CN102716132B - Compound amlodipine/valsartan/hydrochlorothiazide tablet and preparation method thereof - Google Patents
Compound amlodipine/valsartan/hydrochlorothiazide tablet and preparation method thereof Download PDFInfo
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- CN102716132B CN102716132B CN201110076438.4A CN201110076438A CN102716132B CN 102716132 B CN102716132 B CN 102716132B CN 201110076438 A CN201110076438 A CN 201110076438A CN 102716132 B CN102716132 B CN 102716132B
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- amlodipine
- valsartan
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Abstract
The present invention relates to compound amlodipine/valsartan/Aquazide H and preparation method thereof.Described compound amlodipine/valsartan/Aquazide H is made up of the coatings (1) comprising amlodipine and the label (2) that comprises valsartan/hydrochlorothiazide, and coatings (1) is directly wrapped in outside label (2).Compound amlodipine/valsartan/Aquazide H of the present invention, each effective ingredient uniformity of dosage units is good, and dissolution is suitable with commercially available prod EXFORGE HCT.
Description
Technical field
The present invention relates to a kind of compound medicinal formulation and preparation method thereof, be specifically related to a kind of compound amlodipine/valsartan/hydrochlorothiazide tablet and preparation method thereof.
Background technology
Hypertension is one of modal cardiovascular disease, especially middle-aged and elderly people, and long-term hypertension can affect the function of the important organ particularly heart, brain, kidney.Blood pressure increases play pivotal role in the pathogenesis of coronary heart disease and cerebrovascular, and particularly the mortality rate of developing country's coronary heart disease and caused by cerebrovascular disease and disability rate increase rapidly, so one of ultimate challenge that treatment hypertension is medical worker to be faced in the whole world.It is reported, in the old people of China more than 60 years old, 40% ~ 45% suffers from hypertension.Its Major Clinical feature is: 1. sickness rate is high, and hazardness is large.2. the course of disease is long, and symptom is few, and patient often just perceives when blood pressure raises suddenly and occurs cardio-cerebral diseases.3. fluctuation of blood pressure is larger.4. various diseases coexists, and easily develops complications, and treatment difficulty is large.5. drug susceptibility is poor.
For many years, reduce blood pressure, make reach mark blood pressure, be the target that doctor and patient is pursued jointly always.In order to meet the needs of numerous hyperpietics and improve drug compliance, the especially novel fixed dosage compound preparation of antihypertensive drugs therapeutic alliance shows excellent effect gradually in clinical treatment, and its status also seems more and more important.
In May, 2009, the hypertension that the compound preparation of EXFORGE HCT (amlodipine+valsartan+hydrochlorothiazide tablet) listing treatment single medicine or two kinds of medicines composition that FDA ratifies Novartis Co., Ltd can not effectively control, is acted on three kinds of different mechanisms in blood pressure regulating by amlodipine, valsartan, hydrochlorothiazide specific aim.Specifically, amlodipine has blocked the contraction of calcium to heart and vascular smooth muscle cell; Valsartan has blocked angiotensin II on cardiac, vascular smooth muscle, the vasoconstriction of adrenal gland and kidney cell and sodium retention effect; Hydrochlorothiazide then directly facilitates sodium and the excretion of chlorine in kidney, thus causes the minimizing of intravasal volume.
EXFORGE HCT goes on the market in specification, amlodipine content is 5 or 10mg, and hydrochlorothiazide content is 12.5 or 25mg, valsartan content be 160 or 320mg (when valsartan content is 320mg, hydrochlorothiazide content is 25mg, and amlodipine content is 10mg).Chinese Pharmacopoeia specifies, crude drug will be mixed homogeneously with adjuvant.Whether mixing evenly can be evaluated with uniformity of dosage units.The active component that the active component of 10mg or content is less than every sheet weight 5% is less than for dosage in each preparation, all there is the risk of the bad control of uniformity of dosage units.And as can be seen from EXFORGE HCT listing specification, amlodipine content in compound preparation is very little, only have 5mg or 10mg, therefore may occur its skewness and underproof risk of uniformity of dosage units in the formulation, bring difficulty to the preparation of this compound solid preparation.
Chinese patent application CN101478956 discloses monolayer, the bilayer and three layers of solid dosage forms and preparation method thereof of the combination of a kind of valsartan, amlodipine and hydrochlorothiazide.What preparation method disclosed in this patent application adopted is dry method granulation processes, and when this compound preparation be double-layer tablet or three-layer tablet time, need, through repeatedly tabletting, because amlodipine specification is less, easily to cause the uniformity of dosage units of amlodipine defective.
Summary of the invention
Based on the deficiency that prior art exists, the object of the present invention is to provide that a kind of preparation technology is simple, the compound amlodipine/valsartan/hydrochlorothiazide tablet being convenient to quality control and preparation method thereof.
Therefore, one aspect of the present invention provides a kind of compound amlodipine/valsartan/Aquazide H, by comprise the coatings (1) of amlodipine and comprise valsartan, label (2) that hydrochlorothiazide is formed forms, coatings (1) is directly wrapped in outside label (2).
Wherein:
In described compound amlodipine/valsartan/hydrochlorothiazide tablet, three kinds of effective ingredient specifications are: amlodipine is 5mg or 10mg, and valsartan is 160mg or 320mg, and hydrochlorothiazide is 12.5mg or 25mg.
The present invention additionally provides the preparation method of this compound amlodipine/valsartan/hydrochlorothiazide tablet on the other hand, is valsartan and Hydrochlorothiade and acceptable pharmaceutical excipient are mixed, non-slurry pelletizing, and label (2) prepared by tabletting; Amlodipine is crushed between 80 ~ 120 orders, is scattered in purified water or 70% ethanol, adds film-coating material and stir; Calculate coating weight gain scope according to the specification of amlodipine, coated cores (2), to OK range, obtains the coatings (1) containing amlodipine.
Wherein:
Described film-coating material is: the polymer coating material comprising hydroxypropyl emthylcellulose (or hydroxypropyl cellulose or polyphenyl dioctyl phthalate vinylacetate), Polyethylene Glycol, Pulvis Talci, titanium dioxide and pigment, can buy commercially, as the OPADRYY-1-7000 that Shanghai Ka Lekang packaging technique company limited produces.
When in described compound amlodipine/valsartan/hydrochlorothiazide tablet, amlodipine specification is 5mg, controlling coating weight gain scope is 4.30 ~ 5.24% (within the scope of this, in every sheet, amlodipine content is 90 ~ 110% of labelled amount), be preferably 4.77% (during this point value, in every sheet, amlodipine content is 100% of labelled amount); When amlodipine specification is 10mg, controlling coating weight gain scope is 8.60 ~ 10.48% (within the scope of this, in every sheet, amlodipine content is 90 ~ 110% of labelled amount), be preferably 9.54% (during this point value, in every sheet, amlodipine content is 100% of labelled amount).Described amlodipine is amlodipine effective ingredient, is 1.388mg as 1mg amlodipine is converted to Amlodipine Besylate Tablet.
Described pharmaceutical excipient can be one or more in filler, disintegrating agent, lubricant.
Wherein:
Described filler is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch, from cost consideration, is preferably microcrystalline Cellulose.
Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, from cost consideration, is preferably polyvinylpolypyrrolidone.
Described lubricant be selected from magnesium stearate, hard fumaric acid sodium, Pulvis Talci or hydrogenated vegetable oil one or more, from cost consideration, be preferably magnesium stearate.
Compound amlodipine/valsartan/Aquazide H of the present invention, each effective ingredient uniformity of dosage units is good, and dissolution is suitable with commercially available prod EXFORGE HCT.
Accompanying drawing explanation
Fig. 1 is the schematic diagram of compound amlodipine/valsartan/hydrochlorothiazide tablet of the present invention.
Fig. 2 is the EXFORGE HCT stripping curve of embodiment 1 gained sample and same specification.
Specific embodiment
Following embodiment is only to illustrate in greater detail the present invention, instead of restriction the present invention.
Embodiment 1 ~ 7: compound amlodipine/valsartan/hydrochlorothiazide tablet (amlodipine is in coatings)
1, prescription composition (1000)
(1) coating fluid prescription: OPADRY Y-1-7000:70g
Purified water or 70% ethanol: 1000ml
Amlodipine Besylate Tablet: 40g
(2) Core formulation and coating weight gain are in table 1:
Table 1 embodiment 1 ~ 7 Core formulation and coating weight gain
2, preparation technology
(1) to cross 80 mesh sieves for subsequent use for supplementary material, and take the valsartan of recipe quantity, hydrochlorothiazide, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, tabletting, prepare label.
(2) take and be crushed to 80 ~ 120 object amlodipines, be scattered in purified water or 70% ethanol, add coating powder, stir 1.5h for subsequent use.
(3) according to specification and the concentration calculating coating weight gain of amlodipine.
(4) place in coating pan by label, start seed-coating machine, be adjusted to suitable rotating speed, regulate intake air temperature to about 45 DEG C, the spray amount of adjustment spray gun, coating, coating, to suitable weightening finish, continues dry 0.5h.
Embodiment 8 ~ 12: compound amlodipine/valsartan/hydrochlorothiazide tablet (amlodipine is in label)
1, prescription composition (1000)
(1) coating fluid prescription: OPADRY Y-1-7000:70g
Purified water or 70% ethanol: 1000ml
(2) Core formulation and coating weight gain scope are in table 2:
Table 2 embodiment 8 ~ 12 Core formulation and coating weight gain
2, preparation technology
(1) to cross 80 mesh sieves for subsequent use for supplementary material, and take the Amlodipine Besylate Tablet of recipe quantity, valsartan, hydrochlorothiazide, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, tabletting, prepare label.
(2) place in coating pan by label, start seed-coating machine, be adjusted to suitable rotating speed, regulate intake air temperature to about 45 DEG C, the spray amount of adjustment spray gun, coating, coating, to suitable weightening finish, continues dry 0.5h.
Embodiment 13: compound amlodipine/valsartan/hydrochlorothiazide double-layer tablets (valsartan/hydrochlorothiazide layer, amlodipine layer)
1, prescription composition (1000)
(1) coating fluid prescription: OPADRY Y-1-7000:70g
Purified water or 70% ethanol: 1000ml
Table 3 embodiment 13 Core formulation and coating weight gain
2, preparation technology
(1) to cross 80 mesh sieves for subsequent use for supplementary material, and take the valsartan of recipe quantity, hydrochlorothiazide, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule A; Take the Amlodipine Besylate Tablet of recipe quantity, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule B.Granule A and granule B bi-layer tablet press prepare label.
(2) place in coating pan by label, start seed-coating machine, be adjusted to suitable rotating speed, regulate intake air temperature to about 45 DEG C, the spray amount of adjustment spray gun, coating, coating, to suitable weightening finish, continues dry 0.5h.
Embodiment 14: compound amlodipine/valsartan/hydrochlorothiazide double-layer tablets (valsartan layer, hydrochlorothiazide/amlodipine layer)
1, prescription composition (1000)
(1) coating fluid prescription: OPADRY Y-1-7000:70g
Purified water or 70% ethanol: 1000ml
Table 4 embodiment 14 Core formulation and coating weight gain
2, preparation technology
(1) to cross 80 mesh sieves for subsequent use for supplementary material, and take the valsartan of recipe quantity, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule A; Take the Amlodipine Besylate Tablet of recipe quantity, hydrochlorothiazide, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule B.Granule A and granule B bi-layer tablet press prepare label.。
(2) place in coating pan by label, start seed-coating machine, be adjusted to suitable rotating speed, regulate intake air temperature to about 45 DEG C, the spray amount of adjustment spray gun, coating, coating, to suitable weightening finish, continues dry 0.5h.
Embodiment 15: compound amlodipine/valsartan/hydrochlorothiazide double-layer tablets (valsartan/amlodipine layer, hydrochlorothiazide layer)
1, prescription composition (1000)
(1) coating fluid prescription: OPADRY Y-1-7000:70g
Purified water or 70% ethanol: 1000ml
Table 5 embodiment 15 Core formulation and coating weight gain
2, preparation technology
(1) to cross 80 mesh sieves for subsequent use for supplementary material, and take the valsartan of recipe quantity, Amlodipine Besylate Tablet, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule A; Take the hydrochlorothiazide of recipe quantity, filler, disintegrating agent mixing, non-slurry pelletizing, adds the lubricant of recipe quantity, is prepared into granule B.Granule A and granule B bi-layer tablet press prepare label.
(2) place in coating pan by label, start seed-coating machine, be adjusted to suitable rotating speed, regulate intake air temperature to about 45 DEG C, the spray amount of adjustment spray gun, coating, coating, to suitable weightening finish, continues dry 0.5h.
Embodiment 16: Determination of Content Uniformity is tested
Determination of Content Uniformity is carried out to embodiment 1 ~ 15 gained compound amlodipine/valsartan/hydrochlorothiazide tablet sample, the results are shown in Table 6:(and measure according to Chinese Pharmacopoeia 2010 editions two annex X E Content uniformity tests).
Table 6 embodiment 1 ~ 15 sample size cloud test result
Experimental result shows: in embodiment 1 ~ 7 gained sample (amlodipine is in coatings), the amlodipine content uniformity will significantly better than embodiment 8 ~ 12 gained sample (amlodipine is in label) and embodiment 13 ~ 15 gained sample (double-layer tablet).
Embodiment 17: Dissolution experiments
The contrast of EXFORGE HCT (lot number: the F0004) stripping curve of embodiment 1 gained sample and same specification, the results are shown in Table 7.
Method: get test specimen, according to dissolution method (Chinese Pharmacopoeia 2010 editions two annex X C second methods), with phosphate buffer (pH6.8) 900ml for dissolution medium, rotating speed is 50 turns per minute, operate in accordance with the law, through 30 minutes time, get solution appropriate, filter, get subsequent filtrate as need testing solution, get 20 μ l injection liquid chromatographies, measure according to high performance liquid chromatography (Chinese Pharmacopoeia 2010 editions two annex V D), be filler with octadecylsilane chemically bonded silica, phosphate buffer (0.02mol/l potassium dihydrogen phosphate aqueous solution, with phosphorus acid for adjusting pH to 3.5)-acetonitrile (55: 45) is mobile phase, flow velocity is 1.0ml/min, determined wavelength is 225nm.Get hydrochlorothiazide reference substance and be about 31mg and Amlodipine Besylate Tablet reference substance is about 17mg, accurately weighed, put in 50ml measuring bottle, add acetonitrile dissolve and be diluted to scale, precision measures 2ml and puts another accurate title and have in the 100ml measuring bottle of 16mg valsartan reference substance, add stripping medium dissolves and be diluted to scale, shake up, as Amlodipine Besylate Tablet, the mixing reference substance solution of valsartan and hydrochlorothiazide, be measured in the same method, go out the stripping quantity of every sheet with calculated by peak area by external standard method, the stripping limit of valsartan and hydrochlorothiazide is 80% of labelled amount, the stripping limit of amlodipine is 75% of labelled amount, should conform with the regulations.
The dissolution comparing result of table 7 embodiment 1 sample and EXFORGE HCT
Note: A represents amlodipine; B represents valsartan; C represents hydrochlorothiazide
Experimental result shows: in gained compound amlodipine/valsartan/hydrochlorothiazide tablet sample of the present invention, the dissolution of each effective ingredient is suitable with commercially available prod EXFORGE HCT.
Claims (9)
1. compound amlodipine/valsartan/Aquazide H, it is characterized in that: described tablet is made up of the coatings (1) comprising amlodipine and the label (2) that comprises valsartan/hydrochlorothiazide, coatings (1) is directly wrapped in outside label (2), wherein, amlodipine is 5mg or 10mg.
2. tablet according to claim 1, is characterized in that: valsartan is 160mg or 320mg, and hydrochlorothiazide is 12.5mg or 25mg.
3. a preparation method for tablet described in claim 1 or 2 is mixed valsartan, hydrochlorothiazide and acceptable pharmaceutical excipient, non-slurry pelletizing, and label (2) prepared by tabletting; Amlodipine is crushed between 80 ~ 120 orders, is scattered in purified water or 70% ethanol, add film-coating material and water stirs; Calculate coating weight gain scope according to the specification of amlodipine, coated cores (2), to OK range, obtains the coatings (1) comprising amlodipine.
4. preparation method according to claim 3, is characterized in that: when in described tablet, amlodipine specification is 5mg, and described coating weight gain scope is 4.30 ~ 5.24%; When in described tablet, amlodipine specification is 10mg, described coating weight gain scope is 8.60 ~ 10.48%.
5. preparation method according to claim 4, is characterized in that: when in described tablet, amlodipine specification is 5mg, and described coating weight gain scope is 4.77%; When in described tablet, amlodipine specification is 10mg, described coating weight gain scope is 9.54%.
6. preparation method according to claim 3, it is characterized in that: described film-coating material is for comprising hydroxypropyl emthylcellulose or hydroxypropyl cellulose or polyphenyl dioctyl phthalate vinylacetate, and the polymer coating material of Polyethylene Glycol, Pulvis Talci, titanium dioxide and pigment.
7. preparation method according to claim 6, is characterized in that: described film-coating material is OPADRYY-1-7000.
8. preparation method according to claim 3, is characterized in that: described pharmaceutical excipient is selected from one or more in filler, disintegrating agent, lubricant.
9. preparation method according to claim 8, is characterized in that: described filler is selected from one or more in microcrystalline Cellulose, lactose, pregelatinized Starch; Described disintegrating agent is selected from one or more in polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium; Described lubricant be selected from magnesium stearate, hard fumaric acid sodium, Pulvis Talci or hydrogenated vegetable oil one or more.
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| CN103134885A (en) * | 2011-12-01 | 2013-06-05 | 石药集团中奇制药技术（石家庄）有限公司 | Detection method of dissolution rates of amlodipine, valsartan and hydrochlorothiazide compound preparation |
| 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 |
| CN104771379B (en) * | 2014-01-09 | 2019-02-19 | 山东新时代药业有限公司 | A kind of Minodronic acid tablets and preparation method thereof |
| CN110286185A (en) * | 2018-06-11 | 2019-09-27 | 南京济群医药科技股份有限公司 | A kind of Phenylsulfonic acid amido chloro diping dispersion tablet dissolution curve measuring method |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101249083A (en) * | 2008-03-21 | 2008-08-27 | 北京润德康医药技术有限公司 | Compound extended release formulation containing amlodipine and metoprolol and preparation |
| CN101478956A (en) * | 2006-06-27 | 2009-07-08 | 诺瓦提斯公司 | Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same |
| CN101874802A (en) * | 2009-04-30 | 2010-11-03 | 成都自豪药业有限公司 | Slow-release medicinal composition for treating hypertension and high cholesterol |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101478956A (en) * | 2006-06-27 | 2009-07-08 | 诺瓦提斯公司 | Solid dosage forms of valsartan, amlodipine and hydrochlorothiazide and method of making the same |
| CN101249083A (en) * | 2008-03-21 | 2008-08-27 | 北京润德康医药技术有限公司 | Compound extended release formulation containing amlodipine and metoprolol and preparation |
| CN101874802A (en) * | 2009-04-30 | 2010-11-03 | 成都自豪药业有限公司 | Slow-release medicinal composition for treating hypertension and high cholesterol |
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