CN102335176B - Brand-new oral solid medicinal composition and preparation method thereof - Google Patents
Brand-new oral solid medicinal composition and preparation method thereof Download PDFInfo
- Publication number
- CN102335176B CN102335176B CN 201110197280 CN201110197280A CN102335176B CN 102335176 B CN102335176 B CN 102335176B CN 201110197280 CN201110197280 CN 201110197280 CN 201110197280 A CN201110197280 A CN 201110197280A CN 102335176 B CN102335176 B CN 102335176B
- Authority
- CN
- China
- Prior art keywords
- hydrochlorothiazide
- weight portions
- valsartan
- levamlodipine
- weight
- 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 - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 84
- 239000000203 mixture Substances 0.000 title claims abstract description 39
- 239000007787 solid Substances 0.000 title claims abstract description 11
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims abstract description 214
- 229960002003 hydrochlorothiazide Drugs 0.000 claims abstract description 207
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims abstract description 115
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 claims abstract description 114
- 229960004699 valsartan Drugs 0.000 claims abstract description 113
- 229950008554 levamlodipine Drugs 0.000 claims abstract description 111
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 110
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 55
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 55
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 55
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 55
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 55
- 235000012239 silicon dioxide Nutrition 0.000 claims abstract description 55
- 229920002472 Starch Polymers 0.000 claims abstract description 49
- 239000002775 capsule Substances 0.000 claims abstract description 30
- 239000002994 raw material Substances 0.000 claims abstract description 7
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 claims abstract 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 108
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 78
- 239000013078 crystal Substances 0.000 claims description 68
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 54
- 235000019359 magnesium stearate Nutrition 0.000 claims description 54
- 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 claims description 49
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 49
- 238000004132 cross linking Methods 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 49
- 239000000843 powder Substances 0.000 claims description 49
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 49
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 49
- 239000008194 pharmaceutical composition Substances 0.000 claims description 44
- 235000019890 Amylum Nutrition 0.000 claims description 43
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- 238000002156 mixing Methods 0.000 claims description 23
- 239000011259 mixed solution Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- 239000002671 adjuvant Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 15
- 239000008187 granular material Substances 0.000 claims description 12
- 239000011248 coating agent Substances 0.000 claims description 11
- 238000000576 coating method Methods 0.000 claims description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 11
- 229910017488 Cu K Inorganic materials 0.000 claims description 10
- 229910017541 Cu-K Inorganic materials 0.000 claims description 10
- 230000005260 alpha ray Effects 0.000 claims description 10
- 238000009472 formulation Methods 0.000 claims description 10
- 239000012153 distilled water Substances 0.000 claims description 9
- 239000012065 filter cake Substances 0.000 claims description 9
- 238000001291 vacuum drying Methods 0.000 claims description 9
- 238000005520 cutting process Methods 0.000 claims description 7
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 239000008213 purified water Substances 0.000 claims description 7
- 238000005070 sampling Methods 0.000 claims description 7
- 206010013786 Dry skin Diseases 0.000 claims description 6
- 239000004677 Nylon Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 229920001778 nylon Polymers 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 5
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 claims description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 229960005261 aspartic acid Drugs 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
- 229940098895 maleic acid Drugs 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 230000001133 acceleration Effects 0.000 claims description 3
- 238000013019 agitation Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 51
- 206010020772 Hypertension Diseases 0.000 abstract description 29
- 235000019698 starch Nutrition 0.000 abstract description 6
- 239000008107 starch Substances 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 abstract 1
- 235000021355 Stearic acid Nutrition 0.000 abstract 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 abstract 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 abstract 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 abstract 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 abstract 1
- 239000008117 stearic acid Substances 0.000 abstract 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 100
- 239000003826 tablet Substances 0.000 description 50
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 34
- 229960000528 amlodipine Drugs 0.000 description 33
- 238000011282 treatment Methods 0.000 description 33
- 230000000694 effects Effects 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 28
- 230000036772 blood pressure Effects 0.000 description 23
- 229940079593 drug Drugs 0.000 description 18
- 238000004090 dissolution Methods 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 239000003795 chemical substances by application Substances 0.000 description 13
- 208000024172 Cardiovascular disease Diseases 0.000 description 12
- 239000011812 mixed powder Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 10
- 230000003276 anti-hypertensive effect Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 229940082195 hydrochlorothiazide 12.5 mg Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 229940102034 valsartan 80 mg Drugs 0.000 description 9
- 208000007530 Essential hypertension Diseases 0.000 description 8
- 229940125364 angiotensin receptor blocker Drugs 0.000 description 8
- 238000011160 research Methods 0.000 description 8
- 239000002220 antihypertensive agent Substances 0.000 description 7
- 229940127088 antihypertensive drug Drugs 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 229940033919 hydrochlorothiazide / valsartan Drugs 0.000 description 6
- 230000001631 hypertensive effect Effects 0.000 description 6
- 230000001077 hypotensive effect Effects 0.000 description 6
- 230000003907 kidney function Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 229940127291 Calcium channel antagonist Drugs 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 230000035487 diastolic blood pressure Effects 0.000 description 5
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 5
- 239000002866 dihydropyridine calcium channel blocker Substances 0.000 description 5
- -1 diovan compound Chemical class 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 230000035488 systolic blood pressure Effects 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- 206010019280 Heart failures Diseases 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004204 blood vessel Anatomy 0.000 description 4
- 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 4
- 230000006378 damage Effects 0.000 description 4
- 229940103447 exforge hct Drugs 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 239000000480 calcium channel blocker Substances 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 208000014674 injury Diseases 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 description 3
- 238000003908 quality control method Methods 0.000 description 3
- 238000011125 single therapy Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000001360 synchronised effect Effects 0.000 description 3
- 238000011287 therapeutic dose Methods 0.000 description 3
- 210000005239 tubule Anatomy 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 2
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- 208000007177 Left Ventricular Hypertrophy Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 2
- 229940077388 benzenesulfonate Drugs 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 208000015606 cardiovascular system disease Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 2
- 229940074619 diovan Drugs 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000001603 reducing effect Effects 0.000 description 2
- 230000033904 relaxation of vascular smooth muscle Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- HTIQEAQVCYTUBX-QGZVFWFLSA-N (R)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-QGZVFWFLSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- 108010022579 ATP dependent 26S protease Proteins 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 206010051467 Nephrectasia Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 208000035755 Psychosomatic disease Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 206010038468 Renal hypertrophy Diseases 0.000 description 1
- 208000032594 Vascular Remodeling Diseases 0.000 description 1
- 208000033774 Ventricular Remodeling Diseases 0.000 description 1
- 206010047295 Ventricular hypertrophy Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229940051539 amlodipine and hydrochlorothiazide valsartan Drugs 0.000 description 1
- 229960004005 amlodipine besylate Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000012742 biochemical analysis Methods 0.000 description 1
- 230000008081 blood perfusion Effects 0.000 description 1
- 238000009530 blood pressure measurement Methods 0.000 description 1
- 238000009534 blood test Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 229940109239 creatinine Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000011981 development test Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 201000008627 kidney hypertrophy Diseases 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 210000000885 nephron Anatomy 0.000 description 1
- 229960001597 nifedipine Drugs 0.000 description 1
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 201000001474 proteinuria Diseases 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 210000002254 renal artery Anatomy 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 230000029547 smooth muscle hypertrophy Effects 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 210000004026 tunica intima Anatomy 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a brand-new oral solid medicinal composition. The medicinal composition is an oral preparation prepared from hydrochlorothiazide, levamlodipine, valsartan and pharmaceutically acceptable auxiliaries, and the oral preparation comprises but is not limited to tablets or capsules. The composition comprises the following raw materials in parts by weight: 5-25 parts of the hydrochlorothiazide, 2.5-5 parts of the levamlodipine, 80-160 parts of the valsartan, 40-120 parts of microcrystalline cellulose, 30-90 parts of compressible starch, 5-25 parts of cross-linked sodium carboxymethylcellulose, 3-8 parts of silicon dioxide and 1-2 parts of stearic acid. The medicinal composition disclosed by the invention has the advantages of scientific and reasonable prescription, low auxiliary content and high bioavailability, and is a first choice of medicine for treating hypertension.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of New oral solid medicinal composition and method of making the same that comprises hydrochlorothiazide, valsartan and Levamlodipine.
Hypertension is modal cardiovascular disease, is the great public health difficult problem in global range.China carried out sample census to 940,000 crowds more than 15 years old in 1991, and statistics shows: China's Prevalence of Hypertension has reached 11.26%, increased 25% than 1979-1990 between 10 years, and the existing hyperpietic of China surpasses 1.3 hundred million.And the impetus of this rising is still continuing.Statistics also shows, hypertension therapeutic rate city is 17.4%, and the rural area is 5.4%; Control rate (through treatment systolic pressure＜140mmHg, diastolic pressure＜90mmHg) only 2.9%.Can find out that from above-mentioned statistics China's Prevalence of Hypertension constantly increases, but treatment rate, control rate are low, form huge contrast.According to the WHO prediction, will account for 79% of China's cause of death to the year two thousand twenty noninfectious, wherein the cardiovascular diseases will account for the first place.In order to contain the arrival on this cardiovascular diseases peak, the control of Efforts To Develop hypertension, the active treatment hyperpietic, very urgent.
The bad hypertension of long-term control can produce grievous injury to target organs such as the heart, brain, kidneys, actively Treatment of Hypertension can significantly lower main cardiovascular diseases's M ﹠ M, and most hypertensive patients need to could be with controlling of blood pressure in desirable target blood pressure level with depressor.Evidence-based medical shows, low dose of use in conjunction variety classes antihypertensive drugs is better and untoward reaction is less than a certain medicine antihypertensive effect of alone larger dose.Therapeutic alliance can improve efficacy of antihypertensive treatment, in and the untoward reaction that causes of different pharmaceutical, the compensation response that when preventing single therapy, Blood pressure drop triggers increases patient's toleration, improves compliance.
Levamlodipine belongs to long-acting dihydropyridine (D H P) class calcium antagonists; split out on the amlodipine basis; its drug effect is 2 times of racemic amlodipine, and Levamlodipine has the effect of protection EH renal function of patients, not only depends on the decline of system's blood pressure.Also due to the afferent glomerular arteriole of nephrectasia bead lastingly of this medicine, improve renal ischemic, stop the disorder of kidney blood vessel and glomerule 26S Proteasome Structure and Function, alleviate renal hypertrophy, reducing mesenteric tissue catches macromolecular substances, suppress free radical and form, weaken the somatomedin mitosis reaction, improve the mitochondrial calcium load and reduce the nephron metabolism all useful to kidney.Levamlodipine possess onset slowly, long action time, characteristics that the paddy p-ratio is high, the clinical treatment that has been widely used in the cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris.Levamlodipine can change vascular smooth muscle cell calcium ion cross-film to be shifted, reduce flow of calcium ions, make cardiac muscle and vascular smooth muscle relaxation, regulate vascular endothelial cell, smooth muscle cell and macrophage to the picked-up of lipoprotein, regulate cellular cholesterol for body, reduce cholesterol in the deposition of arterial wall, suppress the short vascular smooth muscle hypertrophy of somatomedin, the mononuclear cell that slows down is invaded profit and platelet aggregation, increase erythrocyte deformability, reduce blood viscosity, delay atherosclerotic formation and development.The Levamlodipine Main Function is in all blood vessels, also can act on coronary artery and renal artery, slow with the acceptor site effect, vasorelaxation action is steady, to conducting system of heart and myocardial contraction all without obvious inhibitory action, can reduce cardiac load, reverse ventricular hypertrophy, and blood glucose, blood fat and serum electrolyte are had no adverse effects.
Levamlodipine is calcium channel blocker of new generation, clinically is mainly used in treating hypertension, angina pectoris and corrects Atheromatosis reason state.Dihydropyridine calcium channel blocker is one of the most frequently used clinically cardiovascular drugs, is widely used in the treatment of the cardiovascular disease such as hypertension, angina pectoris and arrhythmia.Along with the research to dihydropyridine calcium channel blocker deepens continuously, find that all dihydropyridine calcium channel blockers have chiral structure except nifedipine, and its enantiomer biological activity is usually different in recent years, even opposite.Amlodipine (amlodipine) is clinical dihydropyridine calcium channel blocker commonly used, has left-handed and two kinds of enantiomer of dextrorotation.Levamlodipine is the renewal product of amlodipine, obtains by the chiral separation technology, and is nontoxic and hypotensive effect arranged, and R（+）-AMLODIPINE toxicity is large and without hypotensive effect.Therefore, Levamlodipine may be more effective than amlodipine, and safety is higher.Levamlodipine possess onset slowly, long action time, characteristics that the paddy p-ratio is high, the clinical treatment that has been widely used in the cardiovascular and cerebrovascular diseases such as hypertension, angina pectoris.
Levamlodipine benzenesulfonate, chemical name: (s) (-) 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-Isosorbide-5-Nitrae-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate.Molecular formula: C20H25N2O5ClC6H6O3S, molecular weight: 567.1.
Valsartan, chemical name: (S)-N-valeryl-N-{[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl }-valine, molecular formula: C
24H
29N
5O
3, molecular weight: 435.53.
Valsartan is a kind of Angiotensin Ⅱ receptor antagonist (ARB) of non-peptide class, has the effects such as blood pressure lowering, expansion blood vessel, can be used for preventing and treating the cardiovascular system diseases such as hypertension, coronary heart disease, heart failure.After being succeeded in developing by Switzerland Novartis Co.,Ltd, at first go on the market in Germany.In December, 1996 obtains drugs approved by FDA, and commodity were called " Diovan " in U.S.'s listing in 1997, and the valsartan of Novartis Co.,Ltd in 1998 obtains registration in China, and commodity are called " DAIWEN ".After the valsartan listing, Novartis Co.,Ltd has developed again diovan compound preparation.After the valsartan and Hydrochlorothiade compound preparation is succeeded in developing, obtain FDA approval listing in October, 1997, and commodity are called " CoDiovan " (multiple DAIWEN); 2006, valsartan newly developed/amlodipine compound preparation was also got permission listing.
Valsartan has advantages of angiotensinⅡtype 1 receptor antagonist of new generation, compare with angiotensin converting enzyme inhibitor (ACEI) medicine, it directly acts on the AT1 receptor competitively, makes vascular smooth muscle relaxation, vasodilation, improves ventricle and vascular remodeling; Simultaneously can improve the renal blood perfusion amount, increase water, sodium excretion, reduce blood volume, and make blood pressure drops; Hypotensive effect is reliable, safety, side effect are little; Obtain simultaneously the treatment that drugs approved by FDA is used for heart failure, can significantly reduce the kinds of risks factors such as patients with atrial fibrillation Incidence of Heart Failure and cardiocerebrovasculaevents events.The different mechanisms that compound preparation can be brought into play medicine produces synergism, makes reach mark blood pressure in the situation that dosage reduces, and improves simultaneously the untoward reaction of patient's arterial compliance and minimizing single dose.
Hydrochlorothiazide is the diuretic that acts on tubular distal of extensive use clinically, mechanism of action mainly suppresses distal tubule leading portion and proximal tubule (acting on lighter) to the heavily absorption of sodium chloride, thereby increase the Na+-K+ exchange of distal tubule and collecting tubule, the K+ secretion increasing.Except the effect of diuresis row sodium, also have the outer mechanism of action of kidney to participate in blood pressure lowering.Be applicable to edema and hypertensive treatment, can effectively control moderate hypertension, adverse reaction rate is low.
Utilize calcium channel blocker amlodipine, angiotensin receptor blocker valsartan and diuretic hydrochlorothiazide, make compound preparation, give full play to three's complementation, synergism, help to control better patient's blood pressure.
Medical evidence shows, low dose of use in conjunction variety classes antihypertensive drugs is better and untoward reaction is less than a certain medicine antihypertensive effect of alone larger dose.Therapeutic alliance can improve efficacy of antihypertensive treatment, in and the untoward reaction that causes of different pharmaceutical, the compensation response that when preventing single therapy, Blood pressure drop triggers increases patient's toleration, improves compliance.
Amlodipine (amlodipine) or its salt are dihydropyridine calcium channel blocker of new generation (CCB) as Amlodipine Besylate Tablet; And valsartan (valsartan) is a kind of angiotensin receptor blocker (ARB).Both all have the effects such as blood pressure lowering, expansion blood vessel, can be used for preventing and treating the cardiovascular system diseases such as hypertension, coronary heart disease, heart failure.
Existing studies show that, CCB and ARB share can certain synergism, discloses the compound antihypertensive drug of a kind of amlodipine and irbesartan as patent documentation CNZL03150996.7; CN1765362A discloses a kind of compositions that comprises amlodipine and angiotensin ii receptor antagonist (ARB), and the weight proportion of wherein having mentioned amlodipine and candesartan Cilexetil is 1: 10-10: 1; WO2006/034631 discloses the compositions of a kind of amlodipine and ARB; CN200610081591.5 discloses a kind of pharmaceutical composition that comprises the treatment hypertension and cardiovascular disease of Levamlodipine officinal salt and ARB.
Wang Xiaolin reports (pharmacological action of Levamlodipine and clinical practice, Shandong medicine thing Qilu Pharmacential Affairs 2010 Vol.29, No.10) Levamlodipine is the more outstanding calcium channel blocker that goes on the market at present, as a line medication of common treatment cardiovascular disease, the advantage such as have and untoward reaction is few long-acting, efficient.Levamlodipine can reduce peripheral vascular resistance, has antiplatelet aggregation, atherosclerosis formation, and the protection tunica intima is improved the pharmacological actions such as myocardial oxygen delivery.In recent years, many research discovery this product are brought into play positive therapeutical effect in multiple cardiovascular disease, along with the research to the darker people of its mechanism of action, will excavate out more wide application prospect.
The people such as Fan Shougen on valsartan and Levamlodipine coupling on the impact of aged patients with hypertension urine microalbumin (, Chongqing Medical the 39th the 8th phase of volume of April in 2010) study, reach a conclusion: the hypotensive effect of Levamlodipine and Combination Valsartan and to improve albuminuretic effect better when alone.
Along with global aging, aged hypertensives becomes the modal disease of Department of Aged, and it has the characteristics such as the course of disease is long, fluctuation of blood pressure is large, complication is many, often needs to unite depressor treatment more than 2 kinds.Hypertensive renal damage is to cause the whole one of the main reasons that latter stage, renal failure increased rapidly of old people simultaneously.And urine microalbumin (mAlb) excretion increase is the sign of hypertension Renal Injury.Merge the urine microalbumin with valsartan and Levamlodipine therapeutic alliance senile hypertension; therapeutic alliance; clinical efficacy is better than single therapy, and has safety preferably, and two medicine use in conjunction can be brought into play the protecting renal function effect by different mechanisms when strengthening effect of easing stress.
what wait quietly the people to valsartan associating Levamlodipine treatment essential hypertension 30 examples be studied (, medicine Leader volume o. 11th November the 27th in 2008), inquire into valsartan and Levamlodipine separately and the hypertensive antihypertensive effect of use in conjunction treatment reach protective effect to renal function, reach a conclusion: valsartan, Levamlodipine treatment essential hypertension all has hypotensive effect preferably, and can reduce microalbumin and microglobulin, improve endogenous creatinine clearance rate, reduce new renal function injury, two medicine use in conjunction can play synergism, more effectively reduce blood pressure, improve Renal function in early period infringement index.
Levamlodipine associating Efficacy of Valsartan in Treatment senile hypertension and left ventricular hypertrophy (clinical psychosomatic disease magazine the 13rd the 6th phase of volume of November in 2007) have been inquired in the Gao Xiang, reach a conclusion: valsartan and Levamlodipine besylate all can improve left chamber diastolic function, reverse the left ventricle that enlarges; The clinical effectiveness of Levamlodipine besylate associating Efficacy of Valsartan in Treatment significantly is better than alone Levamlodipine treatment, can be used as treatment left ventricular hypertrophy in essential hypertension patient's a line medication.
The scholar of class loyalty had once been reported and had been utilized the Levamlodipine Besylate in Treatment essential hypertension, by the treatment to 40 routine outpatients, 25mg, the qd oral administration, observe the antihypertensive effect in the 2nd week and the 8th week, effective percentage is respectively 85.0% and 95.0%, the Levamlodipine antihypertensive effect is described obviously and steadily, is fit to the essential hypertension treatment.
The people such as Zhang Jun have also reported and have utilized amlodipine to treat essential hypertension, light, moderate hypertension patient are divided into two groups immediately, carry out Clinical control experiment, observe basic blood pressure and the variation for the treatment of eight all rear blood pressures, result shows, Levamlodipine besylate can effectively reduce blood pressure, and effective percentage light, the moderate hypertension group is respectively 84.3% and 87.6%, illustrates that Levamlodipine can be used for the treatment of essential hypertension.
The people such as Bi Yanzhen observe (Chinese basic unit medicine the 14th the 3rd phase of volume of March in 2007) to the curative effect of Levamlodipine and Efficacy of Valsartan in Treatment Complicating with Hypentersion; the conclusion that draws is that Levamlodipine, valsartan are treated separately the Complicating with Hypentersion patient; all can obviously reduce blood pressure; reduce excretion quantity of urinary protein; renal function protecting, but hypotensive effect and to improve proteinuria efficacy better during two medicine couplings.
At present, drugs approved by FDA Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound preparation (amlodipine+valsartan+hydrochlorothiazide, Exforge HCT) listing treatment hypertension.This uses a kind of important new selection of poor effect patient after two types of antihypertensive drug therapeutic alliances to those.Existing China application CN200780024142.X (CN101478956A) discloses the solid dosage forms of a kind of valsartan, amlodipine and hydrochlorothiazide and has prepared the method for this solid dosage forms.Specifically disclose a kind of amlodipine+valsartan+hydrochlorothiazide Compound three-layer tablet, be included in and only contain a kind of active substance in each independent stratum.But this dosage form comes with some shortcomings, and three-layer tablet is in preparation process, and technique is comparatively complicated, to having relatively high expectations of equipment.The preparation of three-layer tablet need to be through tabletting repeatedly.In this case, may cause sheet to press to get tension, easy disintegrating does not discharge, in preparation, the shaping finished product rate is relatively low, the phenomenons such as sheet is more occur take, and when the survey dissolution, three-layer tablet can not separate separately to be measured, and can be subject to another two kinds of disintegration of tablet impact when stripping.
China application CN201020197929.5 discloses a kind of compound amlodipine and valsartan hydrochlorothiazide capsule, this utility model preparation comprises capsule body 1 and the active agent formulation of loading in capsule body 1, it is calcium channel blocade amlodipine 2, angiotensin receptor depressant valsartan sheet 3 and diuretic hydrochlorothiazide tablet 4, wherein amlodipine 2 is comprised of acceptable pharmaceutical excipient in the principal agent amlodipine benzenesulphonate of effective therapeutic dose and pharmacy, valsartan sheet 3 is comprised of acceptable pharmaceutical excipient in the principal agent valsartan of effective therapeutic dose and pharmacy, hydrochlorothiazide tablet 4 is comprised of acceptable pharmaceutical excipient in the principal agent hydrochlorothiazide of effective therapeutic dose and pharmacy.In capsule, each medicine burst separates, amlodipine 2, valsartan sheet 3 and hydrochlorothiazide tablet 4 can adopt respectively existing, ripe pharmaceutical preparation, be convenient to quality control, again can be when product inspection, tablet directly takes out from capsule, and three tablets can be tested by standard separately.When taking above-mentioned capsule, after shell capsules was melted in vivo, a capsule preparations resolved into three microplates, can discharge simultaneously medicine by drug release feature separately in vivo, can better play synergistic therapeutic effect.But the complicated process of preparation of above-mentioned compound amlodipine and valsartan hydrochlorothiazide capsule is difficult to carry out quality control effectively, and because each active component makes with adjuvant the content reduction that microplate causes effective ingredient respectively, affects the whole curative effect of preparation.
In view of this, special proposition the present invention.
Summary of the invention
The first purpose of the present invention is to provide a kind of New oral solid medicinal compositions, the oral formulations of described Pharmaceutical composition for being prepared from by acceptable adjuvant on hydrochlorothiazide, Levamlodipine, valsartan and pharmaceutics, described oral formulations includes, but are not limited to be tablet or capsule.Levamlodipine of the present invention includes but not limited to the acid group such as benzenesulfonic acid, maleic acid, L-ASPARTIC ACID and the crystal that forms with Levamlodipine thereof, the crystal of preferred benzenesulfonic acid and Levamlodipine formation.
Compositions of the present invention contains following raw material by weight: hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80-160 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, cross-linking sodium carboxymethyl cellulose 5～25 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion.
Preferably: hydrochlorothiazide 5-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 100 weight portions, microcrystalline Cellulose 50～100 weight portions, amylum pregelatinisatum 30～80 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 160 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, cross-linking sodium carboxymethyl cellulose 8～20 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
More preferably: hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, valsartan 80 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 5 weight portions, valsartan 160 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
Described hydrochlorothiazide is the hydrochlorothiazide crystal, and in the X-ray powder diffraction pattern that described hydrochlorothiazide crystal use Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
Described hydrochlorothiazide crystal is prepared from as follows:
(1) hydrochlorothiazide is dissolved in acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation drip distilled water in acetone soln, occur muddy to solution;
(3) under ultrasonic field in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, standing, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
In described step 1, the acetone soln concentration of hydrochlorothiazide is 0.05-0.2g/ml; The mixing speed of described step 2 is 80-180r/min, and the mixing speed in described step 3 is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of described ultrasonic field is 0.4～0.6KW, and in described organic mixed solution, the volume ratio of ethanol and ether is 2: 3-7: 6, and the volume ratio of described mixed liquor and acetone is 4: 5-8: 5; The standing growing the grain of described step 4 is at 12-18 ℃ of lower growing the grain 1.5-2.5 hour.
The second purpose of the present invention is to provide a kind of preparation method of above-mentioned composition.Described compositions is tablet, and its preparation method comprises the steps:
1) hydrochlorothiazide, valsartan and Levamlodipine are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
3) take above-mentioned standby hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take the valsartan of recipe quantity, with step 3) resulting mixed powder mixing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, namely get described pharmaceutical composition.
The 3rd purpose of the present invention is to provide a kind of preparation method of above-mentioned composition capsule, and this preparation method comprises the steps:
1) hydrochlorothiazide, valsartan and Levamlodipine are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
3) but take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose die mould starch, silicon dioxide, HPMC and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 40 ℃～50 ℃ dryings obtained particulate powder after 1 hour;
4) taking above-mentioned standby hydrochlorothiazide and step 3 by recipe quantity) resulting particulate powder adopts the equivalent method of progressively increasing to mix, obtains the pharmaceutical composition powder, with 24 order nylon screen granulate, the detection of taking a sample;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described pharmaceutical composition.
Below the present invention is further described in detail:
Most of hyperpietics need more than one antihypertensive to control blood pressure, and 3 kinds of the serious hyperpietic's need of minority or more medicine are strictly controlled blood pressure.Prior art discloses hydrochlorothiazide, Levamlodipine and the hypertensive technical scheme of valsartan three coupling treatment, normally adopt the tablet take two or three, as hydrochlorothiazide valsartan Compound Tablet+amlodipine or hydrochlorothiazide tablet+amlodipine+valsartan sheet, and find in the actual clinical test, the above-mentioned mode one of taking is that dosage is large, especially the hyperpietic is generally the old people, takes medicine all must take at least two or three and bring inconvenience to the old people at every turn; The 2nd, because every kind of tablet all contains a large amount of adjuvants, different adjuvants produces Different Effects to the release of active constituents of medicine, therefore, is difficult to control three kinds of active component after taking and discharges with desirable speed, affects therapeutic effect.Therefore, a kind of compound medicinal formulation that contains three components of exploitation is significant.
Drugs approved by FDA Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound preparation listing treatment hypertension.This uses those, and poor effect patient is a kind of important new selection after two types of antihypertensive drug therapeutic alliances.But because said preparation adjuvant content is large, and adopt the mode of dry granulation to prepare, cause the whole curative effect of preparation undesirable.In addition, as stated in the Background Art, prior art also discloses three kinds of effective ingredient has been arranged in every way with the technical scheme in a slice or capsule shells, but find in actual clinical, the curative effect of above-mentioned compound preparation on resisting hypertension is still not remarkable, there is the very large space of improving, in view of this, special proposition the present invention.
The present invention puts forth effort on the compound tablet that contains hydrochlorothiazide, amlodipine and valsartan of a kind of brand-new prescription of exploitation, selects more activated Levamlodipine can obtain better curative effect.Core more, the inventor is devoted to study the selection of this compound preparation adjuvant and consumption with the curative effect of further improvement above-mentioned compound preparation.
Nearest 20 years, many interactional research papers of medicine-adjuvant that relate to have been delivered.These researchs are intended to optimize writes out a prescription, and comprises the aspects such as dissolubility, increase dissolution, increase drug release rate, raising stability, change therapeutic activity and raising bioavailability that improve insoluble medicine.
Those skilled in the art will know that, to the body drug administration, which kind of approaches and methods all need adopt the pharmaceutical dosage form that adapts with it, and adjuvant can be given the physics of pharmaceutical dosage form necessity or physical chemistry, biological property to adapt to medical applications and to guarantee therapeutic effect.In dosage form, active medicine is substantive theme part, is determining the whole direction of effect.Adjuvant guarantee medicine with certain procedure Selection be transported to tissue site, prevent that medicine from disengaging front inactivation from main body, and make medicine in vivo by certain speed and time, discharge at certain position.Therefore, the dosage form that is comprised of suitable adjuvant has positive pivotal role to the practical application of medicine and the performance of curative effect.Therefore the inventor is for the physicochemical property of hydrochlorothiazide, Levamlodipine and valsartan, on the basis of large quantity research and screening test, a kind of brand-new prescription has been proposed, selected the weight proportion that has the adjuvant of synergy with the three and determined each component the best, to reach the purpose of final raising compound preparation curative effect.
Although what adopt in the present composition is prior art adjuvant commonly used, but those skilled in the art will know that, contain the compound preparation of three kinds of medicinal active ingredients due to the large usage quantity of principal agent, common every of compound preparation contains 12.5mg hydrochlorothiazide/2.5mg Levamlodipine/80mg valsartan or 12.5mg/5mg Levamlodipine/160mg valsartan as described in the present invention.For three kinds of effective ingredient can synchronously be discharged, and can reasonably discharge with rational speed in the time, usually need to use a large amount of disintegrating agent and lubricant, so just, increased sheet heavy, cause patient's difficulty of swallowing, therefore, be how the key problem that the present invention need to solve at the consumption that guarantees to reduce under the desirable prerequisite that discharges of medicine adjuvant as far as possible.The inventor is on the basis of great many of experiments, it is unexpected that being used in combination of microcrystalline Cellulose/amylum pregelatinisatum/cross-linking sodium carboxymethyl cellulose/silicon dioxide/magnesium stearate of discovery can overcome the large problem of required supplementary product consumption that exists in prior art, and finally determined following weight proportion:
Hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80-160 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, cross-linking sodium carboxymethyl cellulose 5～25 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion.
Preferably: hydrochlorothiazide 5-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 100 weight portions, microcrystalline Cellulose 50～100 weight portions, amylum pregelatinisatum 30～80 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 160 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, cross-linking sodium carboxymethyl cellulose 8～20 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
More preferably: hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, valsartan 80 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 5 weight portions, valsartan 160 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
Greatly reduce the consumption of adjuvant due to the present invention under the prerequisite that guarantees curative effect, therefore, both reduced sheet heavy, facilitate the patient to take, the quality Control of also having avoided supplementary product consumption to bring greatly simultaneously.
The present invention can adopt commercially available hydrochlorothiazide as crude drug, but as a preferred embodiment of the present invention, the present invention can adopt a kind of hydrochlorothiazide crystal with ideal stability and dissolution.
Those skilled in the art will know that, because hydrochlorothiazide is slightly soluble in water, stripping is slow, has had a strong impact on the bioavailability of medicine, in addition, hydrochlorothiazide is owing to containing sulfonamide structure in molecule, less stable is easy to hydrolysis, easily produces the quality wild effect, therefore, contain the pharmaceutical preparation bioavailability of hydrochlorothiazide generally on the low side.Prior art mainly solves the problems referred to above by dosage form or the preparation method that changes its pharmaceutical preparation.As preparation being made the fast dissolving dosage forms such as dispersible tablet, effervescent tablet, promote its disintegrate by using a large amount of adjuvant (disintegrating agent), reach qualified dissolution.
Although the employing technique scheme can play improvement effect to a certain extent, DeGrain.And often make preparation technology become complicated, be unfavorable for controlling the quality of the pharmaceutical preparations.
Patent application CN101659643A discloses crystal form of a kind of hydrochlorothiazide and uses thereof, the problem slow for the ubiquitous hydrochlorothiazide stripping of prior art, that bioavailability is poor, by hydrochlorothiazide is processed, obtain a kind of new hydrochlorothiazide crystalline form iii (as shown in Figure 2), result shows, the formulation products that the compositions that forms with hydrochlorothiazide crystalline form iii or hydrochlorothiazide III and other types depressor is made, its dissolution rate can reach the level similar to same kind of products at abroad, has solved to a certain extent the slow problem of hydrochlorothiazide dissolution rate.But the stability of preparation does not significantly improve yet, and the curative effect of pharmaceutical preparation is also undesirable.
In view of this, the inventor has obtained certain hydrochlorothiazide crystal unexpectedly after hydrochlorothiazide has carried out long-term large quantity research, and this crystal efficiently solves the existing variety of issue that the hydrochlorothiazide preparation occurs that contains, and has obtained beyond thought technique effect.
As shown in Figure 1, hydrochlorothiazide crystal of the present invention uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
Fig. 2 disclose hydrochlorothiazide crystal in CN101659643A the powder X-ray diffraction pattern, from accompanying drawing as can be known, above-mentioned crystal is different from hydrochlorothiazide crystal of the present invention, in addition, through a large amount of control experiments of inventor, crystal of the present invention significantly is better than the disclosed hydrochlorothiazide crystal of prior art on stability and dissolution.
The preparation method of hydrochlorothiazide crystal of the present invention comprises the steps:
(1) hydrochlorothiazide is dissolved in acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation drip distilled water in acetone soln, occur muddy to solution;
(3) under ultrasonic field in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, standing, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
In described step 1, the acetone soln concentration of hydrochlorothiazide is 0.05-0.2g/ml; The mixing speed of the preferred described step 2 of 0.08-0.15g/ml is 80-180r/min, preferred 120-180r/min, and the mixing speed in described step 3 is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of described ultrasonic field is 0.4～0.6KW, and in described organic mixed solution, the volume ratio of ethanol and ether is 2: 3-7: 6, and the volume ratio of described mixed liquor and acetone is 4: 5-8: 5; The standing growing the grain of described step 4 is at 12-18 ℃ of lower growing the grain 1.5-2.5 hour.
Described preparation method comprises the steps:
(1) hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.1g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 160r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.5KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 25r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 5: 6, and the volume ratio of described mixed liquor and acetone is 1: 1;
(4) continue ultrasonic 2 minutes, standing, 16 ℃ of lower growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
The present invention introduces ultrasound wave and controls in the process of crystallization.Those skilled in the art will know that, crystallization is the process of a complexity, each factor of crystallization process, all can affect formation and the control thereof of crystal as time-temperature of the selection of solvent and consumption thereof, mixing speed, growing the grain etc., the present invention introduces ultrasonic field for after crystallization, ultrasonic power and time are the crystal formation key of impact equally, and the present invention utilizes ultrasound wave to control nucleation and growth course, thereby crystallization process is optimized more.Above-mentioned preparation method is the best preparation method of inventor through finally determining after great many of experiments, and the hydrochlorothiazide crystal of gained possesses the remarkable result that prior art can't obtain.
Hydrochlorothiazide of the present invention is hydrochlorothiazide powder commercially available in prior art, the hydrochlorothiazide crystal of described hydrochlorothiazide crystal for adopting commercially available hydrochlorothiazide powder to be prepared from by method of the present invention.
In addition, the present invention also provides a kind of preparation method of above-mentioned solid pharmaceutical composition tablet, those skilled in the art will know that, compound tablet compositions of the present invention is because prescription is scientific and reasonable, therefore can predict and adopt disclosed other method for preparing tablet thereof of prior art also can obtain eutherapeutic tablet composition, the present invention is preferred but be not limited only to preparation method as described below, and this preparation method comprises the steps:
1) hydrochlorothiazide, valsartan and Levamlodipine are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
3) take above-mentioned standby hydrochlorothiazide, Levamlodipine, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take the valsartan of recipe quantity, with step 3) resulting mixed powder mixing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, namely get described pharmaceutical composition.
The inventor has determined the preparation method of above-mentioned tablet composition for the characteristic of main ingredient, for simplifying production process, keep as far as possible the activity of ingredient, and the present invention adopts direct pressure closing to prepare compound tablet.Can control the reasonable release of hydrochlorothiazide, valsartan and Levamlodipine due to being combined with of microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate, and adopt direct pressure closing to help the quick release of medicine, therefore, Pharmaceutical composition of the present invention can obtain more preferably therapeutic effect than the preparation of prior art.Wherein, the method for a kind of mixed material medicine that the equivalent of the present invention method of progressively increasing is commonly used for those skilled in the art, concrete operations are familiar with by those skilled in the art and are grasped.
The 3rd purpose of the present invention is to provide a kind of preparation method of above-mentioned composition capsule, those skilled in the art will know that, compound preparation of the present invention is because prescription is scientific and reasonable, therefore can predict and adopt disclosed other capsule preparation method thereofs of prior art also can obtain eutherapeutic capsule compositions, the present invention is preferred but be not limited only to preparation method as described below, and this preparation method comprises the steps:
1) hydrochlorothiazide, valsartan and Levamlodipine are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
3) but take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose die mould starch, silicon dioxide, HPMC and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 40 ℃～50 ℃ dryings obtained particulate powder after 1 hour;
4) taking above-mentioned standby hydrochlorothiazide and step 3 by recipe quantity) resulting particulate powder adopts the equivalent method of progressively increasing to mix, obtains the pharmaceutical composition powder, with 24 order nylon screen granulate, the detection of taking a sample;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described pharmaceutical composition.
Wherein, the method for a kind of mixed material medicine that the equivalent method of progressively increasing is commonly used for those skilled in the art, concrete operations are familiar with by those skilled in the art and are grasped.In step 3, the consumption of purified water is as the criterion mixed powder can be carried out wet method cutting granulation, and concrete consumption is to be determined on a case-by-case basis in practical operation, and this selection and judgement are also grasped by those skilled in the art.
Adopt technique scheme: the present invention has following beneficial effect:
1, the medicinal compositions drug content of oral administration solid of the present invention is high, and supplementary product consumption is only the 1/5-1/3 of prior art.
2, the present invention adopt with 3 kinds of medicines be combined in 11 time on the one, this compound tablet is taken more convenient, helps to control better patient's blood pressure.
3, the present invention writes out a prescription rationally, and bioavailability significantly improves, and all 2 above same dose Drug combinations reduce systolic pressure 24%～43% and diastolic pressure 18%～45% more.
Description of drawings
Fig. 1 hydrochlorothiazide crystal powder of the present invention diffraction pattern
The disclosed hydrochlorothiazide crystalline form iii of Fig. 2 CN101659643A powder diagram
The specific embodiment
The following examples will be done to explain more specifically to the present invention, but the present invention is not limited only to these embodiment, and these embodiment do not limit the present invention in any way yet equally.
The preparation of embodiment 1 hydrochlorothiazide crystal
(1) the 1kg hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.1g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 160r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.5KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 25r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 5: 6, and the volume ratio of described mixed liquor and acetone is 1: 1;
(4) continue ultrasonic 2 minutes, standing, 16 ℃ of lower growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, the present embodiment gained hydrochlorothiazide crystal uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
The preparation of embodiment 2 hydrochlorothiazide crystal
(1) the 1kg hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.2g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 120r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.4KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 20r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 2: 3, and the volume ratio of described mixed liquor and acetone is 4: 5;
(4) continue ultrasonic 2 minutes, standing, 12 ℃ of lower growing the grains 1.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, the present embodiment gained hydrochlorothiazide crystal uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
The preparation of embodiment 3 hydrochlorothiazide crystal
(1) the 1kg hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.08g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 180r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.6KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 30r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 7: 6, and the volume ratio of described mixed liquor and acetone is 8: 5;
(4) continue ultrasonic 3 minutes, standing, 18 ℃ of lower growing the grains 2.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, the present embodiment gained hydrochlorothiazide crystal uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
The preparation of embodiment 4 hydrochlorothiazide crystal
(1) the 1kg hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.05g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 130r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.55KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 20r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 1: 1, and the volume ratio of described mixed liquor and acetone is 6: 5;
(4) continue ultrasonic 1.5 minutes, standing, 12 ℃ of lower growing the grains 1.5 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, the present embodiment gained hydrochlorothiazide crystal uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
The preparation of embodiment 5 hydrochlorothiazide crystal
(1) hydrochlorothiazide is dissolved in acetone, obtains the acetone soln that concentration is the 0.15g/ml hydrochlorothiazide;
(2) drip distilled water under under the stirring of 80r/min in acetone soln, occur muddy to solution;
(3) power be under the ultrasonic field of 0.45KW in the step 2 gained solution stream add organic mixed solution of ethanol and ether, continue the stirring of 20r/min; Wherein in organic mixed solution, the volume ratio of ethanol and ether is 5: 6, and the volume ratio of described mixed liquor and acetone is 5: 4;
(4) continue ultrasonic 3 minutes, standing, 18 ℃ of lower growing the grains 2 hours, filter, filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
As shown in Figure 1, the present embodiment gained hydrochlorothiazide crystal uses that in the X-ray powder diffraction pattern that the Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
The preparation of embodiment 6 tablets
Prescription: (making 1000)
Hydrochlorothiazide 12.5g, Levamlodipine besylate 5g, valsartan 160g, microcrystalline Cellulose 80g, amylum pregelatinisatum 50g, cross-linking sodium carboxymethyl cellulose 10g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of the present embodiment is the prepared hydrochlorothiazide crystal of embodiment 2.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 3 hours under 70 ℃ of conditions respectively, cross 70 mesh sieves, standby;
3) take above-mentioned standby hydrochlorothiazide, Levamlodipine besylate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take the valsartan of recipe quantity, with step 3) resulting mixed powder mixing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, namely get described pharmaceutical composition.
The preparation of embodiment 7 tablets
Prescription: (making 1000)
Hydrochlorothiazide 12.5g, Levamlodipine besylate 2.5g, valsartan 80g, microcrystalline Cellulose 50g, amylum pregelatinisatum 50g, cross-linking sodium carboxymethyl cellulose 10g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of the present embodiment is the prepared hydrochlorothiazide crystal of embodiment 1.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 4 hours under 60 ℃ of conditions respectively, cross 60 mesh sieves, standby;
3) take above-mentioned standby hydrochlorothiazide, Levamlodipine besylate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take the valsartan of recipe quantity, with step 3) resulting mixed powder mixing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, namely get described pharmaceutical composition.
The preparation of embodiment 8 tablets
Prescription: (making 1000)
Hydrochlorothiazide 6.25g, Levamlodipine besylate 2.5g, valsartan 160g, microcrystalline Cellulose 70g, amylum pregelatinisatum 90g, cross-linking sodium carboxymethyl cellulose 20g, silicon dioxide 5g and magnesium stearate 1.5g.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 80 ℃ of conditions respectively, cross 80 mesh sieves, standby;
3) take above-mentioned standby hydrochlorothiazide, Levamlodipine besylate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to carry out mixing, obtain mixed powder;
4) take the valsartan of recipe quantity, with step 3) resulting mixed powder mixing, obtain the pharmaceutical composition powder, sampling detects;
5) resulting pharmaceutical composition powder is carried out direct pressed powder, coating, namely get described pharmaceutical composition.
The preparation of embodiment 9 tablets
Compare with embodiment 6, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 12.5g, maleic acid levo amido chloro diping 5g, valsartan 160g, microcrystalline Cellulose 120g, amylum pregelatinisatum 50g, cross-linking sodium carboxymethyl cellulose 8g, silicon dioxide 5g and magnesium stearate 1.5g.
The preparation of embodiment 10 tablets
Compare with embodiment 6, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 6.25g, L-ASPARTIC ACID Levamlodipine 2.5g, valsartan 100g, microcrystalline Cellulose 50g, amylum pregelatinisatum 80g, cross-linking sodium carboxymethyl cellulose 5g, silicon dioxide 5g and magnesium stearate 1.5g.
The preparation of embodiment 11 capsules
Prescription:
Hydrochlorothiazide 12.5g, Levamlodipine besylate 5g, valsartan 100g, microcrystalline Cellulose 100g, amylum pregelatinisatum 30g, cross-linking sodium carboxymethyl cellulose 15g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, in this example, hydrochlorothiazide is the hydrochlorothiazide crystal of embodiment 1 gained.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 3 hours under 70 ℃ of conditions respectively, cross 70 mesh sieves, standby;
3) but take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose die mould starch, silicon dioxide, HPMC and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 45 ℃ of dryings obtained particulate powder after 1 hour;
4) taking above-mentioned standby hydrochlorothiazide and step 3 by recipe quantity) resulting particulate powder adopts the equivalent method of progressively increasing to mix, obtains the pharmaceutical composition powder, with 24 order nylon screen granulate, the detection of taking a sample;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described pharmaceutical composition.
The preparation of embodiment 12 capsules
Prescription: (making 1000)
Hydrochlorothiazide 5g, Levamlodipine besylate 2.5g, valsartan 80g, microcrystalline Cellulose 40g, amylum pregelatinisatum 60g, cross-linking sodium carboxymethyl cellulose 5g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of the present embodiment is the prepared hydrochlorothiazide crystal of embodiment 2.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2 hours under 80 ℃ of conditions respectively, cross 60 mesh sieves, standby;
3) but take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose die mould starch, silicon dioxide, HPMC and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 40 ℃ of dryings obtained particulate powder after 1 hour;
4) taking above-mentioned standby hydrochlorothiazide and step 3 by recipe quantity) resulting particulate powder adopts the equivalent method of progressively increasing to mix, obtains the pharmaceutical composition powder, with 24 order nylon screen granulate, the detection of taking a sample;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described pharmaceutical composition.
The preparation of embodiment 13 capsules
Prescription: (making 1000)
Hydrochlorothiazide 12.5g, Levamlodipine besylate 5g, valsartan 80g, microcrystalline Cellulose 60g, amylum pregelatinisatum 40g, cross-linking sodium carboxymethyl cellulose 15g, silicon dioxide 5g and magnesium stearate 1.5g.Wherein, the described hydrochlorothiazide of the present embodiment is the prepared hydrochlorothiazide crystal of embodiment 2.
Preparation method:
1) hydrochlorothiazide, valsartan and Levamlodipine besylate are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 4 hours under 60 ℃ of conditions respectively, cross 80 mesh sieves, standby;
3) but take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose die mould starch, silicon dioxide, HPMC and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 50 ℃ of dryings obtained particulate powder after 1 hour;
4) taking above-mentioned standby hydrochlorothiazide and step 3 by recipe quantity) resulting particulate powder adopts the equivalent method of progressively increasing to mix, obtains the pharmaceutical composition powder, with 24 order nylon screen granulate, the detection of taking a sample;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described pharmaceutical composition.
The preparation of embodiment 14 capsules
Compare with embodiment 11, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 5g, maleic acid levo amido chloro diping 2.5g, valsartan 80g, microcrystalline Cellulose 120g, amylum pregelatinisatum 30g, cross-linking sodium carboxymethyl cellulose 5g, silicon dioxide 3g and magnesium stearate 1g.
The preparation of embodiment 15 capsules
Compare with embodiment 12, distinctive points only is that the present embodiment prescription is:
Hydrochlorothiazide 25g, L-ASPARTIC ACID Levamlodipine 5g, valsartan 160g, microcrystalline Cellulose 40g, amylum pregelatinisatum 90g, cross-linking sodium carboxymethyl cellulose 25g, silicon dioxide 8g and magnesium stearate 2g.Wherein, the described hydrochlorothiazide of the present embodiment is the prepared hydrochlorothiazide crystal of embodiment 2.
In order further to verify stability, safety and the curative effect thereof of the medicinal composite preparation of oral administration solid that the present invention protects, the inventor has done a series of development test to the present invention, and is specific as follows:
Test example 1 dissolution is investigated
The dissolution with the different tablets of dosage has been investigated in this test.
Experimental group 1: the embodiment of the present invention 7, wherein the hydrochlorothiazide crystal is embodiment 1 gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the present invention 7, distinctive points only is: the principal agent in prescription adopts disclosed hydrochlorothiazide crystalline form iii in CN101659643A;
Experimental group 3: the embodiment of the present invention 7; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: drugs approved by FDA Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound preparation (amlodipine+valsartan+hydrochlorothiazide, Exforge HCT); Every contains valsartan 80mg, hydrochlorothiazide 12.5mg and Levamlodipine 5mg.
Experimental group 5: hydrochlorothiazide/valsartan sheet+Levamlodipine beaylate tablets;
Experimental group 6: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+valsartan sheet.
Wherein, hydrochlorothiazide tablet in experimental group 5,6 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg), Levamlodipine beaylate tablets is selected from Zhejiang Anglikang Pharmaceutical Co., Ltd.'s (containing Levamlodipine besylate 5mg), the valsartan sheet is selected from Novartis Pharma AG's (containing valsartan 80mg), hydrochlorothiazide/valsartan sheet is selected from Zhejiang Yinggelai Pharmaceutical Co., Ltd, (containing valsartan 80mg and hydrochlorothiazide 12.5mg).A, B, C represent respectively hydrochlorothiazide, Levamlodipine besylate and valsartan.
Test method:
According to 2005 editions two appendix dissolution determination first methods of Chinese Pharmacopoeia, with 0.05M, the phosphate buffered solution 1000ml of pH6.8 is as dissolution medium, rotating speed is 50rmp, respectively 0.5min, 0.8min, 1min, 2min, 5min, 8min, 10min, 15min, 20min measure respectively organize tablet in the dissolution of principal agent composition, concrete experimental implementation is grasped by those skilled in the art.
The results are shown in Table 1:
Table 1
Result shows: the claimed compound preparation of the present invention has good dissolution, can continue to realize synchronous release in whole process of the test, experimental group 1 is compared with experimental group 2,3, adopt identical consumption and preparation method, distinctive points only is that experimental group 1 adopts the hydrochlorothiazide crystal of the present invention's preparation, and experimental group 2 adopts disclosed hydrochlorothiazide crystalline form iii in CN101659643A, experimental group 3 adopts commercially available hydrochlorothiazide, experimental group 2,3 also all can be realized synchronous release preferably, but the dissolution of hydrochlorothiazide is lower; In addition, experimental group 1-3 compares with experimental group 4-6, has not only realized synchronous release, and has significantly improved dissolution, therefore more can improve the absorption of medicine in human body, helps to improve the preparation curative effect.This is the beneficial effect that prior art can't obtain.
Other embodiment is carried out same experiment, draw identical conclusion.
Test example 2 study on the stability
Experimental group 1: the embodiment of the present invention 7, wherein the hydrochlorothiazide crystal is embodiment 1 gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the present invention 7, distinctive points only is: the principal agent in prescription adopts disclosed hydrochlorothiazide crystalline form iii in CN101659643A;
Experimental group 3: the embodiment of the present invention 7; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: drugs approved by FDA Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound preparation (amlodipine+valsartan+hydrochlorothiazide, Exforge HCT); Every contains valsartan 80mg, hydrochlorothiazide 12.5mg and Levamlodipine 5mg.
Experimental group 5: hydrochlorothiazide/valsartan sheet+Levamlodipine beaylate tablets;
Experimental group 6: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+valsartan sheet.
Wherein, hydrochlorothiazide tablet in experimental group 5,6 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg), Levamlodipine beaylate tablets is selected from Zhejiang Anglikang Pharmaceutical Co., Ltd.'s (containing Levamlodipine besylate 5mg), the valsartan sheet is selected from Novartis Pharma AG's (containing valsartan 80mg), hydrochlorothiazide/valsartan sheet is selected from Zhejiang Yinggelai Pharmaceutical Co., Ltd, (containing valsartan 80mg and hydrochlorothiazide 12.5mg).A, B, C represent respectively hydrochlorothiazide, Levamlodipine besylate and valsartan.
Test method:
Method: 30 ± 2 ℃ of temperature, placed 3 months under the condition of relative humidity 60 ± 5%, each sampling in the 1st, 2,3 month that tests once, measure respectively drug content, check catabolite with high performance liquid chromatography, and observe the appearance character of tablet, with result contrast in 0 month, the results are shown in Table 2.
Table 2: hydrochlorothiazide/Levamlodipine/valsartan tablet composition study on the stability
Result shows: after accelerating 3 months study on the stability, the drug content of experimental group 1-3 is all significantly stable than experimental group 4-6.Explanation has desirable stability according to the compound preparation of prescription of the present invention and preparation method gained, wherein, the stability of hydrochlorothiazide component is best with experimental group 1, and the stability that adopts hydrochlorothiazide crystal of the present invention more to be conducive to provide compound preparation integral body is described.Other embodiment is carried out same experiment, all draw identical conclusion.
Test example 3 pharmacodynamic experiments
One, data and method
1, case is selected " internal medicine " 2006 editions diagnostic criterias about " essential hypertension " with reference to the Wang Jiyao chief editor, do not take in the antihypertensive drug situation systolic pressure 〉=140mgHg and (or) diastolic pressure 〉=90mgHg, choose at random hyperpietic's 240 examples, the patient is divided into experimental group 1-6 at random, every group of 40 examples, each general clinical setting of organizing those selected sees Table 3:
Table 3: each organizes hyperpietic's general clinical setting
2, research method
All patients inactive blood pressure lowering and other vasoactive agents in 2 weeks before test.According to different groups, the patient takes different antihypertensive drugs, and each organizes all in the morning 6 to 8 o'clock patient medicine time, and be 8 weeks the course for the treatment of.
Experimental group 1: the embodiment of the present invention 7, wherein the hydrochlorothiazide crystal is embodiment 1 gained hydrochlorothiazide crystal;
Experimental group 2: compare with the embodiment of the present invention 7, distinctive points only is: the principal agent in prescription adopts disclosed hydrochlorothiazide crystalline form iii in CN101659643A;
Experimental group 3: the embodiment of the present invention 7; Wherein the hydrochlorothiazide crystal is the commercially available hydrochlorothiazide of prior art;
Experimental group 4: drugs approved by FDA Novartis Co.,Ltd amlodipine+valsartan+hydrochlorothiazide tablet commodity compound preparation (amlodipine+valsartan+hydrochlorothiazide, Exforge HCT); Every contains valsartan 80mg, hydrochlorothiazide 12.5mg and Levamlodipine 5mg.
Experimental group 5: hydrochlorothiazide/valsartan sheet+Levamlodipine beaylate tablets;
Experimental group 6: hydrochlorothiazide tablet+Levamlodipine beaylate tablets+valsartan sheet.
Wherein, hydrochlorothiazide tablet in experimental group 5,6 is selected from Shanxi Heng Ruida pharmaceutical Co. Ltd (containing hydrochlorothiazide 12.5mg), Levamlodipine beaylate tablets is selected from Zhejiang Anglikang Pharmaceutical Co., Ltd.'s (containing Levamlodipine besylate 5mg), the valsartan sheet is selected from Novartis Pharma AG's (containing valsartan 80mg), hydrochlorothiazide/valsartan sheet is selected from Zhejiang Yinggelai Pharmaceutical Co., Ltd, (containing valsartan 80mg and hydrochlorothiazide 12.5mg).A, B, C represent respectively hydrochlorothiazide, Levamlodipine besylate and valsartan.
3, in follow-up method 1 week before treatment, 2 weeks of taking medicine, 4 weeks, 6 weeks, 8 weeks are measured respectively patient's blood pressure situation, add up to follow up a case by regular visits to 5 times, and the instrument of blood pressure measurement and method all adopt prior art to commonly use, and this those skilled in the art of being measured as grasp.
4, drug safety evaluation
The patient all need carry out the drug safety evaluation, comprising generation and the lab index (routine blood test and biochemical analysis) of Adverse Event in acceptance is followed up a case by regular visits at every turn.
5, experimental result: see Table 4, table 5.
The therapeutic effect that table is respectively organized the hyperpietic 4:8 week afterwards compares
Table is respectively organized hyperpietic's adverse effect situation 5:8 week afterwards
The above results shows: after 8 weeks, the compound preparation of experimental group 1-3 significantly is better than experimental group 4-6 in the reducing effect to systolic pressure and diastolic pressure, in addition, 1 week before treatment, take medicine after 2 weeks, 4 weeks, 6 weeks, measure respectively patient's blood pressure situation 8 weeks, find experimental group 1 at the systolic pressure in each stage and diastolic pressure all lower than experimental group 2-5, the antihypertensive effect of visible experimental group 1 is the most desirable.In addition; on a situation arises from Adverse Event; the untoward reaction of experimental group 1-3 significantly is less than experimental group 4-6; wherein experimental group 1 number that untoward reaction occurs only accounts for 7.5%; far below 47.5% of experimental group 6; as seen the claimed compound preparation of the present invention is safe, suitablely applies clinically.
In addition, other embodiment of the present invention are done above-mentioned test, all can draw same conclusions, because length is limit, exemplify no longer one by one herein.
Claims (8)
1. the medicinal compositions of oral administration solid, is characterized in that, the oral formulations of described Pharmaceutical composition for being prepared from by acceptable adjuvant on hydrochlorothiazide, Levamlodipine, valsartan and pharmaceutics, and described oral formulations comprises tablet or capsule;
Described compositions contains following raw material by weight: hydrochlorothiazide 5-25 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80-160 weight portion, microcrystalline Cellulose 40～120 weight portions, amylum pregelatinisatum 30～90 weight portions, cross-linking sodium carboxymethyl cellulose 5～25 weight portions, silicon dioxide 3-8 weight portion and magnesium stearate 1-2 weight portion;
Described hydrochlorothiazide is the hydrochlorothiazide crystal, and in the X-ray powder diffraction pattern that described hydrochlorothiazide crystal use Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
2. Pharmaceutical composition according to claim 1, it is characterized in that: described compositions contains following raw material by weight:
Hydrochlorothiazide 5-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 80 weight portions, microcrystalline Cellulose 40～60 weight portions, amylum pregelatinisatum 40～60 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 100 weight portions, microcrystalline Cellulose 50～100 weight portions, amylum pregelatinisatum 30～80 weight portions, cross-linking sodium carboxymethyl cellulose 5～15 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 6.25-12.5 weight portion, Levamlodipine 2.5-5 weight portion, valsartan 160 weight portions, microcrystalline Cellulose 70～120 weight portions, amylum pregelatinisatum 50～90 weight portions, cross-linking sodium carboxymethyl cellulose 8～20 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
3. Pharmaceutical composition according to claim 2, it is characterized in that: described compositions contains following raw material by weight:
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 2.5 weight portions, valsartan 80 weight portions, microcrystalline Cellulose 50 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions; Or
Hydrochlorothiazide 12.5 weight portions, Levamlodipine 5 weight portions, valsartan 160 weight portions, microcrystalline Cellulose 80 weight portions, amylum pregelatinisatum 50 weight portions, cross-linking sodium carboxymethyl cellulose 10 weight portions, silicon dioxide 5 weight portions and magnesium stearate 1.5 weight portions.
4. Pharmaceutical composition according to claim 1, it is characterized in that: described hydrochlorothiazide crystal is prepared from as follows:
(1) hydrochlorothiazide is dissolved in acetone, obtains the acetone soln of hydrochlorothiazide;
(2) under agitation drip distilled water in acetone soln, occur muddy to solution;
(3) under ultrasonic field in step (2) the gained solution stream add organic mixed solution of ethanol and ether, continue to stir;
(4) continued ultrasonic 1-3 minute, standing, growing the grain filters, and filter cake washs with ether, and vacuum drying gets the hydrochlorothiazide crystal.
5. Pharmaceutical composition according to claim 4 is characterized in that: in described step (1), the acetone soln concentration of hydrochlorothiazide is 0.05-0.2g/ml; The mixing speed of described step (2) is 80-180r/min, and the mixing speed in described step (3) is 20-30r/min; Flow acceleration is 10-15ml/min, and the power of described ultrasonic field is 0.4～0.6kW, and in described organic mixed solution, the volume ratio of ethanol and ether is 2:3-7:6, and the volume ratio of described mixed liquor and acetone is 4:5-8:5; The standing growing the grain of described step (4) is at 12-18 ℃ of lower growing the grain 1.5-2.5 hour.
6. the preparation method of the described Pharmaceutical composition of claim 1, is characterized in that, described compositions is capsule, and its preparation method comprises the steps:
1) hydrochlorothiazide, valsartan and Levamlodipine are sieved respectively, standby;
2) microcrystalline Cellulose, amylum pregelatinisatum, cross-linking sodium carboxymethyl cellulose, silicon dioxide and magnesium stearate were dried by the fire 2～4 hours under 60～80 ℃ of conditions respectively, cross the 60-80 mesh sieve, standby;
3) take above-mentioned standby valsartan, Levamlodipine, microcrystalline Cellulose, amylum pregelatinisatum, silicon dioxide, cross-linking sodium carboxymethyl cellulose and magnesium stearate by recipe quantity, adopt the equivalent method of progressively increasing to mix at wet mixing pelletizer, powder is uniformly mixed; Get appropriate purified water and add and carry out wet method cutting and granulate, put that in the fluidized bed granulation seed-coating machine, 40 ℃～50 ℃ dryings obtained particulate powder after 1 hour;
4) take above-mentioned standby hydrochlorothiazide by recipe quantity and adopt the equivalent method of progressively increasing to mix with the resulting particulate powder of step 3), obtain the pharmaceutical composition powder, with 24 order nylon screen granulate, sampling detects;
5) resulting pharmaceutical composition powder is carried out capsule charge, namely get described Pharmaceutical composition.
7. medicinal compositions of oral administration solid, the oral formulations that said composition is prepared into comprises tablet or capsule, it is characterized in that, described compositions contains following raw material by weight:
Hydrochlorothiazide 5-25 weight portion
The crystal 2 .5-5 weight portion that benzenesulfonic acid, maleic acid or L-ASPARTIC ACID and Levamlodipine form
Valsartan 80-160 weight portion
Microcrystalline Cellulose 40～120 weight portions
Amylum pregelatinisatum 30～90 weight portions
Cross-linking sodium carboxymethyl cellulose 5～25 weight portions
Silicon dioxide 3-8 weight portion
Magnesium stearate 1-2 weight portion;
Described hydrochlorothiazide is the hydrochlorothiazide crystal, and in the X-ray powder diffraction pattern that described hydrochlorothiazide crystal use Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
8. medicinal compositions of oral administration solid, it is characterized in that, the oral formulations that described Pharmaceutical composition is prepared from for acceptable adjuvant on the crystal, valsartan and the pharmaceutics that are formed by hydrochlorothiazide, benzenesulfonic acid and Levamlodipine, described oral formulations comprises tablet or capsule;
Described compositions contains following raw material by weight: hydrochlorothiazide 5-25 weight portion
The crystal 2 .5-5 weight portion that benzenesulfonic acid and Levamlodipine form
Valsartan 80-160 weight portion
Microcrystalline Cellulose 40～120 weight portions
Amylum pregelatinisatum 30～90 weight portions
Cross-linking sodium carboxymethyl cellulose 5～25 weight portions
Silicon dioxide 3-8 weight portion
Magnesium stearate 1-2 weight portion;
Described hydrochlorothiazide is the hydrochlorothiazide crystal, and in the X-ray powder diffraction pattern that described hydrochlorothiazide crystal use Cu-K alpha ray measures, characteristic peak is 4.1 °, 8.2 °, 9.8 °, 12.1 °, 15.1 °, 16.7 °, 19.3 °, 20.0 °, 22.1 °, 23.3 °, 26.8 ° demonstrations at 2 θ.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110197280 CN102335176B (en) | 2011-07-14 | 2011-07-14 | Brand-new oral solid medicinal composition and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110197280 CN102335176B (en) | 2011-07-14 | 2011-07-14 | Brand-new oral solid medicinal composition and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102335176A CN102335176A (en) | 2012-02-01 |
| CN102335176B true CN102335176B (en) | 2013-06-05 |
Family
ID=45511278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201110197280 Expired - Fee Related CN102335176B (en) | 2011-07-14 | 2011-07-14 | Brand-new oral solid medicinal composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102335176B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102614188A (en) * | 2012-04-17 | 2012-08-01 | 北京哈三联科技股份有限公司 | Capsule containing valsartan, levoamlodipine and hydrochlorothiazide and preparing method thereof |
| CN102614190A (en) * | 2012-04-17 | 2012-08-01 | 北京哈三联科技股份有限公司 | Tablet containing valsartan, amlodipine and hydrochlorothiazide and preparing method thereof |
| CN102657657A (en) * | 2012-04-17 | 2012-09-12 | 北京哈三联科技股份有限公司 | Capsule containing valsartan, amlodipine and hydrochlorothiazide |
| CN102614189B (en) * | 2012-04-17 | 2014-10-22 | 北京哈三联科技股份有限公司 | Pellet medicine combination containing valsartan, amlodipine and hydrochlorothiazide |
| CN102702118B (en) * | 2012-06-11 | 2014-04-16 | 吉林三善恩科技开发有限公司 | Valsartan organic pharmaceutical co-crystal and preparation method thereof |
| CN102697754B (en) * | 2012-07-04 | 2014-08-13 | 扬子江药业集团广州海瑞药业有限公司 | Irbesartan capsules and preparation method thereof |
| CN102846625A (en) * | 2012-10-18 | 2013-01-02 | 海口华仕联医药科技有限公司 | Stable valsartan, amlodipine and hydrochlorothiazide pharmaceutical composition and preparation method thereof |
| CN112704667A (en) * | 2021-02-24 | 2021-04-27 | 施慧达药业集团(吉林)有限公司 | Composition containing levamlodipine besylate hydrate and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008484A (en) * | 2009-07-11 | 2011-04-13 | 邬林祥 | Olmesartan-containing compound preparation for treating hypertension |
| CN101647797B (en) * | 2009-09-18 | 2011-06-08 | 海南锦瑞制药股份有限公司 | Pharmaceutical composition containing Amlodipine besilate and valsartan and preparation method thereof |
-
2011
- 2011-07-14 CN CN 201110197280 patent/CN102335176B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN102335176A (en) | 2012-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102335176B (en) | Brand-new oral solid medicinal composition and preparation method thereof | |
| CN103735530A (en) | Capsule formulation of pirfenidone and pharmaceutically acceptable excipients | |
| CN101797230B (en) | Liposome solid preparation of losartan potassium hydrochlorothiazide pharmaceutical composition | |
| CN102327272B (en) | Oral solid pharmaceutical composition and preparation method thereof | |
| CN108156807A (en) | Medicine compound preparation containing Amlodipine, Losartan and Rosuvastatin | |
| CN102349902B (en) | Brand new drug composition containing levamlodipine besylate and candesartan cilexetil and preparation method thereof | |
| CN102276516B (en) | Levamlodipine besylate crystals, preparation method thereof and brand-new medicinal composition containing crystals | |
| CN102342942A (en) | Novel oral solid medicinal composition and preparation method thereof | |
| CN102335178B (en) | Oral solid pharmaceutical composition and preparation method thereof | |
| CN103249415B (en) | Compound formulation comprising Lercanidipine hydrochloride and Valsartan and preparation method thereof | |
| CN102370965A (en) | Pharmaceutical composition containing pharmaceutically acceptable salts of levoamlodipine and pharmaceutically acceptable salts of perindopril | |
| CN101715448B (en) | Therapeutic uses of imidazol-5-carboxylic acid derivatives | |
| CN101416966B (en) | Medical composition capable of treating hypertension | |
| CN109481437B (en) | Losartan potassium pharmaceutical preparation | |
| CN102266333B (en) | Brand new medicinal composition containing levamlodipine and atorvastatin calcium and preparation method thereof | |
| CN102342943B (en) | Brand new oral solid medicinal composition and its preparation method | |
| CN102327271B (en) | Levamlodipine and hydrochlorothiazide medicinal composition and preparation method thereof | |
| CN102335177B (en) | Brand-new oral solid pharmaceutical composition and preparation method thereof | |
| CN106620644A (en) | Stable perindopril indapamide tablet and preparation technology | |
| CN103006651B (en) | Tablet containing olmesartan medoxomil and amlodipine and preparation method of tablet | |
| CN102342948B (en) | New oral solid medicinal composition and preparation method thereof | |
| CN101543483A (en) | Sinetipin capsule and preparation method and quality detection method thereof | |
| CN102526739B (en) | Medicament composition for treating diabetes and application of medicament composition | |
| CN101862302A (en) | Amlodipine besylate liposome tablet | |
| CN104744404A (en) | Stable hydrochlorothiazide crystalline compound, and composite enalapril maleate pharmaceutical composition thereof |
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 | ||
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130605 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |