CN101961336A - 治疗哺乳动物包括人2型糖尿病的药物组合物 - Google Patents
治疗哺乳动物包括人2型糖尿病的药物组合物 Download PDFInfo
- Publication number
- 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
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- pharmaceutically acceptable
- acceptable salt
- pioglitazone
- rosiglitazone
- Prior art date
- Legal status (The legal status 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 status listed.)
- Granted
Links
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title claims abstract description 20
- 241000124008 Mammalia Species 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 title abstract description 26
- 241000282414 Homo sapiens Species 0.000 title abstract description 13
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims abstract description 78
- 150000003839 salts Chemical class 0.000 claims abstract description 69
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims abstract description 66
- 229960005095 pioglitazone Drugs 0.000 claims abstract description 39
- 229960004586 rosiglitazone Drugs 0.000 claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 claims description 44
- -1 electuary Substances 0.000 claims description 24
- 238000011282 treatment Methods 0.000 claims description 22
- 239000003826 tablet Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 18
- 229910019142 PO4 Inorganic materials 0.000 claims description 16
- 239000010452 phosphate Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 10
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- 229940049920 malate Drugs 0.000 claims description 8
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 8
- 229940095064 tartrate Drugs 0.000 claims description 8
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 7
- SPHPDQLTIQBHOY-UHFFFAOYSA-N methyl 2H-pyrazine-1-carboxylate Chemical compound COC(=O)N1CC=NC=C1 SPHPDQLTIQBHOY-UHFFFAOYSA-N 0.000 claims description 7
- 239000002552 dosage form Substances 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 206010012601 diabetes mellitus Diseases 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 claims description 2
- 229940100688 oral solution Drugs 0.000 claims description 2
- 239000007901 soft capsule Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 238000002156 mixing Methods 0.000 abstract description 26
- 238000000034 method Methods 0.000 abstract description 18
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 44
- 150000001875 compounds Chemical class 0.000 description 32
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 23
- 229940016286 microcrystalline cellulose Drugs 0.000 description 23
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 23
- 239000008108 microcrystalline cellulose Substances 0.000 description 23
- 229960003271 rosiglitazone maleate Drugs 0.000 description 23
- 235000019359 magnesium stearate Nutrition 0.000 description 22
- 229920002472 Starch Polymers 0.000 description 21
- 239000008103 glucose Substances 0.000 description 21
- 239000008107 starch Substances 0.000 description 21
- 235000019698 starch Nutrition 0.000 description 21
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 20
- 239000002002 slurry Substances 0.000 description 20
- 229960002827 pioglitazone hydrochloride Drugs 0.000 description 19
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 description 18
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 15
- GHUUBYQTCDQWRA-UHFFFAOYSA-N Pioglitazone hydrochloride Chemical compound Cl.N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 GHUUBYQTCDQWRA-UHFFFAOYSA-N 0.000 description 14
- 235000001727 glucose Nutrition 0.000 description 14
- 238000001035 drying Methods 0.000 description 13
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 13
- 229960004034 sitagliptin Drugs 0.000 description 13
- 238000005550 wet granulation Methods 0.000 description 13
- 238000012360 testing method Methods 0.000 description 12
- 210000002966 serum Anatomy 0.000 description 10
- 210000004369 blood Anatomy 0.000 description 8
- 239000008280 blood Substances 0.000 description 8
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 7
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 7
- 230000003203 everyday effect Effects 0.000 description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 239000003472 antidiabetic agent Substances 0.000 description 5
- 239000012153 distilled water Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 230000003178 anti-diabetic effect Effects 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000007619 statistical method Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- 229940127003 anti-diabetic drug Drugs 0.000 description 3
- 230000003078 antioxidant effect Effects 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- 229940122355 Insulin sensitizer Drugs 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000011262 co‐therapy Methods 0.000 description 2
- 229960001681 croscarmellose sodium Drugs 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 238000009477 fluid bed granulation Methods 0.000 description 2
- 150000002304 glucoses Chemical class 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229940127017 oral antidiabetic Drugs 0.000 description 2
- 238000007410 oral glucose tolerance test Methods 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000012224 working solution Substances 0.000 description 2
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 2
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 102000003779 Dipeptidyl-peptidases and tripeptidyl-peptidases Human genes 0.000 description 1
- 108090000194 Dipeptidyl-peptidases and tripeptidyl-peptidases Proteins 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 102000017011 Glycated Hemoglobin A Human genes 0.000 description 1
- 108010014663 Glycated Hemoglobin A Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- 239000002211 L-ascorbic acid Substances 0.000 description 1
- 235000000069 L-ascorbic acid Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- ZLWULWWXACZTPR-UHFFFAOYSA-N [ClH]=O Chemical compound [ClH]=O ZLWULWWXACZTPR-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007767 bonding agent Substances 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 229960004111 buformin Drugs 0.000 description 1
- XSEUMFJMFFMCIU-UHFFFAOYSA-N buformin Chemical compound CCCC\N=C(/N)N=C(N)N XSEUMFJMFFMCIU-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000007334 copolymerization reaction Methods 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000010389 delta-tocopherol Nutrition 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000006253 efflorescence Methods 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 238000009478 high shear granulation Methods 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229950005770 hyprolose Drugs 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960003243 phenformin Drugs 0.000 description 1
- ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 229960004937 saxagliptin Drugs 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
- 108010033693 saxagliptin Proteins 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- MWZFQMUXPSUDJQ-KVVVOXFISA-M sodium;[(z)-octadec-9-enyl] sulfate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCCOS([O-])(=O)=O MWZFQMUXPSUDJQ-KVVVOXFISA-M 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 235000013599 spices Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- 239000002446 δ-tocopherol Substances 0.000 description 1
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
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
本发明公开了治疗哺乳动物包括人2型糖尿病的药物组合物,特别是含有(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐和罗格列酮或吡格列酮或它们药学上可接受的盐的固定剂量组合的药物组合物,制备所述药物组合物的方法和所述药物组合物治疗哺乳动物包括人2型糖尿病的用途。
Description
技术领域
本发明涉及治疗哺乳动物包括人2型糖尿病的药物组合物,特别是含有罗格列酮或吡格列酮或它们药学上可接受的盐与(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐的固定剂量组合的药物组合物,制备所述药物组合物的方法和所述药物组合物治疗哺乳动物包括人2型糖尿病的用途。
背景技术
人2型糖尿病是由涉及胰岛素抵抗和消弱胰岛素分泌的双重内分泌缺陷的复杂病理生理学导致的慢性和渐进性疾病。人2型糖尿病的治疗一般从饮食和锻炼开始,随后进行口服抗糖尿病药物单一疗法。对于许多患者,这一方案并不能在长期治疗期间充分控制血糖,这就导致在诊断之后的数年内需要进行联合疗法。然而两种或者更多种口服抗糖尿病药物的共-处方对于使用的许多患者而言会导致复杂和困难的治疗方案。将两种或者更多种抗糖尿病试剂合并成单个制剂提供了不会增加患者每日治疗制度复杂性的递送联合疗法的可能方式。
二肽基肽酶-IV(DPP-IV)抑制剂表示一类开发用于治疗或者改进患有2型糖尿病患者中的血糖生成控制的新试剂。在当前临床试验中用于治疗人2型糖尿病的药物有MK-0431、维达列汀(LAF-237)、saxagliptin(BMS-47718)、P93/01(Prosidon)、SYR322(Takeda)、GSK823093、Roche0730699、TS021(Taisho)、E3024(Eisai)和PHX-1149(Phenomix)。比如,已经发现,将维达列汀口服给药至人类2型糖尿病患者可以降低与显著降低的HbAIC水平相关的空腹葡糖和饭后葡糖偏差。关于应用DDP-IV治疗2型糖尿病的综述可以参见以下公开物:(1)H.-U.Demuth等人,“Type 2diabetes-Theraphy with dipeptidylpeptidase IV inhibitors”,Biochim.Biophvs.Acta.1751:33-44(2005)和(2)K.Augustyns等人,“Inhibitors of proline-specific dipeptidylpeptidases:DPP4inhibitors as a novel approach for the treatment of Type 2diabetes”,Expert Opin.Ther.Patants,15:1387-1407(2005)。
目前一些DPP-IV抑制剂已被公开(US5462928、US5543396、WO9515309、WO2003004498、WO2003082817、WO2004032836、WO2004085661),其中Merck公司生成的DPP-IV抑制剂MK-0431显示了良好的DPP-IV抑制活性及选择性,并已于2006年上市。
为了将PPAR抗糖尿病剂,特别是格列酮施用于成年糖尿病患者(体重:50kg),例如,每日剂量通常为0.01到1000mg,优选0.1到500mg。该剂量每天施用一次到几次。特别地,当盐酸吡格列酮用作胰岛素致敏剂时,每天盐酸吡格列酮的剂量通常是7.5到60mg,优选15到45mg。当罗格列酮(或者马来酸盐)用作胰岛素致敏剂时,每天罗格列酮的剂量通常是1到12mg,优选2到12mg。
格列酮优选为吡格列酮、盐酸吡格列酮或者罗格列酮、马来酸吡格列酮或者罗格列酮,特别优选盐酸吡格列酮。
本领域中已经提出抗糖尿病药和噻唑烷二酮衍生物的组合的药物剂型。例如,EP00749751教导了包含胰岛素敏感性增强剂(其是噻唑烷二酮化合物)与其他抗糖尿病剂组合的药物组合物。更特别地,EP00749751教导优选的胰岛素敏感性增强剂是吡格列酮,其可以与其他抗糖尿病剂如罗格列酮、苯乙双胍或者丁双胍组合,并且这些药物可以结合(混合和/或包衣)常规赋形剂以提供味道掩蔽或者持续释放。抗糖尿病药和噻唑烷二酮衍生物的组合的另一实例是美国专利号6,011,049,该专利教导了缓释形式,如渗透泵或者皮肤贴剂形式的含有吡格列酮或者曲格列酮和罗格列酮或吡格列酮的单一药物组合物。抗糖尿病药和噻唑烷二酮衍生物的其他组合可以见美国专利号6,524,621;6,475,521;6,451,342和6,153,632和PCT专利申请WO01/3594,将它们引入本文作为参考。
具有以下结构式(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯是式(I)化合物,该化合物及其盐公开于中国专利申请号200710302335.9中。
式(I)
发明内容
本发明提供了一种治疗哺乳动物包括人2型糖尿病的药物组合物,所述药物组合物含有治疗有效量的罗格列酮或吡格列酮或它们药学上可接受的盐与式(I)化合物或其药学上可接受的盐,其中罗格列酮或其药学上可接受的盐与式(I)化合物或其药学上可接受的盐的重量比为1∶6.25-1∶75,吡格列酮或其药学上可接受的盐与式(I)化合物或其药学上可接受的盐的重量比为1∶3-1∶50。
本发明药物组合物中的两种活性药物成分是立即释放或缓慢释放。本发明的药物组合物可以是片剂形式,并且特别是涂膜片剂,也可以是其他口服剂型例如胶囊剂(包括硬胶囊剂和软胶囊剂)、口服溶液剂、缓释剂、滴丸剂、冲剂、颗粒剂、缓释微丸等。
本发明的一方面涉及用于医学给药式(I)化合物或者其药学上可接受的盐和罗格列酮或吡格列酮或它们药学上可接受的盐的固定剂量组合的剂型。所述剂型可以为粉剂或者固体形式,并且包括片剂、胶囊、小袋等等。具体的固体剂型涉及含有式(I)化合物或者其药学上可接受的盐和罗格列酮或吡格列酮或者其药学上可接受的盐的固定剂量组合的片剂。
本发明还提供了通过干燥或者湿法处理方法制备式(I)化合物或其盐和罗格列酮或吡格列酮或它们盐的固定剂量组合的药物组合物的方法。干法处理方法包括干法压缩和干法成粒,和湿法处理方法包括湿式粒化。
本发明的另一方面提供了本发明药物组合物在治疗哺乳动物包括人2型糖尿病的用途,该用途包括给予需要所述治疗的主体治疗有效量的本发明药物组合物。
在本发明的具体实施方案中,药物组合物包含(1)式(I)化合物或者其药学上可接受的盐,为第一种活性药物成分;(2)罗格列酮或吡格列酮或它们的盐,为第二种活性药物成分;和(3)润滑剂或者助流剂。在本发明该方面的具体实施方案中,药物组合物还可以含有一种或者多种赋形剂,所述赋形剂选自一种或者多种粘合剂(结合剂);一种或者多种稀释剂;一种或者多种表面活性剂或者润湿剂;一种或者多种崩解剂;和一种或者多种抗氧化剂。
式(I)化合物药学上可接受的盐、罗格列酮或吡格列酮的盐包括但不限于,磷酸盐、盐酸盐、硫酸盐、硝酸盐、氢溴酸盐、甲磺酸盐、马来酸盐、酒石酸盐、琥珀酸盐、醋酸盐、三氟醋酸盐、富马酸盐、柠檬酸盐、枸橼酸盐、苯磺酸盐、苯甲酸盐、萘磺酸盐、乳酸盐或苹果酸盐。
合并入本发明药物组合物中的式(I)化合物或者其盐的人日用剂量为25毫克~300毫克。优选式(I)化合物或者其盐的人日用剂量为50毫克~200毫克。离散的人日用剂量为25、50、75、100、150、200、250和300毫克式(I)化合物或者其盐。
合并入本发明固定剂量组合中的罗格列酮或其盐的人日用剂量为1毫克~12毫克,离散的人日用剂量为1、2、4、8、10和12毫克,吡格列酮或其盐的人日用剂量为7.5毫克~60毫克,离散的人日用剂量为7.5、15、30、45和60毫克。罗格列酮或吡格列酮或它们盐的这些日用剂量表示在中国和/或美国批准用于市售治疗人2型糖尿病的日用剂量。
在本发明的固定剂量组合中,式(I)化合物或者其盐和罗格列酮或吡格列酮或它们的盐人日用剂量的具体实施方案如下:
式(I)化合物或其盐(mg)25,50,75,100,150,200,250,300
罗格列酮或其盐(mg)1,2,4,8,12
吡格列酮或其盐(mg)7.5,15,30,45,60
可以是任何治疗有效量的式(I)化合物或其盐与任何治疗有效量的罗格列酮或吡格列酮或它们盐的组合物,例如:50+2,50+4,100+2,100+4或50+7.5,50+15,50+30,50+45,75+7.5,75+15,100+30,100+45等等。
本发明的药物组合物中的两种活性药物成分可以有四种释放形式:
成分:式(I)化合物或其 罗格列酮或吡格列酮
盐 或它们的盐
立即释放 立即释放
立即释放 缓慢释放
缓慢释放 立即释放
缓慢释放 缓慢释放
本发明的药物组合物通过湿法或者干法处理方法进行制备。在一种实施方案中,药物组合物通过湿法处理方法进行制备。在该实施方案的一类中,药物组合物通过湿式粒化方法进行制备。在进行湿式粒化中,可以应用高剪切粒化或者流化床粒化。在一种实施方案中,使用流化床粒化具有使得片剂具有更高径向强度的优点。
可以将通过干法或者湿法处理方法获得的药物组合物压缩成片剂、封装或者计量入小袋中。
药物组合物含有一种或者多种润滑剂或者助流剂。润滑剂的实例包括硬脂酸镁、硬脂酸钙、硬脂酸、硬脂富马酸钠、氢化蓖麻油或其混合物。优选的润滑剂是硬脂酸镁或者硬脂富马酸钠或者其混合物。助流剂的实例包括胶体二氧化硅、磷酸钙、硅酸镁和滑石。
本发明的药物组合物任选含有一种或者多种粘合剂。粘合剂的实施方案包括羟丙基纤维素(HPC)、羟丙基甲基纤维素(HMPC)、羟乙基纤维素、淀粉1500、聚乙烯吡咯烷酮(聚烯吡酮)和共聚烯吡酮。优选的粘合剂是聚乙烯吡咯烷酮。
本发明的药物组合物还可以任选含有一种或者多种稀释剂。稀释剂的实例包括甘露醇、山梨醇、磷酸二氢钙二水合物、微晶纤维素和粉化纤维素。优选的稀释剂是微晶纤维素。微晶纤维素可以得自于数个供应商,包括FMC Corporation制造的Avicel PH 101、Avicel PH 102、Avicel PH 103、Avicel PH 105和Avicel PH 200。
本发明的药物组合物还可以任选含有崩解剂。崩解剂可以是数种改性淀粉、改性纤维素聚合物或者聚羧酸中的一种,比如交联羟甲基纤维素钠、淀粉乙醇酸钠、波拉克林钾和羟甲基纤维素钙(CMCCalcium)。在一种实施方案中,崩解剂是交联羟甲纤维素钠。交联羟甲纤维素钠NF类型A在市场上以商品名“Ac-di-sol”获得。
本发明的药物组合物还可以任选含有一种或者多种表面活性剂或者润湿剂。表面活性剂可以为阴离子、阳离子或者中性表面活性剂。阴离子表面活性剂包括月桂基硫酸钠、十二烷基磺酸钠、油烯基硫酸钠和与硬脂酸脂和滑石混合的月桂酸钠。阳离子表面活性剂包括苯扎氯铵和烷基三甲基溴化铵。中性表面活性剂包括甘油单油酸脂、聚氧乙烯脱水山梨糖醇脂肪酸脂、聚乙烯醇和脱水山梨醇脂。润湿剂的实施方案包括泊洛沙姆、聚氧乙烯烷基醚、聚氧乙烯蓖麻油衍生物和聚氧乙烯硬脂酸脂。
可以任选将抗氧化剂加入到制剂中,从而给予其化学稳定性。抗氧化剂选自α-生育酚、γ-生育酚、δ-生育酚、生育酚富集天然来源的提取物,L-抗坏血酸和它的钠或者钙盐、抗坏血酰棕榈酸酯、棓酸丙酯、棓酸辛酯、棓酸十二烷基酯、丁基化羟基甲苯(BHT)和丁基化羟基苯甲醚(BHA)。在一种实施方案中,抗氧化剂为BHT或者BHA。
本发明药组合物的优选剂型是通过压缩方法制备的片剂。所述片剂可以用比如羟丙基纤维素和羟丙基甲基纤维素的混合物进行涂膜,该混合物中含有二氧化钛和/或其它着色剂,比如氧化铁、染料和色淀;聚乙烯醇(PVA)和聚乙二醇(PEG)的混合物,含有二氧化钛和/或其它着色剂,比如氧化铁、染料和色淀;或者任何其它适宜的即时释放涂覆剂。包衣对最终的片剂提供味道掩蔽和另外的稳定性。市售的涂膜为Colorcon提供的为配制粉末混合物的
最后,如果需要,可以加入甜味剂和/或增香剂。
本发明的罗格列酮或吡格列酮或它们的盐既可以是立即释放也可以是缓慢释放,式(I)化合物或其盐可以是立即释放,也可以是缓慢释放。
本发明的药物片剂组合物还可以含有一种或者多种另外的选自多种药物制剂领域已知的赋形剂中的制剂成分。根据对药物组合的期望的性能,基于它们在制备片剂组合物中的已知用途,可以单独或者联合选择任意种成分。所述成分包括但不限于稀释剂、压缩助剂、助流剂、崩解剂、润滑剂、香料、增香剂、甜味剂和防腐剂。
在此使用的术语“片剂”意图包括所有形状和大小的压缩药物剂量制剂,无论涂覆与否。可以用于涂覆的物质包括羟丙纤维素、羟丙基甲基纤维素、二氧化钛、滑石、甜味剂、着色剂和增香剂。
本发明还提供了通过口服给药需要所述治疗的主体治疗有效量的一种本发明固定剂量组合药物组合物治疗哺乳动物包括人2型糖尿病的方法。在一种实施方案中,需要所述治疗的主体是人类。在另一实施方案中,药物组合物为片剂的形式,也可以是胶囊剂形式。
含有固定剂量组合的药物组合物可以每日一次(QD)、每日两次(BID)或者每日三次(TID)给药。
式(I)化合物或其盐对DPP-IV活性抑制时间比MK-0431长,抑制强度比MK-0431大。通过实验研究,本发明人惊奇地发现:式(I)化合物或其盐和罗格列酮或吡格列酮或它们盐的复方药效显著地高于任一成分的单独用药,尤其是当罗格列酮或其盐和式(I)化合物或其盐的配比为1∶6.25-1∶75,吡格列酮或其盐和式(I)化合物或其盐的配比为1∶3-1∶50时效果更好。因此,式(I)化合物或者其盐与罗格列酮或其盐组成的组合物,式(I)化合物(以下称为化合物A,代号SP2086)或者其盐与吡格列酮或其盐组成的组合物在临床上具有重大意义。
具体实施方式
以下实施例进一步描述和说明了在本发明范围内的实施方案。实施例和试验例仅仅是为了例证说明的目的给出,并不意图将其视为对本发明的限制,其可能存在多种不背离本发明精神和范围的变体。
实施例1、化合物A磷酸盐与马来酸罗格列酮复方片剂
处方 每片含:
化合物A磷酸盐 50mg
马来酸罗格列酮 4mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A磷酸盐,马来酸罗格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例2、化合物A磷酸盐与盐酸吡格列酮复方片剂
处方 每片含:
化合物A磷酸盐 50mg
盐酸吡格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A磷酸盐,盐酸吡格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例3、化合物A盐酸盐与马来酸罗格列酮复方片剂
处方 每片含:
化合物A盐酸盐 50mg
马来酸罗格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A盐酸盐,马来酸罗格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例4、化合物A盐酸盐与盐酸吡格列酮复方片剂
处方 每片含:
化合物A盐酸盐 50mg
盐酸吡格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A盐酸盐,盐酸吡格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例5、化合物A甲磺酸盐与马来酸罗格列酮复方片剂
处方 每片含:
化合物A甲磺酸盐 50mg
马来酸罗格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A甲磺酸盐,马来酸罗格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例6、化合物A甲磺酸盐与盐酸吡格列酮复方片剂
处方 每片含:
化合物A甲磺酸盐 50mg
盐酸吡格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A甲磺酸盐,盐酸吡格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例7、化合物A酒石酸盐与马来酸罗格列酮复方片剂
处方 每片含:
化合物A酒石酸盐 50mg
马来酸罗格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A酒石酸盐,马来酸罗格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例8、化合物A酒石酸盐与盐酸吡格列酮复方片剂
处方 每片含:
化合物A酒石酸盐 50mg
盐酸吡格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A酒石酸盐,盐酸吡格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例9、化合物A苹果酸盐与马来酸罗格列酮复方片剂
处方 每片含:
化合物A苹果酸盐 50mg
马来酸罗格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A苹果酸盐,马来酸罗格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
实施例10、化合物A苹果酸盐与盐酸吡格列酮复方片剂
处方 每片含:
化合物A苹果酸盐 50mg
盐酸吡格列酮 15mg
微晶纤维素 12mg
2%淀粉浆 适量
硬脂酸镁 0.5mg
制备方法:将化合物A苹果酸盐,盐酸吡格列酮,微晶纤维素混匀,用2%淀粉浆湿法粒化。干燥,加入硬脂酸镁,混匀压片。
类似的,通过调节复方中化合物A或其盐,罗格列酮或其盐的用量,来制备含有不同比例的两种活性成分的复方,例如罗格列酮或其盐与化合物A或其盐的比例为1∶6.25、1∶12.5、1∶25、1∶50、1∶75等等。
或者,通过调节复方中化合物A或其盐,吡格列酮或其盐的用量,来制备含有不同比例的两种活性成分的复方,例如吡格列酮或其盐与化合物A或其盐的比例为7.5∶25,7.5∶50,7.5∶75,7.5∶100,7.5∶150,7.5∶375等等。
试验例1:化合物A、MK-0431的体外活性及选择性研究
方法:
解冻DPP-IV-Glo.使用前缓冲并平衡到室温,使用前缓冲冻存的荧光素检测试剂,悬浮DPP-IV-Glo.在底物中加入超纯水轻微混合均匀后,制成1mM的底物,将荧光素检测试剂放入茶色瓶中,加入DPP-IV-Glo.。荧光素检测试剂应在1分钟内溶解,用DMSO溶解所测化合物至最终操作浓度的50倍,每个试管中加入50倍浓度的所测化合物2μL,在反面对照和空白对照中加入2μLDMSO,在每个试管中加入46μL Tris缓冲液,在空白对照中加入48μL Tris缓冲液,在反面对照和测试样的每个试管中加入2μLDPP-IV酶,振动混合并离心试管。将试管中物质全部转移到96-孔平板上,混合底物和DPP-IV-Glo.比例为1∶49。振动混合至充分混合。使用前在室温下静置30-60分钟,在每个96-孔平板孔中加50μL DPP-IV-Glo.和底物的混合液,用封膜封住平板,用平板振荡器在300-500rpm/30s下慢慢混合96孔中物质。在室温下培养30分钟到3小时,在NOVOstar多功能酶标仪检测化学发光计数值。
[表1]
结果:化合物A对DPP-IV的抑制活性优于对照药物MK-0431,选择性也强于MK-0431。
试验例2:不同比例罗格列酮和化合物A药物组合物对正常ICR小鼠
的口服糖耐量研究
雄性ICR小鼠于禁食6小时后口服双蒸水、不同配比的罗格列酮马来酸盐:化合物A磷酸盐=1∶6.25,1∶12.5,1∶25,1∶50,1∶75相同剂量(10mg/kg)的药物组合物,各组于给药30分钟时口服葡萄糖2.5g/kg,做口服糖耐量试验。于给糖后0、30、60、120分钟时取血,测定血清葡萄糖水平。
血清葡萄糖测定方法;
采用葡萄糖试剂盒测定血清中的葡萄糖含量,取250μl酶工作液,加入5μl血清,同时设立空白管(加入5μl双蒸水)及标准管(加入5μl葡萄糖标液),混匀,37℃水浴20分钟,以空白管调零,OD505nm处比色测定。
血清葡萄糖含量BG(nmol/l)=OD样品管/OD标准管×5.55
数据处理和统计分析;
1、采用均值±SD及Student-t test对数据进行统计学分析
2、计算给糖后30分钟时血糖下降百分率以及曲线下面积AUC
[表2]:正常ICR小鼠口服受试药物组合物(10mg/kg)后对口服糖耐量的影响(均值±SD,n=6)
*,P<0.05;与空白对照组相比;
**,P<0.01;与空白对照组相比;
***,P<0.001;与空白对照组相比;
试验例3:不同比例吡格列酮和化合物A药物组合物对正常ICR小鼠
的口服糖耐量研究
雄性ICR小鼠于禁食6小时后口服双蒸水、不同配比(吡格列酮盐酸盐:化合物A磷酸盐=7.5∶25,7.5∶50,7.5∶75,7.5∶100,7.5∶150,7.5∶375)相同剂量(30mg/kg)的混合物,各组于给药30分钟时口服葡萄糖2.5g/kg,做口服糖耐量试验。于给糖后0、30、60、120分钟时取血,测定血清葡萄糖水平。
血清葡萄糖测定方法;
采用葡萄糖试剂盒测定血清中的葡萄糖含量,取250μl酶工作液,加入5μl血清,同时设立空白管(加入5μl双蒸水)及标准管(加入5μl葡萄糖标液),混匀,37℃水浴20分钟,以空白管调零,OD505nm处比色测定。
血清葡萄糖含量BG(nmol/l)=OD样品管/OD标准管×5.55
数据处理和统计分析;
1、采用均值±SD及Student-t test对数据进行统计学分析
2、计算给糖后30分钟时血糖下降百分率以及曲线下面积AUC
[表3]:正常ICR小鼠口服受试复方物(30mg/kg)后对口服糖耐量的影响(均值±SD,n=6)
*,P<0.05;与空白对照组相比;
**,P<0.01;与空白对照组相比;
***,P<0.001;与空白对照组相比;
试验例4:化合物A磷酸盐、MK-0431分别与罗格列酮马来酸盐或吡
格列酮盐酸盐的联合服用在遗传性肥胖且患糖尿病的Wistar肥鼠中的
效应
将14~19周龄的雄性Wistar肥鼠分成9组,每组5~6只,分别服用蒸馏水、化合物A磷酸盐、罗格列酮马来酸盐、吡格列酮盐酸盐、MK-0431、MK-0431+罗格列酮马来酸盐、MK-0431+吡格列酮盐酸盐、化合物A磷酸盐+罗格列酮马来酸盐和化合物A磷酸盐+吡格列酮盐酸盐14天。从尾静脉取血,使用一种商品试剂盒(NC-ROPET,NipponChemiphar CO.)以酶法分别测定血浆葡萄糖和血红蛋白A1.结果表示为每组(n=5-6)的平均值±标准偏差并以Dunnett’s检验分析,在表4中给出。使用1%的显著性水平。
[表4]
*:P<0.01与对照组相比
表4中化合物A磷酸盐与罗格列酮马来酸盐或吡格列酮盐酸盐联合服用很明显地降低了血液葡萄糖和血红蛋白的浓度,其强度大于化合物A磷酸盐、罗格列酮马来酸盐、吡格列酮盐酸盐、MK-0431的单独给药,而且其强度大于MK-0431与罗格列酮马来酸盐或吡格列酮盐酸盐联合用药。
Claims (9)
1.一种治疗哺乳动物包括人2型糖尿病的药物组合物,所述药物组合物含有治疗有效量的罗格列酮或吡格列酮或它们药学上可接受的盐与(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐,其中罗格列酮或其药学上可接受的盐与(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐的重量比为1∶6.25-1∶75,吡格列酮或其药学上可接受的盐与(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐的重量比为1∶3-1∶50。
2.根据权利要求1所述的药物组合物,其中所述(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐的人日用量为25-300mg。
3.根据权利要求1所述的药物组合物,其中所述罗格列酮或其药学上可接受的盐的人日用量为1-12mg,所述吡格列酮或其药学上可接受的盐的人日用量为7.5-60mg。
4.根据权利要求1-3任一项所述的药物组合物,其中所述药物组合物为片剂、硬胶囊剂、软胶囊剂、口服溶液剂、缓释剂、滴丸剂、冲剂、颗粒剂、缓释微丸或其他口服剂型。
5.根据权利要求1-4任一项所述的药物组合物,其中所述的(R)-7-[3-氨基-4-(2,4,5-三氟-苯基)-丁酰基]-3-三氟甲基-5,6,7,8-四氢-咪唑并[1,5-a]吡嗪-1-羧酸甲酯或其药学上可接受的盐是立即释放或缓慢释放。
6.根据权利要求1-5任一项所述的药物组合物,其中所述罗格列酮或吡格列酮或它们药学上可接受的盐是立即释放或缓慢释放。
7.根据权利要求1-6任一项所述的药物组合物,其中所述药物组合物是以一日一次、一日两次或一日三次给药的药用组合物。
8.根据权利要求1-7任一项所述的药物组合物,其中所述药学上可接受的盐选自磷酸盐、盐酸盐、硫酸盐、硝酸盐、氢溴酸盐、甲磺酸盐、马来酸盐、酒石酸盐、琥珀酸盐、醋酸盐、三氟醋酸盐、富马酸盐、柠檬酸盐、枸橼酸盐、苯磺酸盐、苯甲酸盐、萘磺酸盐、乳酸盐或苹果酸盐。
9.如权利要求1-8任一项所述的药物组合物在制备治疗哺乳动物包括人糖尿病的药物中的用途。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 |
PCT/CN2010/074309 WO2011009360A1 (zh) | 2009-07-21 | 2010-06-23 | 治疗哺乳动物包括人2型糖尿病的药物组合物 |
HK11107352.4A HK1153143A1 (en) | 2009-07-21 | 2011-07-15 | Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
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 (2)
Publication Number | Publication Date |
---|---|
CN101961336A true CN101961336A (zh) | 2011-02-02 |
CN101961336B CN101961336B (zh) | 2012-05-30 |
Family
ID=43498754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2009101403973A Expired - Fee Related 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 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN101961336B (zh) |
HK (1) | HK1153143A1 (zh) |
WO (1) | WO2011009360A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108144065A (zh) * | 2016-12-06 | 2018-06-12 | 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 |
Family Cites Families (2)
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 |
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 |
-
2009
- 2009-07-21 CN CN2009101403973A patent/CN101961336B/zh not_active Expired - Fee Related
-
2010
- 2010-06-23 WO PCT/CN2010/074309 patent/WO2011009360A1/zh active Application Filing
-
2011
- 2011-07-15 HK HK11107352.4A patent/HK1153143A1/xx not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108144065A (zh) * | 2016-12-06 | 2018-06-12 | 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 |
Also Published As
Publication number | Publication date |
---|---|
HK1153143A1 (en) | 2012-03-23 |
CN101961336B (zh) | 2012-05-30 |
WO2011009360A1 (zh) | 2011-01-27 |
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 | |
US20100330177A1 (en) | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor | |
CN106075451A (zh) | 使用sglt2抑制剂及其组合物在对先前用其它抗糖尿病药进行的治疗具有耐受的患者中治疗ii型糖尿病的方法 | |
EA006766B1 (ru) | Фармацевтические композиции, включающие метформин и глибенкламид, применяемые для лечения сахарного диабета типа ii | |
KR20160111237A (ko) | 메트포르민 및 시타글립틴을 포함하는 경구용 복합제제 | |
JP2013508370A (ja) | ジペプチジルペプチダーゼ−4阻害剤とピオグリタゾンとの組み合わせの医薬組成物 | |
CN101919851B (zh) | 治疗哺乳动物包括人2型糖尿病的药物组合物 | |
CN103893142A (zh) | 一种沙格列汀分散片及其制备方法 | |
CN101961336B (zh) | 治疗哺乳动物包括人2型糖尿病的药物组合物 | |
EP2402342B1 (en) | Pharmaceutical composition for treatment of 2 type diabetes | |
JP2022544167A (ja) | ニトロキソリンを含む医薬組成物、ニトロキソリン経口固形錠剤、その調製方法、及びその使用 | |
US8476272B2 (en) | Pharmaceutical composition for treatment of type 2 diabetes | |
CN101904840B (zh) | 治疗哺乳动物包括人2型糖尿病的药物组合物 | |
CN103877043A (zh) | 一种磷酸西他列汀分散片及其制备方法 | |
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 | |
TWI462925B (zh) | 治療2型糖尿病的藥物組合物 | |
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 | |
TW201219384A (en) | Pharmaceutical composition for the treatment of type 2 diabetes in mammals including human beings |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1153143 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1153143 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120530 |