CN101327195A - Losartan potassium and hydrochlorothiazide tablets and preparation method thereof - Google Patents
Losartan potassium and hydrochlorothiazide tablets and preparation method thereof Download PDFInfo
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- CN101327195A CN101327195A CNA2008101267480A CN200810126748A CN101327195A CN 101327195 A CN101327195 A CN 101327195A CN A2008101267480 A CNA2008101267480 A CN A2008101267480A CN 200810126748 A CN200810126748 A CN 200810126748A CN 101327195 A CN101327195 A CN 101327195A
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- Prior art keywords
- hydrochlorothiazide
- potassium
- microcrystalline cellulose
- pregelatinized starch
- losartan potassium
- Prior art date
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- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 title claims abstract description 103
- 229960002003 hydrochlorothiazide Drugs 0.000 title claims abstract description 103
- 239000002083 C09CA01 - Losartan Substances 0.000 title claims abstract description 54
- 229960000519 losartan potassium Drugs 0.000 title claims abstract description 52
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 50
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 36
- 229920000881 Modified starch Polymers 0.000 claims abstract description 36
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 36
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 36
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 36
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims abstract description 28
- 229960001021 lactose monohydrate Drugs 0.000 claims abstract description 28
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 9
- 235000007686 potassium Nutrition 0.000 claims description 43
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 41
- 239000011591 potassium Substances 0.000 claims description 41
- 229910052700 potassium Inorganic materials 0.000 claims description 41
- 229960003975 potassium Drugs 0.000 claims description 41
- 239000003814 drug Substances 0.000 claims description 21
- 239000011248 coating agent Substances 0.000 claims description 19
- 238000000576 coating method Methods 0.000 claims description 19
- 239000008187 granular material Substances 0.000 claims description 18
- 229920003081 Povidone K 30 Polymers 0.000 claims description 16
- 238000012056 up-stream process Methods 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 229940079593 drug Drugs 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 7
- 238000012216 screening Methods 0.000 claims description 5
- 238000010298 pulverizing process Methods 0.000 claims description 4
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2r,3r,4s,5r,6s)-2-(hydroxymethyl)-6-[(2r,3s,4r,5r)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical class O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims description 2
- 229960004773 losartan Drugs 0.000 claims description 2
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 229920006316 polyvinylpyrrolidine Polymers 0.000 abstract 1
- 238000004090 dissolution Methods 0.000 description 23
- 206010020772 Hypertension Diseases 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 238000005516 engineering process Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000219000 Populus Species 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000009471 action Effects 0.000 description 4
- 230000003276 anti-hypertensive effect Effects 0.000 description 4
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- 238000011282 treatment Methods 0.000 description 4
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 3
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 3
- 206010013786 Dry skin Diseases 0.000 description 3
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- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 239000002934 diuretic Substances 0.000 description 3
- 230000001882 diuretic effect Effects 0.000 description 3
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- 230000001631 hypertensive effect Effects 0.000 description 3
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- 102000005862 Angiotensin II Human genes 0.000 description 2
- 108050000824 Angiotensin II receptor Proteins 0.000 description 2
- 102000008873 Angiotensin II receptor Human genes 0.000 description 2
- 101800000733 Angiotensin-2 Proteins 0.000 description 2
- 108010064733 Angiotensins Proteins 0.000 description 2
- 102000015427 Angiotensins Human genes 0.000 description 2
- 101800004538 Bradykinin Proteins 0.000 description 2
- 102400000967 Bradykinin Human genes 0.000 description 2
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 229950006323 angiotensin ii Drugs 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 2
- 238000000748 compression moulding Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
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- 239000000945 filler Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007779 soft material Substances 0.000 description 2
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- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 1
- WQKHERPPDYPMNX-UHFFFAOYSA-N 6-chloro-3,4-dihydro-2h-naphthalen-1-one Chemical compound O=C1CCCC2=CC(Cl)=CC=C21 WQKHERPPDYPMNX-UHFFFAOYSA-N 0.000 description 1
- 101150059573 AGTR1 gene Proteins 0.000 description 1
- 235000019890 Amylum Nutrition 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- 208000019025 Hypokalemia Diseases 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102100028255 Renin Human genes 0.000 description 1
- 108090000783 Renin Proteins 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
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- 150000004676 glycans Chemical class 0.000 description 1
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- 229940082195 hydrochlorothiazide 12.5 mg Drugs 0.000 description 1
- 229940082203 hydrochlorothiazide 15 mg Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000000088 lip Anatomy 0.000 description 1
- 229940048175 losartan potassium 50 mg Drugs 0.000 description 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a losartan potassium hydrochlorothiazide tablet and a preparation method thereof. The losartan potassium hydrochlorothiazide tablet comprises a core and a film coat layer and is characterized in that the core is composed of the losartan potassium and the hydrochlorothiazide which serve as the medicinal active components, and a medicinally available accessory. The medicinally available accessory is microcrystalline cellulose, pregelatinized starch, lactose monohydrate, polyvinylpyrrolidone K30 and magnesium stearate. The preparation method of the losartan potassium hydrochlorothiazide tablet is as the following: the hydrochlorothiazide is mixed with the easily-dissolvable losartan potassium and lactose monohydrate, and then the mixture is made into grains; the hydrochlorothiazide is dispersed in the easily-dissolvable losartan potassium and lactose monohydrate, and then mixed with the microcrystalline cellulose, the pregelatinized starch and magnesium stearate; then tablets are made and coated. The tablet hydrochlorothiazide prepared according to the method of the invention dissolves out well and has no moisture absorption under high moisture conditions.
Description
Technical field
The invention belongs to the pharmaceutical technology field, the spy relates to a kind of losastan potassium/hydrochlorothiazide tablets agent that is prepared from by medicinal chemicals Losartan Potassium (LosartanPotassium), hydrochlorothiazide (Hydrochrothiazide) and acceptable accessories fully.
Background technology
Hypertension is one of modal cardiovascular disease in the world today, is the dead and wounded or disabled primary cause of disease of adult.Since the raising of people's living standard, work competition growing tension, and the hypertension number of patients increases greatly.China's hypertension prevalence obviously rises, show according to the China's Statistical data, among Chinese 35 to the 70 years old crowd, hypertensive sickness rate is up to about 27 percent, patient's number is near 100,013,000, and annual with the speed increment more than 300 million peoples, China has become the most serious country of hypertension harm in the world.Hypertension can cause the damage of organs such as the heart, brain, kidney, serious threat human beings'health and life.
The hypertension philtrum has quite a few patient singly to use a kind of depressor, and blood pressure is reduced to normally, need can make blood pressure normal with two or more depressor.So, for ease of clinical rational drug use, improving compliance of patients, the clinical practice of further opening up medicine improves the therapeutic effect of medicine, improves the toleration of medicine, and two kinds of depressor commonly used are put together, makes compound formulation.Losastan potassium/hydrochlorothiazide tablets agent of the present invention is exactly the composite antihypertensive preparation of being made up of Losartan Potassium and hydrochlorothiazide.
Losartan Potassium is the oral non-peptide class angiotensin-ii receptor inhibitor of the first generation by Merck ﹠ Co., Inc.'s exploitation listing, and 1994 at first in Sweden's listing, in 1998 at China's official listing, now in 75 countries in the whole world as the extensive use of clinical treatment medicine.Chemical name is 2-butyl-4-chloro-[[2 '-(1H-tetrazolium-5-yl) [1,1 '-xenyl]-4-yl] methyl]-1H-imidazoles-5-methanol list first salt.Be angiotensin-ii receptor (AT1 type) antagonist.Can block the various pharmacological actions (comprise and impel vasoconstriction, effects such as aldosterone release) that endogenous and ectogenic Angiotensin II produce.Optionally act on the AT1 receptor, do not influence the function of ion channel important in other hormone receptors or the cardiovascular, the angiotensin converting enzyme (kininase II) of the Kallidin I that yet do not suppress to degrade does not influence the metabolic process of Angiotensin II and Kallidin I.Being used for the treatment of essential hypertension clinically, is an antihypertensive line medication, its strong drug action, long action time, better tolerance, has the advantage of few generation dry cough untoward reaction, also has the protective effect mechanism to kidney simultaneously.
Hydrochlorothiazide, another name Hydrochlorothiazide, hydrochlorothiazide, Hydrochlorothiazide, Hydrochlorothiazide, chemistry 6-chloro-3 by name, 4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1, the 1-dioxide is middle effect diuretic.Hydrochlorothiazide mainly suppresses medullary loop ascending branch cortex portion to Na
+And Cl
-Absorption again, thereby promote kidney that the drainage of sodium chloride is produced diuresis.Also have hypotensive effect, and can strengthen the hypotensive effect of other depressor, use as basic depressor and other depressor compatibility clinically, become the drug combination basis of other depressor inefficacy of sure reinforcement.Antihypertensive function addition when Losartan Potassium and hydrochlorothiazide share is compared with the wherein arbitrary composition of independent use, and it is bigger to share the amplitude that brings high blood pressure down.This is because these two kinds of compositions have synergism.And as the result of diuresis, hydrochlorothiazide increases plasma renin activity, increases the aldosterone secretion, falls hypokalemia, increases the angiotensin level.Take Losartan Potassium all physiological actions relevant capable of blocking, and reduce the potassium loss relevant with diuretic by suppressing aldosterone with angiotensin.Losartan Potassium has slight and of short duration uricosuric urine effect.Hydrochlorothiazide can cause uric acid moderate height, unites and uses Losartan Potassium and hydrochlorothiazide can alleviate hyperuricemia due to the diuretic.Sustainable 24 hours of resisting hypertension in the clinical research that schedules to last at least one year, is taken its antihypertensive function of this product continuously and is remained unchanged, although this product can obviously bring high blood pressure down, it does not have the influence of clinical meaning to heart rate.Be used for the treatment of hypertension clinically, be applicable to the patient of drug combination treatment.
The losartan potassium hydrochlorothiazide oral formulations of using clinically is mainly tablet at present.Because shortcomings such as these conventional formulation fabricating technologies and dosage form have, and make this class oral formulations exist disintegration time long, and onset is slow, and bioavailability is lower, thereby influence giving full play to of drug effect.
WO2004/075892 discloses Losartan Potassium and hydrochlorothiazide use in conjunction has been treated hypertensive method.CN1987766A discloses a kind of hypertensive medicine losartan potassium hydrochlorothiazide drop pill and preparation technology thereof of being used for the treatment of.The losartan potassium hydrochlorothiazide drop pill is formulated with drop pill substrate by medicinal chemicals Losartan Potassium (Losartan Potassium), hydrochlorothiazide (Hydrochrothiazide).Bioavailability height of the present invention, stability of drug products is good, is convenient to divided dose, takes easy to carry.Have the molten characteristics such as fast, dissolution height, release fast, quick produce effects of loosing of disintegrate, and production technology is simple, cost is low.
" technical study of losastan potassium/hydrochlorothiazide tablets " is [referring to " technical study of losastan potassium/hydrochlorothiazide tablets " of poplar instruction etc., the medicine Leader, 2007 (12), 12:1491-1493] by screening and influence factor's experiment to prescription, study of the influence of each prescription factor to the tablet molding, selecting microcrystalline Cellulose, the pregelatinized Starch of 1.6 times of Losartan Potassium recipe quantities is filler, 3% polyvinylpyrrolidone is a binding agent, Pulvis Talci, magnesium stearate are hybrid lubricant, and L-hydroxypropyl cellulose is that disintegrating agent prepares losastan potassium/hydrochlorothiazide tablets.Through influence factor test, under high temperature, high humidity, high light condition, significant change does not take place in appearance character, dissolution, but related substance, content all slightly descend, and under super-humid conditions, moisture absorption is obvious.Preparation method in this technical study is for to take by weighing Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pregelatinized Starch and partly to measure L-hydroxypropyl cellulose by recipe quantity, mix homogeneously, make soft material in right amount with 3% polyvinylpyrrolidone (80%), cross aperture 0.833mm (20 order) sieve series grain, wet granular is in 40 ℃ of oven dry; Mixing after adding surplus L-hydroxypropyl cellulose, Pulvis Talci, the magnesium stearate behind the granulate, tabletting, promptly.The present invention finds in the Study on Preparation of carrying out losastan potassium/hydrochlorothiazide tablets because hydrochlorothiazide is water insoluble, when granulating with microcrystalline Cellulose, insoluble microcrystalline cellulose excipients can produce absorption to it, hinder stripping, thereby make the dissolution of its prepared tablet bad, and under super-humid conditions, its moisture absorption is obvious.
In view of this, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of dissolution good, especially the stripping of hydrochlorothiazide is good, and under super-humid conditions the little losastan potassium/hydrochlorothiazide tablets of hygroscopicity.
For achieving the above object, the present invention adopts following technical scheme:
A kind of losastan potassium/hydrochlorothiazide tablets, comprise label and film-coat layer, it is characterized in that, described label is that medicament active composition and pharmaceutically acceptable auxiliaries are formed with Losartan Potassium and hydrochlorothiazide, and described pharmaceutically acceptable auxiliaries is microcrystalline Cellulose, pregelatinized Starch, lactose monohydrate, 30 POVIDONE K 30 BP/USP 30 and magnesium stearate.
" technical study of losastan potassium/hydrochlorothiazide tablets " is [referring to " technical study of losastan potassium/hydrochlorothiazide tablets " of poplar instruction etc., the medicine Leader, 2007 (12), 12:1491-1493] to disclose a kind of prescription be Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pregelatinized Starch, L-hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium stearate and talcous losastan potassium/hydrochlorothiazide tablets.The inventor finds to adopt the stripping of losastan potassium/hydrochlorothiazide tablets of this prescription preparation bad.
In the label prescription of the present invention, Losartan Potassium, hydrochlorothiazide are principal agent, and microcrystalline Cellulose, lactose monohydrate are diluent, and pregelatinized Starch, polyvidone are that binding agent, magnesium stearate are lubricant.
Among the present invention, the prescription of described label is as follows:
Losartan Potassium 40-60 part
Hydrochlorothiazide 10-15 part
Microcrystalline Cellulose 70-90 part
Lactose monohydrate 70-90 part
Pregelatinized Starch 10-14 part
30 POVIDONE K 30 BP/USP 30 2-2.8 parts
Magnesium stearate 2-2.8 part.
Preferably, the prescription of label of the present invention is as follows:
50 parts of Losartan Potassiums
12.5 parts of hydrochlorothiazide
80 parts of microcrystalline Cellulose
80 parts of lactose monohydrates
12 parts of pregelatinized Starch
30 2.4 parts of 30 POVIDONE K 30 BP/USPs
2.4 parts of magnesium stearate.
Another object of the present invention is to provide a kind of preparation method of losastan potassium/hydrochlorothiazide tablets, this method comprises the steps:
A) with Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pregelatinized Starch and lactose monohydrate pulverize separately, sieve, standby;
B) Losartan Potassium that will pulverize, sieve through above-mentioned steps, hydrochlorothiazide and lactose monohydrate mix homogeneously are standby;
C) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
D) the product mix homogeneously that step b) and step c) are obtained is granulated drying, granulate;
E) product that step d) is obtained with through the microcrystalline Cellulose of step a) crushing screening and pregelatinized Starch, magnesium stearate mix homogeneously, tabletting;
F) sheet that step e) is made is put in the coating pan, promptly.
" technical study of losastan potassium/hydrochlorothiazide tablets " is [referring to " technical study of losastan potassium/hydrochlorothiazide tablets " of poplar instruction etc., the medicine Leader, 2007 (12), 12:1491-1493] in the report preparation method for to take by weighing Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pregelatinized Starch and partly to measure L-hydroxypropyl cellulose by recipe quantity, mix homogeneously, make soft material in right amount with 3% polyvinylpyrrolidone (80%), cross aperture 0.833mm (20 order) sieve series grain, wet granular is in 40 ℃ of oven dry; Mixing after adding surplus L-hydroxypropyl cellulose, Pulvis Talci, the magnesium stearate behind the granulate, tabletting, promptly.In this preparation method, hydrochlorothiazide is granulated with microcrystalline Cellulose, and hydrochlorothiazide is water insoluble but the inventor finds, when granulating with microcrystalline Cellulose, insoluble microcrystalline cellulose excipients can hinder stripping to the absorption of its generation.Among the present invention, earlier hydrochlorothiazide is mixed granulation afterwards with easily molten Losartan Potassium, lactose monohydrate, hydrochlorothiazide is dispersed in the Losartan Potassium, lactose monohydrate of Yi Rong, mix with microcrystalline Cellulose, pregelatinized Starch, magnesium stearate again, film-making, coating, the tablet hydrochlorothiazide stripping that makes with this method is good.
Pregelatinized Starch not only has good disintegrate, adhesive effect, and when its replace starch in the general prescription 5% the time, can obviously improve hardness, disintegration and the surface brightness of tablet, the more important thing is the raising dissolution.Make diluent with pregelatinized Starch, easily granulate, granule becomes graininess and compressibility better, and hardness increases.Make binding agent, particularly during dry adhesive, advantages such as the hardness with tablet is good, the embrittlement degree is little, smooth surface.Compare with starch slurry, approximately need 4 times of starch slurries to the pregelatinized Starch amount could suppress the tablet of same hardness.The compression molding of amylum pregelatinisatum is best, only adds 5% and can obtain the bigger tablet of tensile strength; And the compression molding of starch is relatively poor, adds 30% and just can make the qualified tablet of intensity when above.Binding agent is made in pregelatinized Starch among the present invention, and prepared tablet hardness is good, little, the smooth surface of embrittlement degree.In addition, " technical study of losastan potassium/hydrochlorothiazide tablets " is [referring to " technical study of losastan potassium/hydrochlorothiazide tablets " of poplar instruction etc., the medicine Leader, 2007 (12), 12:1491-1493] in pregelatinized Starch make filler, the synergism of possible these adjuvants has also played certain effect to the stripping of tablet of the present invention.
In the above-mentioned preparation method, sieving in the step a) crossed 100 mesh sieves for the Losartan Potassium after will pulverizing and hydrochlorothiazide, and the microcrystalline Cellulose after the pulverizing, pregelatinized Starch and lactose monohydrate are crossed 60 mesh sieves.
In the above-mentioned preparation method, the tabletting in the step e) is at ambient temperature 18-26 ℃, the condition lower sheeting of humidity 45-65%.Environmental condition also can cause direct influence to tabletting, and well-known, when air humidity was too high, the phenomenon that sticking appears in the more intense drug particles of hygroscopicity was very obvious.The inventor finds through a large amount of test, when at ambient temperature 18-26 ℃, and during the condition lower sheeting of relative humidity 45-65%, the good moldability of tablet of the present invention, unilateral bright and clean, the sticking phenomenon does not appear.Preferably, humidity is controlled at 45-50%.
Preferably, the preparation method of losastan potassium/hydrochlorothiazide tablets of the present invention comprises the steps:
A), cross 100 mesh sieves with Losartan Potassium and hydrochlorothiazide pulverize separately; Microcrystalline Cellulose, pregelatinized Starch and lactose monohydrate pulverize separately are crossed 60 mesh sieves, and be standby;
B) Losartan Potassium that will pulverize, sieve through above-mentioned steps, hydrochlorothiazide, lactose monohydrate mix homogeneously are standby;
C) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
D) the product mix homogeneously that step b) and step c) are obtained is granulated with the 18-24 eye mesh screen, and 50-70 ℃ of drying obtains dried granule, and dried granule is crossed 18-24 eye mesh screen granulate;
E) product that step d) is obtained with through the microcrystalline Cellulose of step a) crushing screening and pregelatinized Starch, magnesium stearate mix homogeneously, measure drug content, determine that the heavy back of sheet is at ambient temperature 18-26 ℃, the condition lower sheeting of humidity 45-65%;
F) sheet that step e) is made is put coating in the coating pan, promptly.
The used coating fluid prescription of the present invention is
Solution with the purified water composition.
On the basis of common Opadry, added the adhesive force modifying agent of polysaccharide, make that the bonding force between film and the label is strengthened greatly, very suitable label has cured matter or oiliness surface, or the situation of bridge joint easily takes place.With full water is solvent, the solid content of 15%-20%, and coating efficient improves greatly.Its safety and stability, and cost reduces.Because of its special formulation and technology, make that the stability of color is greatly improved than conventional formulation behind the coating.
Compared with prior art, the present invention has following advantage:
(1) tablet dissolution of the present invention is good, and especially the dissolution of hydrochlorothiazide is good; Hygroscopicity is little under super-humid conditions;
(2) stability of losastan potassium/hydrochlorothiazide tablets of the present invention is better;
(3) in the preparation method of the present invention, earlier hydrochlorothiazide is mixed granulation afterwards with easily molten Losartan Potassium, lactose monohydrate, hydrochlorothiazide is dispersed in the Losartan Potassium, lactose monohydrate of Yi Rong, mix with microcrystalline Cellulose, pregelatinized Starch, magnesium stearate again, film-making, coating, the tablet dissolution that makes with this method is good, and especially the stripping of hydrochlorothiazide is good.
The specific embodiment
Below be the specific embodiment of the present invention, described embodiment is in order to further describe the present invention, rather than restriction the present invention.
Embodiment 1
(1) prescription:
The label prescription:
Losartan Potassium 50mg
Hydrochlorothiazide 12.5mg
Microcrystalline Cellulose 80mg
Lactose monohydrate 80mg
Pregelatinized Starch 12mg
30 POVIDONE K 30 BP/USP 30 2.4mg
Magnesium stearate 2.4mg
Be total to 239.3mg
Coating fluid prescription:
7.2mg
Purified water 36mg
(2) preparation method:
(a) with Losartan Potassium, hydrochlorothiazide, lactose monohydrate mix homogeneously;
(b) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
(c) the product mix homogeneously that step (a) and step (b) are obtained is granulated with 24 eye mesh screens, 60 ℃ of dryings, and dried granule is crossed 24 eye mesh screen granulate;
(d) product that step (c) is obtained and microcrystalline Cellulose, pregelatinized Starch, magnesium stearate mix homogeneously are measured drug content, determine the heavy back of sheet tabletting;
(e) sheet that step (d) is made is put in the coating pan, with 20%
The aqueous solution coating, promptly.
Embodiment 2
(1) prescription:
The label prescription:
Losartan Potassium 40mg
Hydrochlorothiazide 10mg
Microcrystalline Cellulose 70mg
Lactose monohydrate 70mg
Pregelatinized Starch 10mg
30 POVIDONE K 30 BP/USP 30 2mg
Magnesium stearate 2mg
Coating fluid prescription:
7.2mg
Purified water 36mg
(2) preparation method:
(a) with Losartan Potassium, hydrochlorothiazide, lactose monohydrate mix homogeneously;
(b) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
(c) the product mix homogeneously that step (a) and step (b) are obtained is granulated with 24 eye mesh screens, 60 ℃ of dryings, and dried granule is crossed 24 eye mesh screen granulate;
(d) product that step (c) is obtained and microcrystalline Cellulose, pregelatinized Starch, magnesium stearate mix homogeneously are measured drug content, determine the heavy back of sheet tabletting, and tabletting is the condition lower sheeting in 18 ℃ of ambient temperatures, humidity 45%; (e) sheet that step (d) is made is put in the coating pan, with 20%
The aqueous solution coating, promptly.
Embodiment 3
(1) prescription:
The label prescription:
Losartan Potassium 60mg
Hydrochlorothiazide 15mg
Microcrystalline Cellulose 90mg
Lactose monohydrate 90mg
Pregelatinized Starch 14mg
30 POVIDONE K 30 BP/USP 30 2.8mg
Magnesium stearate 2.8mg
(2) preparation method:
(a) with Losartan Potassium, hydrochlorothiazide, lactose monohydrate mix homogeneously;
(b) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
(c) the product mix homogeneously that step (a) and step (b) are obtained is granulated with 24 eye mesh screens, 60 ℃ of dryings, and dried granule is crossed 24 eye mesh screen granulate;
(d) product that step (c) is obtained and microcrystalline Cellulose, pregelatinized Starch, magnesium stearate mix homogeneously are measured drug content, determine the heavy back of sheet tabletting, and tabletting is the condition lower sheeting in 26 ℃ of ambient temperatures, humidity 65%;
(e) sheet that step (d) is made is put in the coating pan, with 20%
The aqueous solution coating, promptly.
[comparative example] influence factor test
Respectively according to embodiments of the invention 1 and " technical study of losastan potassium/hydrochlorothiazide tablets " [referring to " technical study of losastan potassium/hydrochlorothiazide tablets " of poplar instruction etc., the medicine Leader, 2007 (12), 12:1491-1493] the prepared losastan potassium/hydrochlorothiazide tablets of reported method) 1 batch of product of method preparation of (to call documents in the following text), be respectively A and B, carry out influence factor's experiment according to 2000 editions appendix X of Pharmacopoeia of the People's Republic of China IXC.
(1) hot test
With above-mentioned 2 batches of losastan potassium/hydrochlorothiazide tablets, put in 60 ℃ of calorstats and place 10d, respectively at sampling in the 5th, 10 day, measure content, check related substance, dissolution, and and zero the time relatively.The results are shown in Table 1.
Table 1, high temperature experiment be sample appearance, dissolution, hygroscopic capacity, content and related substance check result down
As can be seen from Table 1, the dissolution of losastan potassium/hydrochlorothiazide tablets of the present invention is better than the dissolution of the losastan potassium/hydrochlorothiazide tablets of documents, under hot conditions, there is not hygroscopic effect, appearance character, dissolution, Losartan Potassium and hydrochlorothiazide content and related substance total amount all do not have significant change, its good stability.
(2) high wet test
With above-mentioned 2 batches of losastan potassium/hydrochlorothiazide tablets, put in the climatic chamber [25 ℃, relative humidity (RH) 75%; 25 ℃, RH92.5%] place 10d, respectively at sampling in the 5th, 10 day, measure content, check related substance, dissolution and hygroscopicity, and and zero the time relatively.The results are shown in Table 2.
Table 2, high humidity experiment be sample appearance, dissolution, hygroscopic capacity, content and related substance check result down
As can be seen from Table 2, the dissolution of losastan potassium/hydrochlorothiazide tablets of the present invention is better than the dissolution of the losastan potassium/hydrochlorothiazide tablets of documents, and under super-humid conditions, there is not hygroscopic effect, appearance character, dissolution, Losartan Potassium and hydrochlorothiazide content and related substance total amount all do not have significant change, its good stability.
(3) illumination experiment
With above-mentioned 2 batches of losastan potassium/hydrochlorothiazide tablets, put in the lighting box [light intensity is (4500 ± 500) lx] and place 10d, respectively at sampling in the 5th, 10 day, measure content, check related substance, dissolution, and and zero the time relatively.The results are shown in Table 3.
Table 3, illumination experiment be sample appearance, dissolution, hygroscopic capacity, content and related substance check result down
As can be seen from Table 3, the dissolution of losastan potassium/hydrochlorothiazide tablets of the present invention is better than the dissolution of the losastan potassium/hydrochlorothiazide tablets of documents, under illumination condition, there is not hygroscopic effect, appearance character, dissolution, Losartan Potassium and hydrochlorothiazide content and related substance total amount all do not have significant change, its good stability.
Claims (8)
1, a kind of losastan potassium/hydrochlorothiazide tablets, comprise label and film-coat layer, it is characterized in that, described label is that medicament active composition and pharmaceutically acceptable auxiliaries are formed with Losartan Potassium and hydrochlorothiazide, and described pharmaceutically acceptable auxiliaries is microcrystalline Cellulose, pregelatinized Starch, lactose monohydrate, 30 POVIDONE K 30 BP/USP 30 and magnesium stearate.
2, losastan potassium/hydrochlorothiazide tablets according to claim 1 is characterized in that, the prescription of described label is as follows:
Losartan Potassium 40-60 part
Hydrochlorothiazide 10-15 part
Microcrystalline Cellulose 70-90 part
Lactose monohydrate 70-90 part
Pregelatinized Starch 10-14 part
30 POVIDONE K 30 BP/USP 30 2-2.8 parts
Magnesium stearate 2-2.8 part.
3, losastan potassium/hydrochlorothiazide tablets according to claim 2 is characterized in that, the prescription of described label is as follows:
50 parts of Losartan Potassiums
12.5 parts of hydrochlorothiazide
80 parts of microcrystalline Cellulose
80 parts of lactose monohydrates
12 parts of pregelatinized Starch
30 2.4 parts of 30 POVIDONE K 30 BP/USPs
2.4 parts of magnesium stearate.
4, the preparation method of the described losastan potassium/hydrochlorothiazide tablets of claim 1 is characterized in that, this method comprises the steps:
A) with Losartan Potassium, hydrochlorothiazide, microcrystalline Cellulose, pregelatinized Starch and lactose monohydrate pulverize separately, sieve, standby;
B) Losartan Potassium that will pulverize, sieve through above-mentioned steps, hydrochlorothiazide and lactose monohydrate mix homogeneously are standby;
C) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
D) the product mix homogeneously that step b) and step c) are obtained is granulated drying, granulate;
E) product that step d) is obtained with through the microcrystalline Cellulose of step a) crushing screening and pregelatinized Starch, magnesium stearate mix homogeneously, tabletting;
F) sheet that step e) is made is put in the coating pan, promptly.
5, the preparation method of losastan potassium/hydrochlorothiazide tablets according to claim 4, it is characterized in that, sieving in the step a) crossed 100 mesh sieves for the Losartan Potassium after will pulverizing and hydrochlorothiazide, and the microcrystalline Cellulose after the pulverizing, pregelatinized Starch and lactose monohydrate are crossed 60 mesh sieves.
6, the preparation method of losastan potassium/hydrochlorothiazide tablets according to claim 5 is characterized in that, the tabletting in the step e) is at ambient temperature 18-26 ℃, the condition lower sheeting of humidity 45-65%.
7, the preparation method of losastan potassium/hydrochlorothiazide tablets according to claim 6 is characterized in that, this method comprises the steps:
A), cross 100 mesh sieves with Losartan Potassium and hydrochlorothiazide pulverize separately; Microcrystalline Cellulose, pregelatinized Starch and lactose monohydrate pulverize separately are crossed 60 mesh sieves, and be standby;
B) Losartan Potassium that will pulverize, sieve through above-mentioned steps, hydrochlorothiazide, lactose monohydrate mix homogeneously are standby;
C) 30 POVIDONE K 30 BP/USP 30 is dissolved in 75% ethanol;
D) the product mix homogeneously that step b) and step c) are obtained is granulated with the 18-24 eye mesh screen, and 50-70 ℃ of drying obtains dried granule, and dried granule is crossed 18-24 eye mesh screen granulate;
E) product that step d) is obtained with through the microcrystalline Cellulose of step a) crushing screening and pregelatinized Starch, magnesium stearate mix homogeneously, measure drug content, determine that the heavy back of sheet is at ambient temperature 18-26 ℃, the condition lower sheeting of humidity 45-65%;
F) sheet that step e) is made is put coating in the coating pan, promptly.
8, the preparation method of losastan potassium/hydrochlorothiazide tablets according to claim 7 is characterized in that, the humidity described in the step e) is controlled at 45-50%.
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| CN 200810126748 CN100577152C (en) | 2008-06-20 | 2008-06-20 | Losartan potassium and hydrochlorothiazide tablets and preparation method thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797230A (en) * | 2010-04-19 | 2010-08-11 | 王明 | Liposome solid preparation of losartan potassium hydrochlorothiazide pharmaceutical composition |
| CN102058602A (en) * | 2010-12-21 | 2011-05-18 | 中国药科大学 | Stable oral solid preparation containing losartan potassium and hydrochlorothiazide |
| CN102526063A (en) * | 2012-02-20 | 2012-07-04 | 中国药科大学 | Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation |
-
2008
- 2008-06-20 CN CN 200810126748 patent/CN100577152C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101797230A (en) * | 2010-04-19 | 2010-08-11 | 王明 | Liposome solid preparation of losartan potassium hydrochlorothiazide pharmaceutical composition |
| CN102058602A (en) * | 2010-12-21 | 2011-05-18 | 中国药科大学 | Stable oral solid preparation containing losartan potassium and hydrochlorothiazide |
| CN102058602B (en) * | 2010-12-21 | 2013-04-10 | 中国药科大学 | Stable oral solid preparation containing losartan potassium and hydrochlorothiazide |
| CN102526063A (en) * | 2012-02-20 | 2012-07-04 | 中国药科大学 | Compound preparation containing losartan potassium and hydrochlorothiazide and preparation method for compound preparation |
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|---|---|
| CN100577152C (en) | 2010-01-06 |
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