CN1732952A - Compound dispersible tablet for treating hypertension - Google Patents
Compound dispersible tablet for treating hypertension Download PDFInfo
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- CN1732952A CN1732952A CN 200510097975 CN200510097975A CN1732952A CN 1732952 A CN1732952 A CN 1732952A CN 200510097975 CN200510097975 CN 200510097975 CN 200510097975 A CN200510097975 A CN 200510097975A CN 1732952 A CN1732952 A CN 1732952A
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- hydrochlorothiazide
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Abstract
The invention relates to a medicinal oral preparation containing Valsartan and Hydrochlorothiazide, more specifically the dispersible tablets for enhancing the beneficial effects of Valsartan and Hydrochlorothiazide.
Description
Technical field
The present invention relates to comprise the drug oral preparation of valsartan and hydrochlorothiazide, specifically relate to strengthen the tablet formulation of valsartan and hydrochlorothiazide beneficial effect.
Background technology
Valsartan is Angiotensin II (Angiotensin II) acceptor inhibitor, can suppress Ang I and be converted into Ang II, enzyme 1 receptor (AT1) of the nervous element conversion of antagonizing vessel specifically, to the antagonism of AT1 doubly greater than AT28500, by optionally blocking combining of Ang II and AT1 receptor, suppress the release of vasoconstriction and aldosterone, produce hypotensive effect.(hydrochlorothiazide is a kind of traditional antihypertensive drug HCTZ) to hydrochlorothiazide, imitates diuretic in belonging to.Act on distal renal tubular, activate renin-angiotensin system (RAS).The two use in conjunction can make blood pressure obtain more efficiently control; With respect to single preparations of ephedrine, the dose of every kind of medicine reduces, and the incidence rate of adverse effect also reduces accordingly, and simultaneously, valsartan can suppress owing to taking patient's blood potassium reduction that hydrochlorothiazide causes; And patient takes more conveniently, improves patient's compliance.So valsartan and hydrochlorothiazide compound preparation, because long action time, many advantages such as curative effect is good, and side effect is little become the first-selected medication of hyperpietic day by day.Oral and be its first-selected route of administration through gastrointestinal absorption, peroral dosage forms such as existing at present tablet, capsule.
Behind oral valsartan and the hydrochlorothiazide, blood drug level peaking about 2-4 hour, this mainly is because the inherent character of above-mentioned two kinds of principal agent compositions self determines.Those skilled in the art know, and solid preparation need experience the process of disintegrate, stripping, absorption, and performance is very disadvantageous for effectiveness of insoluble drug for this, thus ordinary preparation this be difficult to satisfy the hyperpietic to the urgent needs of relief of symptoms as early as possible.Therefore, develop valsartan and the hydrochlorothiazide oral formulations that to bring into play therapeutical effect, suitable more extensive crowd's use fast and become the technical problem that those skilled in the art face.
Therefore, those skilled in the art are readily appreciated that, also wish to develop the compound quick-acting preparation of valsartan and hydrochlorothiazide urgently, and it is the beneficial effect of onset and enhanced activity composition rapidly, and can be easily, without any administration with not accommodating any misgivings.Adopt mobile powerful adjuvant to carry out the technology of dry powder direct tabletting or employing dry granulation, though can directly realize preparation, but production cost is raise, this on the other hand technology is not general with respect to wet granulation technique, is unfavorable for generally using in wider scope.
Seemingly a kind of technical scheme that addresses the above problem of tablet formulation.Yet up to now, nobody provides the foundation of science to the development of valsartan and hydrochlorothiazide dosage form.
Summary of the invention
The object of the invention has provided a kind of dispersible tablet, comprises that the valsartan for the treatment of effective dose and hydrochlorothiazide are as active component.
As mentioned above, valsartan and hydrochlorothiazide all belong to insoluble drug.Therefore, at first will provide the compositions that is suitable for preparing dispersible tablet, said composition should be stable and not reduce the bioavailability of active component, even improve the bioavailability of active component significantly.
In pilot test, the inventor makes the dispersible tablet of valsartan and hydrochlorothiazide by the normal preparation dispersible tablet prescription that adopts of those skilled in the art, find under study for action: adopt the most frequently used lactose to be unfavorable for improving stability of formulation, on the one hand, be in a kind of labile state owing to the water of crystallization that contains in the lactose makes the principal agent composition, and easily in the preparation put procedure moisture absorption further disturb stability of formulation; On the other hand, the moisture absorption can influence preparation outward appearance, cause effective ingredient migration, though can be improved, under the situation of environmental abnormality, still be difficult to guarantee the quality of the pharmaceutical preparations, and can cause the increase of pharmaceutical production cost by strengthening packing.Nor be beneficial to the hyperpietic's who suffers from diabetes use; Short disintegrating agent-polyvinylpyrrolidone that another is commonly used also should not use in the present invention, can cause the dissolution of the long-term test specimen of placing to descend.
We have carried out deep research to the physicochemical property of valsartan and hydrochlorothiazide, particularly by screening, prescription and long-term investigation to adjuvant, address the above problem effectively, and the present invention has promptly been finished in further research on this basis.Compare with existing oral solid formulation, the quality of the pharmaceutical preparations of the present invention is stablized the rapid peaking of oral back blood drug level, and relative bioavailability significantly improves, and this effect is that those skilled in the art are unpredictable.
Valsartan and hydrochlorothiazide are all insoluble in water, adopt its dissolution of adjuvant of general aspects generally on the low side, and perhaps dissolution decline appears in the prolongation along with standing time.Its hydrophobicity should be emphasized to improve on the one hand, the hydrophilicity condiment that helps improving valsartan and hydrochlorothiazide stripping need be added on the other hand.Described adjuvant is selected from: mannitol, microcrystalline Cellulose, hyprolose, hydroxypropyl emthylcellulose, various anhydrous calcium salts.Preferably: mannitol, microcrystalline Cellulose, calcium sulfate, calcium phosphate dibasic anhydrous.
Cause the preparation disintegration time long at conventional tablet and the employed adjuvant of capsule, select compound disintegrating agent on the one hand, take the inside and outside method that adds to be improved on the other hand.Described disintegrating agent comprises disintegrating agent and short disintegrating agent, and wherein disintegrating agent is selected from: carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose; Short disintegrating agent is selected from: a kind of in sodium lauryl sulphate, dodecyl sodium sulfate, the tween 80 or their mixing.Preferred tween 80, sodium lauryl sulphate.
At valsartan and all relatively more sticking characteristic of hydrochlorothiazide, the inventor has strengthened the screening operation of wetting agent.Result of the test shows: the selection of wetting agent should be improved under the condition that a large amount of ethanol exist, and meets water viscosity and can't granulate too by force to prevent valsartan and hydrochlorothiazide, perhaps prolongs disintegration time; In ethanol, add simultaneously material,, can improve the uniformity of preparation under dispersity simultaneously to such an extent as to not only can avoid the soft tabletting that is difficult to of granule that uses ethanol to cause in a large number as cellulose family.
By our the surprised discovery of a large amount of screening tests: micropowder silica gel and talcous compositions are satisfactory for result as lubricant.Not only guarantee quick disintegrate, and very helpful to improving dissolution.
To further make non restrictive description below to the present invention.
Active component
By valsartan and hydrochlorothiazide weight, every contains valsartan 10～500mg, preferred 40-320mg, more preferably 80-160mg; Every contains hydrochlorothiazide 5～50mg, preferred 10～25mg.For the more effective dissolution rate that improves preparation that reaches, more advantageously active component is carried out pretreatment, it is crushed to more than 100 orders, more than preferred 120 orders, even micronization.
Filler
If active component (valsartan and hydrochlorothiazide weight sum) is by 1 part of calculating, then
Filler is 0.05～10 part, and is preferred: 0.1～5 part, and more preferably 0.2～3 part.Be selected from: mannitol, microcrystalline Cellulose, hyprolose, various anhydrous calcium salt.Preferably: mannitol, microcrystalline Cellulose, calcium sulfate, calcium phosphate dibasic anhydrous.
Disintegrating agent: comprise disintegrating agent and short disintegrating agent
Disintegrating agent is 0.01～1 part, and is preferred: 0.03～0.5 part, and more preferably 0.05～0.3 part.Be selected from: carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose.
Short disintegrating agent is 0.001～0.5 part, and is preferred: 0.01～0.3 part, and more preferably 0.02～0.2 part.Be selected from: a kind of in sodium lauryl sulphate, dodecyl sodium sulfate, the Tween 80 or their mixing.Preferred tween 80, sodium lauryl sulphate.
Lubricant is 0.001～0.5 part, 0.01～0.3 part, and more preferably 0.02～0.2 part.Be selected from: micropowder silica gel and Pulvis Talci.
We are surprised to find, and add above-mentioned adjuvant when preparation dispersible tablet of the present invention, not only make this dispersible tablet stable, but also disintegrate are rapid, and are rapid-action.Result of the test shows, the unfavorable phenomenon of degradation under prolonged disintegration, the stripping do not occur after the long-term placement of described dispersible tablet, and this is to keeping bioavailability of medicament very favourable.Can think that thus preparation of the present invention also has stable, the advantage that significantly improves of peaking and bioavailability rapidly of active component except the characteristics that have dispersible tablet formulation itself and had.
Other adjuvants
Advantageously, for making the more stable and each side of dispersible tablet sensation better, the present invention also can choose further adding correctives, for example aspartame, steviosin, protein sugar etc. wantonly.
Thus, the invention provides a kind of dispersible tablet that contains valsartan and hydrochlorothiazide, comprising:
A. by valsartan and hydrochlorothiazide weight, every contains valsartan 50～500mg, preferred 80-160mg; Every contains hydrochlorothiazide 5～50mg, preferred 10～25mg.
B. by 1 part, then adjuvant content is 0.05～15 part as if active component (valsartan and hydrochlorothiazide weight sum).Preferred 0.2～7 part, more excellent 0.3～4 part.
Above-mentioned adjuvant comprises filler, disintegrating agent, short disintegrating agent, lubricant, wetting agent.
The present invention does not make specific limited to the preparation method of dispersible tablet, can adopt this area conventional method, for example wet granulation.Described dispersible tablet face shaping is not made specific limited, can be existing arbitrary shape.
Following examples are intended to further specify the present invention, scope of the present invention are not limited.Those skilled in the art can not depart from the improvement and the variation of category of the present invention and spirit to embodiment disclosed herein.
Specific embodiments
Embodiment 1: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 320mg
Hydrochlorothiazide 12.5mg
Microcrystalline Cellulose 150mg
Mannitol 100mg
Carboxymethyl starch sodium 40mg
Low-substituted hydroxypropyl cellulose 10mg
Micropowder silica gel 10mg
Pulvis Talci 5mg
Steviosin 5mg
90% alcoholic solution of 3% hypromellose is an amount of
Sheet heavily amounts to 652.5mg
Technology:
Get valsartan and hydrochlorothiazide raw material, pulverize, behind 200 mesh sieves, standby excessively.
Press recipe quantity, take by weighing valsartan and hydrochlorothiazide, microcrystalline Cellulose, mannitol, steviosin and carboxymethylstach sodium and cross 100 mesh sieve mix homogeneously, pour binding agent system soft material into, cross 40 mesh sieves and granulate 55 ℃ of dryings, 40 order granulate, adding is through low-substituted hydroxypropyl cellulose, micropowder silica gel, the Pulvis Talci of 100 mesh sieves, mix homogeneously detects, and adjustment sheet is heavy, tabletting, check, packing, promptly.
Embodiment 2: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 80mg
Hydrochlorothiazide 25mg
Calcium sulfate 50mg
Microcrystalline Cellulose 100mg
Low-substituted hydroxypropyl cellulose 30mg
Micropowder silica gel 5mg
Pulvis Talci 5mg
Aspartame 5mg
75% alcoholic solution of 2% hypromellose is an amount of
Sheet heavily amounts to 300mg
Technology:
Press recipe quantity, take by weighing the low-substituted hydroxypropyl cellulose of valsartan and hydrochlorothiazide, calcium sulfate, microcrystalline Cellulose, aspartame and recipe quantity 3/4, cross 100 mesh sieve mix homogeneously, the binding agent system of pouring into soft material is crossed 20 mesh sieves and is granulated 50 ℃ of dryings, 20 order granulate add micropowder silica gel, Pulvis Talci and residue low-substituted hydroxypropyl cellulose through 100 mesh sieves, mix homogeneously, detect, adjustment sheet is heavy, tabletting, check, packing, promptly.
Embodiment 3: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 320mg
Hydrochlorothiazide 25mg
Mannitol 75mg
Calcium sulfate 75mg
Carboxymethylstach sodium 50mg
Low-substituted hydroxypropyl cellulose 10mg
Sodium lauryl sulphate 15mg
Micropowder silica gel 10mg
Pulvis Talci 10mg
Protein sugar 20mg
95% alcoholic solution of 5% hypromellose is an amount of
Sheet heavily amounts to 610mg
Technology:
Get valsartan and hydrochlorothiazide raw material, pulverize, behind 180 mesh sieves, standby excessively.
Press recipe quantity, take by weighing valsartan and hydrochlorothiazide, mannitol, calcium sulfate, carboxymethylstach sodium, sodium lauryl sulphate, protein sugar, cross 100 mesh sieve mix homogeneously, the binding agent system of pouring into soft material is crossed 18 mesh sieves and is granulated 60 ℃ of dryings, 20 order granulate add micropowder silica gel, Pulvis Talci and low-substituted hydroxypropyl cellulose through 100 mesh sieves, mix homogeneously, detect, adjustment sheet is heavy, tabletting, check, packing, promptly.
Embodiment 4: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 80mg
Hydrochlorothiazide 12.5mg
Calcium phosphate dibasic anhydrous 150mg
Microcrystalline Cellulose 200mg
Carboxymethylstach sodium 50mg
Micropowder silica gel 5mg
Pulvis Talci 5mg
Steviosin 3mg
70% alcoholic solution of 1% hypromellose is an amount of
Sheet heavily amounts to 505.5mg
Technology:
Press recipe quantity, take by weighing valsartan and hydrochlorothiazide, calcium phosphate dibasic anhydrous, microcrystalline Cellulose, 3/4 carboxymethylstach sodium, micropowder silica gel, steviosin, cross 100 mesh sieve mix homogeneously, the binding agent system of pouring into soft material is crossed 24 mesh sieves, 55 ℃ of dryings, 24 order granulate add Pulvis Talci and remaining carboxymethylstach sodium, mix homogeneously, detect, adjustment sheet is heavy, tabletting, check, packing, promptly.
Embodiment 5: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 160mg
Hydrochlorothiazide 12.5mg
Calcium phosphate dibasic anhydrous 50mg
Mannitol 100mg
Low-substituted hydroxypropyl cellulose 20mg
Tween 80 3mg
Micropowder silica gel 5mg
Pulvis Talci 2mg
Aspartame 3mg
75% alcoholic solution of 3% hypromellose is an amount of
Sheet heavily amounts to 355.5mg
Technology:
Get valsartan and hydrochlorothiazide raw material, pulverize, behind 120 mesh sieves, standby excessively.
Press recipe quantity, take by weighing valsartan and hydrochlorothiazide, calcium phosphate dibasic anhydrous, 3/4 low-substituted hydroxypropyl cellulose, mannitol, micropowder silica gel, aspartame, cross 100 mesh sieve mix homogeneously, pour binding agent and tween 80 system soft material into, cross 40 mesh sieves, 55 ℃ of dryings, 40 order granulate add Pulvis Talci and remaining low-substituted hydroxypropyl cellulose, mix homogeneously, detect, adjustment sheet is heavy, tabletting, check, packing, promptly.
Embodiment 6: prescription (calculating with monolithic)
Constituent content (mg/ sheet)
Valsartan 160mg
Hydrochlorothiazide 25mg
Microcrystalline Cellulose 120mg
Mannitol 100mg
Carboxymethylstach sodium 40mg
Sodium lauryl sulphate 5mg
Micropowder silica gel 5mg
Pulvis Talci 2mg
Steviosin 5mg
90% alcoholic solution of 2% hypromellose is an amount of
Sheet heavily amounts to 462mg
Technology:
Get valsartan and hydrochlorothiazide raw material, pulverize, behind 140 mesh sieves, standby excessively.
Press recipe quantity, take by weighing valsartan and hydrochlorothiazide, microcrystalline Cellulose, mannitol, 3/4 carboxymethylstach sodium, sodium lauryl sulphate, steviosin, cross 100 mesh sieve mix homogeneously, the binding agent system of pouring into soft material is crossed 40 mesh sieves, 55 ℃ of dryings, 40 order granulate add micropowder silica gel, Pulvis Talci and remaining carboxymethylstach sodium, mix homogeneously, detect, adjustment sheet is heavy, tabletting, check, packing, promptly.
Comparative test 1: dissolution in vitro experiment
Chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler; Transferring PH=2.5 with water-acetonitrile (1: 1) with phosphoric acid is mobile phase; Detect wavelength 272nm; Flow velocity is 0.8mL/min; Number of theoretical plate calculates by the valsartan peak should be not less than 1500
Dissolution determination method: get each test specimen, according to dissolution method (two appendix XC first methods of Chinese Pharmacopoeia version in 2000), 900mL is a solvent with pH6.8 phosphate buffer (get 6.8g potassium dihydrogen phosphate and 0.9g sodium hydroxide, add water 1000mL, shake up), rotating speed is that per minute 100 changes, operation in the time of 15 minutes, is got solution 5mL in accordance with the law, filter, get subsequent filtrate and make need testing solution; In addition precision takes by weighing valsartan respectively, the hydrochlorothiazide reference substance is an amount of, makes the valsartan that contains 80 μ g/mL approximately and the hydrochlorothiazide reference substance solution of 12.5 μ g/mL.According to above-mentioned chromatographic condition, sample introduction, record chromatogram; Go out every stripping quantity with calculated by peak area by external standard method.
Testing result such as following table
| Sample | Dissolution accounts for the % of labelled amount | |||||
| 5 minutes | 15 minutes | 30 minutes | ||||
| Valsartan | Hydrochlorothiazide | Valsartan | Hydrochlorothiazide | Valsartan | Hydrochlorothiazide | |
| Embodiment 4 | 71.6％ | 82.8％ | 98.6％ | 98.7％ | 98.7％ | 99.7％ |
| Embodiment 5 | 74.7％ | 85.8％ | 95.3％ | 97.5％ | 99.5％ | 101.4％ |
| Commercially available valsartan and hydrochlorothiazide ordinary tablet | 46.0％ | 49.6％ | 84.3％ | 89.7％ | 97.3％ | 98.8％ |
The dispersible tablet test specimen of different prescriptions, stripping quantity has reached more than 80% of labelled amount in the time of 5 minutes, and stripping quantity is near more than 100% of labelled amount in the time of 15 minutes; And the stripping in 5 minutes of valsartan and hydrochlorothiazide ordinary tablet when just just having reached 50%, 30 minute stripping just near fully, the two significant difference.
Comparative test 2 bioavailability
With rp-hplc valsartan and hydrochlorothiazide blood drug level, calculate relevant pharmacokinetic parameter with 3P87 pharmacokinetics program, its main pharmacokinetic parameter is through three-factor analysis of variance, intersect oral valsartan and hydrochlorothiazide (valsartan 80mg and hydrochlorothiazide 12.5mg) at random, the valsartan and Hydrochlorothiade ordinary tablet of selecting respectively to sell on example 4 samples and the market is tested, and the relative bioavailability of the two is estimated.The result shows, preparation of the present invention significantly improves in the body and absorbs, and significantly improves bioavailability, significantly is better than existing conventional tablet.
Table 1: comparative test result
| Project | Marketed tablet | The prescription of embodiment 4 | ||
| Valsartan | Hydrochlorothiazide | Valsartan | Hydrochlorothiazide | |
| Drug content | 80mg | 12.5mg | 80mg | 12.5mg |
| External disintegration time | 15.5 minute | 1 minute | ||
| 5 minutes dissolution in vitro | 46.0％ | 49.6％ | 71.6％ | 82.8％ |
| 30 minutes dissolution in vitro | 97.3％ | 98.8％ | 98.7％ | 99.7％ |
| The peak time of bioavailability test in the body | 3.25± 1.07hr | 2.77± 1.68hr | 2.37± 0.92hr | 2.21± 1.06hr |
| Relative bioavailability | -- | -- | 117.3± 18.7％ | 120.4± 11.79％ |
Claims (3)
1. the dispersible tablet of valsartan and hydrochlorothiazide wherein contains valsartan, hydrochlorothiazide and the pharmaceutic adjuvant for the treatment of effective dose
A. by valsartan and hydrochlorothiazide, every contains valsartan 10～500mg, preferred 40-320mg, more preferably 80-160mg; Every contains hydrochlorothiazide 5～50mg, preferred 10～25mg.
B. pharmaceutic adjuvant comprises filler, disintegrating agent, short disintegrating agent, lubricant.
Filler is selected from: mannitol, microcrystalline Cellulose, hyprolose, various anhydrous calcium salt.Preferably: mannitol, microcrystalline Cellulose, calcium sulfate, calcium phosphate dibasic anhydrous.
Disintegrating agent is selected from: carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose.
Short disintegrating agent is selected from: a kind of in sodium lauryl sulphate, dodecyl sodium sulfate, the Tween 80 or their mixing.Preferred tween 80, sodium lauryl sulphate.
Lubricant is selected from: micropowder silica gel and Pulvis Talci.
2. the described dispersible tablet of claim 1, wherein active component (valsartan and hydrochlorothiazide weight sum) is by 1 part,
A. filler is 0.05～10 part, and is preferred: 0.1～5 part, and more preferably 0.2～3 part.
B. disintegrating agent is 0.01～1 part, and is preferred: 0.03～0.5 part, and more preferably 0.05～0.3 part.
C. short disintegrating agent is 0.001～0.5 part, and is preferred: 0.01～0.3 part, and more preferably 0.02～0.2 part.
D. lubricant is 0.001～0.5 part, 0.01～0.3 part, and more preferably 0.02～0.2 part.
3. according to the dispersible tablet of claim 1, wherein contain valsartan 80-160mg, hydrochlorothiazide 12.5～25mg in every.
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| CN 200510097975 CN1732952B (en) | 2005-09-02 | 2005-09-02 | Compound dispersible tablet for treating hypertension |
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| CN 200510097975 CN1732952B (en) | 2005-09-02 | 2005-09-02 | Compound dispersible tablet for treating hypertension |
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| CN1732952B CN1732952B (en) | 2010-04-07 |
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| CN101972263A (en) * | 2010-09-13 | 2011-02-16 | 海南美兰史克制药有限公司 | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| CN102631357A (en) * | 2012-04-13 | 2012-08-15 | 重庆康刻尔制药有限公司 | Composite tablet of valsartan and hydrochlorothiazide and preparation method thereof |
| WO2013098576A1 (en) * | 2011-12-31 | 2013-07-04 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Immediate release pharmaceutical composition of valsartan |
| WO2013098578A1 (en) * | 2011-12-31 | 2013-07-04 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Immediate release pharmaceutical composition of valsartan hydrochlorothiazide |
| CN103191125A (en) * | 2013-04-19 | 2013-07-10 | 南京正宽医药科技有限公司 | Valsartan and hydrochlorothiazid tablet and preparation method thereof |
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| CN104274468A (en) * | 2014-10-11 | 2015-01-14 | 江西施美制药有限公司 | Valsartan/hydrochlorothiazide pharmaceutical composition and preparation method thereof |
| CN106619618A (en) * | 2016-12-28 | 2017-05-10 | 华润赛科药业有限责任公司 | Valsartan medicinal composition and preparation method thereof |
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| CN101972263A (en) * | 2010-09-13 | 2011-02-16 | 海南美兰史克制药有限公司 | Valsartan hydrochlorothiazide pharmaceutical composition liposome solid preparation |
| WO2013098576A1 (en) * | 2011-12-31 | 2013-07-04 | Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi | Immediate release pharmaceutical composition of valsartan |
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| WO2023128902A1 (en) * | 2021-12-30 | 2023-07-06 | Pharmactive Ilac Sanayi Ve Ticaret A.S. | Pharmaceutical compositions comprising bosentan and relevant excipients |
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| CN1732952B (en) | 2010-04-07 |
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Assignee: Hainan Aomei Pharmaceutical Co. Ltd. Assignor: Yao Junhua Contract record no.: 2011320000887 Denomination of invention: Compound dispersible tablet for treating hypertension Granted publication date: 20100407 License type: Exclusive License Open date: 20060215 Record date: 20110624 |
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Owner name: JIANGSU VANGUARD PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: YAO JUNHUA Effective date: 20120307 |
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Address after: 226100 Jiangsu Province Haimen Economic Development Zone Dinghai Road No. 688 Patentee after: Jiangsu Wangao Pharmaceutical Co., Ltd. Address before: 226100 Jiangsu Province Haimen Economic Development Zone Dinghai Road No. 688 Patentee before: Jiaosu Wangao Pharmaceutical Co., Ltd. |