CA1041485A - Procede de purification de l'insuline - Google Patents

Procede de purification de l'insuline

Info

Publication number: CA1041485A
Authority: CA; Canada
Prior art keywords: insulin; gel; column; range; percent
Prior art date: 1975-01-29
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Expired

Application number

CA218,970A

Other languages

English (en)

Other versions

CA218970S (en

Inventor

Richard L. Jackson

John G. Stilz

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Eli Lilly and Co

Original Assignee

Eli Lilly and Co

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1975-01-29

Filing date

1975-01-29

Publication date

1978-10-31

1975-01-29 Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co

1975-01-29 Priority to CA218,970A priority Critical patent/CA1041485A/fr

1978-10-31 Application granted granted Critical

1978-10-31 Publication of CA1041485A publication Critical patent/CA1041485A/fr

Status Expired legal-status Critical Current

Links

NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims abstract description 240
102000004877 Insulin Human genes 0.000 title claims abstract description 128
108090001061 Insulin Proteins 0.000 title claims abstract description 128
229940125396 insulin Drugs 0.000 title claims abstract description 120
238000000034 method Methods 0.000 title claims abstract description 47
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims abstract description 15
229910052783 alkali metal Inorganic materials 0.000 claims abstract description 14
150000001340 alkali metals Chemical class 0.000 claims abstract description 14
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 17
239000000243 solution Substances 0.000 claims description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 10
238000010828 elution Methods 0.000 claims description 9
238000011068 loading method Methods 0.000 claims description 8
239000002245 particle Substances 0.000 claims description 7
229920005654 Sephadex Polymers 0.000 claims description 5
239000007864 aqueous solution Substances 0.000 claims description 5
229910017053 inorganic salt Inorganic materials 0.000 claims description 5
239000011780 sodium chloride Substances 0.000 claims description 5
235000015278 beef Nutrition 0.000 claims description 4
230000008961 swelling Effects 0.000 claims description 4
229920002307 Dextran Polymers 0.000 claims description 3
238000012856 packing Methods 0.000 claims description 3
238000002523 gelfiltration Methods 0.000 abstract description 5
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 29
229910052725 zinc Inorganic materials 0.000 description 29
239000011701 zinc Substances 0.000 description 29
239000000499 gel Substances 0.000 description 19
235000018102 proteins Nutrition 0.000 description 16
102000004169 proteins and genes Human genes 0.000 description 16
108090000623 proteins and genes Proteins 0.000 description 16
239000002904 solvent Substances 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
238000000746 purification Methods 0.000 description 9
238000001914 filtration Methods 0.000 description 7
101710114386 Insulin-like protein Proteins 0.000 description 6
108010076181 Proinsulin Proteins 0.000 description 6
102000007327 Protamines Human genes 0.000 description 6
108010007568 Protamines Proteins 0.000 description 6
238000001556 precipitation Methods 0.000 description 6
229940048914 protamine Drugs 0.000 description 6
239000000872 buffer Substances 0.000 description 5
239000004026 insulin derivative Substances 0.000 description 5
238000002360 preparation method Methods 0.000 description 5
238000000926 separation method Methods 0.000 description 5
238000002425 crystallisation Methods 0.000 description 4
230000008025 crystallization Effects 0.000 description 4
206010012601 diabetes mellitus Diseases 0.000 description 4
210000000496 pancreas Anatomy 0.000 description 4
238000005185 salting out Methods 0.000 description 4
150000003839 salts Chemical class 0.000 description 4
239000002585 base Substances 0.000 description 3
238000004587 chromatography analysis Methods 0.000 description 3
239000007863 gel particle Substances 0.000 description 3
239000012535 impurity Substances 0.000 description 3
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
102000003670 Carboxypeptidase B Human genes 0.000 description 2
108090000087 Carboxypeptidase B Proteins 0.000 description 2
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
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 2
102000005237 Isophane Insulin Human genes 0.000 description 2
108010081368 Isophane Insulin Proteins 0.000 description 2
238000010521 absorption reaction Methods 0.000 description 2
238000006243 chemical reaction Methods 0.000 description 2
238000010960 commercial process Methods 0.000 description 2
230000007423 decrease Effects 0.000 description 2
108700022849 desamido- insulin Proteins 0.000 description 2
239000012153 distilled water Substances 0.000 description 2
238000001962 electrophoresis Methods 0.000 description 2
239000000284 extract Substances 0.000 description 2
238000009472 formulation Methods 0.000 description 2
230000002218 hypoglycaemic effect Effects 0.000 description 2
230000002163 immunogen Effects 0.000 description 2
229940006445 isophane insulin Drugs 0.000 description 2
239000000463 material Substances 0.000 description 2
239000000203 mixture Substances 0.000 description 2
ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
239000011148 porous material Substances 0.000 description 2
229940070376 protein Drugs 0.000 description 2
238000011084 recovery Methods 0.000 description 2
238000009938 salting Methods 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000011734 sodium Substances 0.000 description 2
239000000725 suspension Substances 0.000 description 2
JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
OMDQUFIYNPYJFM-XKDAHURESA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[[(2r,3s,4r,5s,6r)-4,5,6-trihydroxy-3-[(2s,3s,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]methoxy]oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O[C@H]2[C@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)[C@H](O)[C@H](O)[C@H](O)O1 OMDQUFIYNPYJFM-XKDAHURESA-N 0.000 description 1
XRBWKWGATZNBFW-UHFFFAOYSA-N 2-[2-(2-ethenoxyethoxy)ethoxy]ethanol Chemical compound OCCOCCOCCOC=C XRBWKWGATZNBFW-UHFFFAOYSA-N 0.000 description 1
101800000263 Acidic protein Proteins 0.000 description 1
229920001817 Agar Polymers 0.000 description 1
229920000936 Agarose Polymers 0.000 description 1
241000199897 Alaria esculenta Species 0.000 description 1
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
239000005695 Ammonium acetate Substances 0.000 description 1
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
108090000317 Chymotrypsin Proteins 0.000 description 1
229920002261 Corn starch Polymers 0.000 description 1
206010013457 Dissociation Diseases 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
230000005526 G1 to G0 transition Effects 0.000 description 1
229920000926 Galactomannan Polymers 0.000 description 1
102000051325 Glucagon Human genes 0.000 description 1
108060003199 Glucagon Proteins 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
235000019759 Maize starch Nutrition 0.000 description 1
101100084155 Mus musculus Prpf40b gene Proteins 0.000 description 1
WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
108091005804 Peptidases Proteins 0.000 description 1
102000035195 Peptidases Human genes 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
239000012507 Sephadex™ Substances 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
241001090187 Trappea Species 0.000 description 1
239000007983 Tris buffer Substances 0.000 description 1
108090000631 Trypsin Proteins 0.000 description 1
102000004142 Trypsin Human genes 0.000 description 1
PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
239000008351 acetate buffer Substances 0.000 description 1
230000002378 acidificating effect Effects 0.000 description 1
239000008272 agar Substances 0.000 description 1
229940043376 ammonium acetate Drugs 0.000 description 1
235000019257 ammonium acetate Nutrition 0.000 description 1
235000019270 ammonium chloride Nutrition 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
XRCFXMGQEVUZFC-UHFFFAOYSA-N anisindione Chemical compound C1=CC(OC)=CC=C1C1C(=O)C2=CC=CC=C2C1=O XRCFXMGQEVUZFC-UHFFFAOYSA-N 0.000 description 1
229960002138 anisindione Drugs 0.000 description 1
238000013459 approach Methods 0.000 description 1
239000006286 aqueous extract Substances 0.000 description 1
238000004166 bioassay Methods 0.000 description 1
LEMUFSYUPGXXCM-JNEQYSBXSA-N caninsulin Chemical compound [Zn].C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC3N=CN=C3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1C=NC=N1 LEMUFSYUPGXXCM-JNEQYSBXSA-N 0.000 description 1
230000015556 catabolic process Effects 0.000 description 1
229960002376 chymotrypsin Drugs 0.000 description 1
239000007979 citrate buffer Substances 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
229920001577 copolymer Polymers 0.000 description 1
239000000287 crude extract Substances 0.000 description 1
239000013078 crystal Substances 0.000 description 1
238000006731 degradation reaction Methods 0.000 description 1
230000001419 dependent effect Effects 0.000 description 1
238000010494 dissociation reaction Methods 0.000 description 1
230000005593 dissociations Effects 0.000 description 1
208000018459 dissociative disease Diseases 0.000 description 1
238000009826 distribution Methods 0.000 description 1
-1 e.g. Proteins 0.000 description 1
230000000694 effects Effects 0.000 description 1
229940088598 enzyme Drugs 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000012847 fine chemical Substances 0.000 description 1
239000000727 fraction Substances 0.000 description 1
238000005194 fractionation Methods 0.000 description 1
210000004907 gland Anatomy 0.000 description 1
102000018146 globin Human genes 0.000 description 1
108060003196 globin Proteins 0.000 description 1
MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
229960004666 glucagon Drugs 0.000 description 1
230000002641 glycemic effect Effects 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
238000010324 immunological assay Methods 0.000 description 1
238000004255 ion exchange chromatography Methods 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
229910052751 metal Inorganic materials 0.000 description 1
239000002184 metal Substances 0.000 description 1
108010066090 neutral insulin Proteins 0.000 description 1
210000004923 pancreatic tissue Anatomy 0.000 description 1
230000000704 physical effect Effects 0.000 description 1
235000015277 pork Nutrition 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
230000001376 precipitating effect Effects 0.000 description 1
235000004252 protein component Nutrition 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008107 starch Substances 0.000 description 1
239000007858 starting material Substances 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000012588 trypsin Substances 0.000 description 1
239000011800 void material Substances 0.000 description 1
239000011592 zinc chloride Substances 0.000 description 1
235000005074 zinc chloride Nutrition 0.000 description 1

Landscapes

Peptides Or Proteins (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

CA218,970A 1975-01-29 1975-01-29 Procede de purification de l'insuline Expired CA1041485A (fr)

Priority Applications (1)

Application Number	Priority Date	Filing Date	Title
CA218,970A CA1041485A (fr)	1975-01-29	1975-01-29	Procede de purification de l'insuline

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
CA218,970A CA1041485A (fr)	1975-01-29	1975-01-29	Procede de purification de l'insuline

Publications (1)

Publication Number	Publication Date
CA1041485A true CA1041485A (fr)	1978-10-31

Family

ID=4102166

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA218,970A Expired CA1041485A (fr)	1975-01-29	1975-01-29	Procede de purification de l'insuline

Country Status (1)

Country	Link
CA (1)	CA1041485A (fr)

1975
- 1975-01-29 CA CA218,970A patent/CA1041485A/fr not_active Expired

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US3876623A (en)	1975-04-08	Process for purifying insulin
EP0567554B1 (fr)	1995-04-12	Procede de purification du facteur de croissance-1 analogue a l'insuline, sous une forme intacte et correctement pliee
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