CN102188385B - Sustained-release pellets containing nebivolol as active component and preparation method thereof - Google Patents
Sustained-release pellets containing nebivolol as active component and preparation method thereof Download PDFInfo
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- CN102188385B CN102188385B CN201010117316.0A CN201010117316A CN102188385B CN 102188385 B CN102188385 B CN 102188385B CN 201010117316 A CN201010117316 A CN 201010117316A CN 102188385 B CN102188385 B CN 102188385B
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Abstract
The invention discloses sustained-release pellets containing nebivolol and pharmaceutical salts thereof as active components, and a preparation method thereof. The nebivolol sustained-release pellets are composed of medicated pellets coated by sustained-release layers, wherein the weight ratio of the medicated pellets to the sustained-release layers is (0.3-30):(0.1-10). The preparation method comprises the steps of: coating nebivolol or pharmaceutical salts thereof on blank pellet cores to prepare the medicated pellets, spraying the outer layers of the medicated pellets by coating liquid containing a retardant, a plasticizer, a pore-foaming agent, an adhesion preventive or an opacifier in a fluidized bed or a coating pan, and encapsulating after drying to obtain sustained-release capsules. The nebivolol sustained-release capsules prepared by the invention enable the medicament to evenly release in a human body in 24 hours with time variation to achieve the effect of stably reducing blood pressure, simultaneously can increase the contact between the medicament and the gastrointestinal tract and improve the bioavailability, and are more suitable for daily application for patients with hypertension.
Description
Technical field
The invention belongs to medical slow releasing preparation field, particularly relate to slow-release micro-pill containing active component nebivolol and officinal salt thereof and preparation method thereof, mainly for the preparation of Hypertension day for human beings common medicine, realize the object of steady blood pressure lowering.
Background technology
Along with the arrival of aged tendency of population, Hypertension number has the trend that continues increase.China's prevalence is about 11.8% at present, and patient has reached people more than 100,000,000, is the most common cardiovascular disease.Hypertension has become China >=40 year old general mortality rate the first risk factor.Announce " Chinese cardiovascular diseases's report " end of the year 2006, China's hypertension awareness, treatment rate and control rate are respectively 30.6%, 24.7% and 6.1%.
Since half a century, beta-blocker has been widely used for Cardiovarscular, and its prevention for cardiovascular disease and cardiovascular protection have the effect of each side and clinical indication widely.In domestic more than 20 cardiovascular disease field authoritative experts write recently " beta-blocker is at the Consensus of experts of cardiovascular disease application ", point out, in the medicine of Cardiovarscular, beta-blocker is really very important.Designate General Board professor Hu great Yi of angiocardiology branch of Chinese Medical Association introduces, and " common recognition " pointed out, beta-blocker is of value to various types of patients with coronary heart disease; It is the first-line drug of hypertension treatment; It is the effective means for the treatment of chronic heart failure; Aspect arrhythmia, can reduce cardiovascular event, reduce general mortality rate.
First generation beta-blocker take propranolol as representative, to β
1, β
2receptor all has retardation, and untoward reaction is more, is especially not suitable for the treatment of patients with dilated cardiomyopathy.Second filial generation beta-blocker is take metoprolol and bisoprolol as representative, and selectively acting is in β
1receptor and to β
2receptor only has slight retardation, but its antihypertensive effect is not obvious, and untoward reaction is more.Third generation beta-blocker, take labetalol and carvedilol as representative, although have antioxidation, can effectively be removed oxygen-derived free radicals, reduces apoptosis of cardiac muscle, but nonselective, to β
2receptor and α receptor also have certain retarding effect, can cause that bronchial smooth muscle and vascular smooth muscle shrink.
Nebivolol is that a pair of enantiomer is 1: 1 equal amount of mixture of (S, R, R, R) and (R, S, S, S) configuration, contains the functional groups such as benzodihydropyran ring, amino, hydroxyl, and molecule has four chiral centres.Nebivolol is a kind of novel β
1receptor blocking agent, has unique mechanism of action: 1) high selectivity β
1receptor retardation, it blocks β
1the intensity of receptor is β
2290 times of receptor, and bisoprolol is 26 times, atenolol is 15 times, propranolol is 1.9 times; 2) regulate blood vessel endothelium to discharge nitric oxide, cause blood vessel physiological dilating effect, this is the remarkable advantage that nebivolol is different from other beta-blockers; 3) induction coronary artery endothelial dependency expansion, have protecting myocardial cell to avoid the effect of single electron oxygen injury, and desired concn is lower than other beta-blocker.Nebivolol enters in body, and 1.5～4h reaches peak concentration, and plasma protein binding rate is 98%.
Clinical research shows, nebivolol was treated after 6 weeks, with baseline value comparison, and experimenter's the systolic pressure 24 ± 14mmHg that on average declined, the diastolic pressure 13 ± 9mmHg that on average declined.Its antihypertensive effect is stronger than diuretic, similar to amlodipine effect; Identical with nifedipine hypotensive effect; Compared with angiotensin converting enzyme inhibitor, its hypotensive effect is identical with lisinopril, and stronger than enalapril.Result of study also shows that nebivolol can make patient's time-to-live obviously extend, time of hospitalization reduces, and its therapeutical effect is not subject to the impact of patient's age, sex and left ventricular ejection fraction.
The Germany's listing in 1997 of this kind, subsequently in the listing of multiple countries such as Britain, Argentina, Austria, Belgium, France, the U.S. of Greece.At present clinically application be mainly conventional tablet, every day 5～40mg, although action time sustainable 19h because discharge inhomogeneously, do not reach the effect of steady blood pressure lowering, if make slow releasing preparation, can make medicine evenly discharge in 24h.Slow releasing capsule belongs to decentralized preparation simultaneously, medicine and gastrointestinal contact area are not only improved to a certain extent, medicine is absorbed in vivo more complete, improve bioavailability, and obtain better drug release rate by the micropill combination of different rate of releasing drug, can be used for hypertensive patient's steady blood pressure lowering.
Summary of the invention
The present invention has overcome the shortcoming and defect of prior art, and a kind of steadily blood pressure lowering, the slow-release micro-pill that contains active component nebivolol that bioavailability is higher are provided.This slow-release micro-pill has better drug release rate, can make the interior release of medicine 24h more even, thereby effectively reduces the paddy peak ratio of hypotensive effect, realizes steady blood pressure lowering.
The nebivolol (Nebivolol) adopting in the present invention is that a pair of enantiomer is 1: 1 equal amount of mixture of (S, R, R, R) and (R, S, S, S) configuration, and molecular formula is C
22h
25f
2nO
4, molecular weight is 405.44, has following structure:
The nebivolol officinal salt adopting in the present invention can be hydrochlorate, sulfate, maleate, succinate, oxalates etc., is generally nebivolol hydrochloride.Structure is as follows:
Slow-release micro-pill of the present invention mainly by the hollow ball core as parent nucleus, be wrapped in the principal agent layer outside ball core and the sustained release coating layer that is wrapped in outside principal agent layer forms.Its hollow core ball core is the blank base ball that comprises base ball and base ball protective layer, and principal agent layer is made up of nebivolol and adjuvant, and its outer surface is coated one deck slow release layer.
Slow-release micro-pill is the pastille micropill of coated slow release layer, and wherein the weight ratio of pastille micropill and slow release layer is 0.3-30: 0.1-10.Wherein pastille micropill is to wrap active medicine or active medicine and adjuvant by celphere to be mixed, and wherein celphere is 5-50: 1-40 with drug weight ratio; Medicine and adjuvant weight ratio are 1: 2.5-100.
Slow-release material in the present invention is mainly made up of blocker, plasticizer, porogen, antitack agent or opacifier.Wherein said blocker is one or more in acrylic resin or ethyl cellulose, wherein acrylic resin refers to Youteqi S-100, RS30D, RL30D, RS100, RL100, E-100 or NE30D, the mixture of one or more in NE30D aqueous dispersion or RS30D and RL30D aqueous dispersion; Ethyl cellulose refers to ethyl cellulose powder or Aquacoat.
Plasticizer described in the present invention is one or more in triethyl citrate, propylene glycol, diethyl phthalate, Polyethylene Glycol-600, citron acid esters, monoacetin, tributyl citrate or dibutyl sebacate.
Porogen described in the present invention is one or more in lactose, microcrystalline Cellulose, hypromellose, Polyethylene Glycol, polyvinylpyrrolidone or Pulvis Talci.
Antitack agent described in the present invention is one or more in Pulvis Talci, stearic acid, silicon dioxide, magnesium stearate or glyceryl monostearate.
Opacifier described in the present invention is titanium dioxide.
In the present invention, slow-release material blocker, plasticizer, porogen, antiplastering aid, opacifier weight ratio are 10-100: 0.1-100: 0.1-100: 0.1-100: 0.1-100.
The present invention also provides the slow-release micro-pill of a kind of nebivolol and salt thereof and the concrete preparation method of corresponding slow releasing capsule, as follows:
(1) preparation of celphere
By after fillibility adjuvant and binding agent mix homogeneously, with comminutor pill-rolling, to required 15-40 order, pill-rolling limit, limit adds lubricant, dries, and obtains celphere.
(2) preparation of pastille micropill
As in fluid bed or coating pan, temperature is controlled between 30-60 ℃ celphere, by the mixing such as nebivolol and binding agent, and is added in appropriate solvent, form mixed liquor, the surface that is coated on celphere forms pastille micropill, is drying to obtain.Pastille micropill also available sucrose is wrapped to form protective layer.
(3) preparation of slow-release micro-pill
Pastille micropill is placed in to fluid bed or coating pan, temperature is controlled in 20-50 ℃, blocker, plasticizer, porogen, antitack agent and opacifier are mixedly configured into coating solution in water or water and alcohol mixeding liquid, the skin that is sprayed at pastille micropill is made slow-release micro-pill, obtain the slow-release micro-pill under different weightening finish conditions, weightening finish scope is preferably 5-30% (percentage by weight).
(4) preparation of slow releasing capsule
In shell, make the slow releasing capsule containing nebivolol 2.5～40mg by incapsulating after slow-release micro-pill forced air drying.
The prepared nebivolol slow releasing capsule of the present invention has following characteristics compared with conventional tablet:
(1) slow-release micro-pill is uniformly distributed in gastrointestinal tract, has reduced the too high gastrointestinal irritation causing of drug level;
(2) having improved the area that medicine contacts with gastrointestinal tract, is that drug absorption is more complete, has increased bioavailability.
(3) utilize the micropill combination of different rate of releasing drug to obtain desirable rate of releasing drug, reduce paddy peak ratio, blood drug level in body is stablized, reach better antihypertensive effect, realize steady blood pressure lowering.
(4) preparation technology is simple, and easy operating control, is suitable for industrialization.
Accompanying drawing explanation
Fig. 1 nebivolol hydrochloric acid slow-release micro-pill release curve
The time front of blood concentration of Fig. 2 nebivolol hydrochloric acid slow-release micro-pill
The specific embodiment
Providing the following example makes person skilled in art's clearer understanding of energy and implements the present invention.They should not be counted as limiting the scope of the invention, and are only illustrative and representational example.
The preparation of embodiment 1 celphere
The microcrystalline Cellulose of recipe quantity or lactose are evenly mixed with starch, add subsequently binding agent sucrose or hypromellose, to 15-40 order, when pill-rolling, add lubricant with centrifugal granulator pill-rolling, dry and obtain celphere.
The preparation of embodiment 2 pastille micropills
Note: the nebivolol in prescription or the consumption of its salt, all by active component nebivolol.
Nebivolol described in above-mentioned prescription (or nebivolol officinal salt), hypromellose (or polyvinylpyrrolidone, microcrystalline Cellulose, lactose), Pulvis Talci, Polyethylene Glycol etc. are joined in water or ethanol (70%, 85% or 90%), stir the liquid that is uniformly mixed after 30min.In fluid bed or coating pan, keep micropill temperature at 30～60 ℃, the surface that mixed liquor is evenly applied to celphere forms pastille micropill.The preparation of embodiment 3 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Youteqi NE30D 18g
Triethyl citrate 4g
Pulvis Talci 5g
Water 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 25-30 ℃.In Youteqi NE30D aqueous dispersion, add triethyl citrate and Pulvis Talci, after stirring, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 4 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Methyl methacrylate: 1: 1.5 copolymer 30g of ethyl acrylate
Triethyl citrate 3.5g
Pulvis Talci 5g
Water: ethanol (1: 1) 180ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 20-40 ℃.By methyl methacrylate: 1: 1.5 copolymer of ethyl acrylate is water-soluble: in ethanol (1: 1) solution, then add triethyl citrate and Pulvis Talci, form coating solution after stirring, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 5 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Youteqi RS100 12g
Youteqi RL100 1.5g
Triethyl citrate 3.6g
Pulvis Talci 10.5g
80% ethanol 150ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 25-35 ℃.Youteqi RS100 and RL100 are dissolved in 80% ethanol, then add triethyl citrate and Pulvis Talci, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 6 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Eudragit RS 30D 15g
Eudragit RL 30D 8g
Tributyl citrate 4.2g
Pulvis Talci 6g
Water 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 30-40 ℃.By Eudragit RS 30D and RL30D formation aqueous dispersion soluble in water, then add tributyl citrate and Pulvis Talci, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 7 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Youteqi E-100 18g
Youteqi NE30D 2g
Tributyl citrate 3.8g
Pulvis Talci 10g
Water 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 20-50 ℃.By Youteqi E-100 and NE30D formation aqueous dispersion soluble in water, then add tributyl citrate and Pulvis Talci, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 8 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Youteqi S-100 24g
Propylene glycol 5g
Pulvis Talci 12g
Water 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 30-50 ℃.By formation aqueous dispersion soluble in water Youteqi S-100, then add propylene glycol and Pulvis Talci, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 9 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Ethyl cellulose 12g
Polyethylene Glycol-600 4g
Hypromellose 6g
90% ethanol 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 25 ℃.Ethyl cellulose and hypromellose are dissolved in 90% ethanol, then add Polyethylene Glycol-600, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 10 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Ethyl cellulose 10g
0.2% diethyl phthalate 3g
Hypromellose 5g
70% ethanol 150ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 30 ℃.Ethyl cellulose and hypromellose are dissolved in 70% ethanol, then add 0.2% diethyl phthalate, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 11 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Aquacoat 15g
Citron acid esters 3g
Polyvinylpyrrolidone 6g
Water 100ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 28 ℃.Aquacoat is soluble in water, then add citron acid esters and polyvinylpyrrolidone, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 12 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Aquacoat 10g
Monoacetin 2g
Microcrystalline Cellulose 4g
Magnesium stearate 3g
Water 100ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 35 ℃.Aquacoat is soluble in water, then add monoacetin, microcrystalline Cellulose and magnesium stearate, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 13 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Aquacoat 10g
Triethyl citrate 2g
Pulvis Talci 4g
Water 100ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 50 ℃.Aquacoat is soluble in water, then add triethyl citrate and Pulvis Talci, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.The preparation of embodiment 14 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Youteqi NE30D 15g
Triethyl citrate 4.5g
Pulvis Talci 4g
Titanium dioxide 3g
Water 120ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 20 ℃.In Youteqi NE30D aqueous dispersion, add triethyl citrate, Pulvis Talci and titanium dioxide, after stirring, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 15 slow-release micro-pill
Prescription
Embodiment 2 pastille micropill 120g
Aquacoat 12g
Triethyl citrate 3g
Pulvis Talci 4g
Titanium dioxide 3.5g
Water 100ml
Require the pastille micropill of embodiment 2 gained to put into fluid bed or coating pan according to prescription, make the temperature of micropill remain on 28 ℃.Aquacoat is soluble in water, then add triethyl citrate, Pulvis Talci and titanium dioxide, after stirring, form coating solution, slow-release micro-pill is made on the surface that is sprayed at pastille micropill.
The preparation of embodiment 16 slow releasing capsule
Slow-release micro-pill under the difference weightening finish condition that embodiment 3-13 obtains, weightening finish scope is preferably 5-30% (percentage by weight).By the slow releasing capsule obtaining in incapsulating after slow-release micro-pill forced air drying containing principal agent 2.5～40mg.
The mensuration of embodiment 17 vitro releases
Adopt ZRS-4 medicament dissolution instrument, solvent is water, and rotating speed is 50 revs/min.Respectively at 1,2,4,8,12,16,24h sampling and measuring release, result is as follows:
The slow-release micro-pill being made by different slow release conditions can evenly discharge in 24h, the not prominent phenomenon of releasing.
The mensuration of blood drug level in embodiment 18 bodies
After the oral sample of rabbit, with different time points blood sampling, separation of serum, 1ml serum, 5ml hexane: dichloromethane (1: 1) extracts, fully, after vibration, separates organic facies, extracts twice, merge extractive liquid,, nitrogen current dries up, and 100 μ l are fixed molten, 50 μ l sample introductions.Concrete measurement result is shown in accompanying drawing 2.
Claims (13)
1. a slow-release micro-pill that contains active component nebivolol, it is characterized in that, active component is nebivolol or its pharmaceutical salts, and slow-release micro-pill is made up of the pastille micropill of the coated slow release layer of skin, and wherein the weight ratio of pastille micropill and slow release layer is 0.3-30:0.1-10; Described pastille micropill is that the mixture of wrapping active component or active component and adjuvant by celphere is made, and wherein celphere and active component weight ratio are 5-50:1-40; Active component and adjuvant weight ratio are 1:2.5-100.
2. slow-release micro-pill claimed in claim 1, the pharmaceutical salts of described active component nebivolol, is selected from hydrochlorate, sulfate, maleate, succinate, oxalates.
3. slow-release micro-pill claimed in claim 2, the pharmaceutical salts of described active component nebivolol is hydrochlorate.
4. the slow-release micro-pill described in claim 1-3 any one, wherein slow release layer is made up of blocker, plasticizer, porogen, antitack agent or opacifier.
5. slow-release micro-pill claimed in claim 4, it is characterized in that wherein said blocker is one or more in acrylic resin or ethyl cellulose, wherein acrylic resin is selected from one or more the mixture in Youteqi S-100, RS30D, RL30D, RS100, RL100, E-100 or NE30D; Ethyl cellulose is the existence form of ethyl cellulose powder or Aquacoat.
6. slow-release micro-pill claimed in claim 4, is characterized in that wherein said plasticizer is one or more in triethyl citrate, propylene glycol, diethyl phthalate, Polyethylene Glycol-600, citron acid esters, monoacetin, tributyl citrate or dibutyl sebacate.
7. slow-release micro-pill claimed in claim 4, is characterized in that wherein said porogen is one or more in lactose, microcrystalline Cellulose, hypromellose, Polyethylene Glycol, polyvinylpyrrolidone or Pulvis Talci.
8. slow-release micro-pill claimed in claim 4, is characterized in that wherein said antitack agent is one or more in Pulvis Talci, stearic acid, silicon dioxide, magnesium stearate or glyceryl monostearate.
9. slow-release micro-pill claimed in claim 4, is characterized in that wherein said opacifier is titanium dioxide.
10. the slow-release micro-pill described in claim 1-3 any one, is characterized in that wherein blocker, plasticizer, porogen, antiplastering aid, opacifier weight ratio are 10-100:0.1-100:0.1-100:0.1-100:0.1-100.
Slow-release micro-pill described in 11. claim 1-3 any one, is characterized in that, can after administration, in 24h, discharge nebivolol, realizes steady blood pressure lowering, for hypertensive patient's daily treatment.
The preparation method of the slow-release micro-pill described in 12. claim 1-3 any one, is characterized in that pastille micropill to wrap the slow release layer of different proportion, makes the micropill of different release properties, then need to be mixed into slow-release micro-pill according to concrete.
13. 1 kinds of slow releasing capsule, are incapsulated the slow releasing capsule that obtains containing nebivolol 2.5～40mg in shell by the slow-release micro-pill described in claim 1-3 any one.
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| CN201010117316.0A CN102188385B (en) | 2010-03-04 | 2010-03-04 | Sustained-release pellets containing nebivolol as active component and preparation method thereof |
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| CN102188385B true CN102188385B (en) | 2014-06-11 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689566A (en) * | 2004-04-23 | 2005-11-02 | 胡才忠 | Compound oral preparation of carvedilol and benidipine |
| CN101019858A (en) * | 2007-03-30 | 2007-08-22 | 北京福瑞康正医药技术研究所 | Medicine composition possessing vasodilation and beta1 receptor blocking effects |
| WO2009137465A2 (en) * | 2008-05-05 | 2009-11-12 | University Of Rochester | Methods and compositions for the treatment or prevention of pathological cardiac remodeling and heart failure |
-
2010
- 2010-03-04 CN CN201010117316.0A patent/CN102188385B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1689566A (en) * | 2004-04-23 | 2005-11-02 | 胡才忠 | Compound oral preparation of carvedilol and benidipine |
| CN101019858A (en) * | 2007-03-30 | 2007-08-22 | 北京福瑞康正医药技术研究所 | Medicine composition possessing vasodilation and beta1 receptor blocking effects |
| WO2009137465A2 (en) * | 2008-05-05 | 2009-11-12 | University Of Rochester | Methods and compositions for the treatment or prevention of pathological cardiac remodeling and heart failure |
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