WO2011009360A1 - Composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains - Google Patents

Composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains Download PDF

Info

Publication number
WO2011009360A1
WO2011009360A1 PCT/CN2010/074309 CN2010074309W WO2011009360A1 WO 2011009360 A1 WO2011009360 A1 WO 2011009360A1 CN 2010074309 W CN2010074309 W CN 2010074309W WO 2011009360 A1 WO2011009360 A1 WO 2011009360A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
pharmaceutically acceptable
acceptable salt
compound
pioglitazone
Prior art date
Application number
PCT/CN2010/074309
Other languages
English (en)
Chinese (zh)
Inventor
袁开红
马淑芹
刘华文
朱亚飞
李雷明
Original Assignee
江苏恒瑞医药股份有限公司
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.)
Filing date
Publication date
Application filed by 江苏恒瑞医药股份有限公司 filed Critical 江苏恒瑞医药股份有限公司
Publication of WO2011009360A1 publication Critical patent/WO2011009360A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients

Definitions

  • composition for treating mammals including human type 2 diabetes
  • the present invention relates to a pharmaceutical composition for treating a mammal, including human type 2 diabetes, particularly comprising rosiglitazone or pioglitazone or a pharmaceutically acceptable salt thereof and (R)-7-[3-amino-4-(2, 4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid
  • Human type 2 diabetes is a chronic and progressive disease caused by the complex pathophysiology of double endocrine defects involving insulin resistance and weakened insulin secretion.
  • Treatment for type 2 diabetes generally begins with diet and exercise followed by oral anti-diabetic monotherapy.
  • this regimen does not adequately control blood glucose during long-term treatment, which results in the need for combination therapy within a few years after diagnosis.
  • co-prescription of two or more oral anti-diabetic drugs can lead to complex and difficult treatment options for many patients used.
  • Combining two or more anti-diabetic agents into a single formulation provides a possible means of delivering combination therapies that do not increase the complexity of the patient's daily treatment regime.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of agents developed to treat or improve glycemic control in patients with type 2 diabetes.
  • the drugs used to treat human type 2 diabetes in current clinical trials include MK-0431, vildagliptin (LAF-237), saxagliptin (BMS-47718), P93/01 (Prosidon), SYR322 ( Takeda), GSK823093, Roche0730699, TS021 ( Taisho ), E3024 ( Eisai ) and PHX-1149
  • DPP-IV inhibitors have been disclosed (US5462928, US5543396, W09515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661), wherein the DPP-IV inhibitor MK-0431 produced by Merck has a good DPP-IV inhibitory activity and selection. Sex, and was listed in 2006.
  • the daily dose is usually 0.01 to 1000 mg, preferably 0.1 to 500 mg. This dose is administered once to several times a day.
  • the daily dose of pioglitazone hydrochloride is usually 7.5 to 60 mg, preferably 15 to 45 mg.
  • the daily dose of rosiglitazone is usually from 1 to 12 mg, preferably from 2 to 12 mg.
  • the glitazone is preferably pioglitazone, pioglitazone hydrochloride or rosiglitazone, pioglitazone maleate or rosiglitazone, particularly preferably pioglitazone hydrochloride.
  • EP 0 749 751 teaches a pharmaceutical composition comprising an insulin sensitivity enhancer which is a thiazolyldione compound in combination with other anti-diabetic agents. More particularly, EP 00749751 teaches that a preferred insulin sensitivity enhancer is pioglitazone, which can be combined with other anti-diabetic agents such as rosiglitazone, phenformin or buformin, and these drugs can be combined (mixed and/or coated) Conventional excipients are provided to provide taste masking or sustained release.
  • U.S. Patent No. 6,011,049 which teaches a sustained release form, such as an osmotic pump or a skin patch containing pioglitazone or troglitazone. And a single pharmaceutical composition of rosiglitazone or pioglitazone.
  • Other combinations of antidiabetic agents and thiazolidinedione derivatives can be found in U.S. Patent No. 6,524. 621; 6, 475, 521; 6, 451, 342 and 6, 153, 632 and PCT patent application WO 0 1/3 594, which are incorporated herein by reference.
  • the present invention provides a pharmaceutical composition for treating a mammal, including human type 2 diabetes, comprising a therapeutically effective amount of rosiglitazone or pioglitazone or a pharmaceutically acceptable salt thereof and a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the weight ratio of rosiglitazone or a pharmaceutically acceptable salt thereof to the compound of the formula (I) or a pharmaceutically acceptable salt thereof is 1:6.25-1:75, pioglitazone or The weight ratio of the pharmaceutically acceptable salt to the compound of formula (I) or a pharmaceutically acceptable salt thereof is from 1:3 to 1:50.
  • the two active pharmaceutical ingredients in the pharmaceutical compositions of the invention are either immediate or slow release.
  • 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 (including hard capsules and soft capsules), oral solutions, sustained release agents, pills. , granules, granules, sustained release pellets, etc.
  • One aspect of the invention relates to a dosage form for the pharmaceutical administration of a fixed dose combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof and rosiglitazone or pioglitazone or a pharmaceutically acceptable salt thereof.
  • the dosage form can be in powder or solid form and includes tablets, capsules, sachets and the like.
  • a specific solid dosage form relates to a tablet containing a combination of a fixed amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and rosiglitazone or pioglitazone or a pharmaceutically acceptable salt thereof.
  • the invention also provides a method for preparing a compound of the formula (I) by a drying or a wet treatment method or A method of combining a salt with a fixed dose of a pharmaceutical composition of rosiglitazone or pioglitazone or a salt thereof.
  • Dry processing methods include dry compression and dry granulation, and wet processing methods include wet granulation.
  • Another aspect of the invention provides the use of a pharmaceutical composition of the invention in the treatment of a mammal, including human type 2 diabetes, comprising administering to a subject in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the invention.
  • the pharmaceutical composition comprises (1) a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is the first active pharmaceutical ingredient; (2) rosiglitazone or pioglitazone or a a salt, which is a second active pharmaceutical ingredient; and (3) a lubricant or a glidant.
  • the pharmaceutical composition may also contain one or more excipients selected from one or more binders (binding agents); one or more a diluent; one or more surfactants or wetting agents; one or more disintegrants; and one or more antioxidants.
  • Salts of the pharmaceutically acceptable salts of the compounds of formula (I), rosiglitazone or pioglitazone include, but are not limited to, phosphates, hydrochlorides, sulfates, nitrates, hydrobromides, methanesulfonates, Malay Acid salt, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, besylate, benzoate, naphthalene sulfonate, milk Acid or malate.
  • the daily dose of the compound of the formula (I) or a salt thereof incorporated in the pharmaceutical composition of the present invention is 25 mg to 300 mg.
  • the daily dose of the compound of formula (I) or a salt thereof is from 50 mg to 200 mg.
  • Discrete human daily doses are 25, 50, 75, 100, 150, 200, 250 and 300 mg of the compound of formula (I) or a salt thereof.
  • the daily dose of rosiglitazone or a salt thereof incorporated in the fixed dose combination of the present invention is 1 mg to 12 mg, and the daily dose for discrete humans is 1, 2, 4, 8, 10 and 12 mg, pioglitazone or The daily dose of the salt is 7.5 mg ⁇ 60 mg, and the daily dose of the discrete person is 7.5, 15, 30, 45 and 60 mg.
  • These daily doses of rosiglitazone or pioglitazone or their salts represent daily doses approved for commercial treatment of human type 2 diabetes in China and/or the United States.
  • a specific embodiment of the daily dose of the compound of the formula (I) or a salt thereof and rosiglitazone or pioglitazone or a salt thereof is as follows:
  • a compound of the formula (I) or a salt thereof (mg) 25 , 50, 75, 100, 150, 200, 250, 300 Rosiglitazone or its salt (mg) 1, 2, 4, 8, 12
  • Pioglitazone or its salt (mg) 7.5, 15, 30, 45, 60
  • the two active pharmaceutical ingredients in the pharmaceutical compositions of the invention may have four release forms:
  • the pharmaceutical composition of the present invention is prepared by a wet or dry treatment method.
  • the pharmaceutical composition is prepared by a wet processing method.
  • the pharmaceutical composition is prepared by a wet granulation process. 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 dry or wet treatment can be compressed into tablets, packaged or metered into sachets.
  • the pharmaceutical composition contains one or more lubricants or glidants.
  • the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated castor oil or a mixture thereof.
  • a preferred lubricant is magnesium stearate or sodium stearyl fumarate or a mixture thereof.
  • the glidant include colloidal silica, calcium phosphate, magnesium silicate, and talc.
  • the pharmaceutical compositions of the invention optionally contain one or more binders.
  • the binder include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HMPC), hydroxyethylcellulose, starch 1500, polyvinylpyrrolidone (polypyrrolidone), and copolymerized olefins. Pyrone.
  • a preferred binder is polyvinylpyrrolidone.
  • compositions of the invention may also optionally contain one or more diluents.
  • the diluent include mannitol, sorbitol, calcium dihydrogen phosphate dihydrate, microcrystalline cellulose, and Powdered cellulose.
  • a preferred diluent is microcrystalline cellulose.
  • Microcrystalline cellulose can be obtained from several suppliers including Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 manufactured by FMC Corporation.
  • the pharmaceutical composition of the present invention may also optionally contain a disintegrant.
  • the disintegrant may be one of several modified starches, modified cellulose polymers or polycarboxylic acids, such as crosslinked hydroxymethylcellulose sodium, sodium starch glycolate, polakolin potassium and hydroxymethylcellulose. CMC Calcium o
  • the disintegrant is cross-linked hydroxymethylcellulose sodium.
  • Crosslinked hydroxymethylcellulose sodium NF type A is commercially available under the trade name "Ac-di-sol".
  • the pharmaceutical compositions of the present invention may also optionally contain one or more surfactants or wetting agents.
  • the surfactant can be an anionic, cationic or neutral surfactant.
  • Anionic surfactants include sodium lauryl sulfate, sodium dodecyl sulfonate, oleyl sulfate, and sodium laurate mixed with stearic acid and talc.
  • Cationic surfactants include benzalkonium chloride and decyltrimethylammonium bromide.
  • Neutral surfactants include glycerol monooleate, polyoxyethylene sorbitan fatty acid esters, polyvinyl alcohol and sorbitan esters.
  • Embodiments of the wetting agent include poloxamers, polyoxyethylene methyl ethers, polyoxyethylene castor oil derivatives, and polyoxyethylene stearates.
  • An antioxidant may optionally be added to the formulation to give it chemical stability.
  • the antioxidant is selected from the group consisting of ⁇ -tocopherol, ⁇ -tocopherol, ⁇ -tocopherol, tocopherol enriched natural extract, L-ascorbic acid and its sodium or calcium salt, ascorbyl palmitate, citric acid Propyl ester, octyl phthalate, dodecyl phthalate, butylated hydroxytoluene (oxime) and butylated hydroxyanisole (oxime).
  • the antioxidant is ruthenium or osmium.
  • a preferred dosage form of the pharmaceutical composition of the invention is a tablet prepared by a compression process.
  • the tablet may be coated with a mixture of, for example, hydroxypropylcellulose and hydroxypropylmethylcellulose, which contains titanium dioxide and/or other colorants such as iron oxide, dyes and lakes; polyvinyl alcohol A mixture of (PVA) and polyethylene glycol (PEG) containing titanium dioxide and/or other colorants such as iron oxide, dyes and lakes; or any other suitable immediate release coating.
  • the coating provides taste masking and additional stability to the final tablet.
  • Commercially available coatings are supplied by Colorcon to Opadry® for the formulation of powder blends.
  • sweeteners and/or flavoring agents can be added if desired.
  • the rosiglitazone or pioglitazone or a salt thereof of the present invention may be either immediate release or slow release, and the compound of the formula (I) or a salt thereof may be released immediately or slowly. freed.
  • the pharmaceutical tablet composition of the present invention may further contain one or more additional formulation ingredients selected from excipients known in the art of various pharmaceutical preparations. Depending on the desired properties of the pharmaceutical combination, any of the ingredients may be selected individually or in combination based on their known use in preparing the tablet composition.
  • additional formulation ingredients include, but are not limited to, diluents, compression aids, glidants, disintegrants, lubricants, perfumes, flavoring agents, sweeteners, and preservatives.
  • tablette as used herein is intended to include compressed pharmaceutical dosage formulations of all shapes and sizes, whether coated or not.
  • Materials which can be used for coating include hydroxypropylcellulose, hydroxypropylmethylcellulose, titanium dioxide, talc, sweeteners, colorants and flavoring agents.
  • the invention further provides a method of treating a mammal, including human type 2 diabetes, a therapeutically effective amount of a fixed dose combination pharmaceutical composition of the invention by oral administration of a subject in need of such treatment.
  • a mammal including human type 2 diabetes
  • a therapeutically effective amount of a fixed dose combination pharmaceutical composition of the invention by oral administration of a subject in need of such treatment.
  • the subject in need of such treatment is a human.
  • the pharmaceutical composition is in the form of a tablet, which may also be in the form of a capsule.
  • the pharmaceutical composition containing the fixed dose combination can be administered once daily (QD), twice daily (BID) or three times daily (TID).
  • the compound (I) or its salt inhibits DPP-IV activity longer than MK-0431, and the inhibition intensity is greater than MK-0431.
  • the present inventors have surprisingly found that the compound efficacy of the compound of the formula (I) or a salt thereof and rosiglitazone or pioglitazone or a salt thereof is remarkably higher than that of either component alone, especially when Rogge column
  • the ratio of the ketone or a salt thereof and the compound of the formula (I) or a salt thereof is 1:6.25 to 1:75, and the ratio of the pioglitazone or a salt thereof and the compound of the formula (I) or a salt thereof is from 1:3 to 1:50. better result.
  • composition of the compound of the formula (I) or a salt thereof and rosiglitazone or a salt thereof, a compound of the formula (I) (hereinafter referred to as a compound A, code SP2086) or a salt thereof and a composition of pioglitazone or a salt thereof It is of great clinical significance.
  • Example 1 Compound A phosphate and rosiglitazone maleate compound tablet Each prescription contains:
  • Magnesium stearate 0.5 mg Preparation method: Compound A phosphate, rosiglitazone maleate, microcrystalline cellulose was mixed and granulated by a 2% starch slurry. Dry, add magnesium stearate, and mix and compress.
  • Example 2 Compound A phosphate and pioglitazone hydrochloride compound tablet
  • Each piece contains:
  • Preparation method Compound A phosphate, pioglitazone hydrochloride, microcrystalline cellulose were mixed and granulated by a 2% starch slurry. Dry, add magnesium stearate, and mix and compress.
  • Example 3 Compound A hydrochloride and rosiglitazone maleate compound tablet
  • Each tablet contains:
  • Magnesium stearate 0.5 mg Preparation method: Compound A hydrochloride, rosiglitazone maleate, microcrystalline cellulose was mixed and granulated by a 2% starch paddle wet method. Dry, add magnesium stearate, and mix and compress.
  • Example 4 Compound A hydrochloride and pioglitazone hydrochloride compound tablet
  • Each prescription contains: Compound A Hydrochloride 50 mg
  • Magnesium stearate 0.5 mg Preparation method: Compound A hydrochloride, pioglitazone hydrochloride, microcrystalline cellulose was mixed and granulated by a 2% starch slurry. Dry, add magnesium stearate, and mix and compress.
  • Example 5 Compound A mesylate salt and rosiglitazone maleate compound tablet
  • Each piece contains:
  • Each tablet contains:
  • Magnesium stearate 0.5 mg Preparation method: Compound A methanesulfonate, pioglitazone hydrochloride, microcrystalline cellulose was mixed and granulated by a 2% starch paddle wet method. Dry, add magnesium stearate, and mix and compress.
  • Example 7 Compound A Tartrate and Rosiglitazone Maleate Compound Tablets Each tablet contains:
  • Magnesium stearate 0.5 mg Preparation method: Compound A tartrate, rosiglitazone maleate, microcrystalline cellulose were mixed and granulated by a 2% starch slurry. Dry, add magnesium stearate, and mix and compress.
  • Example 8 Compound A Tartrate and Pioglitazone Hydrochloride Compound Tablets
  • Each tablet contains:
  • Compound A Tartrate 50 mg Pioglitazone 15 mg Microcrystalline Cellulose 12 mg
  • Magnesium stearate 0.5 mg Preparation method: Compound A tartrate, pioglitazone hydrochloride, microcrystalline cellulose was mixed and granulated by a 2% starch slurry. Dry, add magnesium stearate, and mix and compress.
  • Example 9 Compound A malate and rosiglitazone maleate compound tablet
  • Each piece contains:
  • Preparation method Compound A malate, pioglitazone hydrochloride, microcrystalline cellulose was mixed and granulated by a 2% starch paddle wet method. Dry, add magnesium stearate, and mix and compress.
  • a compound containing two active ingredients in different ratios such as rosiglitazone or a salt thereof and Compound A or a salt thereof, is prepared by adjusting the amount of Compound A or a salt thereof, rosiglitazone or a salt thereof in the compound.
  • the ratio is 1:6.25, 1:12.5, 1:25, 1:50, 1:75, and so on.
  • a compound containing two active ingredients in different ratios for example, a ratio of pioglitazone or a salt thereof to Compound A or a salt thereof, of 7.5:25, is prepared by adjusting the amount of Compound A or a salt thereof, pioglitazone or a salt thereof in the compound. 7.5:50, 7.5:75, 7.5:100, 7.5:150, 7.5:375, etc.
  • Test Example 1 In vitro activity and selectivity of Compound A and MK-0431 Methods:
  • Glucose kit was used to determine the glucose content in the serum. 250 ⁇ 1 enzyme working solution was added, 5 ⁇ 1 serum was added, and a blank tube (add 5 ⁇ 1 double distilled water) and standard tube (add 5 ⁇ 1 glucose standard solution), mix and mix, 37°C water bath After 20 minutes, the blank tube was adjusted to zero, and the colorimetric measurement was performed at OD505nm.
  • Serum glucose content BG (nmol/1) OD sample tube / OD standard tube ⁇ 5 ⁇ 55
  • Test Example 3 Oral glucose tolerance study of different ratios of pioglitazone and Compound A pharmaceutical composition to normal ICR mice
  • Male ICR mice were orally administered after 6 hours of fasting Steamed water, different ratios (pioglitazone hydrochloride: compound A phosphate 7.5:25, 7.5:50, 7.5:75, 7.5:100, 7.5:150, 7.5:375) mixture of the same dose (30mg/kg)
  • Each group was given oral glucose 2.5 g/kg at 30 minutes of administration for oral glucose tolerance test. Blood was taken at 0, 30, 60, and 120 minutes after the sugar was given, and serum glucose levels were measured.
  • Glucose kit was used to determine the glucose content in the serum. 250W enzyme working solution was added, 5 ⁇ serum was added, and a blank tube (5W double distilled water) and a standard tube (5 ⁇ glucose standard solution) were added, and mixed, 37°C water bath. After 20 minutes, the blank tube was adjusted to zero, and the colorimetric measurement was performed at OD505nm.
  • Serum glucose content BG (nmol/1) OD sample tube / OD standard tube X 5.55 Data processing and statistical analysis;
  • Test Example 4 The compound bismuth phosphate, MK-0431 was administered in combination with rosiglitazone maleate or pioglitazone hydrochloride in hereditary obesity and Effect in Diabetic Wistar Rats Male Wistar rats aged 14 to 19 weeks were divided into 9 groups of 5 to 6 each, taking distilled water, Compound A phosphate, rosiglitazone maleate, pioglitazone Hydrochloride, MK-043K MK-0431 + rosiglitazone maleate, MK-0431 + pioglitazone hydrochloride, compound A phosphate + rosiglitazone maleate and compound A phosphate + pioglitazone salt Acid salt for 14 days.
  • Blood was taken from the tail vein, and blood glucose and hemoglobin A1 were measured by enzymatic method using a commercial kit (NC-ROPET, Nippon Chemiphar CO.). The results were expressed as the mean of each group (n 5-6). The standard deviation is analyzed by Dunnett's test and is given in Table 4. Use a 1% level of significance.
  • the combination of the compound A phosphate and the rosiglitazone maleate or pioglitazone hydrochloride in Table 4 significantly reduces the concentration of blood glucose and hemoglobin, which is stronger than the compound A phosphate, rosiglitazone maleic acid.
  • Salt, pioglitazone hydrochloride, MK-0431 are administered alone, and their strength is greater than that of MK-0431 in combination with rosiglitazone maleate or pioglitazone hydrochloride.

Landscapes

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

Abstract

La présente invention porte sur une composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains, notamment sur une composition pharmaceutique qui comporte une dose fixe de carboxylate de (R)-7-[3-amino-4-(2,4,5-trifluoro-phényl)-butyryl]-3-trifluorométhyl-5,6,7,8-tétrahydro-imidazo[1,5-a]pyrazine-1- méthyle ou ses sels de qualité pharmaceutique et de la rosiglitazone ou pioglitazone ou leurs sels de qualité pharmaceutique, sur un procédé de préparation de celle-ci et sur l'utilisation de la combinaison pharmaceutique pour traiter le diabète de type 2 chez des mammifères, comprenant les êtres humains.
PCT/CN2010/074309 2009-07-21 2010-06-23 Composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains WO2011009360A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200910140397.3 2009-07-21
CN2009101403973A CN101961336B (zh) 2009-07-21 2009-07-21 治疗哺乳动物包括人2型糖尿病的药物组合物

Publications (1)

Publication Number Publication Date
WO2011009360A1 true WO2011009360A1 (fr) 2011-01-27

Family

ID=43498754

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2010/074309 WO2011009360A1 (fr) 2009-07-21 2010-06-23 Composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains

Country Status (3)

Country Link
CN (1) CN101961336B (fr)
HK (1) HK1153143A1 (fr)
WO (1) WO2011009360A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108144065B (zh) * 2016-12-06 2023-05-16 江苏恒瑞医药股份有限公司 一种dpp-4抑制剂的药物组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101468988A (zh) * 2007-12-26 2009-07-01 上海恒瑞医药有限公司 哌嗪类衍生物,其制备方法及其在医药上的应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101287495A (zh) * 2005-06-10 2008-10-15 诺瓦提斯公司 Dpp-iv抑制剂和格列酮的直接压片的制剂和制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101468988A (zh) * 2007-12-26 2009-07-01 上海恒瑞医药有限公司 哌嗪类衍生物,其制备方法及其在医药上的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI XIULI: "The study progression of medicaments for the treatment of type 2 diabetes mellitus.", JOURNAL OF CHIFENG UNIVERSITY (NATURAL SCIENCE EDITION)., vol. 24, no. 1, January 2008 (2008-01-01), pages 124 *

Also Published As

Publication number Publication date
CN101961336A (zh) 2011-02-02
HK1153143A1 (en) 2012-03-23
CN101961336B (zh) 2012-05-30

Similar Documents

Publication Publication Date Title
JP5779566B2 (ja) ジペプチジルペプチダーゼ−４インヒビターとメトホルミンとを組み合わせた医薬組成物
US20120059011A1 (en) Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone
JP2011513408A (ja) メトホルミン及びジペプチジルペプチダーゼ−ｉｖ阻害剤の併用医薬組成物
US20120201885A1 (en) Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with pioglitazone
EP2402342B1 (fr) Composition pharmaceutique servant a traiter le diabete de type 2
US8476272B2 (en) Pharmaceutical composition for treatment of type 2 diabetes
WO2011009360A1 (fr) Composition pharmaceutique pour le traitement du diabète de type 2 chez des mammifères comprenant les êtres humains
CN101919851B (zh) 治疗哺乳动物包括人2型糖尿病的药物组合物
TWI494313B (zh) 治療包括人類之哺乳動物中第２型糖尿病的醫藥組成物
CN101904840B (zh) 治疗哺乳动物包括人2型糖尿病的药物组合物
TWI484955B (zh) 治療包括人類之哺乳動物中第２型糖尿病的醫藥組成物
TWI462925B (zh) 治療２型糖尿病的藥物組合物
TW201219384A (en) Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10801919

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 10801919

Country of ref document: EP

Kind code of ref document: A1