CN102846625A - Stable valsartan, amlodipine and hydrochlorothiazide pharmaceutical composition and preparation method thereof - Google Patents
Stable valsartan, amlodipine and hydrochlorothiazide pharmaceutical composition and preparation method thereof Download PDFInfo
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- CN102846625A CN102846625A CN2012103969535A CN201210396953A CN102846625A CN 102846625 A CN102846625 A CN 102846625A CN 2012103969535 A CN2012103969535 A CN 2012103969535A CN 201210396953 A CN201210396953 A CN 201210396953A CN 102846625 A CN102846625 A CN 102846625A
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- amlodipine
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Abstract
The invention discloses a stable valsartan, amlodipine and hydrochlorothiazide pharmaceutical composition. The composition contains valsartan, amlodipine, hydrochlorothiazide and other pharmaceutical auxiliary materials; as wet granulation is used in a preparation process, the problems of small valsartan bulk density, poor flowability, and strong moisture absorption and sticking of valsartan are solved, the particle moisture is strictly controlled in the particle preparation process, and the stability of the stable valsartan, amlodipine and hydrochlorothiazide pharmaceutical composition is guaranteed. The preparation process is simple, and industrial production can be easily realized.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of stable the oral drugs combination and the preparation method that contain valsartan, amlodipine and hydrochlorothiazide.
Background technology
Hypertension agents is one of common disease, and clinical practice for many years proves, 50% hyperpietic needs drug combination, uses compound preparation also to belong to the drug combination category.Multi-medicament associating operational version is all recommended in antihypertensive therapy aspect, various places medicine guide, adopts the compound preparation treatment, and compliance is improved, and curative effect obviously is better than single preparations of ephedrine.
Valsartan is angiotensin (AT) II receptor antagonist, and its chemical name is N-valeryl-N-{[2 '-(1H-tetrazole-5-yl) [1,1 '-biphenyl]-4-yl] methyl }-Valine, molecular formula: C
24H
29N
5NaO
3, molecular weight: 435.52, structural formula is:
Amlodipine is calcium ion antagonist, its chemical name is 3-ethyl-5-methyl-2-(2-ammonia ethoxymethyl)-4-(2-chlorphenyl)-1,4-dihydro-6-methyl-3,5-pyridine dicarboxylate benzene sulfonate, amlodipine commonly used are benzene sulfonate, mesylate and maleate.Molecular formula: C
20H
25ClN
2O
5C
6H
6O
3S, molecular weight: 567.1,
Structural formula is:
[0007] hydrochlorothiazide is diuretic, and its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide, molecular formula: C
7H
8ClN
3O
4S
2, molecular weight: 297.74, structural formula is:
CN101478956A discloses solid preparation and the preparation method of valsartan, amlodipine and three kinds of active ingredients of hydrochlorothiazide, its preparation technology adopts active ingredient to mix with pharmaceutic adjuvant to carry out roll-in to granulate, can be made into single-layer sheet or double-layer tablet, contain in the patent of the disclosure and draw in a large number moist strong disintegrating agent polyvinylpolypyrrolidone, its consumption reach 13.5% very easily draw wet, and the valsartan powder self has hygroscopicity, can cause tablet moisture absorption in producing and preserving, thereby affect the stripping behavior of tablet even cause the active ingredient degraded.
CN102526748A discloses the oral tablet that contains valsartan, hydrochlorothiazide and Amlodipine Besylate Tablet, this patent system is for dry granulation is just arranged, with valsartan, hydrochlorothiazide and Amlodipine Besylate Tablet with carry out dry granulation after pharmaceutic adjuvant mixes, then be pressed into single-layer sheet.
The valsartan bulk density is little, and poor fluidity can't adopt the preparation of direct compression technique, and above-mentioned patent all adopts the roll-in dry granulation, then carries out tabletting, the preparation method of not mentioned wet granulation.
Summary of the invention
Goal of the invention
The invention provides and overcome the prior art defective, a kind of stable combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide is provided.
Technical scheme
A kind of compound preparation of valsartan, contain following composition:
| Numbering | Component | Ratio |
| 1 | Valsartan | 20%～55% |
| 2 | Amlodipine | 0.3%～4% |
| 3 | Hydrochlorothiazide | 1%～8% |
| 4 | Filler | 15%～50% |
| 5 | Binding agent | 0.5%～5% |
| 6 | Disintegrating agent | 3%～10% |
| 7 | Fluidizer | 0.5%～3% |
| 8 | Lubricant | 0.5%～3% |
Wherein:
The amlodipine of one of active ingredient can be the raceme of Amlodipine Besylate Tablet or amlodipine maleate or Amlodipine mesylate, preferred Amlodipine Besylate Tablet.
The amlodipine of one of active ingredient can be Levamlodipine besylate or maleic acid levo amido chloro diping or methanesulfonic acid Levamlodipine, preferred Levamlodipine besylate.
Filler is microcrystalline Cellulose, and it is 15%～50% that the microcrystalline Cellulose consumption accounts for sheet anharmonic ratio example.
Binding agent is selected from hyprolose, polyvidone, and preferred hyprolose, it is 0.5%～5% that its consumption accounts for sheet anharmonic ratio example.
Disintegrating agent is selected from polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose sodium, and preferred polyvinylpolypyrrolidone, it is 3%～10% that its consumption accounts for sheet anharmonic ratio example.
Fluidizer is silicon dioxide, and it is 0.5%～3% that its consumption accounts for sheet anharmonic ratio example.
Lubricant is magnesium stearate, and it is 0.5%～3% that its consumption accounts for sheet anharmonic ratio example.
The invention also discloses a kind of stable preparation method that contains valsartan, amlodipine, hydrochlorothiazide pharmaceutical composition, specifically may further comprise the steps:
(1) with valsartan, microcrystalline Cellulose, disintegrating agent and binding agent mix homogeneously, add water and stir moistening and cross 20 orders～30 mesh sieves and make granule, with 60 ℃ of dryings of wet granular, dried granule control moisture should be not more than 2%.
(2) with amlodipine, hydrochlorothiazide, disintegrating agent, fluidizer, mix lubricant.
(3) with (1) and (2) mix homogeneously, hybrid particles is pressed into the monolayer tablet or filling is made capsule in the stomach dissolution type capsule.
Beneficial effect
The present invention adopts valsartan and pharmaceutic adjuvant wet granulation technology, not only improve molding and the flowability of valsartan, because the binding agent hyprolose has filming function, formed thin film at the valsartan particle surface, valsartan is drawn moistly obviously weaken, more be conducive to tabletting.The granule preparation process, the dried granule of strict control valsartan moisture to guarantee the quality of product, at last the dried granule of valsartan is mixed with amlodipine, hydrochlorothiazide and other pharmaceutic adjuvants, tabletting makes the monolayer tablet or filling makes capsule in Capsules.
The present invention finds, on the basis of the dried granule of strict control, first valsartan and pharmaceutic adjuvant are mixed, method with wet granulation prepares dried granule, improved the flowability of valsartan, and then add other active ingredient and pharmaceutic adjuvant, avoided amlodipine, the unstability of hydrochlorothiazide under wet heat condition.By adjusting the consumption of disintegrating agent and microcrystalline Cellulose, can guarantee the quick disintegrate of tablet, promote the stripping of active ingredient.
The present invention also finds, the valsartan powder has obvious hygroscopicity, and the binding agent hyprolose film property of selecting is good, wet-granulation process valsartan powder surface is wrapped the hyprolose film-coat, obviously reduced the hygroscopicity of valsartan, make the tabletting process can sticking, in addition, the product storage more be difficult for moisture absorption and causes product quality to descend.
The specific embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail, embodiment only is used for explanation the present invention, and should not be considered as limiting the scope of the invention.Those skilled in the art can carry out corresponding conversion to the present invention according to the prior art of the art and the knowledge of this area understanding under the prerequisite of the present invention, and these technical schemes all fall within the scope of the present invention.Used active ingredient and pharmaceutic adjuvant in the following example are the domestic legal crude drug that authentication code is arranged and pharmaceutic adjuvant.
Embodiment 1
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 6.94* | 1.93% |
| 3 | Hydrochlorothiazide | 12.50 | 3.47% |
| 4 | Microcrystalline Cellulose | 144.56 | 40.16% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone | 21.60 | 6.00% |
| 7 | Silicon dioxide | 3.60 | 1.00% |
| 8 | Magnesium stearate | 3.60 | 1.00% |
| Summation | 360.00 | 100% |
Wherein, the 6.94g Amlodipine Besylate Tablet is equivalent to the 5mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add the suitable quantity of water stirring and lubricate, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate adds 2,3,7,8 materials, mix homogeneously, tabletting again.
Embodiment 2
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 53.33% |
| 2 | Levamlodipine besylate | 6.94* | 2.31% |
| 3 | Hydrochlorothiazide | 12.50 | 4.17% |
| 4 | Microcrystalline Cellulose | 144.56 | 40.16% |
| 5 | Hyprolose | 9.00 | 3.00% |
| 6 | Polyvinylpolypyrrolidone | 9.00 | 3.00% |
| 7 | Silicon dioxide | 1.50 | 0.50% |
| 8 | Magnesium stearate | 1.50 | 0.50% |
| Summation | 300.00 | 100% |
Wherein, the 6.94g Levamlodipine besylate is equivalent to 5mg Levamlodipine free alkali.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 20 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add 2,3,7,8 materials, mix homogeneously is filled in the stomach dissolution type Capsules and makes capsule again.
Embodiment 3
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 13.88* | 3.86% |
| 3 | Hydrochlorothiazide | 12.50 | 3.47% |
| 4 | Microcrystalline Cellulose | 125.02 | 34.72% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone (I) | 14.40 | 4.00% |
| 7 | Polyvinylpolypyrrolidone (II) | 14.40 | 4.00% |
| 8 | Silicon dioxide | 5.40 | 1.50% |
| 9 | Magnesium stearate | 7.20 | 2.00% |
| Summation | 360.00 | 100% |
Wherein, the 13.88g Amlodipine Besylate Tablet is equivalent to the 10mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add again 2,3,7,8,9 materials, mix homogeneously, tabletting.
Embodiment 4
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 6.94* | 1.93% |
| 3 | Hydrochlorothiazide | 25.00 | 6.94% |
| 4 | Microcrystalline Cellulose | 131.34 | 36.48% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone (I) | 10.80 | 3.00% |
| 7 | Polyvinylpolypyrrolidone (II) | 10.80 | 3.00% |
| 8 | Silicon dioxide | 3.60 | 1.50% |
| 9 | Magnesium stearate | 4.32 | 1.20% |
| Summation | 360.00 | 100% |
Wherein, the 6.94g Amlodipine Besylate Tablet is equivalent to the 5mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add again 2,3,7,8,9 materials, mix homogeneously, tabletting.
Embodiment 5
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 13.88* | 3.86% |
| 3 | Hydrochlorothiazide | 25.00 | 6.94% |
| 4 | Microcrystalline Cellulose | 110.72 | 30.76% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone (I) | 18.00 | 5.00% |
| 7 | Polyvinylpolypyrrolidone (II) | 14.40 | 4.00% |
| 8 | Silicon dioxide | 7.20 | 2.00% |
| 9 | Magnesium stearate | 3.60 | 1.00% |
| Summation | 360.00 | 100% |
Wherein, the 13.88g Amlodipine Besylate Tablet is equivalent to the 10mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add again 2,3,7,8,9 materials, mix homogeneously, tabletting.
Embodiment 6
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Levamlodipine besylate | 6.94* | 1.93% |
| 3 | Hydrochlorothiazide | 12.50 | 3.47% |
| 4 | Microcrystalline Cellulose | 133.76 | 37.16% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone (I) | 14.40 | 4.00% |
| 7 | Polyvinylpolypyrrolidone (II) | 14.40 | 4.00% |
| 8 | Silicon dioxide | 7.20 | 2.00% |
| 9 | Magnesium stearate | 3.60 | 1.00% |
| Summation | 360.00 | 100% |
Wherein, the 6.94g Levamlodipine besylate is equivalent to 5mg Levamlodipine free alkali.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add again 2,3,7,8,9 materials, mix homogeneously, tabletting.
Embodiment 7
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 6.94* | 1.93% |
| 3 | Hydrochlorothiazide | 25.00 | 6.94% |
| 4 | Microcrystalline Cellulose | 81.36 | 27.12% |
| 5 | Hyprolose | 7.20 | 2.00% |
| 6 | Polyvinylpolypyrrolidone | 15.00 | 5.00% |
| 7 | Silicon dioxide | 3.00 | 1.00% |
| 8 | Magnesium stearate | 1.50 | 0.50% |
| Summation | 300.00 | 100% |
Wherein, the 6.94g Amlodipine Besylate Tablet is equivalent to the 5mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 20 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add 2,3,7,8 materials, mix homogeneously is filled in the stomach dissolution type capsulae vacuus and makes capsule again.
Comparative Examples 1
| Numbering | Component | mg | Ratio |
| 1 | Valsartan | 160.00 | 44.44% |
| 2 | Amlodipine Besylate Tablet | 6.94* | 1.93% |
| 3 | Hydrochlorothiazide | 12.50 | 3.47% |
| 4 | Microcrystalline Cellulose | 130.16 | 36.16% |
| 5 | Hyprolose | 10.80 | 3.00% |
| 6 | Polyvinylpolypyrrolidone (I) | 14.40 | 4.00% |
| 7 | Polyvinylpolypyrrolidone (II) | 14.40 | 4.00% |
| 8 | Silicon dioxide | 7.20 | 2.00% |
| 9 | Magnesium stearate | 3.60 | 1.00% |
| Summation | 360.00 | 100% |
Wherein, the 6.94g Amlodipine Besylate Tablet is equivalent to the 5mg amlodipine free base.
Take by weighing above-mentioned supplementary material, with 1,2,3,4,5,6 mixing of materials, add suitable quantity of water and stir moistening, form the suitable soft material of viscosity, granulate with 24 mesh sieves, 60 ℃ of wet granulars are dried to moisture less than 2%, granulate, add again 7,8,9 materials, mix homogeneously, tabletting.
Test according to two appendix pharmaceutical preparation stability of Chinese Pharmacopoeia version in 2010 guideline, select the representative prescription, investigate character, the related substance situation of change of example 4 product under the tablet that the valsartan wet granulation is mixed with amlodipine, hydrochlorothiazide again, and example 8 contrast prescriptions are mixed together character, the related substance situation of change of product under the tablet that wet granulation makes at valsartan, amlodipine, hydrochlorothiazide.
Each preparation of making of prescription under 40 ℃ ± 2 ℃, RH75% ± 5% experimental condition, 0 month, January, February, March and June sample character, related substance situation of change.
The related substance high performance liquid chromatography
Chromatographic condition: octadecylsilane chemically bonded silica is filler (4.6 * 25cm, 5 μ m), mobile phase A: get triethylamine 10ml and add water to 1000ml, regulate pH value to 2.8 with phosphoric acid, Mobile phase B: methanol-acetonitrile (70:30), and according to the form below carries out gradient elution; The detection wavelength is 237nm; Column temperature is 30 ℃.
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 50 | 50 |
| 3 | 50 | 50 |
| 15 | 30 | 70 |
| 20 | 30 | 70 |
| 20.1 | 50 | 50 |
| 25 | 50 | 50 |
Get 20 of this product, get the fine powder an amount of (approximately being equivalent to 10) of porphyrize, accurately weighed, put in the 50ml measuring bottle, add 50ml water, ultrasonic 5 minutes, be cooled to room temperature, add mobile phase A-Mobile phase B (1:1) and dissolve and be diluted to scale, shake up, filter, subsequent filtrate is got this need testing solution 1ml as the need testing solution of amlodipine and hydrochlorothiazide, put in the 100ml measuring bottle, add mobile phase A-Mobile phase B (1:1) and be diluted to scale, shake up, solution 1 in contrast.
Other gets above-mentioned need testing solution 5ml, put in the 50ml measuring bottle, adding mobile phase A-Mobile phase B (1:1) dissolves and is diluted to scale, shake up, as the valsartan need testing solution, get this need testing solution 1ml, put in the 100ml measuring bottle, add mobile phase A-Mobile phase B (1:1) and be diluted to scale, shake up, solution 2 in contrast.
Precision measures above-mentioned need testing solution, contrast solution 1, contrast solution 2 each 10 μ l respectively, and the injection liquid chromatography records chromatogram to 2 times of main composition retention time respectively, and other single impurity must not be greater than 0.5 times of contrast solution main peak; The summation of each impurity peak area must not be greater than 2 times of contrast solution main peak area in the need testing solution chromatogram.
Product (embodiment 4) study on the stability result
| The investigation project | 0 month | January | February | March | June |
| Character | White tablets | White tablets | White tablets | White tablets | White tablets |
| Maximum single assorted (%) | 0.11 | 0.13 | 0.15 | 0.18 | 0.22 |
| Total impurities (%) | 0.35 | 0.41 | 0.47 | 0.53 | 0.81 |
Comparative Examples 1 study on the stability result
| The investigation project | 0 month | January | February | March | June |
| Character | White tablets | White tablets | White tablets | White tablets | White tablets |
| Maximum single assorted (%) | 0.37 | 0.44 | 0.50 | 0.57 | 0.64 |
| Total impurities (%) | 0.68 | 0.73 | 0.85 | 0.98 | 1.52 |
Embodiment 4 and Comparative Examples 1 are carried out dissolution relatively
Adopt 2010 editions dissolution determination methods of Chinese Pharmacopoeia, take the pH6.8 phosphate buffer as dissolution medium, 50 turn/min oar method, at 30min sampling and measuring dissolution.
Conclusion (of pressure testing):
In sum, valsartan of the present invention, amlodipine and hydrochlorothiazide pharmaceutical composition and preparation technology thereof can guarantee the stability of product.According to embodiment 4 and contrast 1 result of the test as can be known, the independent wet granulation of valsartan, then add the preparation technology of amlodipine and hydrochlorothiazide, the preparation technology who directly mixes wet granulation with three kinds of active ingredients compares, and the former related substance of product is less, all in controlled range, and the former active ingredient stripping is all high than the latter, when three kinds of active ingredients are mixed together granulation, easily produces interaction, thereby affect the stripping behavior of active ingredient, make stripping partially slow.Pharmaceutical composition of the present invention, preparation production technique is simple, is easy to realize suitability for industrialized production.
Claims (10)
1. a combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide is characterized in that it is made of following proportioning
。
2. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described amlodipine is the raceme of Amlodipine Besylate Tablet or amlodipine maleate or Amlodipine mesylate.
3. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 2 is characterized in that described amlodipine is the levo form of Amlodipine Besylate Tablet or amlodipine maleate or Amlodipine mesylate.
4. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described filler is microcrystalline Cellulose.
5. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described binding agent is selected from hyprolose, at least a in the polyvidone.
6. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described disintegrating agent is selected from polyvinylpolypyrrolidone, at least a in cross-linked carboxymethyl cellulose sodium.
7. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described fluidizer is silicon dioxide.
8. a kind of combination of oral medication that contains valsartan, amlodipine and hydrochlorothiazide according to claim 1 is characterized in that described lubricant is magnesium stearate.
9. each the peroral dosage form of pharmaceutical composition preparation of claim 1～9 comprises tablet, capsule.
10. the preparation method of valsartan according to claim 1, amlodipine, hydrochlorothiazide pharmaceutical composition specifically may further comprise the steps:
(1) with valsartan, microcrystalline Cellulose, disintegrating agent and binding agent mix homogeneously, add water and stir moistening and cross 20 orders～30 mesh sieves and make granule, with 60 ℃ of dryings of wet granular, dried granule control moisture should be not more than 2%;
(2) with hybrid particles, amlodipine, hydrochlorothiazide, disintegrating agent, fluidizer, the mix lubricant of step (1);
(3) hybrid particles of step (2) is pressed into the monolayer tablet or filling is made capsule in the stomach dissolution type Capsules.
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| CN103271926A (en) * | 2013-06-22 | 2013-09-04 | 昆明赛诺制药有限公司 | Compound combination containing left-handed amlodipine mesylate and used for curing hypertension |
| CN103285014A (en) * | 2013-06-22 | 2013-09-11 | 昆明赛诺制药有限公司 | Amlodipine mesylate-containing composition for high blood pressure treatment |
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| WO2019135691A1 (en) * | 2018-01-04 | 2019-07-11 | Jamjoom Pharmaceuticals Factory Company Limited | A stable mono-layer solid dosage form containing combination of two active ingredients |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
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| WO2019135691A1 (en) * | 2018-01-04 | 2019-07-11 | Jamjoom Pharmaceuticals Factory Company Limited | A stable mono-layer solid dosage form containing combination of two active ingredients |
| CN109260169A (en) * | 2018-10-30 | 2019-01-25 | 天津仁生医药科技有限公司 | A kind of valsartan amlodipine tablet and preparation method thereof |
| CN114814060A (en) * | 2021-01-28 | 2022-07-29 | 上海博志研新药物技术有限公司 | Detection method of valsartan amlodipine tablet related substances |
| CN114814060B (en) * | 2021-01-28 | 2024-05-10 | 上海博志研新药物研究有限公司 | Detection method of valsartan amlodipine tablet related substances |
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