WO2012130136A1 - 胰高血糖素样肽-1类似物单体、二聚体及其制备方法与应用 - Google Patents
胰高血糖素样肽-1类似物单体、二聚体及其制备方法与应用 Download PDFInfo
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- WO2012130136A1 WO2012130136A1 PCT/CN2012/073173 CN2012073173W WO2012130136A1 WO 2012130136 A1 WO2012130136 A1 WO 2012130136A1 CN 2012073173 W CN2012073173 W CN 2012073173W WO 2012130136 A1 WO2012130136 A1 WO 2012130136A1
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/605—Glucagons
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- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention relates to the field of diabetes-related drugs, and in particular, to a GLP-1 analog dimer having an in vivo half-life of prolonged glucagon-like peptide (GLP-1).
- GLP-1 GLP-1 analog dimer having an in vivo half-life of prolonged glucagon-like peptide
- the present invention also relates to a process for the preparation of the GLP-1 analog dimer and its use in the preparation of a medicament for the treatment of diabetes drugs, for the treatment and/or prevention of stagnation. Background technique
- Glucagon-like peptide-1 (GLP- 1 ) is a 37 amino acid polypeptide secreted mainly by small intestinal L cells. Its active form is
- GLP-1 (7-37) OH and GLP-1 (7-36) NH 2 (Mojsov S, J Clin Invest. 1987 Feb; 79(2): 616-9). GLP-1 significantly reduces blood sugar after eating, stimulates insulin production, and also has a certain weight loss effect, and does not cause hypoglycemia (Drucker DJ, Diabetes. 1998 Feb; 47(2): 159-69 ). Recent studies have also shown that GLP-1 has pancreatic regeneration (Drucker DJ, 2003 Dec; 144(12): 5145-8). In addition, because GLP-1 is a fully humanized polypeptide, it has a large safety advantage as a clinical drug. However, the serum half-life of GLP-1 (7-37) is only 3-5 minutes, and multiple injections per day are very inconvenient in clinical use.
- Another object of the present invention is to provide a process for the preparation of a GLP-1 analog dimer and a monomer thereof.
- Still another object of the present invention is to provide a use of a GLP-1 analog dimer for the preparation of a medicament for treating diabetes, and the GLP-1 analog dimer in the preparation of a medicament for treating and/or preventing obesity Applications.
- a further object of the present invention is to provide a pharmaceutical composition comprising a GLP-1 analogue dimer as an active ingredient, which comprises the above-mentioned GLP-1 analog dimer.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients
- the pharmaceutical composition is preferably an injection, further preferably a lyophilized powder or a solution for injection.
- the invention provides a glucagon-like peptide-1 analog monomer having the following formula I:
- X 1Q is glycine or cysteine
- X 15 is aspartic acid or cysteine
- X 22 is glycine or cysteine
- x 23 is leucine or cysteine
- x 3 is leucine or cysteine
- x 33 is valine or cysteine
- x 1 () , x 15 , x 22 , x 23 , x 3 Only one of x and 33 is cysteine.
- glucagon-like peptide-1 analog monomer as described above, which is selected from the group consisting of:
- the present invention provides a glucagon-like peptide-1 analog dimer formed by the joining of two monomeric molecules conforming to Formula I, forming two of said dimers Individual monomers may be the same or different;
- the analog dimer is linked by a disulfide bond formed by the monomer through cysteine Made.
- the present invention provides a method for producing the glucagon-like peptide-1 analog monomer or dimer, which comprises Fmoc strategy solid phase synthesis of cysteine-containing glucagon-like peptide -1 analog monomer.
- the cysteine of the produced glucagon-like peptide-1 analog monomer is further formed into a monomeric disulfide bond.
- a step of. the present invention provides the use of a glucagon-like peptide-1 analog monomer or dimer as described above for the preparation of a medicament for the treatment and/or diabetes and diabetes related diseases.
- the present invention provides the use of a glucagon-like peptide-1 analog monomer or dimer as described above for the preparation of a medicament for the treatment and/or prevention of obesity and obesity-related diseases.
- the obesity and obesity-related diseases are obesity and obesity-related diseases caused by diabetes.
- the present invention provides a pharmaceutical composition comprising a glucagon-like peptide-1 analog monomer or dimer as described above.
- the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.
- the pharmaceutical composition is an injection.
- the pharmaceutical composition is a lyophilized powder injection or a solution injection.
- the present invention provides a glucagon-like peptide-1 analog monomer of the present invention or the glucagon-like peptide-1 analog dimer for treating and/or preventing diabetes, Diabetes-related diseases or obesity and obesity-related diseases.
- the present invention provides a method of treating and/or preventing diabetes, a diabetes-related disease or an obesity and an obesity-related disease, the method comprising: administering to a subject a therapeutically effective amount of the present invention according to the present invention Glucagon-like peptide-1 analog monomer or glucagon-like peptide-1 analog dimer of the invention.
- the obesity and obesity-related diseases are obesity and obesity-related diseases caused by diabetes.
- the subject is a mammal, preferably a mammal. The following is a detailed description of the invention:
- the formula of the cysteine-containing GLP-1 analogue monomer of the present invention is as follows:
- the above cysteine-containing GLP-1 analog monomer is a synthetic sequence which is modified at amino acid 10, 15, 22, 23, 30 or 33 of GLP-1, and replaced by cysteine.
- the original amino acid forms a GLP-1 analogue monomer containing cysteine, and the sequence is as follows:
- the GLP-1 analog dimer is a cysteine-containing GLP-1 analog monomer which is formed by the formation of a disulfide bond by cysteine.
- One of the above amino acid sequences may be selected as one of the monomers of the analog dimer, and the other sequence may be the same sequence or other sequence.
- the pharmaceutical composition of the present invention is a pharmaceutical composition comprising a GLP-1 analog dimer which can be combined with one or more pharmaceutically acceptable excipients, the excipients comprising: a water-soluble filler, a pH adjuster , stabilizers, water for injection, osmotic pressure regulators, etc.
- the water-soluble filler adjuvant of the present invention is one or more selected from the group consisting of mannitol, low molecular dextran, sorbitol, polyethylene glycol, glucose, lactose, galactose and the like.
- the pH adjusting agent is one or more selected from the group consisting of non-volatile acids such as capric acid, phosphoric acid, lactic acid, tartaric acid, hydrochloric acid, and potassium hydroxide, sodium hydroxide or potassium hydroxide or ammonium hydroxide, and carbonic acid.
- non-volatile acids such as capric acid, phosphoric acid, lactic acid, tartaric acid, hydrochloric acid, and potassium hydroxide, sodium hydroxide or potassium hydroxide or ammonium hydroxide, and carbonic acid.
- Physiologically acceptable organic or inorganic acids and bases and salts such as sodium or potassium carbonate or ammonium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate or ammonium hydrogencarbonate.
- the stabilizer is one or more selected from the group consisting of: EDTA-2Na, sodium thiosulfate, sodium metabisulfite, sodium sulfite, dipotassium hydrogen phosphate, sodium hydrogencarbonate, sodium carbonate, arginine, glutamic acid, polyethylene Alcohol 6000, polyethylene glycol 4000, sodium lauryl sulfate or trihydroxydecylaminodecane.
- EDTA-2Na sodium thiosulfate
- sodium metabisulfite sodium sulfite
- sodium sulfite dipotassium hydrogen phosphate
- arginine sodium carbonate
- glutamic acid polyethylene Alcohol 6000
- polyethylene glycol 4000 polyethylene glycol 4000
- sodium lauryl sulfate or trihydroxydecylaminodecane Preferably, one or more of sodium metabisulfite, dipotassium hydrogen phosphate, arginine, polyethylene glycol 6000, and trishydroxyalkyla
- the osmotic pressure adjusting agent is sodium chloride and/or potassium chloride.
- the pharmaceutical composition of the present invention can be administered by intramuscular, intravenous or subcutaneous injection, and the preferred dosage form is a lyophilized powder or a solution for injection.
- Preparation method of lyophilized injection Take appropriate amount of GLP-1 analog dimer solution, add water-soluble filler, stabilizer, osmotic pressure regulator, etc., add appropriate amount of water for injection, adjust pH to 4-8 to dissolve, Dilute to the appropriate concentration with water, add 0.1-0.5% activated carbon, stir at 0 - 10 °C for 10-20 minutes, decarburize, filter and sterilize by microporous membrane filtration, filtrate for partial packing, freeze-drying method, White loose mass, sealed, each specification contains a GLP-1 analog dimer between 5 g and 1 mg.
- Preparation method of solution injection Take GLP-1 analog dimer solution or lyophilized powder, add water-soluble filler, stabilizer, osmotic pressure regulator, etc., add appropriate amount of water for injection, adjust pH to 4-8 Dissolve it, dilute to the appropriate concentration with water, add 0.1-0.5% activated carbon, stir at 0-10 °C for 10-20 minutes, decarburize, filter and sterilize by microporous membrane, the filtrate is divided, and the seal is obtained.
- Each specification contains a GLP-1 analog dimer between 5 g and 1 mg.
- the GLP-1 analog dimer of the present invention can be used in the preparation of a therapeutic drug for diabetes.
- the composition of the present invention can be administered in the form of intravenous, intramuscular or subcutaneous injection.
- the dosage will vary depending on the subject, mode of administration, symptoms and other factors.
- the GLP-1 analog dimers of the invention are effective over a relatively wide dosage range. In the treatment of adults, the dose ranges from 5 g/person to 1 mg/person, once daily or once every few days.
- the actual dose should be determined by the doctor according to the relevant circumstances, including the physical condition of the subject, the route of administration, age, weight, individual response of the patient to the drug, the severity of the patient's symptoms, etc., so the above dose range is The scope of the invention is not limited in any way.
- the GLP-1 analog dimer of the present invention overcomes the problem of short half-life of GLP-1, and the half-life of the GLP-1 analog dimer provided in the body can reach 8 to 96 hours or more, compared with GLP administered alone.
- the half-life of -1 (half-life is only 3-5 minutes) is significantly prolonged, greatly facilitating its clinical promotion and application.
- Figure 1 shows the hypoglycemic test of the GLP-1 analog dimer in Example 2, wherein each time period from left to right is SEQ 1 / 1 , SEQ 1 / 2, SEQ 1/3, SEQ 1/4, SEQ 1 /5, SEQ 1/6, SEQ 1 7 and physiological saline;
- Figure 2 shows the hypoglycemic test of the GLP-1 analog dimer in Example 3, wherein each time period from left to right is SEQ 2/1, SEQ 2/2, SEQ 2/3, SEQ 2/4, SEQ 2 /5, SEQ2/6, SEQ 2/7 and physiological saline;
- Figure 3 shows the hypoglycemic test of the GLP-1 analog dimer in Example 4, wherein each time period from left to right is SEQ. 3/4, SEQ3/5, SEQ 3/6, SEQ3 and physiological saline.
- Figure 4 shows the hypoglycemic test of the GLP-1 analog dimer in Example 5, wherein each time period from left to right is SEQ 4/5, SEQ 4/6, SEQ 4/7 and physiological saline;
- Figure 5 shows the hypoglycemic test of the GLP-1 analog dimer in Example 6, wherein each time period is SEQ 5/6, SEQ 5/7 and physiological saline from left to right;
- Figure 6 shows a hypoglycemic test of the GLP-1 analog dimer in Example 7, wherein each time period is SEQ 6/6, SEQ 6/7 and physiological saline from left to right;
- Fig. 7 shows a hypoglycemic test of the GLP-1 analog dimer in Example 8, wherein each time period is SEQ 7/7 and physiological saline from left to right. The best way to implement the invention
- mice used in the following examples were Kunming mice of 6-8 weeks, each weighing about 20 g.
- Example 1 Solid phase synthesis of polypeptide
- the synthesis of the cysteine-containing GLP-1 analog monomer of the present invention was carried out using a solid phase polypeptide synthesis method of the Fmoc strategy using a CS 336X type instrument manufactured by CSBio. The method of synthesis is carried out according to the manufacturer's instructions.
- the prepared cysteine-containing GLP-1 analog monomer was purified using a HPLC C18 semi-preparative column, and the mobile phase was acetonitrile.
- the dry powder of the GLP-1 analogue monomer containing cysteine is obtained by desalting and freeze-drying.
- the disulfide bond in this embodiment is formed by ammonium hydrogencarbonate or other reducing agent.
- Example 2 Hypoglycemic function associated with GLP-1 analog dimer (formed by SEO ID NO 1 and other GLP-1 analog monomers)
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 1 and SEQ ID NO 1 , respectively ( SEQ 1 / 1 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 1 and SEQ ID NO 2, respectively ( SEQ 1/2 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 1 and SEQ ID NO 3, respectively ( SEQ 1/3 ) ;
- the cysteine-containing GLP-1 analog monomers are SEQ ID NO 1 and SEQ ID NO, respectively.
- the cysteine-containing GLP-1 analog monomers are the analog dimers of SEQ ID NO 1 and SEQ ID NO 5 ( SEQ 1/5 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 1 and SEQ ID NO 6 , respectively ( SEQ 1 / 6 );
- the cysteine-containing GLP-1 analog monomer is the GLP-1 analog dimer of SEQ ID NO 1 and SEQ ID NO 7 (SEQ 1-7), respectively.
- mice 200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences.
- the blank in this example is subcutaneous injection of physiological saline (Saline). 30 minutes after administration of 400 ⁇ ⁇ glucose injection to each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection, respectively, after the first measurement of blood glucose, each time thereafter The same dose of glucose was given again two hours before the blood glucose was measured.
- Example 3 GLP-1 analog dimer (formed by SEO ID NO 2 and other GLP-1 analog monomers) associated hypoglycemic function.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 2 and SEQ ID NO 2, respectively ( SEQ 2/2 );
- the cysteine-containing GLP-1 analog monomers are SEQ ID NO 2 and SEQ ID NO, respectively.
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 2 and SEQ ID NO 4, respectively ( SEQ 2/4 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 2 and SEQ ID NO 5, respectively ( SEQ 2/5 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 2 and SEQ ID NO 6 , respectively ( SEQ 2/6 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 2 and SEQ ID NO 7 (SEQ2 ⁇ ), respectively.
- mice 200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences.
- the blank in this example is subcutaneous injection of physiological saline (Saline). 30 minutes after administration of 400 ⁇ ⁇ glucose injection to each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are SEQ ID NO 3 and SEQ ID NO 4, respectively.
- a GLP-1 analogue dimer SEQ 3/4 ) ;
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 3 and SEQ ID NO 5, respectively ( SEQ 3/5 ) ;
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 3 and SEQ ID NO 6 , respectively ( SEQ 3/6 ) ;
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 3 and SEQ ID NO 7 (SEQ. 3/7), respectively.
- mice 200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences.
- the blank in this example is injection saline (Saline).
- 400 glucose was injected into each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 4 and SEQ ID NO 5, respectively ( SEQ 4/5 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 4 and SEQ ID NO 6 , respectively ( SEQ 4/6 ) ;
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 4 and SEQ ID NO 7 (SEQ. 4/7), respectively.
- mice 200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences.
- the blank in this example is injection saline (Saline).
- 400 glucose was injected into each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 5 and SEQ ID NO 6 ( SEQ 5/6 );
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 5 and SEQ ID NO 7 (SEQ. 5/7), respectively.
- mice 200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences.
- the blank in this example is injection saline (Saline).
- 400 glucose was injected into each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomer is the GLP-1 analog dimer of SEQ ID NO 6 and SEQ ID NO 7 (SEQ 6/7).
- the analog dimer was dissolved in physiological saline at a concentration of 1 mg/mL and injected subcutaneously into mice (200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences).
- the blank in this example is Saline (Saline) was injected. After 30 minutes of administration, 400 glucose was injected into each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
- GLP-1 analog dimer employed is as follows:
- the cysteine-containing GLP-1 analog monomers are the GLP-1 analog dimers of SEQ ID NO 7 and SEQ ID NO 7 (SEQ 7/8), respectively.
- the analog dimer was dissolved in physiological saline at a concentration of 1 mg/mL and injected subcutaneously into mice (200 ⁇ 7, 6/group, purchased from Shanghai Experimental Animal Center of Chinese Academy of Sciences).
- the blank in this example is Saline (Saline) was injected. After 30 minutes of administration, 400 glucose was injected into each mouse.
- the blood glucose of the mice was measured at 2 hours, 24 hours, 48 hours, 72 hours, and 96 hours after the glucose injection. After the first measurement of blood glucose, the same dose of glucose was again given two hours before each blood glucose measurement.
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Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
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EP12763905.2A EP2894168A1 (en) | 2011-03-29 | 2012-03-28 | Glucagon-like peptide-1 analogue monomer and dimer, preparation method therefor and application thereof |
US14/405,066 US20150232527A1 (en) | 2011-03-29 | 2012-03-28 | Glucagon-like peptide-1 analogue monomer and dimer, preparation method therefor and application thereof |
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CN201110076380.3 | 2011-03-29 | ||
CN201110076380.3A CN102718858B (zh) | 2011-03-29 | 2011-03-29 | 胰高血糖素样肽-1类似物单体、二聚体及其制备方法与应用 |
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US11622996B2 (en) | 2018-05-07 | 2023-04-11 | Novo Nordisk A/S | Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid |
US12029779B2 (en) | 2017-10-12 | 2024-07-09 | Novo Nordisk A/S | Semaglutide in medical therapy |
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CN106554408A (zh) * | 2015-09-30 | 2017-04-05 | 天津药物研究院有限公司 | 长效胰高血糖素样肽-1类似物二聚体及其应用 |
CN107236033B (zh) * | 2016-03-29 | 2019-12-17 | 天津药物研究院有限公司 | 一种胰高血糖素样肽-1类似物及其制备方法和用途 |
CN107236034B (zh) * | 2016-03-29 | 2020-01-07 | 天津药物研究院有限公司 | 一种胰高血糖素样肽-1类似物及其制备方法和用途 |
CN107266555B (zh) * | 2016-04-06 | 2021-05-04 | 天津药物研究院有限公司 | 长效胰高血糖素样肽-1类似物二聚体及其医药应用 |
CN110845601B (zh) * | 2019-10-12 | 2021-01-19 | 广东药科大学 | 不同构型的glp-1类似肽修饰二聚体及其制备方法在治疗ii型糖尿病中的应用 |
CN115463208B (zh) * | 2021-10-09 | 2023-05-30 | 上海海赜生物科技有限公司 | 一种口服降糖组合物 |
CN115960202B (zh) * | 2021-10-09 | 2023-07-14 | 合肥天汇生物科技有限公司 | 一种glp-1类似物及其制备方法和应用 |
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CN102718858A (zh) | 2012-10-10 |
EP2894168A1 (en) | 2015-07-15 |
US20150232527A1 (en) | 2015-08-20 |
CN102718858B (zh) | 2014-07-02 |
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