CN1327840C - Medicinal composition and its use in treatment of diabetes - Google Patents
Medicinal composition and its use in treatment of diabetes Download PDFInfo
- Publication number
- CN1327840C CN1327840C CNB2004100194836A CN200410019483A CN1327840C CN 1327840 C CN1327840 C CN 1327840C CN B2004100194836 A CNB2004100194836 A CN B2004100194836A CN 200410019483 A CN200410019483 A CN 200410019483A CN 1327840 C CN1327840 C CN 1327840C
- Authority
- CN
- China
- Prior art keywords
- pioglitazone
- metformin
- hydrochloride
- tablet
- layer
- 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.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 38
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 24
- 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 108
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 61
- 229960005095 pioglitazone Drugs 0.000 claims abstract description 57
- 229960003105 metformin Drugs 0.000 claims abstract description 49
- 238000002360 preparation method Methods 0.000 claims abstract description 31
- 229960002827 pioglitazone hydrochloride Drugs 0.000 claims description 36
- 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 claims description 35
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 25
- 239000003826 tablet Substances 0.000 claims description 25
- -1 Hydroxypropyl Chemical group 0.000 claims description 20
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 14
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 229960004329 metformin hydrochloride Drugs 0.000 claims description 12
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 12
- 239000008187 granular material Substances 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 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 claims description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 6
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000008101 lactose Substances 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 5
- 239000000725 suspension Substances 0.000 claims description 5
- 229940103776 metformin hydrochloride 500 mg Drugs 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 3
- 239000000306 component Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 239000007939 sustained release tablet Substances 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims 3
- 229940103770 metformin hydrochloride 750 mg Drugs 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 79
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 17
- 150000003839 salts Chemical class 0.000 abstract description 17
- 201000010099 disease Diseases 0.000 abstract description 9
- 238000013329 compounding Methods 0.000 abstract 1
- 241001465754 Metazoa Species 0.000 description 89
- 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 39
- 230000003203 everyday effect Effects 0.000 description 32
- 210000004369 blood Anatomy 0.000 description 23
- 239000008280 blood Substances 0.000 description 23
- 230000000694 effects Effects 0.000 description 21
- 241000700159 Rattus Species 0.000 description 20
- 229940125396 insulin Drugs 0.000 description 20
- 229940111334 metformin / pioglitazone Drugs 0.000 description 20
- 102000004877 Insulin Human genes 0.000 description 19
- 108090001061 Insulin Proteins 0.000 description 19
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 19
- 231100000111 LD50 Toxicity 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 239000008103 glucose Substances 0.000 description 12
- 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 11
- 210000002966 serum Anatomy 0.000 description 11
- 229940079593 drug Drugs 0.000 description 10
- 238000010171 animal model Methods 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 8
- 238000007689 inspection Methods 0.000 description 8
- 231100000915 pathological change Toxicity 0.000 description 8
- 230000036285 pathological change Effects 0.000 description 8
- 206010012735 Diarrhoea Diseases 0.000 description 7
- 231100000331 toxic Toxicity 0.000 description 7
- 230000002588 toxic effect Effects 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 6
- 206010022489 Insulin Resistance Diseases 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 241000700157 Rattus norvegicus Species 0.000 description 5
- 208000017169 kidney disease Diseases 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 229940123208 Biguanide Drugs 0.000 description 4
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 4
- 238000011047 acute toxicity test Methods 0.000 description 4
- 239000003472 antidiabetic agent Substances 0.000 description 4
- 150000004283 biguanides Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 201000001421 hyperglycemia Diseases 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 210000002784 stomach Anatomy 0.000 description 4
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 4
- 210000001835 viscera Anatomy 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 229940127003 anti-diabetic drug Drugs 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 230000005021 gait Effects 0.000 description 3
- 230000002641 glycemic effect Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 230000003345 hyperglycaemic effect Effects 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000003285 pharmacodynamic effect Effects 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 208000001280 Prediabetic State Diseases 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 229940123464 Thiazolidinedione Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 238000004378 air conditioning Methods 0.000 description 2
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000035622 drinking Effects 0.000 description 2
- 230000001610 euglycemic effect Effects 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 201000009104 prediabetes syndrome Diseases 0.000 description 2
- 238000003672 processing method Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 238000009423 ventilation Methods 0.000 description 2
- SLYRGJDSFOCAAI-UHFFFAOYSA-N 1,3-thiazolidin-2-one Chemical compound O=C1NCCS1 SLYRGJDSFOCAAI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 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 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
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000282894 Sus scrofa domesticus Species 0.000 description 1
- 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 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 238000000861 blow drying Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 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
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011208 chromatographic data Methods 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- FMGSKLZLMKYGDP-USOAJAOKSA-N dehydroepiandrosterone Chemical compound C1[C@@H](O)CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC=C21 FMGSKLZLMKYGDP-USOAJAOKSA-N 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 201000005577 familial hyperlipidemia Diseases 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 206010061989 glomerulosclerosis Diseases 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000010562 histological examination Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000035861 hyperketonemia Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 201000009925 nephrosclerosis Diseases 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940030882 pioglitazone 15 mg Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 108010016297 plasmin drug combination deoxyribonuclease Proteins 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 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
- 210000003462 vein Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses a medical composition which contains pioglitazone of 5 mg to 60 mg or salt of pioglitazone which is acceptable on pharmacy, metformin of less than 3000 mg or salt of metformin which is acceptable on pharmacy, and one kind or more than one kind of carrier which is acceptable on pharmacy. Compound preparations of different compounding ratios are prepared, a mode of taking medicine is improved, the number of times of taking medicine is reduced, a patient takes the medical composition once a day, and the patient can conveniently take the medical composition for a long time. The present invention simultaneously discloses application of the composition for preparing medicine for treating and/or preventing diabetes diseases which are relevant to diabetes, and concurrent diseases.
Description
Technical field
The invention belongs to treatment diabetes medicament field, more particularly relate to the pharmaceutical composition of a kind of pioglitazone and metformin, and said composition preparation be used for the treatment of and/or prevent diabetes, with diabetes diseases associated and some complication thereof in application.
Background technology
Diabetes are one group of clinical syndromes that caused by the h and E factor interaction.Estimate that according to Epidemiological study present global diabetics sum has exceeded 100,000,000, wherein about 90% is type ii diabetes, its pathogeny is that insulin resistant is main, is main with defect of insulin secretion or defect of insulin secretion, and companion's insulin resistant and liver glucose produce to be increased.The type ii diabetes patient is often with diseases such as obesity, hypertension, hyperlipemia, fatty liver and coronary heart disease.
United States Patent (USP) discloses biguanides antihyperglycemic metformin No. 3174901, and the auxiliary mechanism of its blood sugar control is to suppress liver to produce glucose and increase the periphery ingestion of glucose, reduces insulin resistance thus.
The clear 61-267580 of Japan Patent, European patent Ep193256, U.S. Pat 4687777 discloses the hyperglycemia of thiazolidinediones euglycemic agent pioglitazone and has regulated the lipid metabolism effect, its mechanism of action exists relevant with insulin, can reduce the insulin resistance of peripheral tissues and liver, increase the glucose that relies on insulin and handle, and reduce the output of glycogen.Following document discloses the example of pioglitazone and metformin use in conjunction: Pioglitazonehydrochloride in combination with metformin in the treatment of type 2 diabetesmellitus:a randomized such as (1) Einhorn D, placebo-controlled study.Clin Ther.2000Dec; 22 (12): 1395-409. discloses when using the metformin poor blood glucose control separately, with the therapeutic effect and the toleration of pioglitazone hydrochloride use in conjunction.
(2) Effects of combined pioglitazone and metformin on diabetes andobesity in Wistar fatty rats.Clin Exp Pharmacol Physiol.2002 Apr such as Suzuki M; 29 (4): 269-74. discloses pioglitazone hydrochloride and metformin hydrochloride use in conjunction, to the therapeutic effect of the Wistar obese rat of hyperglycemia, hyperglyceridemia, hyperketonemia.
Hypoglycemic effect and safety when (3) Pan Changyu etc. discloses pioglitazone hydrochloride and sulphanylureas or biguanides use in conjunction in " effectiveness of metformin hydrochloride treatment type ii diabetes and the multiple center clinical study of safety ".
Pioglitazone is a kind of thiazolidone para-insulin opposing improving agent, reduces insulin resistant, protection β cell function, and sugar, the fat that can effectively treat the noninsulindependent diabetes obese patient are unusual.Metformin now has been widely accepted and has been light, moderate diabetes mellitus type obese patient's first-selected hyperglycemia medicine particularly.Even, intervention effect is also arranged for the interstage-IGT (glucose tolerance attenuating) of type ii diabetes, can stop or delay to enter the diabetes stage by the IGT state.
Insulin resistant is the major defect of type ii diabetes starting stage.Insulin resistant is through the generation of type ii diabetes, the development overall process, and thiazolidinediones pioglitazone hydrochloride and metformin all tool reduce the insulin resistant effect, but the mechanism of action difference of the two, the site of action of the two also has difference, pioglitazone mainly promotes peripheral tissues's (skeletal muscle) ingestion of glucose, the insulin resistance that can be used for type ii diabetes, and metformin mainly suppresses hepatic glucose output, so the two share, effect concentrates on metabolic deficiency, the anti-diabetic effect can be strengthened, and helps to use more separately metformin to reach better blood sugar control.
Summary of the invention
Now, there is wonderful reality to show, the combination medicine form of pioglitazone and metformin can provide useful especially glycemic control effect and not observe side effect, observed synergism is hypoglycemic remarkable improvement, therefore this combination medicine form is particularly useful for treating diabetes, especially II type sugar sick and with the diabetes diseases associated.
Therefore, the invention provides a kind of mammal such as people's treatment of diabetes method, this method comprises euglycemic agent such as pioglitazone or its pharmaceutically acceptable salt of effective, the nontoxic and pharmaceutically acceptable amount of the mammal that needs this treatment, pharmaceutical composition with biguanides antihyperglycemic agents such as metformin or its pharmaceutically acceptable salt, wherein, the consumption of pioglitazone or its pharmaceutically acceptable salt is 5-60mg, and the consumption of metformin or its pharmaceutically acceptable salt is for being no more than 3000mg.
Should be appreciated that pioglitazone and metformin be respectively with its pharmaceutically acceptable form as suitable related drugs active agent delivery, comprise its pharmaceutically acceptable derivates such as pharmaceutically acceptable salt, ester and solvate.Should be understood that all pharmaceutically acceptable forms that the present invention includes activating agent itself.The suitable pharmaceutically acceptable form of metformin is an acid-addition salts, example hydrochloric acid salt, acetate, benzoate, mesylate, maleate etc., yet, preferably use metformin itself or its hydrochlorate.Obtain the officinal salt of metformin by metformin and corresponding acid reaction with reference to the US3174901 method.
The pharmaceutically acceptable salt that pioglitazone is suitable comprises hydrochlorate, formates, fumarate, acetate, benzoate, mesylate, sulfate, maleate etc., yet, preferably use pioglitazone itself or its hydrochlorate.The officinal salt that can prepare pioglitazone with reference to the EP193256 method.
A particular aspects, this method comprises and gives 5～60mg pioglitazone or pioglitazone hydrochloride, especially when the every day administration.
Particularly, this method comprise give 5～15,15～30,30～45 every day, 45～60mg pioglitazone or pioglitazone hydrochloride.
Particularly, this method comprises and gives 5～15mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 15～30mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 30～45mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Particularly, this method comprises and gives 45～60mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 5mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 10mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 15mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 30mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 45mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
Preferably, this method comprises and gives 60mg pioglitazone or pioglitazone hydrochloride every day, especially when the every day administration.
A particular aspects, this method comprises metformin or the metformin hydrochloride that is no more than 3000mg, especially when the every day administration.Particularly preferably be, the consumption of metformin or metformin hydrochloride is 250mg, 750mg, 1000mg, especially when the every day administration.
The invention solves diabetics needs long-term worry of repeatedly taking medicine, and by making the compound preparation of different proportionings, improves medicining mode, has reduced medicining times, once a day, makes things convenient for the patient to take for a long time.
On the other hand, the invention provides a kind of pioglitazone and metformin preparation be used for the treatment of and/or prevent diabetes, with the diabetes diseases associated, and the application in some complication, particularly, the treatment diabetes especially type ii diabetes and with the method for diabetes diseases associated in application.This method comprises pioglitazone and metformin administration simultaneously.Administration simultaneously comprises the preparation that gives pioglitazone and metformin, perhaps with the independent preparation while administration basically of every kind of activating agent.
Confirm that through vast amount of clinical if type ii diabetes is diagnosed in back 3 years only with a kind of medicine treatment, glucose control progressivity descends, and has two medicine therapeutic alliances of complementary action often to be used to obtain the maximum therapy effect and to reduce side effect.Pioglitazone and metformin two medicine use in conjunction not only effectively blood sugar control, reduce insulin resistant, protection β cell function, reduced hypoglycemic incidence rate simultaneously, played synergism.Two medicine use in conjunction can delay and stop advancing of disease, and the long-term complications of prevent diabetes is as heart disease, blind, amputation and renal failure.
Term used herein " with the diabetes diseases associated " comprise those diseases relevant with the prediabetes state, with diabetes self diseases associated and with the diabetes complications associated with arterial system.
Term used herein " those diseases relevant with the prediabetes state " comprises such as insulin resistance disease, comprises that heritability insulin resistant, glucose tolerance weaken and hyperinsulinemia.
Term used herein " with diabetes self diseases associated " comprises hyperglycemia, and insulin resistant comprises insulin resistant and the obesity day after tomorrow.Other and diabetes diseases associated comprise hypertension and cardiovascular disease, especially atherosclerosis and with the insulin diseases associated.Comprise polycystic ovary syndrome and inductive insulin resistant of steroid and gestational diabetes with the insulin diseases associated.
" with the diabetes complications associated with arterial system " comprises kidney disease, especially relevant with type ii diabetes kidney disease, neuropathy and retinopathy.
The kidney disease relevant with type ii diabetes comprises nephropathy, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and late period kidney disease.
Term used herein " pharmaceutically acceptable " comprises any veterinary purpose: for example term " pharmaceutically acceptable " comprises veterinarily acceptable chemical compound.
Useful especially glycemic control effect by the present invention's treatment provides is designated as the synergism with respect to contrast, and this contrast is contemplated to the effect summation of independent active agents.
One preferred aspect, when treatment and when using according to the present invention, the dosage level of used various activating agents will less than reach add merely and the glycemic control effect dosage that may need.
On the one hand, the invention provides a kind of pharmaceutical composition that contains pioglitazone and metformin again.Said composition contains 5～60mg pioglitazone or pioglitazone hydrochloride and is no more than 3000mg, metformin or metformin hydrochloride and one or more pharmaceutically acceptable carrier.
Usually said composition is suitable for oral administration, and still, they also are fit to other administering mode, for example parenteral, sublingual administration or percutaneous dosing.
In order to reach the concordance of administration, the present composition is preferably single agent form.
The single agent representation that is used for oral administration can be tablet and capsule, can contain following excipient such as filler, lactose, sucrose, starch, microcrystalline Cellulose, sorbitol, calcium phosphate; Binding agent, for example syrup, gelatin, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, starch, dextrin; Disintegrating agent, for example microcrystalline Cellulose, carboxymethyl starch sodium, sodium carboxymethyl cellulose, crospolyvinylpyrrolidone; Lubricant, for example magnesium stearate; High-molecular bone frame material, for example hydroxypropyl emthylcellulose, hydroxypropyl cellulose, ethyl cellulose, Brazil wax, hydrogenated vegetable oil, acrylic resin; Filmogen, for example hydroxypropyl emthylcellulose, polyvinylpyrrolidone, acrylic resin etc.
The preparation method of preferred pharmaceutical composition of the present invention, can be made into the double-layer tablet up and down that contains 5～60mg rapid release pioglitazone or its pharmaceutical salts and be no more than 3000mg SRM or its pharmaceutical salts, or can be made into internal layer for being no more than 3000mg SRM or its pharmaceutical salts, outer for containing the pioglitazone of 5～60mg rapid release or the double-layer tablet of its pharmaceutical salts.
Metformin or its pharmaceutical salts are made the slow releasing tablet that only need take every day once among the present invention, can slowly discharge in vivo, it is steady to keep blood drug level, half-life prolongs, safety, efficient, low toxicity, taking convenience, and side effect and incompatibility are less, and convenient and pioglitazone or its pharmaceutical salts are made the compound preparation of different proportionings, and patient's taking convenience is difficult for missing, and has increased the obedient type of medication.
These compositionss are preferably to make unit dosage forms with the amount that relevant daily dose suits.
The unit dose of suitable pioglitazone comprises 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44, the 45mg pioglitazone.
Compositions of the present invention can administration every day 1～3 time, but preferred administration every day 1 or 2 times.
The pioglitazone given dose is 5mg/ days, 10mg/ days, and 15mg/ days, 30mg/ days, 45mg/ days, 60mg/ days.
The metformin proper dosage comprises and is no more than 3000mg every day, and preferably with the unit dose administration of 250mg, 500mg, 1000mg, 1500mg or 2000mg, an example of metformin dosage is each 1000mg, once a day.
The unit dose that pioglitazone and metformin are suitable also comprises the known dose of these chemical compounds, as describing among handbook Chinese Pharmacopoeia, American Pharmacopeia, British Pharmacopoeia, European Pharmacopoeia and PHYSICINS ' the DESK REFERENCE or mentioning.
Below by acute, the toxicity test of pharmacology, pharmacokinetics is tested, and pharmacodynamic experiment is further set forth the present invention.
One, compound metformin/pioglitazone acute toxicity test:
1, test objective:
Mice produces after different proportioning (500: 7.5,500: 15,500: 30) the single oral administrations of observation compound metformin/pioglitazone acute toxic reaction and dead distribution situation are calculated LD
50Value.For pharmacodynamics test, repeatedly the compound recipe proportioning of the toxicity test of repetitively administered and dosage design and clinical safety provide reference.
2, experiment material:
(1) laboratory animal
Kunming mouse, male and female half and half, body weight 18-22g.Laboratory Animal Facility: secondary; The quality certification number: accurate No. 012 of the real moving facility in Tianjin; The laboratory animal quality certification: No. the 001st, the accurate word of the real kinoplaszm R in W-J Tianjin.Experimental situation and condition: 22 ± 4 ℃ of room temperatures, humidity 60 ± 20%.The central air-conditioning automatic ventilation.Illumination 12 hours.Freely ingest and drinking public water supply.Change water every day once.
(2) experiment medicine
Compound metformin/pioglitazone, medicine are mixed with the suspendible medicinal liquid of 100mg/ml with 1%CMC.
3, experimental technique and result:
(1) experimental technique:
50 of Kunming mouses, male and female half and half are divided into 5 groups at random by sex, are respectively 5000,4000,3200,2560, five dosage groups of 2048mg/kg.Animal fasting administration in 6 hours.Medicine is mixed with the medicinal liquid of 100mg/ml with the 1%CMC suspendible, adopts the not isopyknic mode administration of isoconcentration, the administration volume is respectively 0.50,0.40,0.32,0.26,0.20ml/10g.Observe toxic reaction and the time of origin thereof of animal behind the medicine, death condition and time, dead animal carries out anatomical examination, carries out histological examination in case of necessity; Surviving animals was observed 14 days continuously, weighed at 0,1,3,7,14 day that tests, and at the 14th day the part surviving animals was carried out anatomic observation.Statistics animal dead situation, the variation of calculating median lethal dose(LD 50) and the weight of animals.
(2) experimental result:
Compound metformin/pioglitazone (500: 7.5) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 7.5), animal appearance activity in 10-30 minute reduces behind the medicine, part animal occur closing one's eyes (1-6/10); Behind the medicine 1 hour, diarrhoea appearred in 5 animals; Behind the medicine 2 hours, diarrhoea appearred in 10 animals.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 5 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (6), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3137.3mg/kg.(the results are shown in Table 1,2).
Table 1. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 7.5) to the surviving animals body weight
| Dosage (mg/kg) | 0d | 1d | 3d | 7d | 14d |
| 5000 4000 3200 | 19.8±0.9 19.9±1.0 19.8±1.1 | 20.8±2.5 21.0±1.2 | 2 3.0±2.8 23.4±1.5 | 26.5±3.5 25.6±1.7 | 29.3±3.9 28.8±1.8 |
| 2560 2048 | 19.9±1.0 19.7±1.1 | 20.6±1.1 20.9±1.4 | 22.3±1.2 2 3.1±1.9 | 24.8±1.6 26.1±2.2 | 28.6±2.3 29.2±2.7 |
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 2 for each group surviving animals number.
Table 2. mice single oral gives compound metformin/pioglitazone (500: 7.5) LD
50Measurement result
| Dosage (mmg/kg) | Number of animals (only) | Dead number of elements (♂) | Dead number of elements (♀) | Dead sum (only) | Mortality rate (%) | LD 50(mg/kg) (95% fiducial limit) |
| 5000 4000 3200 2560 2048 | 10 10 10 10 10 | 5 3 3 1 0 | 5 5 3 1 0 | 10 8 6 2 0 | 100 80 60 20 0 | 3137.3 (2834.9-3472.1) |
Compound metformin/pioglitazone (500: 15) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 15), animal appearance activity in 10-30 minute reduces behind the medicine, part animal occur closing one's eyes (1-4/10); Behind the medicine 1 hour, diarrhoea, myasthenia of limbs behind 1 animal, instability of gait appearred in 3 animals; Behind the medicine 2 hours, diarrhoea appearred in 9 animals, and 1 animal is dying.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 4 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (4), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3348.8mg/kg.(the results are shown in Table 3,4).
Table 3. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 15) to the surviving animals body weight
| Dosage (mg/kg) | 0d | 1d | 3d | 7d | 14d |
| 5000 4000 3200 | 19.7±0.9 19.6±1.1 19.5±1.0 | 20.3±1.0 21.1±1.3 | 22.3±1.0 2 3.4±1.1 | 26.0±1.3 26.8±1.9 | 29.0±2.6 29.7±2.5 |
| 2560 2048 | 19.7±1.0 19.7±1.0 | 21.2±1.2 21.1±1.1 | 22.8±1.7 23.4±1.3 | 26.2±1.8 26.7±1.6 | 29.8±2.0 29.8±2.3 |
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 4 for each group surviving animals number.
Table 4. mice single oral gives compound metformin/pioglitazone (500: 15) LD
50Measurement result
| Dosage (mg/kg) | Number of animals (only) | Dead number of elements (♂) | Dead number of elements (♀) | Dead sum (only) | Mortality rate (%) | LD 50(mg/kg) (95% fiducial limit) |
| 5000 4000 3200 2560 2048 | 10 10 10 10 10 | 5 3 3 0 0 | 5 4 2 1 0 | 10 7 5 1 0 | 100 70 50 10 0 | 3348.8 (3029.6-3701.7) |
Compound metformin/pioglitazone (500: 30) oral administration acute toxicity test:
Orally give compound metformin/pioglitazone (500: 30), 10-30 minute animal activity reduces behind the medicine, part animal close one's eyes (1-4/10); Behind the medicine 1 hour, 4 animals diarrhoea; Behind the medicine 2 hours, 1 animal instability of gait, 7 animals diarrhoea.Time, number of animals and the order of severity and dosage that toxic reaction takes place are proportionate.Animal dead appears at behind the medicine 5 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal (10), other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of mice oral administration is 3726.7mg/kg.(the results are shown in Table 5,6).
Table 5. mice single oral gives the influence (g) of compound metformin/pioglitazone (500: 30) to the surviving animals body weight
| Dosage (mg/kg) | 0d | 1d | 3d | 7d | 14d |
| 5000 4000 3200 | 20.3±1.0 20.2±1.1 20.4±0.9 | 21.3±1.2 21.9±1.6 | 22.8±1.2 23.5±2.0 | 25.2±1.3 26.2±2.6 | 28.8±1.8 28.5±2.4 |
| 2560 2048 | 20.3±0.9 20.2±1.1 | 22.0±0.5 21.9±0.9 | 24.1±1.7 23.8±1.0 | 26.6±2.3 26.7±1.4 | 29.7±2.6 29.6±2.5 |
Annotate: the 0d the weight of animals is a body weight after the fasting, and number of animals sees Table 6 for each group surviving animals number.
Table 6. mice single oral gives compound metformin/pioglitazone (500: 30) LD
50Measurement result
| Dosage (mg/kg) | Number of animals (only) | Dead number of elements (♂) | Dead number of elements (♀) | Dead sum (only) | Mortality rate (%) | LD 50(mg/kg) (95% fiducial limit) |
| 5000 4000 3200 2560 2048 | 10 10 10 10 10 | 5 3 2 0 0 | 5 1 1 1 0 | 10 4 3 1 0 | 100 40 30 10 0 | 3726.7 (3338.6-4159.8) |
4, conclusion:
The mice single oral gives the toxic reaction basically identical of compound metformin/pioglitazone appearance of three kinds of proportionings, 10-30 minute part animal activity reduces, closes one's eyes after the administration, 1 hour part animal diarrhoea, instability of gait behind the medicine, the number of animals that toxic reaction takes place and the order of severity and dosage are proportionate.Animal dead appears at behind the medicine 4-5 hour the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal, other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period, the weight of animals growth is not subjected to obviously to influence.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.The median lethal dose(LD 50) of the different proportionings of mice orally give compound metformin/pioglitazone (500: 7.5,500: 15,500: 30) is respectively 3137.3,3348.8,3726.7mg/kg.
Two, the pharmacokinetic of compound metformin/pioglitazone blood sugar lowering:
Compound antihypelipidemic is the compound preparation of biguanides antidiabetic drug metformin and Thiazolidine ketone antidiabetic drug pioglitazone, and (500: 30, w/w), because mechanism of action difference, compatibility was in the hope of reaching better hypoglycemic effect to be called for short compound antihypelipidemic.This test is intended to illustrate the similarities and differences that absorb between compound preparation and the single preparations of ephedrine by the absorption test of rat.
1, material
(1) medicine:
Metformin: face with preceding and become 15mg/ml with water dissolution, the administration capacity is the 1ml/100g body weight, is equivalent to 150mg/kg.
Pioglitazone: face with preceding and become 0.9mg/ml with the 1%CMCNa suspendible, the administration capacity is the 1ml/100g body weight, is equivalent to 9mg/kg.
Compound antihypelipidemic: face with preceding and become 15mg metformin and 0.9mg pioglitazone/ml with the 1%CMCNa suspendible, the administration capacity is the 1ml/100g body weight, is equivalent to 150mg/kg metformin and 9mg/kg pioglitazone.
(2) reagent:
Methanol: top grade is pure, Tianjin Concord Technology Co., Ltd.'s product, lot number 031204.Potassium dihydrogen phosphate: AR, Red Star chemical plant, Beijing product, lot number 851011-1.B7: Tianjin chemical reagent two factory's products.Acetonitrile: AR, Tianjin Concord Technology Co., Ltd.'s product, lot number 031015.Sodium acetate: Tianjin Bazhou City's chemical industry subsidiary factory of quartzy Clock Factory product, lot number 980303.
(3) instrument:
NL-200TPA analytical balance: day island proper Tianjin company.
TGL-16C high speed tabletop centrifuge: Anting Scientific Instrument Factory, Shanghai.
HPLC:WATERS 515 pumps; 717 automatic samplers; The RAININ UV-detector;
ANASTAR chromatographic data work station.
(4) animal:
Healthy Wistar rat, female, the about 210g of body weight, the Laboratory Animal Facility quality certification " accurate No. 013 of Tianjin Laboratory Animal Facility " is issued by Tianjin management of laboratory animal committee, meets primary standard.The normal raising after three days for examination.
2, method:
(1) sample collecting and processing:
12 of healthy Wistar rats, female, fasting 16 hours is divided into three groups by weight average, and promptly pioglitazone 9mg/kg organizes, metformin 150mg/kg group and compound antihypelipidemic group.In 8:00 in morning oral administration gavage said medicine respectively, behind medicine 0.33,0.66,1.0,1.5,2.0,4.0,6.0,12.0,24.0 and 36.0 hours eye socket blood sampling 0.5ml respectively, centrifugalize serum.
Quantitatively draw the serum 50 μ l of metformin group and compound antihypelipidemic treated animal, add equal-volume 10% perchloric acid, the shake well protein precipitation, centrifugal, supernatant 20 μ l sample introductions, HPLC analyzes.Manage operation preparation standard serum sample again with blank serum, concentration is respectively 0,0.5,1,2,5,10 and 20 μ g/ml, and as standard curve, processing method is the same.
Quantitatively draw the serum 150 μ l of pioglitazone group and compound antihypelipidemic treated animal, add the 1ml dichloromethane, shake well, centrifugal, get 800 μ l lower floor organic faciess and place another centrifuge tube, air blow drying, 75 μ l mobile phases are redissolved, centrifugal 20 μ l sample introductions, and HPLC analyzes.Manage operation preparation standard serum sample again with blank serum, concentration is respectively 0,0.1,0.5,1,5 and 10 μ g/ml, and as standard curve, processing method is the same.
(2) chromatographic condition:
Metformin: immobile phase: C
18The ODS post, 4.6 * 250mm, 10 μ, post 22I25117
Mobile phase: methanol: 0.005M potassium dihydrogen phosphate (pH2.5)=10: 90
Column temperature: 40 ℃
UV detects: 233nm
Pioglitazone: immobile phase: C
10The ODS post, 4.6 * 100mm, 5 μ, post 22K10040
Mobile phase: acetonitrile: 0.1M sodium acetate (pH4.5)=39: 61
Column temperature: 30 ℃
UV detects: 269nm
(3) result:
Metformin:
The linear equation of serum standard curve (0～20 μ g/ml) is: C=0.0000353A+0.10355 (r=0.9992).The response rate is 95.04%.The blood drug level of different time sees Table 7 behind rat oral administration of metformin and the compound antihypelipidemic, and curve is seen Fig. 1 during medicine; The average out to peak time was respectively 1.1 and 1.0 hours; Peak concentration is respectively 19.6 and 20.4 μ g/ml; AUC is respectively 239.8 and 249.9 μ gh/ml.Compound recipe is 101.7% with respect to the bioavailability of folk prescription.
The blood drug level of different time behind table 7. rat oral administration of metformin and the compound antihypelipidemic
| Group | Through the time blood drug level (μ g/ml) | ||||||||||
| 0.33 | 0.67 | 1 | 1.5 | 2 | 4 | 6 | 8 | 12 | 24 | 36h | |
| The folk prescription metformin | |||||||||||
| 1 2 3 4 | 13.5 12.2 14.5 13.6 | 16.3 15.1 13.7 15.3 | 19.3 24.6 14.5 16.3 | 19.3 20.0 18.4 14.0 | 16.1 16.9 13.7 14.9 | 8.3 9.3 10.8 7.2 | 8.2 5.5 5.8 5.1 | 6.7 5.4 5.2 4.9 | 6.0 10.4 5.6 4.7 | 3.1 13.1 4.6 5.4 | 3.5 2.3 2.8 1.9 |
| mean | 13.4 | 15.1 | 18.7 | 17.9 | 15.4 | 8.9 | 6.2 | 5.5 | 6.7 | 6.6 | 2.6 |
| Compound antihypelipidemic | |||||||||||
| 1 2 3 4 | 12.6 12.5 11.6 15.9 | 19.6 15.6 18.7 17.9 | 27.2 16.3 19.1 19.1 | 21.6 15.1 16.1 15.4 | 14.9 15.9 16.2 18.8 | 14.7 10.2 10.7 10.3 | 8.5 6.9 7.3 8.0 | 7.3 6.5 6.3 6.8 | 6.8 6.5 5.3 6.7 | 6.6 5.7 4.3 6.8 | 2.5 2.9 2.6 3.4 |
| mean | 13.1 | 18.0 | 20.4 | 17.1 | 16.4 | 11.5 | 7.7 | 6.7 | 6.3 | 5.8 | 2.8 |
Pioglitazone:
The linear equation of serum standard curve (0～10 μ g/ml) is: C=0.0000310A-0.1488 (r=0.9988).The response rate is 71.7%.The blood drug level of different time sees Table 8 behind oral pioglitazone of rat and the compound antihypelipidemic, and curve is seen Fig. 2 during medicine; The average out to peak time was respectively 4.0 and 3.9 hours; Peak concentration is respectively 6.8 and 5.3 μ g/ml; AUC is respectively 80.4 and 85.0 μ gh/ml.Compound recipe is 105.7% with respect to the bioavailability of folk prescription.
The blood drug level of different time behind oral pioglitazone of table 8. rat and the compound antihypelipidemic
| Group | Through the time blood drug level (μ g/ml) | ||||||||||
| 0.33 | 0.67 | 1 | 1.5 | 2 | 4 | 6 | 8 | 12 | 24 | 36h | |
| The folk prescription pioglitazone | |||||||||||
| 1 2 3 4 | 0.68 5.84 3.51 0.81 | 2.95 10.81 2.84 2.36 | 3.49 8.09 3.62 3.00 | 5.32 10.73 3.96 3.23 | 3.71 7.60 4.85 3.74 | 4.72 7.32 4.47 4.54 | 4.36 5.90 4.93 6.06 | 4.13 5.12 4.07 6.14 | 2.48 3.25 3.10 3.57 | 0.36 0.66 0.69 0.39 | nd 0.34 0.42 nd |
| mean | 2.71 | 4.74 | 4.55 | 5.81 | 4.97 | 5.26 | 5.31 | 4.87 | 3.10 | 0.52 | 0.38 |
| Compound antihypelipidemic | |||||||||||
| 1 2 | 1.05 0.42 | 2.29 0.46 | 2.80 3.16 | 2.87 3.81 | 2.85 3.19 | 3.26 5.49 | 2.38 5.95 | 1.86 5.09 | 1.12 3.41 | 2.58 1.73 | 0.40 2.47 |
| 3 4 | 0.44 3.33 | 3.37 4.21 | 4.21 5.41 | 5.41 5.93 | 5.48 4.57 | 5.95 3.64 | 5.09 5.28 | 3.40 3.22 | 1.68 1.85 | 2.44 0.80 | 0.69 1.31 |
| mean | 1.31 | 2.58 | 3.90 | 4.51 | 4.02 | 4.59 | 4.67 | 3.39 | 2.01 | 1.89 | 1.22 |
3, conclusion:
The average out to peak time was respectively 1.1 and 1.0 hours behind rat oral administration folk prescription metformin and the compound antihypelipidemic; Peak concentration is respectively 19.6 and 20.4 μ g/ml; AUC is respectively 239.8 and 249.9 μ gh/ml.Compound recipe is 101.7% with respect to the bioavailability of folk prescription.Average out to peak time behind oral pioglitazone of rat and the compound antihypelipidemic was respectively 4.0 and 3.9 hours; Peak concentration is respectively 6.8 and 5.3 μ g/ml; AUC is respectively 80.4 and 85.0 μ gh/ml.Compound recipe is 105.7% with respect to the bioavailability of folk prescription.The interior absorption of the rat body of two kinds of antidiabetic drugs that comprised in the compound antihypelipidemic is noiseless substantially, with the folk prescription there was no significant difference.
Description of drawings
Fig. 1 is curve during medicine behind rat oral administration metformin and the compound preparation;
Fig. 2 is curve during medicine after rat oral administration pioglitazone and the compound preparation administration.
Three, compound metformin/pioglitazone pharmacodynamics test:
1. experiment material
1.1 laboratory animal:
The Wistar rat, body weight 140-160g.The laboratory animal quality certification: No. the 001st, the accurate word of the real kinoplaszm R in W-J Tianjin.
1.2 experimental situation and condition
The Laboratory Animal Facility secondary, the quality certification number: accurate No. 012 of the real moving facility in Tianjin; 22 ± 4 ℃ of room temperatures, humidity 60 ± 20%.The central air-conditioning automatic ventilation.Illumination 12 hours.Freely ingest and drinking public water supply.Change water every day once.
1.3 medicine:
Metformin hydrochloride; Pioglitazone hydrochloride.Behind two medicine grind into powder mixings, be mixed with suspension with 1%CMC.
1.4 reagent and instrument:
Streptozotocin (Streptozotocin, STZ), Sigma, S-0130, the import packing, Beijing is glad to be provided through biotech company of section.Specification: 1g/ bottle.Purity: 98%.
Capital of a country blood glucose meter (SUPER GLUCOCARD II) and test strip, Japan produces, and Maibang Biological Engineering Technology Co., Beijing provides.
The insulin test kit: Tianjin Shu Pu biotechnology company provides.Lot number: 06043-A
SUNRISE remote control microplate reader, the TECAN product.
2. experimental technique and result
The Wistar rat, male, 300,140g-160g, fasting 16hr, the STZ of lumbar injection 30mg/kg (is dissolved in the citrate buffer solution of the pH value 4.4 of 0.1mol/L in 4 ℃ of ice baths, use immediately after joining), every day 1 time, continuous 3 times, administration was fed with high-sugar-fat-diet (normal feedstuff 55%, Adeps Sus domestica 25% after 2 weeks, sucrose 20%), feed 6 week the back survey rat FBG (fasting 12h before surveying), select 64 of the rats of FBG 〉=12.0mmol/L, be divided into 8 groups at random, every group 8, be made as 300: 1.5 groups of model control group and compound recipes respectively, 300: 3 groups of compound recipes, 300: 4.5 groups of compound recipes, 300: 6 groups of compound recipes, 300: 6.75 groups of compound recipes, 300: 9 groups of compound recipes, 300: 27 groups of compound recipes.Other get 8 normal male Wistar rats (with above-mentioned rat with batch getting, FBG≤5.0mmol/L) as the physiology matched group.Physiology contrast and model control group are irritated stomach and are given 1%CMC, and 7 compound recipe groups are irritated stomach successively and given 300mg: the compound medicine of 1.5mg/kg, 300mg: 3mg/kg, 300mg: 4.5mg/kg, 300mg: 6mg/kg, 300mg: 6.75mg/kg, 300mg: 9mg/kg, 300mg: 27mg/kg (metformin hydrochloride: pioglitazone hydrochloride).To be subjected to the reagent thing to be mixed with the suspension of variable concentrations with 1%CMC, i.g administration in morning every day, the administration volume is 1ml/100g, and physiology contrast and model control group filling stomach give isopyknic 1%CMC.Successive administration 21d, 22d 9:00 in morning gets 1 of blood (getting the preceding fasting 12h of blood) with glass capillary from the eyeground vein clump, surveys FBG with blood-sugar detecting instrument, and other gets blood 1ml, centrifuging and taking serum is pressed the test kit illustration method and is adopted the ELASE method to survey serum insulin (FINS) on an empty stomach.Calculate: blood sugar lowering absolute value before and after the administration (FBG before blood sugar lowering absolute value=administration 21dFBG-administration), blood sugar lowering percentage rate (blood sugar lowering percentage rate=[FBG * 100% before (FBG before the administration 21dFBG-administration)/administration]) and insulin resistance index (IR) (IR=FBG * FINS/22.5).Every data represent that with mean+SD the t check compares between each group and model control group employing group.The result: the FBG of the reduction hyperglycemic rat that the compound medicine of each ratio all can be in various degree, above dosage of compound recipe 300mg: 3mg/kg and model control group relatively, there were significant differences for blood sugar lowering absolute value and blood sugar lowering percentage rate, and certain dosage correlation is arranged; The compound medicine of each ratio all can obviously reduce the FINS and the IR level of hyperglycemic rat.See Table 9,10.
Table 9 compound metformin hydrochloride-pioglitazone is to the influence of rat fasting blood-glucose
| Group | Number of animals | FBG (mmol/L) before the administration | Administration 21dFBG (mmol/L) | FBG difference (21d-1d) (mmol/L) | Administration 21d blood sugar lowering percentage rate (%) |
| 300: 9 compounds of 300: 6.75 compounds of 300: 6 compounds of 300: 4.5 compounds of 300: 3 compounds of 300: 1.5 compounds of blank model contrast compound 300: 27 | 8 8 8 8 8 8 8 8 8 | 3.7±0.5 *** 20.5±3.9 20.3±5.2 20.5 ±4.9 20.4±4.3 20.5±4.2 20.3±4.0 20.5±5.5 20.3±3.6 | 3.8±0.5 *** 20.0±3.5 17.9±3.9 17.6±3.2 17.7±4.3 17.3±6.0 16.4±3.0 15.9±4.3 16.2±3.4 | 0.1±0.4 -0.5±1.3 -2.4±2.5 -2.9±2.4 * -2.7±2.6 -3.2±2.8 * -3.9±2.2 ** -4.6±2.3 *** -4.1±2.5 ** | 2.7±11.7 -2.1±6.0 -10.7±10.1 -12.8±8.8 * -13.1±11.5 * -17.3±16.4 * -1 8.7±8.5 *** -22.5±9.4 *** -20.0±12.2 ** |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
Table 10 compound metformin hydrochloride-pioglitazone is to the influence of rat limosis insulin and insulin resistant
| Group | Number of animals | Administration 21dFBG (mmol/L) | Administration 21dFINS (mmol/L) | Administration 21d insulin resistance index (logarithm) |
| 300: 9 compounds of 300: 6.75 compounds of 300: 6 compounds of 300: 4.5 compounds of 300: 3 compounds of 300: 1.5 compounds of blank model contrast compound 300: 27 | 8 8 8 8 8 8 8 8 8 | 3.8±0.5 *** 20.0±3.5 17.9±3.9 17.6±3.2 17.7±4.3 17.3±6.0 16.4±3.0 15.9±4.3 16.2±3.4 | 3.86±0.82 *** 32.35±15.93 8.80±4.63 ** 6.53±4.00 ** 12.68±9.63 ** 8.27±4.56 ** 7.28±4.04 ** 9.18±5.00 ** 9.64±4.33 ** | -0.20±0.12 *** 1.40±0.29 0.79±0.25 *** 0.65±0.22 *** 0.87±0.31 ** 0.70±0.25 ** 0.66±0.25 *** 0.72±0.37 *** 0.79±0.25 *** |
Annotate: compare with model control group,
*P＜0.05,
*P＜0.01,
* *P＜0.001
3. experiment conclusion
Compound metformin hydrochloride-pioglitazone (300mg: 1.5mg/kg, 300mg: 3mg/kg, 300mg: 4.5mg/kg, 300mg: 6mg/kg, 300mg: 6.75mg/kg, 300mg: 9mg/kg, 300mg: 27mg/kg) the continuous gastric infusion 21d of difference, the compound medicine of each ratio all can be in various degree FBG, FINS and the IR level of reduction hyperglycemic rat, especially obvious to the reduction of FINS and IR.
The specific embodiment
The present invention will be further described below in conjunction with embodiment, but these embodiment are not limitation of the present invention.In order to explain enforcement of the present invention more fully, provide following example of formulations.Preparation can adopt the form of any one compositions among the present invention.The different proportioning of elite compound metformin/pioglitazone (1) was representative in 500: 15 (2) 750: 15 (3) 1000: 15.
Preparation 1
Bilayer tablet up and down:
| Upper component | Consumption/sheet | Weight concentration (%) |
| Pioglitazone hydrochloride | 15mg | 12.1 |
| Microcrystalline Cellulose | 55mg | 44.4 |
| Lactose | 45mg | 36.3 |
| Polyvinylpyrrolidone | 3mg | 2.4 |
| Carboxymethyl starch sodium | 4.5mg | 3.6 |
| Magnesium stearate | 0.5mg | 0.4 |
| Pulvis Talci | 1mg | 0.8 |
| Following composition of layer | Consumption/sheet | Consumption/sheet | Consumption/sheet |
| Metformin hydrochloride | 500mg | 750mg | 1000mg |
| Hydroxypropyl emthylcellulose | 190g | 205mg | 210mg |
| Polyvinylpyrrolidone | 14.0mg | 19.1mg | 24.2mg |
| Magnesium stearate | 7.1mg | 9.7mg | 12.3mg |
Preparation method:
Pioglitazone hydrochloride preparation method of granules: active component, lactose, microcrystalline Cellulose are sieved, and fully mix, mix with above-mentioned powder with polyvinylpyrrolidonesolution solution, sieve, make wet granular in 50-60 ℃ of drying, with carboxymethyl starch sodium, magnesium stearate and Pulvis Talci sieve in advance, join then in the above-mentioned granule.
Metformin hydrochloride preparation method of granules: active component, hydroxypropyl emthylcellulose are sieved, and fully mix, mix with above-mentioned powder with the polyvinylpyrrolidone alcoholic solution, sieve, make wet granular in 50-60 ℃ of drying, add magnesium stearate in above-mentioned granule.
Above-mentioned granule is put double-layer tablet tablet machine tabletting.
Preparation 2
Inside and outside bilayer tablet:
| Interior composition of layer | Consumption/sheet | Consumption/sheet | Consumption/sheet |
| Metformin hydrochloride | 500mg | 750mg | 1000mg |
| Hydroxypropyl emthylcellulose | 190g | 205mg | 210mg |
| Polyvinylpyrrolidone | 14.0mg | 19.1mg | 24.2mg |
| Magnesium stearate | 7.1mg | 9.7mg | 12.3mg |
| Outer composition of layer | Consumption/sheet |
| Pioglitazone hydrochloride | 15mg |
| Hydroxypropyl emthylcellulose | 43.6mg |
| PEG400 | 4.5mg |
Preparation method:
Diabecron sustained-release tablet core preparation method: active component, hydroxypropyl emthylcellulose are sieved, and fully mix, mix with above-mentioned powder with the polyvinylpyrrolidone alcoholic solution, sieve, make wet granular in 50-60 ℃ of drying, add magnesium stearate in above-mentioned granule, tabletting.
The pioglitazone hydrochloride coating solution: with pioglitazone hydrochloride and hydroxypropyl emthylcellulose mix homogeneously, get an amount of PEG400 and add in the entry and dissolve, stir down, slowly add said mixture, make into suspension, the coating solution solids content is about 9%.
Suspension is crossed 80 mesh sieves, coating under the suitable condition, and the control gain in weight makes the hydrochloric pioglitazone 15mg of every agreement that contracts a film or TV play to an actor or actress.
Although the present invention has done detailed description in conjunction with its special embodiment, clearly concerning the skilled people in present technique field, still can make various changes and improvements, can not depart from spirit of the present invention and protection domain.
Claims (9)
1, a kind of pharmaceutical composition, it is characterized in that: contain 15mg pioglitazone hydrochloride and 500mg or 750mg metformin hydrochloride and one or more pharmaceutically acceptable carriers, described compositions is a double-layer tablet, be divided into release layer and slow release layer, the hydrochloric pioglitazone of release layer, the hydrochloric metformin of slow release layer, described double-layer tablet are up and down bilayer tablet or inside and outside bilayer tablet; The internal layer of described inside and outside bilayer tablet is the metformin slow release layer, and skin is the pioglitazone hydrochloride release layer.
2, pharmaceutical composition as claimed in claim 1 is characterized in that wherein said compositions contains the 500mg metformin hydrochloride.
3, pharmaceutical composition as claimed in claim 1 is characterized in that wherein said compositions contains the 750mg metformin hydrochloride.
4, pharmaceutical composition as claimed in claim 1 is characterized in that wherein said double-layer tablet is double-layer tablet up and down, and wherein every upper strata is contained:
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 55mg
Lactose 45mg
Polyvinylpyrrolidone 3mg
Carboxymethyl starch sodium 4.5mg
Magnesium stearate 0.5mg
Pulvis Talci 1mg
Every lower floor is contained:
Metformin hydrochloride 500mg
Hydroxypropyl emthylcellulose 190mg
Polyvinylpyrrolidone 14mg
Magnesium stearate 7.1mg.
5, pharmaceutical composition as claimed in claim 1 is characterized in that wherein said double-layer tablet is double-layer tablet up and down, and wherein every upper strata is contained:
Pioglitazone hydrochloride 15mg
Microcrystalline Cellulose 55mg
Lactose 45mg
Polyvinylpyrrolidone 3mg
Carboxymethyl starch sodium 4.5mg
Magnesium stearate 0.5mg
Pulvis Talci 1mg
Every lower floor is contained:
Metformin hydrochloride 750mg
Hydroxypropyl emthylcellulose 205mg
Polyvinylpyrrolidone 19.1mg
Magnesium stearate 9.7mg.
6, pharmaceutical composition as claimed in claim 1 is characterized in that, described double-layer tablet is inside and outside double-layer tablet, and wherein every internal layer contains:
Metformin hydrochloride 500mg
Hydroxypropyl emthylcellulose 190mg
Polyvinylpyrrolidone 14.0mg
Magnesium stearate 7.1mg
Every skin contains:
Pioglitazone hydrochloride 15mg
Hydroxypropyl emthylcellulose 43.6mg
Polyethylene Glycol-400 4.5mg.
7, pharmaceutical composition as claimed in claim 1 is characterized in that, described double-layer tablet is inside and outside double-layer tablet, and wherein every internal layer contains:
Metformin hydrochloride 750mg
Hydroxypropyl emthylcellulose 205mg
Polyvinylpyrrolidone 19.1mg
Magnesium stearate 9.7mg
Every skin contains:
Pioglitazone hydrochloride 15mg
Hydroxypropyl emthylcellulose 43.6mg
Polyethylene Glycol-400 4.5mg.
8, a kind of method for preparing the pharmaceutical composition of arbitrary claim among the claim 1-7, it comprises: (1) is the preparation of bilayer tablet up and down:
(A) the particulate preparation of pioglitazone hydrochloride:
Active component, lactose, microcrystalline Cellulose sieved and fully mix mixture; Mix with said mixture with polyvinylpyrrolidonesolution solution, sieve, the wet granular that makes is in 50-60 ℃ of drying; Carboxymethyl starch sodium, magnesium stearate and Pulvis Talci are sieved in advance, join then in the above-mentioned granule;
(B) the particulate preparation of metformin hydrochloride:
Active component, hydroxypropyl emthylcellulose are sieved and fully mix to such an extent that mixture sieves, make wet granular, add magnesium stearate in above-mentioned granule in 50-60 ℃ of drying;
(C) above-mentioned (A) and granule (B) are placed the bi-layer tablet press tabletting, obtain double-layer tablet; Or (2) inside and outside bilayer tablet preparation:
(A) preparation of diabecron sustained-release tablet core:
Active component and hydroxypropyl emthylcellulose are sieved, and fully mix, get mixture; Alcoholic solution with polyvinylpyrrolidone mixes with said mixture, sieves, and the wet granular that makes is in 50-60 ℃ of drying; Add magnesium stearate in above-mentioned granule, tabletting obtains label;
(B) preparation of pioglitazone hydrochloride coating solution:
With pioglitazone hydrochloride and hydroxypropyl emthylcellulose mix homogeneously, get mixture; Taking polyethylene glycol-400 adds in the entry and dissolves, and stirs down, slowly adds above-mentioned mixture, makes into suspension, crosses 80 mesh sieves, obtains the pioglitazone hydrochloride coating solution;
(C) with the coating solution of above-mentioned (B) the label coating to (A), the control gain in weight makes every pioglitazone hydrochloride that contains scheduled volume.
9, the application of each pharmaceutical composition in preparation treatment diabetes medicament among the claim 1-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100194836A CN1327840C (en) | 2004-06-08 | 2004-06-08 | Medicinal composition and its use in treatment of diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100194836A CN1327840C (en) | 2004-06-08 | 2004-06-08 | Medicinal composition and its use in treatment of diabetes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1582928A CN1582928A (en) | 2005-02-23 |
| CN1327840C true CN1327840C (en) | 2007-07-25 |
Family
ID=34600526
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100194836A Expired - Lifetime CN1327840C (en) | 2004-06-08 | 2004-06-08 | Medicinal composition and its use in treatment of diabetes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1327840C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490921A (en) * | 2014-12-09 | 2015-04-08 | 成都恒瑞制药有限公司 | Solid oral preparation containing metformin hydrochloride and colesevelam hydrochloride |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7785627B2 (en) | 2002-09-20 | 2010-08-31 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US8084058B2 (en) | 2002-09-20 | 2011-12-27 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US7959946B2 (en) | 2002-09-20 | 2011-06-14 | Watson Pharmaceuticals, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| US9060941B2 (en) | 2002-09-20 | 2015-06-23 | Actavis, Inc. | Pharmaceutical formulation containing a biguanide and a thiazolidinedione derivative |
| CN101347511B (en) * | 2008-09-05 | 2011-08-17 | 刘全胜 | Medicament composition with function for reducing blood sugar |
| CN102008472B (en) * | 2010-10-18 | 2012-08-22 | 中国科学院上海药物研究所 | Compound pioglitazone hydrochloride/metformin hydrochloride bilayer osmotic pump controlled release preparation and preparation method thereof |
| CN103432131A (en) * | 2013-09-11 | 2013-12-11 | 中国药科大学 | Compound preparation containing pioglitazone hydrochloride and metformin hydrochloride and preparing method thereof |
| CN106138061B (en) * | 2015-04-03 | 2019-06-04 | 中国人民解放军第三军医大学第三附属医院 | The compound and its preparation and purposes of prevention or decrease pulmonary fibrosis |
| CN105125539A (en) * | 2015-08-05 | 2015-12-09 | 浙江华海药业股份有限公司 | Pioglitazone metformin tablet and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1145783A (en) * | 1995-06-20 | 1997-03-26 | 武田药品工业株式会社 | Pharmaceutical composition for diabetes |
| CN1260716A (en) * | 1997-06-18 | 2000-07-19 | 史密丝克莱恩比彻姆有限公司 | Treatment of diabetes with thiazolidinedione and metformin |
| CN1348369A (en) * | 1998-11-12 | 2002-05-08 | 史密丝克莱恩比彻姆有限公司 | Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent |
-
2004
- 2004-06-08 CN CNB2004100194836A patent/CN1327840C/en not_active Expired - Lifetime
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1145783A (en) * | 1995-06-20 | 1997-03-26 | 武田药品工业株式会社 | Pharmaceutical composition for diabetes |
| CN1260716A (en) * | 1997-06-18 | 2000-07-19 | 史密丝克莱恩比彻姆有限公司 | Treatment of diabetes with thiazolidinedione and metformin |
| CN1429551A (en) * | 1997-06-18 | 2003-07-16 | 史密丝克莱恩比彻姆有限公司 | Treating diabetes by thiazolidine-diketo and dimethylbiguanide |
| CN1348369A (en) * | 1998-11-12 | 2002-05-08 | 史密丝克莱恩比彻姆有限公司 | Pharmaceutical composition for modified release of an insulin sensitiser and another antidiabetic agent |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490921A (en) * | 2014-12-09 | 2015-04-08 | 成都恒瑞制药有限公司 | Solid oral preparation containing metformin hydrochloride and colesevelam hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1582928A (en) | 2005-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11564886B2 (en) | Pharmaceutical compositions | |
| US20220287980A1 (en) | Pharmaceutical composition and uses thereof | |
| CN101309688B (en) | The compositions of sustained release Beta-alanine and method | |
| CN105147662A (en) | Pharmaceutical composition comprising glucopyranosyl diphenylmethane derivatives, pharmaceutical dosage form thereof, process for their preparation and uses thereof for improved glycemic control in a patient | |
| CN104138370A (en) | SGLT-2 inhibitor for treating type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance or hyperglycemia | |
| HUE031088T2 (en) | Pharmaceutical composition comprising linagliptin and a sglt2 inhibitor,and uses thereof | |
| CN101590007A (en) | A kind of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions and preparation thereof | |
| CN1327840C (en) | Medicinal composition and its use in treatment of diabetes | |
| JP2008536879A (en) | Drug or nutrition combination preparation and preparation, method for improving absorption by internal use, and application method thereof | |
| WO2008022557A1 (en) | Liquid composition of sirolimus | |
| CN102727894B (en) | A kind of pharmaceutical composition and application thereof for the treatment of diabetes and complication thereof | |
| KR20100025427A (en) | Pharmaceutical compositions, formulations and absorption of talniflumate extended release tablets | |
| KR20090086686A (en) | Pharmaceutical composition comprising silymarin with improved dissolution rate and method for preparing the same | |
| US6248361B1 (en) | Water-soluble folic acid compositions | |
| CN102228457B (en) | Pharmaceutical composition for treating diabetes and complication thereof | |
| AU2012343332B2 (en) | Improved synergistic anti-diabetic compositions | |
| CN104434856A (en) | Gastric floating glipizide controlled release tablet and preparation process thereof | |
| CN104840480B (en) | Metformin/folic acid/vitamin B12New application of pharmaceutical composition | |
| CN107595799A (en) | A kind of compound enteric-coated oral disintegrating tablet and preparation method thereof | |
| TWI749204B (en) | A pharmaceutical composition capable of improving the bioavailability of oral statins and its use | |
| CN101385719A (en) | Osmotic pump preparation composition for treating hyperlipemia | |
| EP0835654A1 (en) | Glucomannan-containing orally administered pharmaceutical preparations with sustained effect | |
| CN102218062A (en) | Medicine composition for treating diabetes mellitus | |
| CN103127115A (en) | Composition capable of curing abnormal blood lipid | |
| JP2024522639A (en) | Oral preparations containing 1-(3-cyano-1-isopropyl-indol-5-yl)pyrazole-4-carboxylic acid |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: JIANGSU DEYUAN PHARMACEUTICAL Co.,Ltd. Assignor: Tianjin Institute of Pharmaceutical Research|Lianyungang Deyuan Pharmaceutical Co.,Ltd. Contract fulfillment period: 2009.7.18 to 2014.7.18 Contract record no.: 2009320001428 Denomination of invention: Medicinal composition and its use in treatment of diabetes Granted publication date: 20070725 License type: Exclusive license Record date: 20090807 |
|
| LIC | Patent licence contract for exploitation submitted for record |
Free format text: EXCLUSIVE LICENSE; TIME LIMIT OF IMPLEMENTING CONTACT: 2009.7.18 TO 2014.7.18; CHANGE OF CONTRACT Name of requester: JIANGSU DEYUAN MEDICINE CO., LTD. Effective date: 20090807 |
|
| EC01 | Cancellation of recordation of patent licensing contract |
Assignee: JIANGSU DEYUAN PHARMACEUTICAL Co.,Ltd. Assignor: Tianjin Institute of Pharmaceutical Research|Lianyungang Deyuan Pharmaceutical Co.,Ltd. Contract record no.: 2009320001428 Date of cancellation: 20131113 |
|
| LICC | Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU DEYUAN PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: LIANYUNGANG DEYUAN PHARMACEUTICAL CO., LTD. Effective date: 20131211 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20131211 Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee after: Tianjin Institute of Pharmaceutical Research Patentee after: JIANGSU DEYUAN PHARMACEUTICAL Co.,Ltd. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research Patentee before: Lianyungang Deyuan Pharmaceutical Co.,Ltd. |
|
| C56 | Change in the name or address of the patentee |
Owner name: TIANJIN PHARMACEUTICAL INSTITUTE CO., LTD. Free format text: FORMER NAME: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee after: Tianjin Institute of Pharmaceutical Research Co.,Ltd. Patentee after: JIANGSU DEYUAN PHARMACEUTICAL Co.,Ltd. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research Patentee before: JIANGSU DEYUAN PHARMACEUTICAL Co.,Ltd. |
|
| CX01 | Expiry of patent term |
Granted publication date: 20070725 |
|
| CX01 | Expiry of patent term |