WO2021057661A1 - Composition pharmaceutique pour diminuer la glycémie - Google Patents

Composition pharmaceutique pour diminuer la glycémie Download PDF

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Publication number
WO2021057661A1
WO2021057661A1 PCT/CN2020/116525 CN2020116525W WO2021057661A1 WO 2021057661 A1 WO2021057661 A1 WO 2021057661A1 CN 2020116525 W CN2020116525 W CN 2020116525W WO 2021057661 A1 WO2021057661 A1 WO 2021057661A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
compound
metformin
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PCT/CN2020/116525
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English (en)
Chinese (zh)
Inventor
孙晶超
景小龙
Original Assignee
深圳信立泰药业股份有限公司
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Priority to CN202080066833.1A priority Critical patent/CN114401724B/zh
Publication of WO2021057661A1 publication Critical patent/WO2021057661A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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

Definitions

  • the present invention belongs to the field of medical invention, and specifically relates to a pharmaceutical composition for the treatment of type II diabetes in mammals including humans, in particular a fixed dose containing compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition for the treatment of type II diabetes in mammals including humans in particular a fixed dose containing compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof
  • Diabetes affects millions of people around the world and is considered to be one of the main threats to human death in the 21st century. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys, and nerves. Worldwide, the socio-economic burden of diabetes is very heavy.
  • Type II diabetes T2DM
  • Type I diabetes is characterized by lack of insulin, which is mainly caused by autoimmune-mediated destruction of pancreatic ⁇ -cells.
  • Type II diabetes is characterized by abnormal insulin secretion and subsequent insulin resistance. To prevent ketoacidosis, patients with type I diabetes must take exogenous insulin to survive. Although patients with type II diabetes are not as dependent on exogenous insulin as patients with type I diabetes, they may need exogenous insulin to control blood sugar levels.
  • Metformin has the effect of improving the blood glucose tolerance of type II diabetic patients and reducing the basal and postprandial blood glucose.
  • Metformin hydrochloride does not stimulate insulin secretion. It mainly acts on the peripheral tissues of the pancreatic islets, increases the sensitivity of peripheral tissues to insulin, increases the uptake and utilization of glucose, inhibits the absorption of glucose by the intestinal wall, and helps reduce postprandial blood sugar. It can also inhibit the production and output of glycogen on New Year's Day and help control fasting blood sugar.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a class of new agents developed for the treatment or improvement of blood glucose production control in patients with type II diabetes. Oral bioavailable DPP-4 inhibitors can retain the biological function of GLP-1 by truncating the biological activity of DPP-4. Therefore, these oral effective inhibitors have gradually become the main intervention measures for patients with T2DM.
  • the main representative drugs are the following: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin, Alogliptin and Trelagliptin.
  • PCT/CN2010/080370 describes a series of DPP-IV inhibitors with a new core structure. Compared with other DPP-IV inhibitors, this series of compounds has the advantages of higher effectiveness and higher selectivity. Among them, including compound A, its chemical name is: (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-tri (Azin-4(5H)-yl)methyl)-4-fluorobenzonitrile, molecular formula: C 17 H 19 FN 6 O, molecular weight: 342, chemical structural formula is the following formula (I):
  • the object of the present invention is to provide a combination of compound A and/or its chemically acceptable salt and metformin and/or its chemically acceptable salt for inhibiting the activity of dipeptidyl peptidase IV, the pharmaceutical composition can achieve reduction
  • the synergistic effect of sugar is beneficial to improve the hypoglycemic effect and reduce adverse drug reactions.
  • Compound A and/or its chemically acceptable salt and metformin and/or its chemically acceptable salt are significantly more effective than the single drug, especially when compound A is used alone.
  • the effect is better when the ratio of its salt to metformin or its salt is 1:20-1:350. Therefore, the combination of compound A or its salt and metformin or its salt has great clinical significance.
  • a hypoglycemic pharmaceutical composition characterized in that the pharmaceutical composition is composed of compound A and/or its pharmaceutically acceptable salt and metformin and/or its pharmaceutically acceptable salt, wherein the compound A or its pharmaceutically acceptable salt
  • the weight ratio of the above acceptable salt to metformin or its pharmaceutically acceptable salt is 1:20 to 1:350.
  • the aforementioned compound A and/or its pharmaceutically acceptable salt is a hypoglycemic pharmaceutical composition containing Compound A, or a pharmaceutically acceptable salt containing Compound A, or a pharmaceutically acceptable salt containing Compound A and Compound A Mix the resulting mixture in any ratio.
  • the mass ratio of the aforementioned compound A and/or its salt to metformin and/or its pharmaceutically acceptable salt is 1:20 to 1:350; specifically, in animal in vivo pharmacodynamics experimental studies, different dosage ratios There is a certain difference in the synergistic effect produced by the combination of compound A and metformin.
  • the mass ratio of the compound A and/or its salt to metformin and/or its pharmaceutically acceptable salt is 1:20 to 1:350
  • the drug combination has a relatively high synergistic potential; more specifically, the mass ratio of the compound A and/or its salt to metformin and/or its salt can be any specific value between 1:20 and 1:350 , Such as: 1:20, 6:125, 6:212.5, 6:250, 6:375, 6:425, 6:500, 6:750, 6:850, 6:1000, 6:1500, 6:2000 , 1:350, etc.; preferably, the mass ratio of the compound A and/or its salt to metformin and/or its salt is 6:125, 6:212.5, 6:250, 6:375, 6:425, 6 : 500, 6: 750, 6: 850, 6: 1000, 6: 1500, 6: 2000.
  • the aforementioned compound A and/or its pharmaceutically acceptable salt has a daily human dosage of 6-24 mg, and the aforementioned metformin and/or its pharmaceutically acceptable salt has a human daily dosage of 250-2000 mg.
  • the aforementioned pharmaceutical composition can be divided into specific dosage units according to the clinical administration dose.
  • the aforementioned pharmaceutical composition can be divided and prepared to contain Compound A and/or its pharmaceutically acceptable compounds.
  • the metformin and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition may be 250 mg, or 500 mg, Or 750 mg, or 850 mg, or 1000 mg, or 1250 mg, or 1350 mg, or 1500 mg, or 1700 mg, or 1750 mg, or 2000 mg; when the compound A and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 12 mg When it contains metformin and/or its pharmaceutically acceptable salt may be 250mg, or 500mg, or 750mg, or 850mg, or 1000mg, or 1250mg, or 1350mg, or 1500mg, or 1700mg, or 1750mg, or 2000mg; When the compound A and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition is 24 mg, the metformin and/or its pharmaceutically acceptable salt contained in the pharmaceutical composition may be 500 mg, or 750 mg, or 850 mg, or 1000mg, or 1250mg, or 1350mg, or 1500mg, or 1700mg, or 1750mg, or 2000m
  • Another object of the present invention is to provide a method for preparing the aforementioned pharmaceutical composition, which has simple steps and strong operability, and can realize industrial production to prepare the aforementioned pharmaceutical composition.
  • a method for preparing the aforementioned pharmaceutical composition comprises the step of mixing compound A and/or its salt with metformin and/or its pharmaceutically acceptable salt.
  • the mixing of the compound A and/or its salt with metformin and/or its pharmaceutically acceptable salt is a direct physical mixing of the two;
  • the physical mixing method includes, but is not limited to, a direct mixing method and an equal incremental method;
  • the equipment used for the physical mixing can be a conventional powder mixing equipment, preferably a V-type mixer.
  • the present invention provides a fixed-dose combination pharmaceutical composition of compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
  • the two active pharmaceutical ingredients of the pharmaceutical composition of the present invention are released immediately or slowly.
  • the pharmaceutical composition of the present invention may be in the form of a tablet, and particularly a film-coated tablet, or other oral dosage forms such as capsules and the like.
  • One aspect of the present invention relates to a fixed-dose combination dosage form of Compound A or its pharmaceutically acceptable salt and metformin or its pharmaceutically acceptable salt for medical administration.
  • the dosage form may be in powder or solid form, and includes tablets, hard capsules, soft capsules, oral solutions, sustained release agents, dripping pills, granules, granules, sustained release pellets or other oral dosage forms, and the like.
  • a specific solid dosage form relates to a tablet containing a fixed-dose combination of Compound A or a pharmaceutically acceptable salt thereof and metformin or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for preparing a fixed-dose combination pharmaceutical composition of compound A or its salt and metformin or its salt by dry granulation method and wet granulation method.
  • Another aspect of the present invention provides the use of the pharmaceutical composition of the present invention in the treatment of type 2 diabetes mellitus in mammals including humans, and the use includes administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a subject in need of the treatment.
  • Pharmaceutically acceptable salts of compound A or metformin include, but are not limited to, p-toluenesulfonate, benzoate, methanesulfonate, benzenesulfonate, phosphate, hydrochloride, sulfate, nitrate, di Phosphate, hydrobromide, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, palmitate, naphthalenesulfonate Acid salt, hydroxynaphthoate, laurate, lactate, malate, camphorsulfonate, ethanesulfonate, gluconate, glutamate, isethionate, mandelate , Pamoate (pamoate), mucate and pantothenate.
  • the two active pharmaceutical ingredients in the pharmaceutical composition of the present invention can have four release forms:
  • the pharmaceutical composition of the present invention is prepared by a wet granulation method, a dry granulation method, or a powder direct compression method.
  • the pharmaceutical composition is prepared by a wet granulation method. In one such embodiment, the pharmaceutical composition is prepared by a wet granulation method. In the wet granulation, high-shear granulation or fluidized bed granulation can be applied. In one embodiment, the use of fluidized bed granulation has the advantage of providing tablets with higher radial strength.
  • the pharmaceutical composition obtained by the powder direct compression method, dry granulation method, or wet granulation method can be compressed into tablets, packaged or metered into sachets.
  • the pharmaceutical composition comprises (1) Compound A or its pharmaceutically acceptable salt, which is the first active pharmaceutical ingredient; (2) Metformin or its salt such as hydrochloride, is the second Kinds of active pharmaceutical ingredients; and (3) one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include binders, fillers, disintegrants, surfactants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, sunscreens, and release agents.
  • binders fillers, disintegrants, surfactants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, sunscreens, and release agents.
  • binders fillers, disintegrants, surfactants, lubricants, plasticizers, preservatives, flavoring agents, solubilizers, colorants, dispersants, sunscreens, and release agents.
  • the binder includes, but is not limited to, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, starch slurry (such as corn starch slurry), sodium carboxymethyl cellulose, methyl cellulose, ethyl fiber Vegetarian, polyethylene glycol (such as PEG4000, PEG6000), gelatin solution, sucrose solution.
  • the fillers include, but are not limited to, microcrystalline cellulose, lactose, mannitol, starch (such as compressible starch), dextrin, sucrose, calcium bicarbonate, calcium sulfate, calcium sulfate dihydrate.
  • the filler can be used alone or in a mixture of two types.
  • the disintegrant can be a conventional disintegrant, such as croscarmellose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, dry starch, etc., or It is a new type of disintegrant.
  • the disintegrant can be used alone, or two or more different disintegrants can be used in combination.
  • the surfactant can be an anionic, cationic or neutral surfactant.
  • Anionic surfactants include sodium lauryl sulfate, sodium lauryl sulfonate, sodium oleyl sulfate, and sodium laurate mixed with stearate and talc.
  • Cationic surfactants include benzalkonium chloride and alkyl trimethyl ammonium bromide.
  • Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and sorbitan ester.
  • Embodiments of the wetting agent include poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearates.
  • the lubricant includes, but is not limited to, stearic acid, sodium stearyl fumarate, magnesium stearate and other stearates, talc, micronized silica gel, sodium lauryl sulfate, hydrogenated vegetable oil (such as hydrogenated castor oil) , Glyceryl behenate, polyethylene glycol, magnesium lauryl sulfate, pregelatinized starch (starch1500).
  • the plasticizer includes, but is not limited to, polyethylene glycol, propylene glycol, and glycerin.
  • the preservatives include, but are not limited to, benzoic acid, sodium benzoate, sorbic acid, potassium sorbate, sodium potassium sorbate, calcium propionate, sodium propionate, paraben, isopropyl paraben.
  • the correctives include sweeteners, fragrances, glues and effervescent agents, wherein the sweeteners can be sucrose, stevioside, monosyrup, aromatic syrup, glycerin, sorbitol, sodium saccharin, and protein sugar;
  • the mucilage agent can be sodium alginate, gum arabic, gelatin, methyl cellulose, sodium carboxymethyl cellulose;
  • the effervescent agent can be an organic acid such as citric acid, tartaric acid, and sodium bicarbonate.
  • the solubilizing agent includes, but is not limited to, sorbitan fatty acids, polysorbates, polyoxyethylene fatty acid esters, phospholipids, cholesterol, stearates (such as sodium stearate), oleates (such as sodium oleate) , Sodium lauryl sulfate, sodium dodecyl sulfonate.
  • the coloring agent includes but not limited to beet red, carmine, carotene, lemon yellow, pine leaf blue, sodium copper chlorophyllin, caramel, aluminum lake, yellow iron oxide, brilliant blue.
  • the dispersing agents include, but are not limited to, sodium tripolyphosphate, sodium hexametaphosphate, sodium pyrophosphate, silicates, triethylhexyl phosphoric acid, methylpentanol, cellulose derivatives, polyacrylamide, Gol Gum, fatty acid polyethylene glycol ester.
  • the sunscreen includes, but is not limited to, titanium dioxide, zinc oxide, and yellow iron oxide.
  • the release rate regulator is selected from sucrose, sodium chloride, surfactant, polyethylene glycol (PEG).
  • the present invention will appropriately add one or more of the above-mentioned excipients.
  • the above-mentioned auxiliary materials can be appropriately used according to the ordinary technical knowledge and common knowledge that they have mastered, and the present invention will not be further described.
  • the pharmaceutical composition can be prepared into a dosage form suitable for oral administration, such as: tablets (including ordinary tablets and coated tablets), buccal tablets, throat relievers, aqueous or oily suspensions, dispersible powders or Granules, emulsions, hard or soft capsules, syrups, pills, freeze-dried powders or tinctures. It can also be prepared into injections and creams, gels, ointments, emulsions, solutions, lotions, suspensions, tinctures, pastes, foams, aerosols, enemas, sprays suitable for topical administration. Suppositories, etc.
  • metformin or its salt such as hydrochloride of the present invention may be released immediately or slowly, and compound A or its salt may be released immediately or slowly.
  • the present invention also provides a method for treating mammals including human type 2 diabetes by oral administration of a therapeutically effective amount of a fixed-dose combination pharmaceutical composition of the present invention to a subject in need of the treatment.
  • the subject in need of the treatment is a human.
  • the pharmaceutical composition is in the form of a tablet, but may also be in the form of a capsule.
  • the pharmaceutical composition containing the fixed-dose combination can be administered once a day (QD), twice a day (BID), or three times a day (TID).
  • the present invention has the following advantages and beneficial effects:
  • a method for preparing the aforementioned pharmaceutical composition which has simple steps and strong operability, and can realize industrial production to prepare the aforementioned pharmaceutical composition.
  • the pharmaceutical composition of the present invention is more suitable for development as an excellent medicine for treating type II diabetes, which can be applied to the clinic, effectively guarantee the quality of the product, and provide a good guarantee for the safety and effectiveness of the medication.
  • the present invention will be further described in detail below in conjunction with examples, but the implementation of the invention is not limited thereto.
  • the doses of compound A benzoate used in the present invention are all based on compound A, and the doses of metformin hydrochloride are all based on metformin hydrochloride.
  • compound A benzoate-metformin hydrochloride pharmaceutical compositions with other mass ratios such as compound A benzoate-metformin hydrochloride drugs with mass ratios of 6:125, 6:250, 6:850, etc. combination.
  • mice general grade, weighing 17-20g, animal source: purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • ICR mice 300 ICR mice were adaptively reared for one week and the experiment started, and 280 were selected for this experiment. After fasting for 5 hours, they were randomly divided into 28 groups according to body weight and blood glucose base value, with 10 animals in each group. The dosage design is shown in Table 2-1.
  • the administration volume is 5mL/kg.
  • mice Each group of mice was orally orally administered with double distilled water, single drugs, and compound drugs in different proportions (see Table 2-1 for specific dosages). After 60 minutes, each group of mice received oral glucose 2.5g/kg. A small amount of blood was taken from the tail vein of the mice at 0, 15, 30, 60, and 120 minutes after the administration of glucose. The blood glucose changes of the mice were detected by the Roche blood glucose meter, and 120 minutes after the glucose load was calculated. The area under the blood glucose curve AUC 0-120min Glu (mmol/L.hr) decreasing rate and synergistic effect.
  • AUC 0-120min Glu decrease rate (AUC 0-120min Glu blank control group-AUC 0-120min Glu administration group)/AUC 0-120min Glu blank control group ⁇ 100%
  • Synergistic effect reduction rate of compound drug AUC 0-120min Glu- (compound A benzoate AUC 0-120min Glu reduction rate + metformin hydrochloride AUC 0-120min Glu reduction rate)
  • Compound A benzoate 0.6 mg/kg + metformin hydrochloride 200 mg/kg group drug dose ratio combination (6:2000) has a synergistic effect of -8%, mainly because the hypoglycemic effect of this dose ratio combination has reached the drug effect platform. It failed to show a synergistic effect, but the same dose ratio combination (compound A benzoate 0.15 mg/kg + metformin hydrochloride 50 mg/kg group) had a synergistic effect of 9%, indicating that this ratio has a synergistic effect.
  • mice general grade, weighing 17-20g, animal source: purchased from Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.
  • mice were adaptively reared for one week and the experiment was started, and 60 mice were selected for this experiment. After fasting for 5 hours, they were randomly divided into 6 groups according to body weight and blood glucose base value, with 10 animals in each group. The dosage design is shown in Table 3-1.
  • Control group single Intragastric administration
  • Compound A Benzoate 0.6 single Intragastric administration
  • the experimental method is the same as 2.3 experimental method.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • Emergency Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Est divulguée une composition pharmaceutique pour diminuer la glycémie, contenant le composé A (la formule structurale de celui-ci est telle que représentée dans la formule I ci-dessous) et/ou un sel pharmaceutiquement acceptable de celui-ci et de la metformine et/ou un sel pharmaceutiquement acceptable de celle-ci. La composition pharmaceutique peut réaliser l'effet synergique de diminution de la glycémie.
PCT/CN2020/116525 2019-09-27 2020-09-21 Composition pharmaceutique pour diminuer la glycémie WO2021057661A1 (fr)

Priority Applications (1)

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CN202080066833.1A CN114401724B (zh) 2019-09-27 2020-09-21 一种降糖药物组合物

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CN201910923261 2019-09-27
CN201910923261.3 2019-09-27

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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN102791701A (zh) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物
CN109692164A (zh) * 2017-10-20 2019-04-30 深圳信立泰药业股份有限公司 化合物a或其盐的药物组合物及其制备方法

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CN101904840B (zh) * 2009-06-08 2012-02-08 江苏恒瑞医药股份有限公司 治疗哺乳动物包括人2型糖尿病的药物组合物
EP3452003A4 (fr) * 2016-05-05 2019-06-26 Triastek, Inc. Forme pharmaceutique à libération contrôlée
CN108578419B (zh) * 2018-07-27 2019-10-15 深圳市泛谷药业股份有限公司 一种人参皂苷Rg1和二甲双胍的降糖药物组合物
CN113423404B (zh) * 2019-12-02 2023-09-29 成都苑东生物制药股份有限公司 一种黄嘌呤衍生物药物组合物及其制备方法

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CN102791701A (zh) * 2009-12-30 2012-11-21 上海复尚慧创医药研究有限公司 作为二肽基肽酶iv(dpp-iv)抑制剂的3-(3-氨基哌啶-1-基)-5-氧代-1,2,4-三嗪衍生物
CN109692164A (zh) * 2017-10-20 2019-04-30 深圳信立泰药业股份有限公司 化合物a或其盐的药物组合物及其制备方法

Non-Patent Citations (1)

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Title
YANG WENMING: "Treating Type2 Diabetes Mellitus using Saxagliptin, a Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, Combined with Metformin and its Effect on Islet β-Cell Function", JOURNAL OF CLINICAL MEDICAL LITERATURE, vol. 5, no. 101, 17 December 2018 (2018-12-17), pages 97 - 98, XP009526889, ISSN: 2095-8242, DOI: 10.16281/j.cnki.jocml.2018.a1.058 *

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