WO2019022436A2 - Composition pharmaceutique comprenant un inhibiteur de nep et un bêta-bloquant - Google Patents

Composition pharmaceutique comprenant un inhibiteur de nep et un bêta-bloquant Download PDF

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WO2019022436A2
WO2019022436A2 PCT/KR2018/008169 KR2018008169W WO2019022436A2 WO 2019022436 A2 WO2019022436 A2 WO 2019022436A2 KR 2018008169 W KR2018008169 W KR 2018008169W WO 2019022436 A2 WO2019022436 A2 WO 2019022436A2
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pharmaceutical composition
week
beta
heart failure
blocker
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PCT/KR2018/008169
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English (en)
Korean (ko)
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WO2019022436A3 (fr
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동을원
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에리슨제약(주)
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the present invention relates to pharmaceutical compositions for the treatment of heart failure comprising NEP inhibitors and beta -blockers.
  • Heart failure refers to a group of diseases caused by a structural or functional abnormality of the heart resulting from the relaxation of the heart by the heart, or by the failure of the blood supply to the body tissue due to a decrease in the contractile function of the blood.
  • the causes of heart failure are very diverse. Cardiovascular (coronary) diseases such as myocardial infarction are the most common causes, and heart muscle diseases such as myocardial infarction and hypertension are the main causes.
  • long-term tachycardia persistent excessive drinking, and extreme stress can cause reversible heart failure, and some of the anticancer drugs may cause heart failure due to cumulative dose.
  • Acute heart failure is a sudden or worsening heart failure, usually within a week, and it is the goal of treatment to find out the causes or exacerbations of heart failure and to improve symptoms.
  • chronic heart failure the sympathetic nervous system and the hormonal system are activated by the body's compensatory action against heart failure. This is an important cause of disease progression, so blocking the progress of the heart function is the goal of treatment.
  • ACE angiotensin II receptor blockers
  • beta-blockers beta-blockers
  • aldosterone antagonists which are known to prolong the life span of chronic heart failure patients.
  • the drugs include diuretics, nitrates, vasodilators such as hydralazine, and digoxin.
  • Hypertension is the main cause of heart failure, 90 ⁇ 95% of the primary (primary) hypertension, the cause of the disease is not clear.
  • psychological and environmental factors such as drinking, smoking, aging, lack of exercise, obesity, eating habits, and stress are known risk factors related to hypertension.
  • children whose parents are hypertensive can become hypertensive patients at a high rate, and genetic factors are also known to be an important cause of the disease.
  • hypertension treatment drugs are taken for a long time, the combination therapy of drugs having different action mechanisms can exert a better therapeutic effect. Moreover, co-administration can reduce the side effects of long-term administration of the drug by reducing the amount of single drug used.
  • Drugs used to treat hypertension are broadly divided into diuretics, sympathomimetics, and vasodilators. Of these, vasodilators are again divided into ACE inhibitors, ARB, and calcium channel blockers.
  • Neutral endopeptidase is a zinc-containing metalloprotease that degrades many peptide substrates at the amino terminal portion of aromatic amino acids.
  • the substrate for this enzyme is atrial natriuretic factor (ANF), cerebral natriuretic peptide (BNP), met and leu enkephalin, bradykinin, neurokinin A and substance P ).
  • Endogenous atrium sodium diuretic peptide also referred to as atrial sodium diuretic factor (ANF) is a class of vasodilators, diuretics and antihypertensive peptides that have diuretic, sodium diuretic and vasodilatory functions in mammals.
  • ANP Endogenous atrium sodium diuretic peptide
  • ANF atrial sodium diuretic factor
  • the function of ANP is to maintain homeostasis of salt and water and regulate blood pressure.
  • ANP is rapidly inactivated by at least two processes, namely receptor mediated clearance and enzymatic inactivation via NEP. It has already been demonstrated that NEP inhibitors stimulate hypotension, diuretic, sodium diuretics and plasma ANP responses by pharmacologic injection of ANP in experimental animals.
  • NEP inhibitors The antihypertensive action of NEP inhibitors is mediated through ANP, because antibodies to ANP neutralize blood pressure lowering.
  • NEP inhibitors such as thiorphan, candoxatril and candoxatrilat have been studied as potential therapeutic agents.
  • NEP inhibitors are disclosed as a treatment for hypertension and cardiovascular diseases in combination with various drugs.
  • WO2007 / 054975 discloses a pharmaceutical composition for the treatment of cardiovascular diseases, which comprises an endothelin converting enzyme inhibitor (ECE inhibitor) and / or a NEP inhibitor.
  • ECE inhibitor endothelin converting enzyme inhibitor
  • WO2015 / 154673 discloses a pharmaceutical composition for treating hypertension and cardiovascular diseases, Calcium channel blockers.
  • WO2006 / 086456 discloses a combination composition of a renin inhibitor, a NEP inhibitor, an ARB and a diuretic, a composition comprising an ARB, a calcium channel blocker and further a renin inhibitor or a NEP inhibitor in WO 2007/056324 and a composition comprising an aldosterone receptor antagonist A combination of NEP inhibitors.
  • WO2006 / 000564 is NEP- inhibitor, endogenous endothelin inhibitors and AT of the manufacturing system 1 to the combination of a receptor antagonist
  • WO2006 / 064016 is NEP- inhibitor, endogenous endo combination of inhibitor and HMG CoA reductase inhibitors of endothelin producing system
  • WO2006 / 087371 disclose combinations of NEP-inhibitors, inhibitors of the endogenous endothelin production system and diuretics.
  • Beta-blockers are beta 1 -receptors in the heart and beta 1 -blockers and beta 2 -blockers that block beta 2 -receptors in the peripheral blood vessels or bronchi.
  • Representative beta-blockers are propranolol and are used in the treatment of angina, arrhythmia, hypertension, and are called classical beta-blockers because they block both beta 1 - and beta 2 -receptors.
  • Pratolol, metoprolol, atenolol, and the like are selective beta 1 -blockers, and butoxamine is referred to as selective beta 2 -blockers.
  • Hypertensive vascular disease if not controlled for an extended period, ultimately causes a number of pathological changes in target organs such as the heart and kidney. Persistent hypertension increases the likelihood of heart attack.
  • the characteristics of hypertensive vascular disease are multifactorial, and a combination of drugs with various mechanisms of action is required. However, since any combination of drugs with multiple mechanisms of action does not necessarily lead to beneficial effects, there is a need for a combination therapy in which harmful side effects are less likely to occur.
  • the present inventors have studied to obtain a synergistic antihypertensive effect together with a therapeutic effect on heart failure, in particular, chronic heart failure by combination of hypertensive drugs, and achieved this object by combining NEP inhibitor and selective? 1 -blocker, It was.
  • the present invention provides a pharmaceutical composition for the treatment of heart failure, which comprises a NEP inhibitor and a beta -blocker.
  • the NEP inhibitor may be sacubitril or a pharmaceutically acceptable salt thereof
  • the beta -blocker may be nebivolol or a pharmaceutically acceptable salt thereof.
  • compositions of the present invention comprise saccharide and naviborol in a weight ratio of about 2: 1 to 300: 1, preferably about 2: 1 to 80: 1, more preferably about 4: 1, and most preferably in a weight ratio of about 20: 1.
  • the NEP inhibitor and the beta -blocker exist in a separated state, and the NEP inhibitor and the beta -blocker are present in separate layers, respectively.
  • the method for preparing a pharmaceutical composition for treating heart failure comprises:
  • step (c) titrating the sacbitur granules of step (a) and the naviporol granules of step (b) into a bi-layer tablet.
  • the present invention provides methods of preventing and treating heart failure, particularly chronic heart failure, by administering a pharmaceutical composition comprising a NEP inhibitor, especially sacabitril and a beta-blocker, especially nebivolol .
  • NP sodium diuretic peptide
  • RAAS renin-angiotensin-aldosterone
  • SNS sympathetic nervous system
  • Pharmacological adjustments have been developed by down-regulating RAAS by ACE inhibitors, ARBs and mineralocorticoid antagonists, and down-regulation of SNS by beta-blockers to counter neuroendocrine dysregulation disorders.
  • the NP system which is a new class of drugs for managing heart failure, is increasingly interested in promoting the transition of concepts in heart failure therapy, which shifts from the inhibition of RAAS and SNS to the integrated target of rebalancing neuroendocrine control disorders can do.
  • Chronic heart failure is a complex pathological physiology syndrome in which neuroendocrine activation plays an important role, characterized by early activation of different neuroendocrine systems, namely SNS and NP, in the presence of asymptomatic LV contraction dysfunction.
  • SNS and NP neuroendocrine systems
  • SNS and RAAS responses play a compensatory role in supporting cardiac output and increasing peripheral vasoconstriction in an effort to maintain circulating homeostasis.
  • prolonged activation of both systems is detrimental and contributes to the progression and worsening of heart failure, eventually leading to congestion.
  • pharmacologic adjustment aiming at balancing neuroendocrine control disorders in heart failure will be effective and advantageous.
  • Current therapeutic approaches are based on pharmacological adjustments to down-regulate RAAS through ACE inhibitors or ARB, aldosterone, or mineralocorticoid receptor blockers (MRA) and down-regulate SNS by beta-blockers. That is, triple therapy with ACE inhibitors (or ARB), beta-blockers, and MRA represents the current optimal therapeutic approach (Clinical Science (2016) 130, 57-77 doi: 10.1042 / CS20150469)
  • the combination of the NEP inhibitor and the beta 1 -blocker which have an antihypertensive effect and an advantageous effect on the heart failure, through the activation of the NP system, has a therapeutic effect of heart failure, especially chronic heart failure, To prevent and treat vascular diseases, and to reduce side effects.
  • the Saku bit reel (Sacubitril) a NEP inhibitor is 4 - ⁇ [(2 S, 4 R) -1- (4- biphenylyl) -5-ethoxy-4-methyl-5-oxo-2-fentanyl ] Amino ⁇ -4-oxobutanoic acid having the following structure:
  • Sacbital is a prodrug that is activated by saccharinization by the deethylation of esterase to form neprilysin, which breaks down blood pressure lowering peptides, atrial and brain sodium renal peptides, neprilysin, NEP).
  • Nebivolol an optional beta 1 -receptor blocker, is a selective inhibitor of 1- (6-fluorocroman-2-yl) - ⁇ [2- (6- fluorocroman- Ethyl] amino ⁇ ethanol, which is also used in Europe as a hypertensive remedy for left ventricular dysfunction.
  • Navi-borer is prescribed in patients with essential hypertension and chronic heart failure in Korea. Navi-borer is started once daily as 1.25 mg, if necessary 2.5 mg once daily, 5 mg once a day, 1 day 1 The dose can be increased up to 10 mg per day, and the maximum dose per day is 10 mg.
  • a generally preferred dosage is from about 20 mg to about 800 mg, preferably from about 50 mg to about 700 mg, more preferably from about 100 mg to about 600 mg , And even more preferably from about 100 mg to about 300 mg.
  • the pharmaceutical composition according to one embodiment of the present invention comprises saccharide and naviborol in a weight ratio of about 2: 1 to 300: 1, preferably about 2: 1 to 80: 1, more preferably about 4 : 1 to 40: 1, and most preferably in a weight ratio of about 20: 1.
  • the synergistic action of NEP inhibitors in particular, squibbitle and? -Blocker, especially naviborol, together with the treatment for heart failure, especially chronic heart failure, is accompanied by synergistic antihypertensive action and thereby cardiovascular diseases And to improve the compliance of patients by reducing the side effects of each drug while enhancing the prophylactic or therapeutic effect.
  • the pharmaceutical composition of the present invention comprising NEP inhibitors and beta -blockers can be effectively used for the prevention or treatment of heart failure, especially chronic heart failure, hypertension and cardiovascular diseases.
  • Cardiac fibrosis is a phenomenon in which cardiac tissue is excessively deposited between cardiac cells, resulting in a hardening of the heart. It is the main cause of decreased cardiac function in patients with heart failure. In patients with chronic heart failure, the management of heart rate and stroke rate is more important than excessive blood pressure reduction.
  • the pharmaceutical composition according to the present invention is effective for the treatment of heart failure caused by various causes due to the reduction of left ventricular ejection fraction and inhibition of cardiac fibrosis, thereby alleviating, preventing and treating heart failure.
  • the pharmaceutical composition is also useful for prevention of hypertension and cardiovascular diseases Can be used.
  • the NEP inhibitor and the beta -blocker are separately granulated, preferably as separate layers, so that the two drugs are present in separate states, thereby minimizing the possibility of problems caused by the complex formulation.
  • the method for producing the pharmaceutical composition of the present invention is, for example,
  • step (c) titrating the squibitre granules of step (a) and the naviborol granules of step (b) into a bi-layer tablet.
  • compositions according to the present invention can be prepared by known methods and are suitable for intestinal, for example oral or rectal, and parenteral administration, of mammals including humans.
  • oral preparations include tablets, capsules, liquid preparations and the like, and injections include solutions and suspensions.
  • Pharmaceutically acceptable additives which may be added to the pharmaceutical composition according to the invention include, for example, microcrystalline cellulose, lactose (lactose hydrate), mannitol, sodium citrate, calcium phosphate, glycine, starch, (For example, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, sucrose, gelatin and acacia gum) and a binder such as sodium carboxymethylcellulose, Calcium hydrogen phosphate can be mentioned.
  • lubricants such as colloidal silicon dioxide, hydrous silicon dioxide, magnesium stearate, sodium stearyl fumarate (Pruv), glyceryl behenate (trade name: compritol 888), calcium stearate, stearic acid and talc .
  • the composite preparation according to the present invention can be coated with a film, and conventional coating agents such as hydroxypropylmethylcellulose, opadyl series, and udrazit series can be used as a coating agent that can be used for the film coating layer , But is not limited thereto.
  • compositions comprising NEP inhibitors, in particular squibitir and beta-blockers, in particular navivorol, according to the present invention are useful for the treatment of heart failure by contributing to the normalization of effusion and fibrosis in heart failure, especially chronic heart failure, Can be used for the prevention or treatment of diseases, and the drug is excellent in the tolerance by reducing side effects.
  • FIGS. 1A and 1B are graphs showing changes in mean blood pressure according to administration of a drug in a Dahl saline-sensitive (DSS) rat model.
  • FIG. 1A is a graph showing changes in blood pressure (Week 12), and
  • FIG. 1B shows a comparison of mean blood pressures at the start of drug administration (week 8) and at the end (week 12).
  • FIGS. 2A and 2B are graphs showing the changes in the ejection fraction (EF) according to drug administration in a Dahl saline-sensitive (DSS) rat model.
  • FIG. (Week 8 to week 12), and FIG. 2B is a comparison of release rates at the start of drug administration (week 8) and at the end of week 12 (week 12).
  • FIG. 3A and FIG. 3B are graphs showing changes in the fraction shortening ratio (FS) according to drug administration in the Dahl saline-sensitive (DSS) rat model.
  • FIG. (8th week to 12th week) and FIG. 3b is a comparison of compartment shortening rates at the start of drug administration (8th week) and at the end (12th week).
  • Figure 4 is a graph showing the extent of fibrosis following drug administration in a Dahl saline-sensitive (DSS) rat model.
  • Figure 5 is a graph showing plasma levels of aldosterone following drug administration in a Dahl saline-sensitive (DSS) rat model.
  • the components of the navibole layer were granulated and dried to form 20 meshes.
  • the constituents of the sacbutyrate layer were likewise granulated, dried and sized to 20 mesh. Navi-borer granules and sacbitur granules were tableted in a bilayer form and film-coated with a coating agent.
  • the ingredients except Opa Dry White were granulated and dried to form 20 mesh.
  • the tablets obtained by tableting the granules were film-coated with a coating agent.
  • composition of the above ingredients was prepared as a hard capsule according to the conventional preparation method of capsules.
  • Capsule No. 3 was used in Preparation Example 7, No. 1 was used in Production Example 8, and No. 0 capsule was used in Production Example 9.
  • DSS Dahl Salt Sensitive
  • BP Blood pressure
  • Echocardiography was performed noninvasively to determine whether the ejection fraction of left ventricle (LVEF) Respectively.
  • Experimental treatment was as follows: DSS rats were fed 0.3% NaCl, and the experimental group was fed with high salt diet (8% NaCl feed) for 8 weeks to induce heart failure. From the 8th week, the medication was started, and the medication was administered once a day for 4 weeks until 12 weeks. Heart failure induction was confirmed by measuring left ventricular ejection fraction using echocardiography.
  • Blood pressure was measured in the tail vein of rats 1 time before high salt diet and 5 times at weekly intervals from 8 weeks to 12 weeks after high salt diet.
  • Echocardiograms were measured 5 times before and 7 weeks, 8 weeks, 10 weeks, and 12 weeks after the high feed diets and the ejection fraction (EF) and the shortening rate (FS ; fractional shortening).
  • EF ejection fraction
  • FS shortening rate
  • the calibration curves were prepared using standard products (aldosterone, Abcam, Cat No. Ab136933), and the absorbance of each well was measured and quantitatively analyzed using an ELISA reader.
  • the sacrificed heart was weighed and fixed in 10% formalin for one week. After paraffin treatment, a paraffin block was made and the cardiac tissue slide was cut, followed by MT stain (Masson's trichrome stain). The slides were mounted to cover the cover glasses and the Maison trichrome staining was completed. The completed tissue slides were imaged and analyzed using a slide scanner, and cardiac fibrosis was evaluated by confirming the connective tissue such as collagen tissue in the heart tissue.
  • the blood pressure of the rats was measured at 8 wk (8 w), 9 wk (9 w), 10 wk (10 w), 11 wk (11 w) and 12 wk And the mean blood pressure was confirmed.
  • Table 5 below shows the change in the mean blood pressure of each group.
  • FIGS. 1A and 1B are graphs showing changes in mean blood pressure according to administration of a drug in a Dahl salt-sensitive (DSS) rat model.
  • FIG. 1A is a graph showing changes in blood pressure (Week 12), and
  • FIG. 1B shows the comparison of mean blood pressures at the start of drug administration (week 8) and at the end (week 12).
  • the mean blood pressures in G2, G3, G4 and G5 were significantly higher in the 8th week, 9th week, 10th week, 11th week and 12th week (P ⁇ 0.05, 0.01), respectively.
  • the mean blood pressures in G2, G3, G4 and G5 were significantly increased (P ⁇ 0.05, 0.01) compared to that of G1, and the mean blood pressures in G3, G4 and G5, which is lower than that of model G2.
  • the mean blood pressure of patients treated with sacvitil and naviborrh (G5) and those treated with naviborol alone (G3) was lowered when the drug was administered for 4 weeks than when heart failure occurred due to high salt diet, It was confirmed that the mean blood pressure was increased in the bitiril alone administration group (G4), and the antihypertensive effect of the composition according to the present invention was confirmed.
  • the rat heart was measured by echocardiography before high feed diet (0 w), high salt diet (7 w), after 8 wk (8 w), after 10 wk (10 w) and after 12 wk FS.
  • Tables 6 and 7 below show the changes in the ejection fraction (EF) and the shortening ratio (FS) of each group, respectively.
  • FIG. 2 is a graph showing changes in ejection fraction (EF) according to drug administration in a Dahl saline-sensitive (DSS) rat model.
  • FIG. (Week 12), and FIG. 2B is a comparison of release rates at the start of drug administration (week 8) and at the end (week 12).
  • the rate of excretion of G2 in the disease model group was significantly lower than that of the 0th week (P ⁇ 0.01) (P ⁇ 0.01) .
  • the excretion rate at the 12th week was significantly increased (P ⁇ 0.05) as compared with that of G2, and the administration rate of the naviborol alone group (G3) (G4) compared with that of the bitiril alone group (G4). That is, it is confirmed that the composition according to the present invention contributes to normalization of the thinning rate.
  • FIG. 3A and FIG. 3B are graphs showing changes in the fraction shortening ratio (FS) according to drug administration in the Dahl saline-sensitive (DSS) rat model.
  • FIG. (8th week to 12th week) and FIG. 3b is a comparison of compartment shortening rates at the start of drug administration (8th week) and at the end (12th week).
  • the compartment shortening rate in the disease model group G2 was significantly decreased (P ⁇ 0.001) compared to the 0th week (P ⁇ 0.001) )
  • And sacubitil alone group (G4) were significantly decreased in the 12th week compared to the 0th week.
  • the compartment shortening rates of G2, G3, G4 and G5 were significantly decreased (P ⁇ 0.05, 0.001) compared with G1.
  • Histologic analysis was performed by autopsy, cardiac weights were measured, and LV thickness and degree of fibrosis were confirmed by trichrome staining. Table 8 shows the degree of fibrosis in each group.
  • Figure 4 is a graph showing the extent of fibrosis following drug administration in a Dahl saline-sensitive (DSS) rat model.
  • Hematologic analysis was performed by collecting the blood samples before the autopsy and separating the plasma.
  • the level of aldosterone in plasma was analyzed by ELISA kit. Table 9 below shows the concentration of aldosterone in each group.
  • Figure 5 is a graph showing plasma levels of aldosterone following drug administration in a Dahl saline-sensitive (DSS) rat model.
  • the combination composition of squibbitle and naviborol according to the present invention has a lower ejection fraction (EF) and a shorter partition ratio (FS) that can confirm the left ventricular function as compared with naviborol or sacbutyr alone administration group ) was increased and the left ventricular function was improved, and cardiac fibrosis was also decreased.
  • the aldosterone level was reduced by the negative control group, and compared with the compound that inhibits both NEP and ACE, or both NEP and ARB, You can expect.
  • prevention of hypertension and cardiovascular diseases can be expected.

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Abstract

La présente invention concerne une composition pharmaceutique qui, grâce à la combinaison de médicaments ayant différents mécanismes d'action, permet le traitement de l'insuffisance cardiaque et présente des effets synergiques antihypertenseurs, et réduit les réactions indésirables. La composition pharmaceutique comprenant un inhibiteur de NEP et un bêta-bloquant peut être utilisée pour traiter une insuffisance cardiaque, en particulier une insuffisance cardiaque chronique, et pour prévenir ou traiter des maladies cardiovasculaires grâce à l'effet antihypertenseur synergique, et la tolérance au médicament est excellente car les réactions indésirables sont réduites.
PCT/KR2018/008169 2017-07-27 2018-07-19 Composition pharmaceutique comprenant un inhibiteur de nep et un bêta-bloquant WO2019022436A2 (fr)

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KR1020180083494A KR20190013509A (ko) 2017-07-27 2018-07-18 Nep 저해제 및 베타-차단제를 포함하는 약제학적 조성물

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EP2174658A1 (fr) * 2005-05-31 2010-04-14 Mylan Laboratories, Inc Compositions comportant du nebivolol
ES2524596T3 (es) * 2008-08-07 2014-12-10 Spa Societa' Prodotti Antibiotici S.P.A. Tratamiento a largo plazo de la insuficiencia cardiaca sintomática
CN103596928B (zh) * 2011-05-31 2017-02-15 施万生物制药研发Ip有限责任公司 脑啡肽酶抑制剂
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HUE052337T2 (hu) * 2015-07-23 2021-04-28 Bayer Pharma AG Oldható guanilát-cikláz stimulátorai/aktivátorai a neutrális endopeptidáz egy inhibitorával (NEP-inhibitor) és/vagy egy angiotenzin All-antagonistával kombinációban és ezek alkalmazása

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