CN101961336A - Medicainal composition for treating type 2 diabetes of mammals including human beings - Google Patents
Medicainal composition for treating type 2 diabetes of mammals including human beings Download PDFInfo
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- CN101961336A CN101961336A CN2009101403973A CN200910140397A CN101961336A CN 101961336 A CN101961336 A CN 101961336A CN 2009101403973 A CN2009101403973 A CN 2009101403973A CN 200910140397 A CN200910140397 A CN 200910140397A CN 101961336 A CN101961336 A CN 101961336A
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- 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
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- 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
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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Abstract
The invention discloses a medicinal composition for treating type 2 diabetes of mammals including human beings, particularly a medicinal composition prepared by mixing (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8,-tetrahydro-imidazo[1,5-a]-carboxylic methyl ether or pharmaceutically acceptable salt thereof and rosiglitazone or pioglitazone or pharmaceutically acceptable salts of the rosiglitazone or pioglitazone in fixed dose ratio, a method for preparing the medicinal composition, and application of the medicinal composition to treating type 2 diabetes in mammals including human beings.
Description
Technical field
The present invention relates to treat the pharmaceutical composition that mammal comprises people's type 2 diabetes mellitus; particularly contain rosiglitazone or pioglitazone or their pharmaceutically acceptable salts with (R)-7-[3-amino-4-(2; 4; 5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6; 7; 8-tetrahydrochysene-imidazo [1; 5-a] pharmaceutical composition of fixed dosage combination of pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt, prepare the method for described pharmaceutical composition and the purposes that described medicine composite for curing mammal comprises people's type 2 diabetes mellitus.
Background technology
People's type 2 diabetes mellitus is by relating to insulin resistant and slackening the chronic and gradual disease that the complicated pathophysiology of the dual endocrine defects of insulin secretion causes.The treatment of people's type 2 diabetes mellitus generally from diet and exercise, is carried out oral antidiabetic thing monotherapy subsequently.For many patients, this scheme can not be during long-term treatment abundant blood sugar control, this just causes needing to carry out conjoint therapy in several years after diagnosis.Yet two kinds or more kinds of oral antidiabetic things altogether-prescription can cause therapeutic scheme complicated and difficulty for the many patients that use.Two kinds or more kinds of anti-diabetic reagent are merged into single preparation to be provided and can not increase the possible mode of sending conjoint therapy that the patient treats the system complexity every day.
Dipeptidyl peptidase-IV (DPP-IV) inhibitor represents that class exploitation is used for the treatment of or improves the novel agent of the blood glucose generation control of suffering among the type 2 diabetes mellitus patient.At the medicine that in pre-Clinical, is used for the treatment of people's type 2 diabetes mellitus MK-0431, row spit of fland, Victor (LAF-237), saxagliptin (BMS-47718), P93/01 (Prosidon), SYR322 (Takeda), GSK823093, Roche0730699, TS021 (Taisho), E3024 (Eisai) and PHX-1149 (Phenomix) are arranged.Such as, have been found that row spit of fland, Victor is administered orally to human type 2 diabetes mellitus patient can reduce empty stomach glucose relevant with significantly reduced HbAIC level and glucose deviation after meal.Can be referring to the following discloses thing about the summary of using DDP-IV treatment type 2 diabetes mellitus: people such as (1) H.-U.Demuth, " Type 2diabetes-Theraphy with dipeptidylpeptidase IV inhibitors ", people such as Biochim.Biophvs.Acta.1751:33-44 (2005) and (2) K.Augustyns, " Inhibitors of proline-specific dipeptidylpeptidases:DPP4inhibitors as a novel approach for the treatment of Type 2diabetes ", Expert Opin.Ther.Patants, 15:1387-1407 (2005).
Some DPP-IV inhibitor are disclosed (US5462928, US5543396, WO9515309, WO2003004498, WO2003082817, WO2004032836, WO2004085661) at present, wherein the DPP-IV inhibitor MK-0431 of Merck company generation has shown that good DPP-IV suppresses activity and selectivity, and in listing in 2006.
For with the PPAR antidiabetic, particularly lattice row ketone be applied to the maturity-onset diabetes patient (body weight: 50kg), for example, every day, dosage was generally 0.01 to 1000mg, preferred 0.1 to 500mg.This dosage is used once and arrive several times every day.Especially, when pioglitazone hydrochloride was used as insulin sensitizers, every day, the dosage of pioglitazone hydrochloride normally 7.5 arrived 60mg, preferred 15 to 45mg.When rosiglitazone (perhaps maleate) was used as insulin sensitizers, every day, the dosage of rosiglitazone normally 1 arrived 12mg, preferred 2 to 12mg.
Lattice row ketone is preferably pioglitazone, pioglitazone hydrochloride or rosiglitazone, maleic acid pioglitazone or rosiglitazone, preferred especially pioglitazone hydrochloride.
The pharmaceutical dosage form of the combination of antidiabetic drug and thiazolidine diketone derivative has been proposed in this area.For example, EP00749751 has instructed the pharmaceutical composition that comprises insulin sensitivity enhancer (it is a thiazolidinedione compound) and the combination of other antidiabetics.More particularly, it is pioglitazone that EP00749751 instructs preferred insulin sensitivity enhancer, it can make up with other antidiabetics such as rosiglitazone, phenformin or buformin, and these medicines can discharge taste masked to be provided or to continue in conjunction with (mixing and/or coating) conventional excipients.Another example of the combination of antidiabetic drug and thiazolidine diketone derivative is a U.S. Patent number 6,011,049, this patent has been instructed the slow release form, as the single medicine compositions that contains pioglitazone or troglitazone and rosiglitazone or pioglitazone of osmotic pumps or skin patch form.Other combinations of antidiabetic drug and thiazolidine diketone derivative can be seen U.S. Patent number 6,524,621; 6,475,521; 6,451,342 and 6,153,632 and PCT patent application WO01/3594, they are incorporated herein by reference.
Have following structural formula (R)-7-[3-amino-4-(2,4,5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6,7,8-tetrahydrochysene-imidazo [1; 5-a] pyrazine-1-carboxylate methyl ester is formula (I) chemical compound, this chemical compound and salt thereof are disclosed in the Chinese patent application numbers 200710302335.9.
Formula (I)
Summary of the invention
The invention provides a kind of pharmaceutical composition that mammal comprises people's type 2 diabetes mellitus for the treatment of, described pharmaceutical composition contains rosiglitazone or pioglitazone or their pharmaceutically acceptable salts and formula (I) chemical compound or its pharmaceutically acceptable salt for the treatment of effective dose, wherein the weight ratio of rosiglitazone or its pharmaceutically acceptable salt and formula (I) chemical compound or its pharmaceutically acceptable salt is 1: 6.25-1: 75, and the weight ratio of pioglitazone or its pharmaceutically acceptable salt and formula (I) chemical compound or its pharmaceutically acceptable salt is 1: 3-1: 50.
Two kinds of active pharmaceutical ingredients in the pharmaceutical composition of the present invention are to discharge immediately or slowly discharge.Pharmaceutical composition of the present invention can be a tablet form, and particularly film coated tablets also can be for example capsule (comprising hard capsule and soft capsule), oral solution, slow releasing agent, drop pill, electuary, granule, slow-release micro-pill etc. of other peroral dosage forms.
An aspect of of the present present invention relates to the dosage form of the fixed dosage combination that is used for medical science Medicine-feeding type (I) chemical compound or its pharmaceutically acceptable salt and rosiglitazone or pioglitazone or their pharmaceutically acceptable salts.Described dosage form can be powder or solid form, and comprises tablet, capsule, pouch or the like.Concrete solid dosage forms relates to the tablet of the fixed dosage combination that contains formula (I) chemical compound or its pharmaceutically acceptable salt and rosiglitazone or pioglitazone or its pharmaceutically acceptable salt.
The present invention also provides the method by the pharmaceutical composition of the fixed dosage combination of drying or wet treatment method preparation formula (I) compound or its salt and rosiglitazone or pioglitazone or their salt.The dry process method comprises that dry method compression and dry granulation and wet treatment method comprise wet granulation.
Another aspect of the present invention provides pharmaceutical composition of the present invention to comprise that the treatment mammal purposes of people's type 2 diabetes mellitus, this purposes comprise that the main body that needs described treatment treats the pharmaceutical composition of the present invention of effective dose.
In specific embodiments of the present invention, pharmaceutical composition comprises (1) formula (I) chemical compound or its pharmaceutically acceptable salt, is first kind of active pharmaceutical ingredient; (2) rosiglitazone or pioglitazone or their salt are second kind of active pharmaceutical ingredient; (3) lubricant or fluidizer.In the specific embodiments of the present invention aspect this, pharmaceutical composition can also contain one or more excipient, and described excipient is selected from one or more binding agents (bonding agent); One or more diluent; One or more surfactants or wetting agent; One or more disintegrating agents; With one or more antioxidants.
The salt of formula (I) chemical compound pharmaceutically acceptable salt, rosiglitazone or pioglitazone includes but not limited to phosphate, hydrochlorate, sulfate, nitrate, hydrobromate, mesylate, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, benzene sulfonate, benzoate, naphthalene sulfonate, lactate or malate.
Integrating with formula (I) chemical compound in the pharmaceutical composition of the present invention or the day for human beings of its salt is 25 milligrams～300 milligrams with dosage.The day for human beings of preferred formula (I) chemical compound or its salt is 50 milligrams～200 milligrams with dosage.The discrete day for human beings is 25,50,75,100,150,200,250 and 300 milligrams of formula (I) chemical compounds or its salt with dosage.
Integrating with the rosiglitazone in the fixed dosage of the present invention combination or the day for human beings of its salt is 1 milligram～12 milligrams with dosage, the discrete day for human beings is 1,2,4,8,10 and 12 milligram with dosage, the day for human beings of pioglitazone or its salt is 7.5 milligrams～60 milligrams with dosage, and the discrete day for human beings is 7.5,15,30,45 and 60 milligrams with dosage.The daily dose form of these of rosiglitazone or pioglitazone or their salt is shown in the daily dosage that the approval of China and/or the U.S. is used for commercially available treatment people type 2 diabetes mellitus.
In fixed dosage combination of the present invention, formula (I) chemical compound or its salt and rosiglitazone or pioglitazone or their the salt day for human beings are as follows with the specific embodiments of dosage:
Formula (I) compound or its salt (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
Can be formula (I) compound or its salt and the rosiglitazone of any treatment effective dose or the compositions of pioglitazone or their salt of any treatment effective dose, for example: 50+2,50+4,100+2,100+4 or 50+7.5,50+15,50+30,50+45,75+7.5,75+15,100+30,100+45 or the like.
Two kinds of active pharmaceutical ingredients in the pharmaceutical composition of the present invention can have four kinds of releasing patterns:
Composition: formula (I) chemical compound or its rosiglitazone or pioglitazone
Salt or their salt
Discharge immediately immediately and discharge
Discharge slowly immediately and discharge
Slowly discharge immediately and discharge
Slowly discharge slowly and discharge
Pharmaceutical composition of the present invention is prepared by wet method or dry process method.In one embodiment, pharmaceutical composition is prepared by wet treatment method.At an apoplexy due to endogenous wind of this embodiment, pharmaceutical composition is prepared by the wet granulation method.In carrying out wet granulation, can use high shear granulation or fluid bed granulation.In one embodiment, using fluid bed granulation to have makes tablet have the more advantage of high radial strength.
The pharmaceutical composition that obtains by dry method or wet treatment method can be compressed into tablet, encapsulate or be metered in the pouch.
Pharmaceutical composition contains one or more lubricants or fluidizer.The example of lubricant comprises magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, castor oil hydrogenated or its mixture.Preferred lubricant is magnesium stearate or sodium stearyl fumarate or its mixture.The example of fluidizer comprises silica sol, calcium phosphate, magnesium silicate and Talcum.
Optional one or more binding agents that contains of pharmaceutical composition of the present invention.The embodiment of binding agent comprises hydroxypropyl cellulose (HPC), hydroxypropyl emthylcellulose (HMPC), hydroxyethyl-cellulose, starch 1500, polyvinylpyrrolidone (polyvinyl pyrrolidone) and copolymerization alkene pyrrone.Preferred adhesive is a polyvinylpyrrolidone.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferable absorbent is a microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH 101, Avicel PH 102, Avicel PH 103, Avicel PH 105 and Avicel PH 200 that FMC Corporation makes.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain disintegrating agent.Disintegrating agent can be a kind of in several modified starches, modified cellulose polymer or the polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is a croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also be chosen wantonly and contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprise sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and with stearate and the blended sodium laurate of Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.The neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
Can choose wantonly antioxidant is joined in the preparation, thereby give its chemical stability.Antioxidant is selected from the extract of alpha-tocopherol, Gamma-Tocopherol, Delta-Tocopherol, tocopherol enrichment natural origin, L-ascorbic acid and its sodium or calcium salt, anti-bad blood acyl cetylate, propyl gallate, gallate monooctyl ester, gallate dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet by the compression method preparation.Described tablet can contain titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian with filming such as the mixture of hydroxypropyl cellulose and hydroxypropyl emthylcellulose in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG) contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Perhaps any other suitable instant-free applies agent.Coating provides taste masked and other stability to final tablet.Commercially available film for Colorcon provide for the preparation mixture of powders
At last, if desired, can add sweeting agent and/or fumet.
Rosiglitazone of the present invention or pioglitazone or their salt both can be that to discharge immediately also can be slow release, and formula (I) compound or its salt can be to discharge immediately, also can be slow release.
Pharmaceutical tablet composition of the present invention can also contain one or more other preparation compositions that is selected from the known excipient of multiple field of pharmaceutical preparations.According to performance,, can separately or unite and select kind composition arbitrarily based on they known application in the preparation tablet composition to the expectation of drug regimen.Described composition includes but not limited to diluent, compression aid, fluidizer, disintegrating agent, lubricant, spice, fumet, sweeting agent and antiseptic.
Term " tablet " intention comprises the compression pharmaceutical dosage formulation of all shapes and size as used herein, no matter whether applies.The material that can be used to apply comprises hyprolose, hydroxypropyl emthylcellulose, titanium dioxide, Talcum, sweeting agent, coloring agent and fumet.
The present invention also provides by oral administration needs the fixed dosage composition of medicine combination treatment mammal a kind of of the present invention of the main body treatment effective dose of described treatment to comprise the method for people's type 2 diabetes mellitus.In one embodiment, it is human needing the main body of described treatment.In another embodiment, pharmaceutical composition is the form of tablet, also can be Capsule form.
Contain pharmaceutical composition (QD), every day twice (BID) or three (TID) administrations every day once a day of fixed dosage combination.
Formula (I) compound or its salt is to the active time ratio MK-0431 length that suppresses of DPP-IV, and inhibition strength is bigger than MK-0431.Research by experiment, the inventor is surprised to find: the compound recipe drug effect of formula (I) compound or its salt and rosiglitazone or pioglitazone or their salt is higher than the independent medication of arbitrary composition significantly, especially the proportioning when rosiglitazone or its salt and formula (I) compound or its salt is 1: 6.25-1: 75, and the proportioning of pioglitazone or its salt and formula (I) compound or its salt is 1: 3-1: 50 o'clock better effects if.Therefore, the compositions that formula (I) chemical compound or its salt and rosiglitazone or its salt are formed, the compositions that formula (I) chemical compound (hereinafter referred to as compd A, code name SP2086) or its salt and pioglitazone or its salt are formed is significant clinically.
The specific embodiment
Following examples have further described and have illustrated embodiment within the scope of the present invention.Embodiment and test example only are that for the purpose of illustration purpose provides, and are not intended it is considered as limitation of the present invention, and may there be the multiple variant that does not deviate from spirit and scope of the invention in it.
Embodiment 1, compd A phosphate and rosiglitazone maleate compound tablet
Write out a prescription every and contain:
Compd A phosphate 50mg
Rosiglitazone maleate 4mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with compd A phosphate, rosiglitazone maleate, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 2, compd A phosphate and pioglitazone hydrochloride compound tablet
Write out a prescription every and contain:
Compd A phosphate 50mg
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with compd A phosphate, pioglitazone hydrochloride, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 3, compd A hydrochlorate and rosiglitazone maleate compound tablet
Write out a prescription every and contain:
Compd A hydrochlorate 50mg
Rosiglitazone maleate 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A hydrochlorate, rosiglitazone maleate, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 4, compd A hydrochlorate and pioglitazone hydrochloride compound tablet
Write out a prescription every and contain:
Compd A hydrochlorate 50mg
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A hydrochlorate, pioglitazone hydrochloride, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 5, compd A mesylate and rosiglitazone maleate compound tablet
Write out a prescription every and contain:
Compd A mesylate 50mg
Rosiglitazone maleate 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A mesylate, rosiglitazone maleate, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 6, compd A mesylate and pioglitazone hydrochloride compound tablet
Write out a prescription every and contain:
Compd A mesylate 50mg
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A mesylate, pioglitazone hydrochloride, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 7, compd A tartrate and rosiglitazone maleate compound tablet
Write out a prescription every and contain:
Compd A tartrate 50mg
Rosiglitazone maleate 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A tartrate, rosiglitazone maleate, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 8, compd A tartrate and pioglitazone hydrochloride compound tablet
Write out a prescription every and contain:
Compd A tartrate 50mg
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A tartrate, pioglitazone hydrochloride, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 9, compd A malate and rosiglitazone maleate compound tablet
Write out a prescription every and contain:
Compd A malate 50mg
Rosiglitazone maleate 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A malate, rosiglitazone maleate, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Embodiment 10, compd A malate and pioglitazone hydrochloride compound tablet
Write out a prescription every and contain:
Compd A malate 50mg
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 12mg
2% starch slurry is an amount of
Magnesium stearate 0.5mg
Preparation method: with the compd A malate, pioglitazone hydrochloride, the microcrystalline Cellulose mixing is with 2% starch slurry wet granulation.Drying adds magnesium stearate, the mixing tabletting.
Similarly, by regulating compd A or its salt in the compound recipe, the consumption of rosiglitazone or its salt prepares the compound recipe of two kinds of active component that contain different proportion, and for example the ratio of rosiglitazone or its salt and compd A or its salt is 1: 6.25,1: 12.5,1: 25,1: 50,1: 75 or the like.
Perhaps, by regulating compd A or its salt in the compound recipe, the consumption of pioglitazone or its salt, the compound recipe for preparing two kinds of active component that contain different proportion, for example the ratio of pioglitazone or its salt and compd A or its salt is 7.5: 25,7.5: 50,7.5: 75,7.5: 100,7.5: 150,7.5: 375 or the like.
Test example 1: the external activity of compd A, MK-0431 and selectivity research
Method:
Before using, the DPP-IV-Glo. that thaws cushions and equilibrates to room temperature, the frozen fluorescein detectable of buffering suspension DPP-IV-Glo. adds the slight mix homogeneously of ultra-pure water in substrate after, is made the substrate of 1mM before using, the fluorescein detectable is put into amber bottle, add DPP-IV-Glo..The fluorescein detectable should be dissolved in 1 minute, with the DMSO dissolving institute chemical compound of surveying to finally operating 50 times of concentration, add in each test tube 50 times of concentration the chemical compound of surveying 2 μ L, in negative control and blank, add 2 μ LDMSO, in each test tube, add 46 μ L Tris buffer, add 48 μ L Tris buffer in blank, add 2 μ LDPP-IV enzymes in each test tube of negative control and test specimens, vibration mixes and centrifuge tube.Material in the test tube is all transferred on the flat board of 96-hole, and mixing substrate and DPP-IV-Glo. ratio is 1: 49.Vibration is mixed to abundant mixing.At room temperature left standstill before the use 30-60 minute, and in each 96-hole plate well, added the mixed liquor of 50 μ L DPP-IV-Glo. and substrate, seal flat board, under 300-500rpm/30s, slowly mix material in 96 holes with oscillator plate with the envelope film.At room temperature cultivated 30 minutes to 3 hours, and detected the chemiluminescence count value in the multi-functional microplate reader of NOVOstar.
[table 1]
The result: compd A is better than control drug MK-0431 to the inhibition activity of DPP-IV, and selectivity also is better than MK-0431.
Test example 2: different proportion rosiglitazone and compd A pharmaceutical composition are to normal ICR mice
The research of oral glucose tolerance
Male ICR mouse is in the rosiglitazone maleate of fasting oral distilled water, different proportionings after 6 hours: compd A phosphate=1: 6.25,1: 12.5,1: 25,1: 50,1: 75 same dose (10mg/kg) pharmaceutical composition, each is organized in administration oral glucose 2.5g/kg in the time of 30 minutes, does the oral glucose tolerance test.In getting blood in the time of 0,30,60,120 minute for the sugar back, measure serum level of glucose.
The serum glucose assay method;
Adopt the glucose content in the glucose kit mensuration serum, get 250 μ l enzyme working solutions, add 5 μ l serum, set up blank pipe (adding 5 μ l distilled waters) and standard pipe (adding 5 μ l glucoses mark liquid) simultaneously, mixing, 37 ℃ of water-baths 20 minutes are with the zeroing of blank pipe, the colorimetric determination of OD505nm place.
Serum glucose level BG (nmol/l)=OD
Sample cell/ OD
Standard pipe* 5.55
Date processing and statistical analysis;
1, adopt mean value SD and Student-t test that data are carried out statistical analysis
2, calculate blood glucose decline percentage rate and area under curve AUC when giving sugared back 30 minutes
[table 2]: the back influence to oral carbohydrate tolerance of normal ICR mice oral test pharmaceutical composition (10mg/kg) (mean value SD, n=6)
*, P＜0.05; Compare with the blank group;
*, P＜0.01; Compare with the blank group;
* *, P＜0.001; Compare with the blank group;
Test example 3: different proportion pioglitazone and compd A pharmaceutical composition are to normal ICR mice
The research of oral glucose tolerance
Male ICR mouse is in fasting oral distilled water, different proportioning (pioglitazone hydrochlorate: compd A phosphate=7.5: 25 after 6 hours, 7.5: 50,7.5: 75,7.5: 100,7.5: 150,7.5: the 375) mixture of same dose (30mg/kg), each is organized in administration oral glucose 2.5g/kg in the time of 30 minutes, does the oral glucose tolerance test.In getting blood in the time of 0,30,60,120 minute for the sugar back, measure serum level of glucose.
The serum glucose assay method;
Adopt the glucose content in the glucose kit mensuration serum, get 250 μ l enzyme working solutions, add 5 μ l serum, set up blank pipe (adding 5 μ l distilled waters) and standard pipe (adding 5 μ l glucoses mark liquid) simultaneously, mixing, 37 ℃ of water-baths 20 minutes are with the zeroing of blank pipe, the colorimetric determination of OD505nm place.
Serum glucose level BG (nmol/l)=OD sample cell/OD standard pipe * 5.55
Date processing and statistical analysis;
1, adopt mean value SD and Student-t test that data are carried out statistical analysis
2, calculate blood glucose decline percentage rate and area under curve AUC when giving sugared back 30 minutes
[table 3]: the back influence to oral carbohydrate tolerance of normal ICR mice oral test compound recipe thing (30mg/kg) (mean value SD, n=6)
*, P＜0.05; Compare with the blank group;
*, P＜0.01; Compare with the blank group;
* *, P＜0.001; Compare with the blank group;
The test example 4: compd A phosphate, MK-0431 respectively with rosiglitazone maleate or pyrrole
Uniting in the fertile Mus of the Wistar that takes and trouble diabetes fat of lattice row keto hydrochloride in heritability
Effect
The fertile Mus of the male Wistar in 14～19 ages in week is divided into 9 groups, every group 5～6, took distilled water, compd A phosphate, rosiglitazone maleate, pioglitazone hydrochlorate, MK-0431, MK-0431+ rosiglitazone maleate, MK-0431+ pioglitazone hydrochlorate, compd A phosphate+rosiglitazone maleate and compd A phosphate+pioglitazone hydrochlorate respectively 14 days.Get blood from the tail vein, use a kind of commercially available reagent box (NC-ROPET, NipponChemiphar CO.) measuring plasma glucose and HbA1 respectively with enzyme process. the result is expressed as the meansigma methods ± standard deviation of every group (n=5-6) and with Dunnett ' s check analysis, provides in table 4.Use 1% significance level.
[table 4]
*: P＜0.01 is compared with matched group
Compd A phosphate is united with rosiglitazone maleate or pioglitazone hydrochlorate and is taken the concentration that has clearly reduced blood-glucose and hemoglobin in the table 4, its intensity is individually dosed greater than compd A phosphate, rosiglitazone maleate, pioglitazone hydrochlorate, MK-0431's, and its intensity is greater than MK-0431 and rosiglitazone maleate or pioglitazone hydrochlorate drug combination.
Claims (9)
1. treat the pharmaceutical composition that mammal comprises people's type 2 diabetes mellitus for one kind; described pharmaceutical composition contain the rosiglitazone for the treatment of effective dose or pioglitazone or their pharmaceutically acceptable salts with (R)-7-[3-amino-4-(2; 4; 5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6; 7; 8-tetrahydrochysene-imidazo [1; 5-a] pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt, wherein rosiglitazone or its pharmaceutically acceptable salt with (R)-7-[3-amino-4-(2,4; 5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6,7,8-tetrahydrochysene-imidazo [1; 5-a] weight ratio of pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt is 1: 6.25-1: 75; pioglitazone or its pharmaceutically acceptable salt with (R)-7-[3-amino-4-(2,4,5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6; 7, the weight ratio of 8-tetrahydrochysene-imidazo [1,5-a] pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt is 1: 3-1: 50.
2. pharmaceutical composition according to claim 1, wherein said (R)-7-[3-amino-4-(2,4; 5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5,6,7; people's consumption per day of 8-tetrahydrochysene-imidazo [1,5-a] pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt is 25-300mg.
3. pharmaceutical composition according to claim 1, people's consumption per day of wherein said rosiglitazone or its pharmaceutically acceptable salt is 1-12mg, people's consumption per day of described pioglitazone or its pharmaceutically acceptable salt is 7.5-60mg.
4. according to each described pharmaceutical composition of claim 1-3, wherein said pharmaceutical composition is tablet, hard capsule, soft capsule, oral solution, slow releasing agent, drop pill, electuary, granule, slow-release micro-pill or other peroral dosage forms.
5. according to each described pharmaceutical composition of claim 1-4; wherein said (R)-7-[3-amino-4-(2; 4; 5-three fluoro-phenyl)-bytyry]-3-trifluoromethyl-5; 6; 7,8-tetrahydrochysene-imidazo [1,5-a] pyrazine-1-carboxylate methyl ester or its pharmaceutically acceptable salt are to discharge immediately or slowly discharge.
6. according to each described pharmaceutical composition of claim 1-5, wherein said rosiglitazone or pioglitazone or their pharmaceutically acceptable salts are to discharge immediately or slowly discharge.
7. according to each described pharmaceutical composition of claim 1-6, wherein said pharmaceutical composition be with once-a-day, the Pharmaceutical composition of twice on the one or three administrations on the one.
8. according to each described pharmaceutical composition of claim 1-7, wherein said pharmaceutically acceptable salt is selected from phosphate, hydrochlorate, sulfate, nitrate, hydrobromate, mesylate, maleate, tartrate, succinate, acetate, trifluoroacetate, fumarate, citrate, citrate, benzene sulfonate, benzoate, naphthalene sulfonate, lactate or malate.
9. comprise purposes in the medicine of people's diabetes as each described pharmaceutical composition of claim 1-8 preparation treatment mammal.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101403973A CN101961336B (en) | 2009-07-21 | 2009-07-21 | Medicainal composition for treating type 2 diabetes of mammals including human beings |
| PCT/CN2010/074309 WO2011009360A1 (en) | 2009-07-21 | 2010-06-23 | Pharmaceutical composition for treatment of type 2 diabetes in mammals including human beings |
| HK11107352.4A HK1153143A1 (en) | 2009-07-21 | 2011-07-15 | Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2009101403973A CN101961336B (en) | 2009-07-21 | 2009-07-21 | Medicainal composition for treating type 2 diabetes of mammals including human beings |
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| CN101961336A true CN101961336A (en) | 2011-02-02 |
| CN101961336B CN101961336B (en) | 2012-05-30 |
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| CN2009101403973A Active CN101961336B (en) | 2009-07-21 | 2009-07-21 | Medicainal composition for treating type 2 diabetes of mammals including human beings |
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| Country | Link |
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| CN (1) | CN101961336B (en) |
| HK (1) | HK1153143A1 (en) |
| WO (1) | WO2011009360A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108144065A (en) * | 2016-12-06 | 2018-06-12 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition of DPP-4 inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101287495A (en) * | 2005-06-10 | 2008-10-15 | 诺瓦提斯公司 | Direct compression formulation of DPP-IV inhibitors and glitazones, and process |
| CN101468988A (en) * | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | Piperazine derivative, preparation thereof and use thereof in medicine |
-
2009
- 2009-07-21 CN CN2009101403973A patent/CN101961336B/en active Active
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- 2010-06-23 WO PCT/CN2010/074309 patent/WO2011009360A1/en active Application Filing
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108144065A (en) * | 2016-12-06 | 2018-06-12 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition of DPP-4 inhibitor |
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| Publication number | Publication date |
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| CN101961336B (en) | 2012-05-30 |
| WO2011009360A1 (en) | 2011-01-27 |
| HK1153143A1 (en) | 2012-03-23 |
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