CN102228457A - Pharmaceutical composition for treating diabetes and complication thereof - Google Patents
Pharmaceutical composition for treating diabetes and complication thereof Download PDFInfo
- Publication number
- CN102228457A CN102228457A CN 201110102614 CN201110102614A CN102228457A CN 102228457 A CN102228457 A CN 102228457A CN 201110102614 CN201110102614 CN 201110102614 CN 201110102614 A CN201110102614 A CN 201110102614A CN 102228457 A CN102228457 A CN 102228457A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- pioglitazone
- aretigenin
- group
- diabetes
- 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
- 206010012601 diabetes mellitus Diseases 0.000 title claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 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 80
- 239000000203 mixture Substances 0.000 claims abstract description 41
- 229960005095 pioglitazone Drugs 0.000 claims abstract description 40
- 239000003814 drug Substances 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 12
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 5
- 206010012655 Diabetic complications Diseases 0.000 claims abstract description 4
- 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 32
- 229960002827 pioglitazone hydrochloride Drugs 0.000 claims description 31
- 239000008187 granular material Substances 0.000 claims description 21
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 7
- 239000003795 chemical substances by application 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
- 239000002775 capsule Substances 0.000 claims description 5
- 239000002671 adjuvant Substances 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
- 239000000080 wetting agent Substances 0.000 claims description 3
- 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
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000007919 dispersible tablet Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 2
- 210000000214 mouth Anatomy 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 9
- NQWVSMVXKMHKTF-JKSUJKDBSA-N (-)-Arctigenin Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1[C@@H](CC=2C=C(OC)C(O)=CC=2)C(=O)OC1 NQWVSMVXKMHKTF-JKSUJKDBSA-N 0.000 abstract description 6
- YYGRXNOXOVZIKE-UHFFFAOYSA-N Arctigenin Natural products COC1CCC(CC2COC(=O)C2CC3CCC(O)C(C3)OC)CC1OC YYGRXNOXOVZIKE-UHFFFAOYSA-N 0.000 abstract description 4
- OIFFJDGSLVHPCW-UHFFFAOYSA-N Guayarol Natural products COc1ccc(CC2C(Cc3ccc(O)c(O)c3)COC2=O)cc1OC OIFFJDGSLVHPCW-UHFFFAOYSA-N 0.000 abstract description 4
- NQWVSMVXKMHKTF-UHFFFAOYSA-N L-Arctigenin Natural products C1=C(OC)C(OC)=CC=C1CC1C(CC=2C=C(OC)C(O)=CC=2)C(=O)OC1 NQWVSMVXKMHKTF-UHFFFAOYSA-N 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 4
- NWFYESYCEQICQP-UHFFFAOYSA-N methylmatairesinol Natural products C1=C(OC)C(OC)=CC=C1CC1C(=O)OCC1CC1=CC=C(O)C(OC)=C1 NWFYESYCEQICQP-UHFFFAOYSA-N 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 description 27
- 239000008280 blood Substances 0.000 description 27
- 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 18
- 241000700159 Rattus Species 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 235000019197 fats Nutrition 0.000 description 13
- 238000000034 method Methods 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- XOJVHLIYNSOZOO-SWOBOCGESA-N Arctiin Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1[C@@H](CC=2C=C(OC)C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)=CC=2)C(=O)OC1 XOJVHLIYNSOZOO-SWOBOCGESA-N 0.000 description 9
- 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 9
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 9
- 230000036772 blood pressure Effects 0.000 description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- BPYGTFFYYOWDBC-LOVSFRALSA-N arctiin Natural products COc1ccc(C[C@H]2COC(=O)[C@@H]2Cc3ccc(O[C@@H]4O[C@H](C)[C@@H](O)[C@H](O)[C@H]4O)c(OC)c3)cc1OC BPYGTFFYYOWDBC-LOVSFRALSA-N 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 235000001727 glucose Nutrition 0.000 description 6
- 208000017169 kidney disease Diseases 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 235000000346 sugar Nutrition 0.000 description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 description 5
- 206010022489 Insulin Resistance Diseases 0.000 description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 5
- 230000008901 benefit Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- 210000002700 urine Anatomy 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 206010013786 Dry skin Diseases 0.000 description 4
- 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 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 230000002218 hypoglycaemic effect Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 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
- 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 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 231100000304 hepatotoxicity Toxicity 0.000 description 3
- 201000001421 hyperglycemia Diseases 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 230000007056 liver toxicity Effects 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000007779 soft material Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- 229960001052 streptozocin Drugs 0.000 description 3
- 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
- 108010010803 Gelatin Proteins 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 102000000536 PPAR gamma Human genes 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000002641 glycemic effect Effects 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 201000008980 hyperinsulinism Diseases 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 235000010356 sorbitol Nutrition 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 235000019489 Almond oil Nutrition 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007247 Carbuncle Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 235000008495 Chrysanthemum leucanthemum Nutrition 0.000 description 1
- 244000192528 Chrysanthemum parthenium Species 0.000 description 1
- 235000000604 Chrysanthemum parthenium Nutrition 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 201000000297 Erysipelas Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 108010023302 HDL Cholesterol Proteins 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 208000001280 Prediabetic State Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 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 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 241000282894 Sus scrofa domesticus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008168 almond oil Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- -1 antibiotic Chemical compound 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000004071 biological effect Effects 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
- 230000002213 calciumantagonistic effect Effects 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
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 238000011841 epidemiological investigation Methods 0.000 description 1
- 230000001610 euglycemic effect Effects 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 235000008384 feverfew Nutrition 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000004153 glucose metabolism Effects 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229940084936 gonak Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 235000009200 high fat diet Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 210000003026 hypopharynx Anatomy 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000006680 metabolic alteration Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- FJQXCDYVZAHXNS-UHFFFAOYSA-N methadone hydrochloride Chemical compound Cl.C=1C=CC=CC=1C(CC(C)N(C)C)(C(=O)CC)C1=CC=CC=C1 FJQXCDYVZAHXNS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- 201000009104 prediabetes syndrome Diseases 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 238000010850 salt effect Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000002278 tabletting lubricant Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 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
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a pharmaceutical composition for treating diabetes and complication thereof, and particularly relates to a composition containing arctigenin and PioglitaZone or pharmaceutically acceptable salts thereof and to the purpose of the composition in preparing medicines for treating diabetes, diabetic complication and diseases related to diabetes.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of pharmaceutical composition for the treatment of diabetes and complication thereof, particularly a kind of pharmaceutical composition that contains aretigenin and pioglitazone or its officinal salt.
Background technology
According to The World Health Organization (WHO) statistics, present global diabetics is about 1.94 hundred million, also will double to the year two thousand thirty.The diabetics of China has reached about 4,000 ten thousand, is only second to India and occupies the second place of the world.The type 2 diabetes mellitus patient accounts for the 90%-95% of diabetics sum in the diabetic population of China.Type 2 diabetes mellitus has become one of principal disease that threatens China's national health.The up-to-date Chinese Diabetes Epidemiological Investigation of finishing of diabetology branch of Chinese Medical Association shows: at present, in China's urban population, diabetics probably has 4,100 ten thousand people, and prevalence has reached 3.2%, and annual average rate of increase is near 10%.In the flourishing relatively big cities such as Beijing and Shanghai of economy, the sickness rate of diabetes reaches about 8% especially.
Pioglitazone, English name PioglitaZone belongs to euglycemic agent, and mechanism of action is relevant with the existence of insulin, can reduce the insulin resistant of peripheral tissues and liver, increases the processing of the glucose that relies on insulin, and reduces the output of glycogen.Different with sulfonylurea, pioglitazone does not promote insulin secretion, its mechanism of action is the exciting microperoxisome growth factor activation receptor-gamma [PPAR-γ] of high selectivity, the transcribing of the insulin related gene of many control glucoses of the activation scalable of PPAR-γ and lipid metabolism.Zoopery shows, pioglitazone can reduce the hyperglycemia, hyperinsulinism of insulin resistant because of disease and high triglyceride.The increase that the metabolic alterations that pioglitazone causes has caused the tissue of dependence insulin to be replied.Clinical research shows that pioglitazone can improve insulin resistant patient's insulin sensitivity, improves the reactivity of insulin pair cell, and improves glucose metabolism obstacle in the body.This drug side effect mainly is lower, the liver toxicity of drug effect, abnormal liver function, edema, weight increase, the anemia of light moderate.
Aretigenin is arctigenin (Arctigenin) again, CAS 7770-78-7, and molecular formula is C21H24O6, molecular weight is 372.41.Aretigenin is mainly derived from Fructus Arctii, Fructus Arctii is the dry mature fruit of feverfew Fructus Arctii, be conventional Chinese medicine, have the function of dispelling wind and heat pathogens, lung qi dispersing rash, resolving toxin and disinhibiting the throat, be used for anemopyretic cold, cough with copious phlegm, measles, rubella, laryngopharynx swelling and pain, itch cheek erysipelas, carbuncle sore tumefacting virus.This Chinese medicine contains Lignanoids compounds, mainly is Arctiin (arctiin) and aretigenin (arctigenin) etc.According to the literature, aretigenin has stronger biological activity than Arctiin, such as antibiotic, antiviral, antitumor, anti-paf receptor and calcium antagonistic activity significantly.Application number is 200310105686.2 to disclose the application in the medicine of preparation treatment diabetes and complication thereof of Arctiin and aglycon thereof, and application number is 200410097292.1 to disclose Arctiin and the application of aglycon in preparation treatment diabetic nephropathy drugs thereof.
At present, find by retrieval domestic and international public publication, the existing report of aretigenin and pioglitazone or its salt folk prescription treatment diabetes and complication thereof in the prior art, but do not find at present aretigenin and pioglitazone or its salt as compound medicine treatment diabetes with and the relevant report of complication.
Summary of the invention
The inventor is by the surprised discovery of big quantity research, and aretigenin and pioglitazone combination medicine form can provide useful especially blood pressure and blood lipoid control effect, and do not find side reaction.This combination medicine form can be good especially be applied to treat diabetes, especially type 2 diabetes mellitus and the disease relevant with diabetes, reach blood sugar lowering, blood fat, improve the purpose of diabetes, its effect significantly is better than any single component, has significantly reduced liver toxicity, the incidence rate of side reactions such as abnormal liver function simultaneously.
The invention provides a kind of pharmaceutical composition that contains effective dose active component aretigenin and pioglitazone or its pharmaceutically acceptable salt, with and preparation treatment diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
Pioglitazone pharmaceutically acceptable salt of the present invention is hydrochlorate, formates, fumarate, acetate, benzoate, mesylate, sulfate or maleate.Preferred pioglitazone itself or its hydrochlorate of using.The officinal salt that can prepare pioglitazone with reference to the EP193256 method.
The weight ratio of aretigenin and pioglitazone or its pharmaceutically acceptable salt is (0.01-1000) in the compositions of the present invention: 1, the weight ratio of preferred aretigenin and pioglitazone or its pharmaceutically acceptable salt is (0.05-500): 1, and most preferably aretigenin and pioglitazone hydrochloride weight ratio are 5: 1.The compositions of aretigenin and pioglitazone or its pharmaceutically acceptable salt effect aspect treatment diabetes and complication thereof is extremely remarkable, compare with individually dosed aretigenin or pioglitazone or its pharmaceutically acceptable salt, have synergism aspect treatment diabetes and the complication thereof.
The pharmaceutical composition of aretigenin of the present invention and pioglitazone, during with oral form administration, consumption every day of aretigenin is the 0.01-100mg/kg body weight, consumption every day of pioglitazone or its pharmaceutically acceptable salt is the 0.01-10mg/kg body weight.Administration time and administration number of times need be decided the diagnostic result of the state of an illness according to the doctor.To be applied on the person the diabetes of mice, the therapeutic scheme of diabetic complication, all medicines can convert by the effective dose of this medicine to mice to people's effective dose, and this is conspicuous for the person of ordinary skill of the art.
The inventor is by a large amount of discovering, aretigenin and pioglitazone compositions can provide useful especially blood pressure and blood lipoid control effect, and do not find side reaction.This combination medicine form can be good especially be applied to treat diabetes, especially type 2 diabetes mellitus and the disease relevant with diabetes, reach blood sugar lowering, blood fat improves the purpose of diabetes, its effect significantly is better than any single component.
Wherein, especially preferably contain aretigenin and pioglitazone hydrochloride pharmaceutical composition as effective ingredient and an amount of acceptable accessories composition.Pharmaceutical composition of the present invention can improve the effect that insulin resistant reaches hypoglycemic.Drug combination absorbs from reducing, and strengthens metabolism two aspects and works, and drug effect significantly is better than single medicine.The drug combination of pharmaceutical composition of the present invention can reduce the consumption of pioglitazone, has reduced because the excessive hypoglycemia odds that causes of pioglitazone consumption has significantly reduced liver toxicity, the incidence rate of side reactions such as abnormal liver function simultaneously.
Pioglitazone itself has certain heart toxic and side effects, and pioglitazone can increase the blood plasma volume, causes that cardiac preload increases and induces cardiac hypertrophy, and the discovery that the inventor is surprised pharmaceutical composition of the present invention can significantly improve the heart side reaction of pioglitazone.The diabetes patient is in hyperglycemia, mostly with hyperlipidemia, obesity.Pharmaceutical composition of the present invention can blood sugar lowering, again can blood fat reducing, thus more effective, and be the long-acting lasting diabetes of improving.An advantage of the present invention is when using according to the inventive method, used various active dose levels will less than reach add merely and the blood pressure and blood lipoid control action dosage that may need.
Pharmaceutical composition of the present invention is aretigenin and the pioglitazone compositions of containing provided by the invention, as required, also contains an amount of acceptable accessories in the said composition.
The compositions of aretigenin of the present invention and pioglitazone can be tablet, capsule, powder, granule, oral cavity disintegration tablet, dispersible tablet, or such as liquid preparation forms such as oral or aseptic parenteral solution or suspensions.
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, and can contain conventional excipients such as binding agent, for example syrup, arabic gum, gelatin, sorbitol or polyvinylpyrrolidone; Filler, for example lactose, corn starch, calcium phosphate, glycine; Tabletting lubricant, for example magnesium stearate; Disintegrating agent, for example starch, Explotab; Or pharmaceutically acceptable wetting agent, as dodecyl sodium sulfate.
Solid oral composition can prepare with conventional mixing, filling or pressed disc method.Repeating married operation can be used for activating agent fully is distributed to the compositions of using a large amount of filleies.Well-known method coating during tablet can prepare according to conventional medicine, particularly enteric coated.
Oral liquid can make example emulsion, syrupy form, or can be used as dry products exists, and water or other suitable carriers reconstitute again before the use.This liquid can have conventional additives, such as suspending agent, and for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethyl-cellulose, carboxymethyl cellulose, aluminium stearate gel, hydrogenation edible fat; Emulsifying agent, for example lecithin or arabic gum; Anhydrous carrier is as almond oil, hydrogenated coconut oil, propylene glycol.Can also add conventional flavoring agent or coloring agent if desired.
For parenteral, can utilize this chemical compound and sterile carrier to prepare the liquid unit dosage forms, and, can suspend or be dissolved in the carrier according to used concentration.When preparation solution, can be filled into sealing in bottle or the peace bottle afterwards with this compound dissolution in water for injection and filtration sterilization.For enhanced stability, be filled in the bottle after can be with said composition freezing, and under vacuum, remove moisture.The parenteral suspension uses the identical mode of essence to prepare, and just chemical compound is not to be dissolved in the carrier, but is suspended in the carrier, and sterilization is not accomplished by filtration.Can comprise surfactant or wetting agent in the said composition and distribution all be arranged to promote this chemical compound.
Can contain 0.1% to 99% weight, be preferably the active substance of 10-60% weight according to different medication compositionss.These compositionss are prepared according to conventional method, such as in the canonical reference book, and those disclosed in Britain and American Pharmacopeia, Remington ' S pharmaceutical science, Extra Pharmacopoeia Martindale and Harry ' S cosmetic conduct and learning for example.
Term used herein " disease relevant with diabetes " comprises those diseases relevant with the prediabetes state, with diabetes self diseases associated and with diabetes relevant complication; Comprise such as the insulin resistance disease, comprise heritability insulin resistance, glucose tolerance weakening and hyperinsulinemia; Comprise hyperglycemia, insulin resistance comprises insulin resistance and obesity and the hyperlipidemia day after tomorrow; Other and diabetes self diseases associated comprise hypertension and cardiovascular disease, especially atherosclerosis and hyperlipidemia.Term used herein " with the diabetes complications associated with arterial system " comprises kidney disease, especially with H type diabetes relevant kidney disease, neuropathy and retinopathy.
Term herein " pharmaceutically acceptable " comprises people and veterinary purpose, and for example term " pharmaceutically acceptable " comprises the still acceptable chemical compound of veterinary.
Provide the blood pressure and blood lipoid control action of having a mind to especially to be designated as with respect to the synergism that contrasts by treatment of the present invention, this contrast is contemplated to the effect summation of independent active agents.
Glycemic control can utilize conventional method to describe its feature, for example by measuring glycemic control index commonly used, for example fasting plasma glucose or glycolated hemoglobin (HbAlc).These indexs can utilize standard method to measure.Blood fat control can utilize conventional method to describe its feature, for example by measuring blood fat control characteristic commonly used, as low density lipoprotein, LDL LDL content in the blood plasma.These indexs can utilize standard method to measure.
To sum up, pharmaceutical composition of the present invention compared with prior art, particularly compare with the folk prescription administration, obtained beyond thought technique effect aspect horizontal improving blood glucose, blood fat reducing and saccharifying serum albumin, have significant advantage, and the tool synergism, control as kidney disease preventing and/or treating diabetes and complication thereof simultaneously, especially relevant with H type diabetes kidney disease, neuropathy and retinopathy has extremely significant advantage, and obtained good synergy.
The specific embodiment
Below further describe the present invention by specific embodiment, but range of application of the present invention is not limited to the following example, some is modified and equivalent variations is conspicuous for those of ordinary skill in the art and comprises within the scope of the invention.
Embodiment 1: granule
Prescription:
5% polyvinylpyrrolidone aqueous solution is an amount of
Preparation method: it is standby that pioglitazone hydrochloride, aretigenin and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5% polyvinylpyrrolidone aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60 ℃ of dryings, cross 24 mesh sieve granulate.With aretigenin and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule.
Embodiment 2: granule
Prescription:
5% polyvinylpyrrolidone aqueous solution is an amount of
Preparation method: it is standby that pioglitazone hydrochloride, aretigenin and adjuvant are crossed 80 mesh sieves respectively.Take by weighing pioglitazone hydrochloride, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5% polyvinylpyrrolidone aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60 ℃ of dryings, cross 24 mesh sieve granulate.With aretigenin and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, direct packaging is made granule.
Embodiment 3: tablet
Prescription:
Preparation technology: the pioglitazone hydrochloride in will writing out a prescription, aretigenin are crossed 80 mesh sieves, microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves, take by weighing pioglitazone hydrochloride, aretigenin and low-substituted hydroxypropyl cellulose, the microcrystalline Cellulose mix homogeneously of recipe quantity, adding 2% Gonak granulates in right amount, 60 ℃ of dryings, 16 mesh sieve granulate, the magnesium stearate mixing of adding recipe quantity in the dried granule, tabletting is promptly.
Embodiment 4: capsule
Prescription:
5% polyvinylpyrrolidone aqueous solution is an amount of
Preparation method: it is standby that maleic acid pioglitazone, aretigenin and adjuvant are crossed 80 mesh sieves respectively.Take by weighing maleic acid pioglitazone, lactose, starch, L-HPC according to prescription, behind equivalent incremental method mixing, add 5% polyvinylpyrrolidone aqueous solution system soft material, cross 24 mesh sieves and granulate, after 60 ℃ of dryings, cross 24 mesh sieve granulate.With aretigenin and microcrystalline Cellulose mix homogeneously, adopt dry granulation, cross 24 mesh sieves and granulate.Behind above two kinds of granules and magnesium stearate, micropowder silica gel mix homogeneously, incapsulate, make capsule.
Embodiment 5: the pharmacodynamic experiment of pioglitazone hydrochloride, aretigenin compound recipe
1. animal model: high fat diet adds low dose of streptozotocin (STZ) and sets up type 2 diabetes mellitus and merge the hyperlipidemia rats model.Male SD rat, be 9 week～10 weeks age in week, body weight (180 ± 25) g, the cleaning level, 90 of quantity are divided into normal control group (10) and modeling group (80) at random.The normal control group gives normal feedstuff, and the modeling group gives high-sugar-fat-diet (containing sucrose 20%, Adeps Sus domestica 10%, cholesterol 2.5%, cholate 0.25%, normal feedstuff 67.25%).After raising for 5 weeks, fasting 12h, the model group rat is by 40mg/kg body weight lumbar injection STZ (be mixed with preceding citric acid-sodium citrate buffer with 0.1mol/L, pH4.2 1% solution), and the normal control group is only injected equivalent citric acid-sodium citrate buffer.STZ is after one week in injection, and docking is got blood and surveyed fasting glucose (FBG) and blood fat.With fasting glucose＞11mmol/L, TG, LDL-C exist significant difference (P＜0.05) for becoming the mould standard with the normal control group.STZ is after one week for the injection of modeling group rat, and 72 reach into the mould standard, and the fasting glucose average is (18.5 ± 4.05) mmol/L, and becoming the mould rate is 90%.
2. grouping: the rat that will meet into the mould standard is divided into following each group, every group each 9 at random.The experiment grouping is as follows with the administration final concentration:
Aretigenin low dose group: 0.5mg/kg aretigenin
Aretigenin high dose group: 50.0mg/kg aretigenin
Pioglitazone hydrochloride low dose group: 0.1mg/kg pioglitazone hydrochloride
Pioglitazone hydrochloride high dose group: 10mg/kg pioglitazone hydrochloride
Compositions A group: 50.0mg/kg aretigenin+0.1mg/kg pioglitazone hydrochloride
Compositions B group: 5.0mg/kg aretigenin+1.0mg/kg pioglitazone hydrochloride
Compositions C group: 0.5mg/kg aretigenin+10.0mg/kg pioglitazone hydrochloride
3. experimental procedure: each medicine group is irritated stomach and is given corresponding medicine, and normal control group and model group give isopyknic D-hank ' s liquid and irritate stomach, and every morning administration 1 time in 5 weeks of continuous irrigation stomach, was weighed 1 time satellite recanalization dosage in per 3 days.Fasting 12h after the last administration, pentobarbital sodium anesthesia, abdominal aortic blood, centrifugal back separation of serum; The content of oxidation enzymatic assays serum FBG, LDL-C, HDL-C.
4, the result of the test result draws with every group of (n=6) meansigma methods ± SD and with Dunnett ' S check analysis.
4.1 each composition medicine is to the influence of blood glucose:
| Group | FBGmmol/L |
| The pioglitazone hydrochloride low dose group | 20.0±1.0 |
| The pioglitazone hydrochloride high dose group | 17.0±1.8 |
| The aretigenin low dose group | 20.5±2.3 |
| The aretigenin high dose group | 18.5±1.9 |
| Compositions A group | 11.0±1.6 |
| Compositions B group | 10.0±1.8 |
| Compositions C group | 12.0±2.2 |
| Model group | 22.0±4.3 |
| The normal control group | 5.5±0.88 |
Interpretation of result: from experimental result, compositions A group, B organize, the C group is compared with low dose group, aretigenin high dose group and low dose group, model group, normal control group with the pioglitazone hydrochloride high dose group has utmost point significant difference (p＜0.01).
Pioglitazone hydrochloride group, Arctiin tuple, and medicine group of the present invention with respect to model group, blood sugar lowering that can both be to a certain degree.But best with medicine group hypoglycemic effect of the present invention, and obviously be better than pioglitazone hydrochloride high dose group and low dose group, aretigenin high dose group and low dose group, have utmost point significant difference (p＜0.01).
4.2 respectively organize the influence of medicine to blood fat:
| Group | HDL-Cmmol/L | LDL-Cmmol/L |
| The pioglitazone hydrochloride low dose group | 0.48±0.11 | 1.43±0.30 |
| The pioglitazone hydrochloride high dose group | 0.56±0.15 | 1.30±0.35 |
| The aretigenin low dose group | 0.30±0.18 | 2.00±0.50 |
| The aretigenin high dose group | 0.44±0.09 | 1.88±0.60 |
| Compositions A group | 0.77±0.15 * | 0.80±0.25 # |
| Compositions B group | 0.80±0.14 * | 0.70±0.31 # |
| Compositions C group | 0.78±0.13 * | 0.83±0.52 # |
| Model group | 0.18±0.13 | 2.76±0.58 |
| The normal control group | 0.83±0.14 | 0.33±0.10 |
Compare with pioglitazone hydrochloride high dose group or low dose group, aretigenin high dose or low dose group, model group, normal control group:
*P＜0.05;
#P＜0.05; Compare with model group
*P＜0.01;
#P＜0.01.
Interpretation of result: from experimental result, pioglitazone hydrochloride high dose group or low dose group, aretigenin high dose or low dose group, and pharmaceutical composition A of the present invention, B, C organize with respect to model group blood fat reducing that can both be to a certain degree.But best, and obviously be better than pioglitazone hydrochloride high dose group or low dose group, aretigenin high dose or low dose group (p＜0.01) with pharmaceutical composition A of the present invention, B, C group lipid-lowering effect.
Experiment conclusion: experimental result shows that medicine of the present invention has the effect of blood sugar lowering, has the effect of blood fat reducing simultaneously.When reaching equal hypoglycemic effect, in the pharmaceutical composition of the present invention the amount of employed pioglitazone than the amount of using separately pioglitazone lack many, the reducing blood sugar and blood fat effect of medicine of the present invention is better than using separately its arbitrary component, medicine of the present invention can be treated diabetes, the patient of especially diabetes complicated hyperlipidemia safely and effectively.
4.3 respectively organize medicine to urinating the influence of micro-albumin content and renal index
(1) the micro-albumin content of urine is measured
1, reagent: 1, the glacial acetic acid solution of 10% (v/v) (PH2.8).
2,0.303mol/L glycine-glacial acetic acid buffer (PH3.0): take by weighing the 22.72g glycine, be diluted to 1000ml with 10% glacial acetic acid solution, add NaN3100mg, the room temperature sealing can be stablized 1 year.
3, bromophenol blue (1.924mmol/L) stock solution: accurately take by weighing 257.36mgBPB, molten to 200ml with dehydrated alcohol, 4 ℃ of refrigerators can be stablized 1 year.
4, bromophenol blue (0.231mmol/L) developer: get the 60mlBPB stock solution, add 2.5mlTriton X-100, be diluted to 500ml with glycine-glacial acetic acid buffer, the room temperature sealing can be preserved 1 year.
The collection of specimen and detection: the 5th weekend rat is put in the metabolic cage respectively and raises, collect 12 hours overnight urine, accurate recording urine amount.Get 4ml, after sodium azide was handled, centrifugal (2000r/min) 10min got supernatant and puts-20 ℃ of refrigerators and preserves the micro-albumin of urine to be measured.The urine trace albumin titer 400 μ L that get respective concentration respectively add 200 μ L developers in the cup of correspondence, mixing (preventing to produce bubble) is used ultraviolet spectrophotometer, measures absorbance A down in 600nm.
(2) mensuration of renal index
After accurately taking by weighing rat body weight, the dislocation of cervical vertebra method is put to death rat, opens the abdominal cavity, takes out kidney, claims weight in wet base.Draw the kidney of rats exponential quantity with the total weight in wet base/body weight of two kidneys.
Each organizes medicine is urinated micro-albumin and renal index to diabetes rat influence
| Group | n | Absorbance A (600nm) | Renal index (%) |
| Model group | 6 | 0.660±0.231 | 0.98±0.055 |
| The aretigenin low dose group | 6 | 0.642±0.209 | 0.88±0.045 |
| The aretigenin high dose group | 6 | 0.551±0.145 | 0.85±0.065 |
| The pioglitazone hydrochloride low dose group | 6 | 0.582±0.124 | 0.89±0.034 |
| The pioglitazone hydrochloride high dose group | 6 | 0.459±0.215 | 0.80±0.011 * |
| Compositions A group | 6 | 0.356±0.314 * | 0.71±0.018 ** |
| Compositions B group | 6 | 0.332±0.291 ** | 0.68±0.124 ** |
| Compositions C group | 6 | 0.385±0.081 * | 0.70±0.054 ** |
| The normal control group | 6 | 0.311±0.108 ** | 0.66±0.078 ** |
*Compare with model group, P＜0.05,
*Compare P＜0.01 with model group.
Interpretation of result: from experimental result, pharmaceutical composition A of the present invention, B, C organize with respect to model group, compares with model group,
*There is significant difference p＜0.05; Compare with model group,
*There is the utmost point significant difference p＜0.01.Illustrate that aretigenin and pioglitazone or its officinal salt use in conjunction urinate and good synergism is arranged aspect micro-albumin and the renal index influencing rat.
4.4 respectively organize the influence of medicine to the hypertension model rat blood pressure
Since first weekend, carry out an arteria caudalis systolic pressure per two weeks and measure.The result shows that each administration group and model group all have significant difference, illustrates that aretigenin and pioglitazone or its officinal salt use in conjunction have hypotensive effect preferably, aspect the reduction rat blood pressure good synergism is being arranged.
Table 3 compound recipe is to the influence (kPa) of rat blood pressure
| Group | n | 1 weekend | 3 weekends | 5 weekends |
| Model group | 6 | 18.88±3.6 | 18.51±4.1 | 18.80±4.2 |
| The aretigenin low dose group | 6 | 18.90±4.0 | 19.01±1.8 | 18.70±3.1 |
| The aretigenin high dose group | 6 | 18.04±3.2 | 18.12±3.5 | 18.10±3.3 |
| The pioglitazone hydrochloride low dose group | 6 | 17.74±2.1 | 17.45±2.4 | 17.07±2.3 |
| The pioglitazone hydrochloride high dose group | 6 | 17.63±2.2 | 16.89±2.1 | 16.79±2.8 |
| Compositions A group | 6 | 17.87±3.4 | 16.82±3.8 | 16.05±2.6* |
| Compositions B group | 6 | 17.56±2.6 | 16.34±3.3* | 16.33±1.9* |
| Compositions C group | 6 | 17.70±3.8 | 17.00±2.7 | 16.22±2.4* |
*Compare P＜0.05 with model group.
Experiment conclusion: experimental result shows, pharmaceutical composition of the present invention compared with prior art, particularly compare with the folk prescription administration, obtained beyond thought technique effect aspect horizontal improving blood glucose, blood fat reducing and saccharifying serum albumin, has significant advantage, and tool synergism, control as kidney disease preventing and/or treating diabetes and complication thereof simultaneously, especially relevant with H type diabetes aspects such as kidney disease have extremely significant advantage, and have obtained good synergy.
Claims (10)
1. pharmaceutical composition is characterized in that it contains active component aretigenin and pioglitazone or its pharmaceutically acceptable salt.
2. pharmaceutical composition as claimed in claim 1 is characterized in that the weight ratio of aretigenin and pioglitazone or its pharmaceutically acceptable salt is 0.01-1000 in the compositions: 1.
3. pharmaceutical composition as claimed in claim 2 is characterized in that the weight ratio of aretigenin and pioglitazone or its pharmaceutically acceptable salt is 0.05-500 in the compositions: 1.
4. pharmaceutical composition as claimed in claim 1 is characterized in that described pioglitazone or its pharmaceutically acceptable salt are its hydrochlorate, formates, fumarate, acetate, benzoate, mesylate, sulfate or maleate.
5. pharmaceutical composition as claimed in claim 4 is characterized in that described pioglitazone or its pharmaceutically acceptable salt are pioglitazone hydrochloride.
6. pharmaceutical composition as claimed in claim 5 is characterized in that the weight ratio of aretigenin and pioglitazone hydrochloride is 5: 1 in the compositions.
7. pharmaceutical composition as claimed in claim 1 is characterized in that also containing in the described pharmaceutical composition acceptable accessories.
8. pharmaceutical composition as claimed in claim 7 is characterized in that described adjuvant comprises in binding agent, filler, wetting agent, lubricant or the disintegrating agent one or more.
9. pharmaceutical composition as claimed in claim 8 is characterized in that described pharmaceutical composition is tablet, capsule, powder, granule, oral cavity disintegration tablet or dispersible tablet.
10. as the arbitrary described pharmaceutical composition of claim 1-9, it is characterized in that described pharmaceutical composition preparation treatment diabetes, diabetic complication, with the medicine of diabetes diseases associated in purposes.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110102614 CN102228457B (en) | 2011-04-25 | 2011-04-25 | Pharmaceutical composition for treating diabetes and complication thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110102614 CN102228457B (en) | 2011-04-25 | 2011-04-25 | Pharmaceutical composition for treating diabetes and complication thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102228457A true CN102228457A (en) | 2011-11-02 |
| CN102228457B CN102228457B (en) | 2013-07-24 |
Family
ID=44841091
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110102614 Active CN102228457B (en) | 2011-04-25 | 2011-04-25 | Pharmaceutical composition for treating diabetes and complication thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102228457B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103479616A (en) * | 2012-06-11 | 2014-01-01 | 鲁南制药集团股份有限公司 | Applications of arctigenin on preparing drugs for curing atherosclerosis or myocardial infarction |
| CN106511354A (en) * | 2017-01-18 | 2017-03-22 | 刘�英 | Application of pioglitazone-containing pharmaceutical composition in diabetes prevention |
| CN110638771A (en) * | 2019-10-28 | 2020-01-03 | 仁和堂药业有限公司 | Preparation process of glipizide tablets |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1686123A (en) * | 2005-04-19 | 2005-10-26 | 北京正大绿洲医药科技有限公司 | Pyrolidone hydrochloride drip pill and its preparation method |
| CN1689579A (en) * | 2003-11-21 | 2005-11-02 | 山东绿叶天然药物研究开发有限公司 | Application of burdock glycoside or its aglycon in preparation of medicine for treating diabetes or its complications |
-
2011
- 2011-04-25 CN CN 201110102614 patent/CN102228457B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689579A (en) * | 2003-11-21 | 2005-11-02 | 山东绿叶天然药物研究开发有限公司 | Application of burdock glycoside or its aglycon in preparation of medicine for treating diabetes or its complications |
| CN1686123A (en) * | 2005-04-19 | 2005-10-26 | 北京正大绿洲医药科技有限公司 | Pyrolidone hydrochloride drip pill and its preparation method |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103479616A (en) * | 2012-06-11 | 2014-01-01 | 鲁南制药集团股份有限公司 | Applications of arctigenin on preparing drugs for curing atherosclerosis or myocardial infarction |
| CN103479616B (en) * | 2012-06-11 | 2016-03-09 | 鲁南制药集团股份有限公司 | Aretigenin is for the preparation of the purposes in treatment atherosclerosis or myocardial infarction medicine |
| CN106511354A (en) * | 2017-01-18 | 2017-03-22 | 刘�英 | Application of pioglitazone-containing pharmaceutical composition in diabetes prevention |
| CN110638771A (en) * | 2019-10-28 | 2020-01-03 | 仁和堂药业有限公司 | Preparation process of glipizide tablets |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102228457B (en) | 2013-07-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102670864B (en) | Medicine composition with antioxidant function for treating cardiovascular and cerebrovascular diseases and sugar diabetes | |
| 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 | |
| CN101304753B (en) | Treatment of chronic kidney disease (CKD) subjects using lanthanum compounds | |
| CN107432869A (en) | Include net double-layer tablets of Metformin hydrochloride and En Gelie and preparation method thereof | |
| CN102228457B (en) | Pharmaceutical composition for treating diabetes and complication thereof | |
| CN102267959B (en) | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same | |
| CN105213335A (en) | Glipizide tablet and preparation method thereof and application | |
| CN103622946A (en) | Medical application of anhydroicaritin | |
| CN101632646B (en) | Olopatadine hydrochloride tablet as well as preparation method and detecting method thereof | |
| CN102727894B (en) | A kind of pharmaceutical composition and application thereof for the treatment of diabetes and complication thereof | |
| CN106110310A (en) | A kind of compound for reducing blood suger containing pioglitazone and preparation method thereof | |
| CN101972263B (en) | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation | |
| CN102218062B (en) | Medicine composition for treating diabetes mellitus | |
| CN101757627A (en) | Combined drug and drug combination for treating diabetes | |
| CN101947210B (en) | Levoamlodipine besylate liposome tablet | |
| CN100490808C (en) | Gliquilone slow-releasing preparation | |
| CN102631357B (en) | Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof | |
| CN1969855B (en) | Pharmaceutical composition having target organ protection function and usage thereof | |
| CN102125546B (en) | Composition for preventing renal calculi | |
| CN101693045B (en) | Effective portion of conical hydrangea, preparation method thereof, and composition and usage thereof | |
| CN106176717A (en) | A kind of probucol lovastatin compound and preparation method | |
| CN103169707B (en) | New medical application of lauric acid monoglyceride | |
| Tablets et al. | Pr SANDOZ SAXAGLIPTIN | |
| EP0005733A1 (en) | Pharmaceutical compositions for use in the treatment of diabetic nephropathy and method for preparing them | |
| CN101612334A (en) | A kind of pharmaceutical composition that is used for the treatment of acute and chronic nephritis |
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 | ||
| ASS | Succession or assignment of patent right |
Owner name: NANTONG FANGDU HIGH-TECH VENTURE PARK SERVICE CO., Free format text: FORMER OWNER: LIU SHUQIN Effective date: 20140514 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 276014 LINYI, SHANDONG PROVINCE TO: 226112 NANTONG, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140514 Address after: 226112, Jiangsu, Nantong Haimen town Sanxing village 15 groups Patentee after: Nantong Textile Science and Technology Pioneer Park Service Co., Ltd. Address before: 276014 No. 56 Industrial Street, Luozhuang District, Shandong, Linyi Patentee before: Liu Shuqin |
|
| DD01 | Delivery of document by public notice |
Addressee: Nantong Textile Science and Technology Pioneer Park Service Co., Ltd. Document name: Notification of Passing Examination on Formalities Addressee: Nantong Textile Science and Technology Pioneer Park Service Co., Ltd. Document name: Approval notice for cost mitigation |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 226112, Jiangsu, Nantong Haimen town Sanxing village 15 groups Patentee after: Nantong textile Capital Management Co.,Ltd. Address before: 226112, Jiangsu, Nantong Haimen town Sanxing village 15 groups Patentee before: Nantong Textile Science and Technology Pioneer Park Service Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200723 Address after: Sanxing Zhen Nan Cun, Haimen City, Nantong City, Jiangsu Province Patentee after: Jiangsu Dieshiqiao Investment Co., Ltd Address before: 226112, Jiangsu, Nantong Haimen town Sanxing village 15 groups Patentee before: Nantong textile Capital Management Co.,Ltd. |
|
| TR01 | Transfer of patent right |