer acetata; i
d) pročišćavanje glatiramer acetata.
3. Postupak prema patentnom zahtjevu 2, naznačen time, da nadalje sadrži podvrgavanje produkta iz stupnja d) ultrafiltraciji da se odstrane polipeptidne vrste s molekulskom masom manjom od 5000 daltona.
4. Postupak prema bilo kojem od patentnih zahtjeva 1-3, naznačen time, da otopina bromovodične kiseline u octenoj kiselini jest 10%-36%-tna bromovodična kiselina u octenoj kiselini.
5. Postupak prema patentnom zahtjevu 4, naznačen time, da otopina bromovodične kiseline u octenoj kiselini jest 33%-tna bromovodična kiselina u octenoj kiselini.
6. Postupak prema bilo kojem od patentnih zahtjeva 1-5, naznačen time, da hvatač broma jest fenol.
7. Postupak prema bilo kojem od patentnih zahtjeva 1-6, naznačen time, da je boja otopine bromovodične kiseline u octenoj kiselini manja od 2000 APHA.
8. Postupak za pripremanje farmaceutskog sastava koji sadrži glatiramer acetat, naznačen time, da glatiramer acetat ima predodređeni postotak bromiranog tirozina, prihvatljivog za uključivanje u farmaceutski sastav, koji postupak sadrži
dobivanje šarže glatiramer acetata;
mjerenje postotka bromiranog tirozina šarže postupkom koji sadrži
a) hidroliziranje šarže da se dobije hidrolizat;
b) eluiranje hidrolizata preko kromatografske kolone;
c) mjerenje razine bromtirozina u hidrolizatu;
d) pripremanje otopina uzoraka amino kiselinskih komponenata šarže i bromtirozina;
e) eluiranje otopina uzoraka preko kolone iz stupnja b); i
f) izračunavanje postotka bromiranog tirozina u šarži; i
uključivanje šarže u farmaceutski sastav samo onda, kada je njen postotak tako izmjerenog bromiranog tirozina manji od 0,3%.
9. Postupak prema patentnom zahtjevu 8, naznačen time, da je šarža prihvatljiva za uključivanje u farmaceutski sastav samo onda, kada je njen postotak tako izmjerenog bromiranog tirozina manji od 0,2%.
10. Postupak prema patentnom zahtjevu 9, naznačen time, da je šarža prihvatljiva za uključivanje u farmaceutski sastav samo onda, kada je njen postotak tako izmjerenog bromiranog tirozina manji od 0,1%.
11. Glatiramer acetat, naznačen time, da nema više od 0,1% bromiranog tirozina i da ima manje od 1000 ppm nečistoća metalnim ionima.
12. Glatiramer acetat prema patentnom zahtjevu 11, naznačen time, da ima prosječnu molekulsku masu od 4700 daltona do 11000 daltona.
13. Postupak za proizvodnju glatiramer acetata, naznačen time, da sadrži stupanj skidanja zaštite sa zaštićenog glatiramer acetata otopinom bromovodične kiseline u octenoj kiselini, pri čemu poboljšanje sadrži:
prethodnu obradu otopine bromovodične kiseline u octenoj kiselini hvatačem broma prije primjene otopine za skidanje zaštite sa zaštićenog glatiramer acetata.
14. Postupak prema patentnom zahtjevu 13, naznačen time, da otopina bromovodične kiseline u octenoj kiselini jest 10%-36%-tna bromovodična kiselina u octenoj kiselini.
15. Postupak prema patentnom zahtjevu 13, naznačen time, da otopina bromovodične kiseline u octenoj kiselini jest 33% bromovodična kiselina u octenoj kiselini.
16. Trifluoracetil glatiramer acetat, naznačen time, da nema više od 0,1% bromiranog tirozina i da ima manje od 1000 ppm nečistoća metalnim ionima.
17. Trifluoracetil glatiramer acetat prema patentnom zahtjevu 16, naznačen time, da ima prosječnu molekulsku masu od 4700 daltona do 11000 daltona.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60884304P | 2004-09-09 | 2004-09-09 | |
PCT/US2005/032395 WO2006029393A2 (en) | 2004-09-09 | 2005-09-09 | Process for preparation of mixtures of polypeptides using purified hydrobromic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
HRP20100164T1 true HRP20100164T1 (hr) | 2010-07-31 |
Family
ID=36037047
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HR20100164T HRP20100164T1 (hr) | 2004-09-09 | 2010-03-19 | Postupak za pripremu smjesa polipeptida uz primjenu pročišćene bromovodične kiseline |
HRP20120209TT HRP20120209T1 (hr) | 2004-09-09 | 2012-03-02 | Postupak za pripremu smjesa trifluoracetil glatirameracetata korištenjem pročišćene bromovodične kiseline |
HRP20140216TT HRP20140216T1 (hr) | 2004-09-09 | 2014-03-10 | Postupak za pripremu smjesa trifluoroacetil glatiramer acetata korištenjem proäśišä†ene bromovodiäśne kiseline |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
HRP20120209TT HRP20120209T1 (hr) | 2004-09-09 | 2012-03-02 | Postupak za pripremu smjesa trifluoracetil glatirameracetata korištenjem pročišćene bromovodične kiseline |
HRP20140216TT HRP20140216T1 (hr) | 2004-09-09 | 2014-03-10 | Postupak za pripremu smjesa trifluoroacetil glatiramer acetata korištenjem proäśišä†ene bromovodiäśne kiseline |
Country Status (28)
Country | Link |
---|---|
US (2) | US7495072B2 (hr) |
EP (3) | EP2177528B1 (hr) |
JP (1) | JP5149008B2 (hr) |
KR (1) | KR101317131B1 (hr) |
CN (1) | CN101166754B (hr) |
AT (2) | ATE454396T1 (hr) |
AU (1) | AU2005282249B2 (hr) |
BR (1) | BRPI0515033B1 (hr) |
CA (1) | CA2579656C (hr) |
CY (1) | CY1110280T1 (hr) |
DE (1) | DE602005018800D1 (hr) |
DK (3) | DK2361924T3 (hr) |
ES (3) | ES2382298T3 (hr) |
HK (3) | HK1100780A1 (hr) |
HR (3) | HRP20100164T1 (hr) |
IL (2) | IL181596A (hr) |
IS (1) | IS8622A (hr) |
MX (1) | MX2007002760A (hr) |
NO (1) | NO20071632L (hr) |
NZ (1) | NZ554018A (hr) |
PL (3) | PL1799703T3 (hr) |
PT (3) | PT1799703E (hr) |
RS (3) | RS51257B (hr) |
RU (1) | RU2388764C2 (hr) |
SI (3) | SI1799703T1 (hr) |
UA (1) | UA91029C2 (hr) |
WO (1) | WO2006029393A2 (hr) |
ZA (1) | ZA200702591B (hr) |
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EP1098902A4 (en) | 1998-07-23 | 2002-07-24 | Yeda Res & Dev | TREATMENT OF AUTOIMMUNE DISEASES BY COPOLYMER 1 AND SIMILAR COPOLYMERS AND PEPTIDES |
ES2527760T3 (es) * | 1998-07-23 | 2015-01-29 | Yeda Research And Development Co., Ltd. | Tratamiento de enfermedad de Crohn con copolímero 1 y polipéptidos |
US6800287B2 (en) | 1998-09-25 | 2004-10-05 | Yeda Research And Development Co., Ltd. | Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use |
WO2002076503A1 (en) * | 2000-06-20 | 2002-10-03 | Mayo Foundation For Medical Education And Research | Treatment of central nervous system diseases by antibodies against glatiramer acetate |
ES2349033T3 (es) * | 2001-12-04 | 2010-12-22 | Teva Pharmaceutical Industries, Ltd. | Procedimientos para la medida de la actividad del acetato de glatiramer. |
US20070244056A1 (en) * | 2004-03-03 | 2007-10-18 | Liat Hayardeny | Combination Therapy With Glatiramer Acetate and Riluzole |
SI1797109T1 (sl) * | 2004-09-09 | 2016-07-29 | Yeda Research And Development Co., Ltd. | Zmesi polipeptidov, sestavki, ki jih vsebujejo, in postopki za njihovo pripravo ter njihove uporabe |
CN101166754B (zh) * | 2004-09-09 | 2014-04-23 | 特瓦制药工业有限公司 | 使用纯化的氢溴酸制备多肽混合物的方法 |
US8324641B2 (en) * | 2007-06-29 | 2012-12-04 | Ledengin, Inc. | Matrix material including an embedded dispersion of beads for a light-emitting device |
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EP1848415B1 (en) * | 2005-02-17 | 2013-04-03 | Teva Pharmaceutical Industries, Ltd. | Combination therapy with glatiramer acetate and rasagiline for the treatment of multiple sclerosis |
EP1891233A4 (en) * | 2005-04-25 | 2010-03-24 | Yeda Res & Dev | MARKERS ASSOCIATED WITH THERAPY EFFECTIVENESS OF GLATIRAMERATE ACETATE |
US20090035816A1 (en) * | 2007-08-02 | 2009-02-05 | Scinopharm Taiwan Ltd. | Process for the preparation of a polypeptide |
AU2008330093A1 (en) * | 2007-11-28 | 2009-06-04 | Yeda Research And Development Co., Ltd. | Method of delaying the onset of clinically definite multiple sclerosis |
RU2010146489A (ru) | 2008-04-16 | 2012-05-27 | Момента Фармасьютикалз, Инк. (Us) | Анализ композиций сополимера аминокислот |
PL2307448T3 (pl) * | 2008-08-07 | 2015-10-30 | Sigma Aldrich Co Llc | Wytwarzanie polilizyny i poliornityny o małym ciężarze cząsteczkowym z wysoką wydajnością |
NZ590872A (en) * | 2008-08-07 | 2012-10-26 | Scinopharm Taiwan Ltd | Process for the preparation of polypeptide glatiramer acetate |
ES2523732T5 (es) * | 2009-04-03 | 2023-10-23 | Momenta Pharmaceuticals Inc | Control de composiciones de copolímeros |
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USRE49251E1 (en) | 2010-01-04 | 2022-10-18 | Mapi Pharma Ltd. | Depot systems comprising glatiramer or pharmacologically acceptable salt thereof |
US8759302B2 (en) * | 2010-03-16 | 2014-06-24 | Teva Pharmaceutical Industries, Ltd. | Methods of treating a subject afflicted with an autoimmune disease using predictive biomarkers of clinical response to glatiramer acetate therapy in multiple sclerosis |
MX2012012489A (es) * | 2010-04-27 | 2012-12-17 | Reddys Lab Ltd Dr | Preparacion de polipeptidos y sales de los mismos. |
PT2627669T (pt) | 2010-10-11 | 2016-11-24 | Teva Pharma | Biomarcadores de citocina como biomarcadores preditivos de resposta clínica para acetato de glatirâmero |
WO2012123959A2 (en) | 2011-02-14 | 2012-09-20 | Usv Limited | Copolymer-1, process for preparation and analytical methods thereof |
JP5701103B2 (ja) * | 2011-03-02 | 2015-04-15 | 昭和シェル石油株式会社 | 潤滑油のための消泡剤組成物及びそれを用いた消泡方法 |
WO2012143924A1 (en) | 2011-04-21 | 2012-10-26 | Mapi Pharma Ltd. | Random pentapolymer for treatment of autoimmune diseases |
WO2013009864A1 (en) | 2011-07-11 | 2013-01-17 | Momenta Pharmaceuticals, Inc. | Structure assessment of heterogeneous polypeptide mixtures |
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