CN101974077A - Novel polypeptide compound - Google Patents
Novel polypeptide compound Download PDFInfo
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- CN101974077A CN101974077A CN2010102811879A CN201010281187A CN101974077A CN 101974077 A CN101974077 A CN 101974077A CN 2010102811879 A CN2010102811879 A CN 2010102811879A CN 201010281187 A CN201010281187 A CN 201010281187A CN 101974077 A CN101974077 A CN 101974077A
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Abstract
The invention relates to a novel polypeptide compound, in particular to a polypeptide compound capable of reducing plasma lipid, the synthesis of the polypeptide compound and the use of the polypeptide in the field of medicines. The amino acid sequence of the polypeptide compound is as follows: H X1 Q G T F T S D Y S K Y L X2 X3 Q A A K E F I A W L X4 X5 X6 X7 X8 X9 X10 N I A.
Description
Technical field
The present invention relates to a kind of new polypeptide compound, in particular to a kind of polypeptide compound that can reduce blood plasma lipide, and the application of the synthetic and field of medicaments of this polypeptide compound.
Background technology
Metabolism of fat or transhipment cause one or more lipids in the blood plasma to be higher than normal level unusually and are called hyperlipidemia.Hyperlipidemia is a kind of systemic disease, is meant that blood cholesterol (TC) and/or triglyceride level (TG) are too high or high density lipoprotein cholesterol (HDL-C) is low excessively, and modern medicine is referred to as hyperlipemia.Lipid is insoluble or be slightly soluble in water, must exist with the lipoprotein form with protein bound, and therefore, hyperlipidemia is generally hyperlipoproteinemia, and promptly serum lipoprotein concentration raises.Generally acknowledge hyperlipidemia at present, comprised hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia (Hypertriglyceridemia) and the plyability hyperlipidemia that the two is all high.
Hyperlipidemia is concealment, carrying out property and general to the infringement of health.It directly causes and quickens systemic atherosclerosis.Because the vitals of whole body all will rely on artery blood supply, oxygen supply,, will cause serious consequence in case artery is stopped up by atheromatous plaque.Wherein modal a kind of mortality disease is exactly a coronary heart disease.A large amount of research datas show, hyperlipidemia is the independent and important risk of mortality cardiovascular and cerebrovascular diseases such as cerebral apoplexy, coronary heart disease, myocardial infarction, cardiac sudden death.And serious chylomicronemia can cause acute pancreatitis in the hyperlipidemia, and this is a kind of mortality disease equally.
In addition, hyperlipidemia also is to promote advancings of disease such as hypertension, impaired glucose tolerance, diabetes.Hyperlipidemia also can cause fatty liver, liver cirrhosis, cholelithiasis, pancreatitis, retinal hemorrhage, blind, peripheral vascular disease, limping, hyperuricemia.Tendon shape, nodositas, palm plane and eye socket xanthoma, arcus juvenilis etc. on every side also can appear in some primary and familial hyperlipemia.
Fat-reducing medicament commonly used clinically at present is a trihydroxy-trimethylammonium glutaryl CoA reductase inhibitor (HMG-CoA reductase enzyme).This class medicine is that the synthetic rate-limiting enzyme of cell inner cholesterol is the inhibitor of HMG-CoA reductase enzyme, is a most widely used clinically at present class fat regulation medicine, because the English name of this class medicine all contains " statin ", so often abbreviate Statins as.From first his spit of fland medicine in 1987 was since lovastatin (lovastatin) is approved for the treatment hyperlipidaemia, and now existing a plurality of statinses can supply clinical selecting for use.The mechanism of stanin fat-reducing effect is thought at present because such rate-limiting enzyme that can suppress the synthetic commitment of cell inner cholesterol is the HMG-CoA reductase enzyme, cause the endocellular liberation cholesterol to reduce, and raise the expression of cell surface ldl receptor by feedback, thereby cell ldl receptor number increased and increased activity, quickened the removing of the residual grain of VLDL (or IDL) and LDL in the blood circulation.
Find in the clinical use that there is certain side effect in such medicine, mainly show as gastrointestinal reaction and the property crossed an ALT rising and kidney function damages such as stomachache, abdominal distension, diarrhoea, therefore be subjected to certain restriction in the clinical use, should forbid such medicine as pregnant woman and lactating women, liver, renal insufficiency person need careful this type of medicine of using.
Summary of the invention
An object of the present invention is to provide a kind of polypeptide compound of novelty, concrete aminoacid sequence is as follows:
H?X
1?Q?G?T?F?T?S?D?Y?S?K?Y?L?X
2?X
3?Q?A?A?K?E?F?I?A?W?L?X
4?X
5?X
6?X
7?X
8?X
9?X
10N?N?I?A
Wherein X1～X10 is selected from combination I or the listed amino-acid residue of combination II:
| Combination | X1 | X2 | X3 | X4 | X5 | X6 | X7 | X8 | X9 | X10 |
| I | S | D | E | M | N | T | K | R | N | R |
| II | A | E | G | V | K | G | R | P | S | K |
When X1～X10 is that the polypeptide of gained is when being selected from combination I
(polypeptide 1): H S Q G T F T S D Y S K Y L D E Q A AK E F I A W L M N T K R N R N N I A
When X1～X10 is that the polypeptide of gained is when being selected from combination II:
(polypeptide 2): H A Q G T F T S D Y S K Y L E G Q A
AKE F I A W L V K G R P S K N N I A
A further object of the invention provides another kind of novel polypeptide compound, and concrete aminoacid sequence is as follows:
H
dS?Q G T F T S X
1?Y S K X
2?L E E E A V R L FV Q W L M N T K R N R N D I A
X wherein
1Be selected from D or E; X
2Be selected from F or Y; That is:
(polypeptide 3): H
dS Q G T F T S D Y S K F L E E E A VR L F V Q W L M N T K R N R N D I A;
(polypeptide 4): H
dS Q G T F T S D Y S K Y L E E E A VR L F V Q W L M N T K R N R N D I A;
(polypeptide 5): H
dS Q G T F T S E Y S K F L E E E A VR L F V Q W L M N T K R N R N D I A;
(polypeptide 6): H
dS Q G T F T S E Y S K Y L E E E A VR L F V Q W L M N T K R N R N D I A;
Preferred X
1X during for D
2Be F, perhaps X
1X during for E
2Be Y; That is:
(polypeptide 3): H
dS Q G T F T S D Y S K F L E E E A VR L F V Q W L M N T K R N R N D I A;
(polypeptide 6): H
dS Q G T F T S E Y S K Y L E E E A VR L F V Q W L M N T K R N R N D I A;
The abbreviation of amino-acid residue used herein is as follows:
The amino acid trigram letter abbreviations amino acid trigram letter abbreviations of abridging of abridging
L-Ala Ala A leucine Leu L
Arginine Arg R Methionin Lys K
L-asparagine Asn N methionine(Met) Met M
Aspartic acid Asp D phenylalanine Phe F
Halfcystine Cys C proline(Pro) Pro P
Histidine His H Serine Ser S
Isoleucine Ile I Threonine Thr T
Glutamine Gln Q tryptophane Trp W
L-glutamic acid Glu E tyrosine Tyr Y
Padil Gly G Xie Ansuan Val V
2 serine residues are the D configuration among the polypeptide 3-6 that the present invention put down in writing, and use
dS represents.Except that illustrating in addition, all the other concrete amino acid are the L type.
Another object of the present invention provides the purposes of aforementioned polypeptides compound in treatment animal hyperlipidaemia.
Serum total cholesterol (TC) and triglyceride level (TG) all are the important indicators of serum lipid, also are the main projects of present clinical lipid determination.Generally acknowledge hyperlipidemia at present, comprised hypercholesterolemia (Hypercholesterolemia), hypertriglyceridemia (Hypertriglyceridemia) and the plyability hyperlipidemia that the two is all high.
The contriver is by giving the rat high fat diet, cause the animal high blood lipid model, model prepares the successfully described polypeptide of back subcutaneous injection, and test-results shows that polypeptide compound of the present invention can significantly reduce animal pattern serum TC, TG level, has the effect of tangible blood lipid reducing.
Further object of the present invention provides the purposes of aforementioned polypeptides compound aspect reduction animal ingestion amount.
On the other hand, the contriver has studied the influence of polypeptide that the present invention puts down in writing to the mouse food ration, test-results show mouse after the described polypeptide that gets an injection under the skin in half an hour food ration obviously descend.Thereby this effect shows polypeptide of the present invention and can have the effect that alleviates the weight of animals by reducing the animal ingestion amount, can be used for prevention and treatment of obesity.
The effect of polypeptide compound provided by the present invention aspect treatment animal hyperlipidemia and reduction food ration, wherein animal is mainly Mammals, refers in particular to the mankind.
Polypeptide of the present invention can form polypeptide drug composition with pharmacy suitable carriers or auxiliary material, by including but not limited to that following approach gives animal or human body: in the per os, nose, hypogloeeis, interior, subcutaneous, the straight colon of duodenum, vagina, mucous membrane, lung, transdermal, vein, muscle, intraocular, intracutaneous etc., the preferred vein or subcutaneous that adopts most preferably adopts subcutaneous mode administration.Resulting polypeptide drug composition can the unit dosage administration according to administering mode.Suitable formulation includes but not limited to powder agent, tablet, pill, capsule, lozenge, suppository, paster, intranasal spray, injection, implantable extended release preparation, lipid complex etc., preferred injection and the implantable extended release preparation of adopting most preferably adopts the subcutaneous injection agent in the injection.Polypeptide of the present invention can be united use with acceptable medical auxiliary materials of one or more physiology or carrier usually, the absorption that acceptable medical auxiliary materials of described physiology or carrier can be used for stablizing polypeptide of the present invention or increase or reduce polypeptide of the present invention.Acceptable medical auxiliary materials of physiology or carrier for example can comprise carbohydrate such as glucose, sucrose, dextran; oxidation inhibitor is xitix or gsh for example; sequestrant; low molecular weight protein; protection and absorption enhancer be lipid for example; reduce the removing of polypeptide of the present invention or the composition of hydrolysis, or vehicle or other stablizers and or buffer reagent.Wetting agent, emulsifying agent, dispersion agent be can also comprise, or microorganism growth or the sanitas that works are particularly useful for preventing.Various sanitass are known and comprise for example phenol and xitix.Those skilled in the art will recognize that the selection of acceptable medical auxiliary materials of multiple physiology or carrier for example depends on the route of administration of polypeptide of the present invention and specific physicochemical property.
Polypeptide of the present invention adopts the polypeptide synthesis method of present technique field routine synthetic.The preferred solid-phase synthesis that adopts is synthetic.
Embodiment
Embodiment does not limit protection scope of the present invention.Based on content disclosed by the invention, those skilled in the art can determine and use can be used for implementing other components of the present invention and working method.
The preparation of embodiment 1 polypeptide
(polypeptide 1): H S Q G T F T S D Y S K Y L D E Q A A KE F I A W L M N T K R N R N N I A;
(polypeptide 2): H A Q G T F T S D Y S K Y L E G Q A
AKE F I A W L V K G R P S K N N I A;
(polypeptide 3): H
dS Q G T F T S D Y S K F L E E E A V RL F V Q W L M N T K R N R N D I A;
(polypeptide 4): H
dS Q G T F T S D Y S K Y L E E E A V RL F V Q W L M N T K R N R N D I A;
(polypeptide 5): H
dS Q G T F T S E Y S K F L E E E A V RL F V Q W L M N T K R N R N D I A;
(polypeptide 6): H
dS Q G T F T S E Y S K Y L E E E A VR L F V Q W L M N T K R N R N D I A;
Aforementioned polypeptides is synthetic according to the polypeptide solid phase synthesis technique of this area routine.Concrete steps are as follows:
1, the preparation of resin
The FMOC-His of reincarnate (TRT)-2-Cl-TRT RESIN resin 350mg is placed the medium size reactor of Peptide synthesizer, add methylene dichloride (DCM) and soak 5min, add an amount of dimethyl formamide (DMF) and make the abundant swelling of resin.
2, the prolongation of peptide chain
After solution is drained in the reactor, 20% piperidines/DMF solution reaction concussion the 30min that adds 3ml, remove 9-fluorenylmethyloxycarbonyl (Fmoc), [A:20g phenol adds dehydrated alcohol (analytical pure) 5ml to wash back adding triketohydrindene hydrate detection reagent with DMF and DCM, add 147ml and heavily steam pyridine, after the dissolving, mix; The B:5g triketohydrindene hydrate is dissolved into 100ml dehydrated alcohol (analytical pure)] carry out triketohydrindene hydrate and detect, carry out next step reaction after presenting positive structure.
Order according to designed peptide sequence, choose successively Fmoc-AA-OH place reactor to carry out the prolongation of peptide sequence (promptly select amino acid with the Fmoc protection according to polypeptide 1,2,3,4,5,6 sequences successively from C end beginning, selected Fmoc-AA-OH is the amino acid side chain protecting group wherein: for the side chain protecting group tert-butyl ester (OtBu) of Asp, Glu; The side chain protecting group of Ser, Tyr, Thr is the tertiary butyl (tBu), is trityl (Trt) for Asn, Cys, Gln and His; For Lys, Trp is tertbutyloxycarbonyl (Boc); For Arg is 2,2,4,6,7-pentamethyl-Dihydrobenzofuranes-5-alkylsulfonyl (Pbf).Concrete steps are as follows:
Hydroxyl-benzo-triazole (anhydrous) (HOBT) to take by weighing 0.5mmolFmoc-AA-OH and 0.5mmol (0.068mg) 1-, be dissolved among the 1ml DMF, add 100 μ l (0.5mmol) DIC (DIC), mix 2min, join and react 1h in the reactor, determine reaction end with ninhydrin reaction, wash with DMF and DCM.
Repeat above-mentioned peptide elongation process successively according to each peptide sequence, finish to 37 peptide condensations.After solution is drained in the reactor, add 20% piperidines/DMF solution reaction concussion 30min of 3ml, remove 9-fluorenylmethyloxycarbonyl (Fmoc).Use DMF at last, DCM and methyl alcohol wash, vacuum is drained 2h, (proportioning of cutting reagent is: TFA/ water/thioanisole/phenol/EDT=82.5: 5: 5: 5: 2.5) the stirring at room reaction is 3 hours to add cutting reagent, after cutting finishes, be filled in the 40ml ice ether, add 1ml TFA again and wash resin one time with rubber suction bulb, in being filled into ether, adding diethyl ether, it is the fullest to be added to.Place 0 ℃ of precooling 30min.Supernatant is removed in centrifugation then, and vacuum-drying obtained thick peptide in 2 hours, and resulting polypeptide 1-6 is white powder.
Adopt dull and stereotyped isoelectric focusing method to survey polypeptide 1-6 iso-electric point (PI):
PI
Polypeptide 1=7.50-9.40; PI
Polypeptide 2=7.85-9.95; PI
Polypeptide 3=4.10-7.20; PI
Polypeptide 4=5.05-7.40; PI
Polypeptide 5=5.80-8.45; PI
Polypeptide 6=4.55-7.30;
ESI-MS measures
Embodiment 2HPLC assay
Acquisition polypeptide 1,2 is measured under following HPLC condition:
Chromatographic column: 4.6mm * 250mm, Inertsil ODS-SP;
Detect wavelength: 220nm;
Sampling volume: 10 μ l;
Flow velocity: 1.0ml/min
Moving phase: A:0.1%trifluoroacetic in 100%acetonitrile
B：0.1％trifluoroacetic?in?100％water；
Type of elution: gradient elution
The result:
Polypeptide 1 (peak 1)
| Peak# | Ret.time | Area | height | Area％ |
| 1 | 22.794 | 342160 | 10204 | 9.601 |
| 2 | 23.387 | 3221572 | 233329 | 90.399 |
| total | 3563732 | 243533 | 100 |
Polypeptide 2 (peak 4)
| Peak# | Ret.time | Area | height | Area％ |
| 1 | 10.827 | 442237 | 34990 | 2.311 |
| 2 | 17.756 | 423269 | 18450 | 2.211 |
| 3 | 18.217 | 545830 | 50649 | 2.852 |
| 4 | 18.551 | 17682808 | 1285203 | 92.389 |
| 5 | 22.765 | 45473 | 4581 | 0.238 |
| total | 19139617 | 1393873 | 100 |
The research of embodiment 3 reducing blood lipid
1.1 laboratory animal
60 of cleaning level wistar rats, body weight 140～160g, the male and female dual-purpose, Nanjing Medical University's animal center provides.
1.2 laboratory apparatus and medicine
The HITACH717 automatic clinical chemistry analyzer;
Methimazole sheet (Shanghai Zhongxi Pharmaceutical Co., Ltd.); Commercially available cholesterol, cholate, lard, yolk powder.
Polypeptide 1, polypeptide 2, polypeptide 3, polypeptide 4, polypeptide 5, polypeptide 6 adopt 1 record method of embodiment to prepare.Be mixed with desired concn with physiological saline during experiment.
1.3 high lipid food preparation
High lipid food is made by following material mixing: basal feed 78%, yolk powder 10%; Cholesterol 1%, cholate 0.5%, lard 10%, methimazole 0.5%.
2. experimental technique
Get 80 of qualified rats, be divided into 8 groups at random, 10 every group, i.e. polypeptide 1,2,3,4,5,6, group, hyperlipidemia model group and intact animal group.All the other each treated animal is equipped with high lipid food feeds every day except that normal group.Beginning in the 28th day taked rat blood serum to measure serum lipid concentrations in per 7 days after administration respectively, compared with the blank group until the animal serum lipid content to occur obviously changing, and showed the modeling success.Model prepares successfully follow-up continuous high fat feeds, and each polypeptide group is distinguished subcutaneous injection polypeptide 1,2,3,4,5,6 for three days on end, and model group and blank group wait capacity physiological saline.Take rat blood serum after administration finishes, measure the influence of 1,2,3,4,5,6 pairs of high fat rat blood serum lipids of polypeptide.Fasting be can't help water 12 hours before the each blood sampling of duration of test.
3, experimental result
Table 1 polypeptide 1,2,3,4,5,6 is for the influence (n=10) of high fat rat TG
Annotate:
*Compare with the blank group p＜0.01;
##Compare with model group p＜0.01.
Table 2 polypeptide 1,2,3,4,5,6 is for the influence (n=10) of high fat rat TC
Annotate:
*Compare with the blank group p＜0.05;
#Compare with model group p＜0.05.
Test-results shows that model prepares successfully in the time of the 42nd day, gives for three days on end after the polypeptide of the present invention that TG, TC content obviously descend in the high fat rat blood serum.Experimental result shows effectively blood lipid reducing of polypeptide provided by the present invention, has tangible reducing blood lipid.
Embodiment 4 reduces the food ration experiment
1. laboratory animal
The purebred mouse of C57BL6, this Leco Corp. of Shanghai.
2. experiment material
Polypeptide 1, polypeptide 2, polypeptide 3, polypeptide 4, polypeptide 5, polypeptide 6 adopt 1 record method of embodiment to prepare.Physiological saline is mixed with desired concn.
3. experimental technique
Get normal type (50 of the mouse of 20g ± 2g), be divided into 5 groups at random, physiological saline group, polypeptide 1 small dose group (100 μ g/kg), polypeptide 1 heavy dose of group (200 μ g/kg), polypeptide 2 small dose group (100 μ g/kg), polypeptide 2 heavy dose of groups (200 μ g/kg); All animal pellet feeds are normally fed, and freely drink water.All the other respectively organize the subcutaneous injection medicine except that the physiological saline group, physiological saline group subcutaneous injection equal-volume physiological saline.Weighing feed consumption in the different time sections.
4. experimental result
Table 3: polypeptide 1,2,3,4,5,6 influences (n=10) for the mouse food ration
*P＜0.05,
*P＜0.01,
* *Compare with the physiological saline group P＜0.001.
The short period of time can significantly be suppressed animal appetite after experimental result showed single administration, reduce food ration, and there is not the bad inhibition of any potential in 24 hours food rations of animal, when this experimental result shows the physiologically active of polypeptide of the present invention, also demonstrated suitable security.
Claims (8)
1. polypeptide compound, concrete aminoacid sequence is as follows:
H?X
1?Q?G?T?F?T?S?D?Y?S?K?Y?L?X
2?X
3?Q?A?A?K?E?F?I?A?W?L?X
4?X
5?X
6?X
7?X
8?X
9?X
10N?N?I?A，
Wherein X1～X10 is selected from combination I or the listed amino-acid residue of combination II:
2. the described polypeptide compound of claim 1, wherein aminoacid sequence is as follows:
H S Q G T F T S D Y S K Y L D E Q A A K E FI A W L M N T K R N R N N I A。
3. the described polypeptide compound of claim 1, wherein aminoacid sequence is as follows:
H A Q G T F T S D Y S K Y L E G Q A
A K E FI A W L V K G R P S K N N I A。
4. the polypeptide compound of a novelty, concrete aminoacid sequence is as follows:
H
dS?Q G T F T S X
1?Y S K X
2?L E E E A V R L FV Q W L M N T K R N R N D I A
X wherein
1Be selected from D or E; X
2Be selected from F or Y.
5. the described polypeptide compound of claim 4, feature is X
1X during for D
2Be F.
6. the described polypeptide compound of claim 4, feature is X
1X during for E
2Be Y.
7. the application of the arbitrary described polypeptide compound of claim 1-6 in preparation treatment hyperlipidemia medicine.
8. the application of the arbitrary described polypeptide compound of claim 1-6 in preparation inhibition animal ingestion amount medicine.
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| CN2010102811879A CN101974077A (en) | 2010-09-15 | 2010-09-15 | Novel polypeptide compound |
| CN201110283227.8A CN102432675B (en) | 2010-09-15 | 2011-09-14 | Novel polypeptide compound |
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|---|---|---|---|
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| EP2884994A4 (en) * | 2012-07-25 | 2016-07-20 | Hanmi Pharm Ind Co Ltd | Composition for treating hyperlipidemia comprising oxyntomodulin derivative |
| US9522946B2 (en) | 2011-06-10 | 2016-12-20 | Hanmi Science Co., Ltd. | Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
| US9724420B2 (en) | 2012-11-06 | 2017-08-08 | Hanmi Pharm. Co., Ltd. | Liquid formulation of protein conjugate comprising an oxyntomodulin derivative covalently linked to a non-peptidyl polymer to an immunoglobulin FC region |
| US9731031B2 (en) | 2011-06-17 | 2017-08-15 | Hanmi Science Co., Ltd. | Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof |
| US10233230B2 (en) | 2014-09-16 | 2019-03-19 | Hanmi Pharm. Co., Ltd. | Use of a long acting GLP-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease |
| US10513550B2 (en) | 2014-12-30 | 2019-12-24 | Hanmi Pharm Co., Ltd | Glucagon derivatives |
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Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0511986D0 (en) * | 2005-06-13 | 2005-07-20 | Imp College Innovations Ltd | Novel compounds and their effects on feeding behaviour |
| EP2487184A1 (en) * | 2007-02-15 | 2012-08-15 | Indiana University Research and Technology Corporation | Glucagon/GLP-1 receptor co-agonists |
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2010
- 2010-09-15 CN CN2010102811879A patent/CN101974077A/en active Pending
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2011
- 2011-09-14 CN CN201110283227.8A patent/CN102432675B/en active Active
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| US9522946B2 (en) | 2011-06-10 | 2016-12-20 | Hanmi Science Co., Ltd. | Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
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| US10442848B2 (en) | 2011-06-10 | 2019-10-15 | Hanmi Science Co., Ltd. | Oxyntomodulin derivatives and pharmaceutical composition for treating obesity comprising the same |
| US9731031B2 (en) | 2011-06-17 | 2017-08-15 | Hanmi Science Co., Ltd. | Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof |
| US11872283B2 (en) | 2011-06-17 | 2024-01-16 | Hanmi Science Co., Ltd | Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof |
| US10363320B2 (en) | 2011-06-17 | 2019-07-30 | Hanmi Science Co., Ltd. | Conjugate comprising oxyntomodulin and an immunoglobulin fragment, and use thereof |
| US9901621B2 (en) | 2012-07-25 | 2018-02-27 | Hanmi Pharm. Co., Ltd. | Composition for treating hyperlipidemia comprising oxyntomodulin derivative |
| CN107854691A (en) * | 2012-07-25 | 2018-03-30 | 韩美药品株式会社 | Treatment hyperlipidemia includes the composition for secreting acid regulation peptide derivant |
| EP2884994A4 (en) * | 2012-07-25 | 2016-07-20 | Hanmi Pharm Ind Co Ltd | Composition for treating hyperlipidemia comprising oxyntomodulin derivative |
| US10493132B2 (en) | 2012-07-25 | 2019-12-03 | Hanmi Pharm. Co., Ltd. | Composition for treating hyperlipidemia comprising oxyntomodulin derivative |
| US10550168B2 (en) | 2012-11-06 | 2020-02-04 | Hanmi Pharm. Co., Ltd. | Composition for treating diabetes or diabesity comprising oxyntomodulin analog |
| US10279041B2 (en) | 2012-11-06 | 2019-05-07 | Hanmi Pharm Co. Ltd. | Liquid formulation of long-lasting protein conjugate comprising the oxyntomodulin and an immunoglobulin fragment |
| US9724420B2 (en) | 2012-11-06 | 2017-08-08 | Hanmi Pharm. Co., Ltd. | Liquid formulation of protein conjugate comprising an oxyntomodulin derivative covalently linked to a non-peptidyl polymer to an immunoglobulin FC region |
| US11071785B2 (en) | 2012-11-06 | 2021-07-27 | Hanmi Pharm. Co., Ltd. | Liquid formulation of long-lasting protein conjugate comprising the oxyntomodulin and an immunoglobulin Fc region |
| US10435459B2 (en) | 2014-09-16 | 2019-10-08 | Hanmi Pharm. Co., Ltd. | Use of a long acting GLP-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease |
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| US11254724B2 (en) | 2014-12-30 | 2022-02-22 | Hanmi Pharm. Co., Ltd. | Glucagon derivatives |
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| Publication number | Publication date |
|---|---|
| CN102432675B (en) | 2014-09-10 |
| CN102432675A (en) | 2012-05-02 |
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