Pharmaceutical compositions including valsartan and inhibitors of neutral endopeptitas (nep)

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to pharmaceutical combination including: i) antagonist AT-1 valsartan or its pharmaceutically acceptable salt in single day dose from approximately 20 mg to approximately 320 mg, and (ii) inhibitor NEP representing ethyl ether of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenylmethyl)-4-amino-2R-methylbutane acid or N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenylmethyl)-4-amino-2R-methylbutanic acid or their pharmaceutically acceptable salt in a single day dose from approximately 20 mg to approximately 800 mg. In addition, invention relates to kit for treatment including said combination.

EFFECT: synergetic effect of hypertensia treatment when using said combination.

5 cl, 6 tbl, 7 ex

 

Angiotensin II interacts with specific receptors on the surface of target cells. It was possible to identify the receptor subtypes, which are called, for example, receptors AT 1 and AT 2. Recently made great efforts to identify substances that bind to the receptor AT 1. Such active ingredients are often referred to as antagonists of angiotensin II. Due to inhibition of the receptor AT 1 such antagonists can be used, for example, as antihypertensive agents or other indications for the treatment of congestive heart failure. Therefore, it is implied that antagonists of angiotensin II are those active ingredients that are associated with a subtype of the receptor AT 1.

The system inhibitors of the renin-angiotensin are well-known drugs that lower blood pressure and have shown beneficial effects in hypertension and congestive heart failure, as described, for example, N.Eng. J.Med. 316, 23 (1987), 1429-1435. There are a large number of peptide and ones inhibitor system the renin-angiotensin most widely studied are inhibitors of angiotensin-converting enzyme (ACE), which include drugs captopril, enalapril, lisinopril, benazepril and spirapril. Although the main type of action of ACE inhibitors include preduprezhdeny the education vasoconstrictor peptide Ang II, in Hypertension, 16, 4 (1990), 363-370 reported that ACE cleaves various peptide substrates, including affecting the vessels of the peptides bradykinin and substance P. Was shown to prevent the degradation of bradykinin by ACE inhibitors and reported to Circ. Res., 66, 1 (1990), 242-248 that the activity of ACE inhibitors in certain conditions mediated rather reduced levels of bradykinin than inhibition of the formation of Ang II. Therefore, it cannot be assumed that the effect of the ACE inhibitor can be explained only by preventing the formation of angiotensin and subsequent inhibition system the renin-angiotensin.

Neutral endopeptidase (EC 3.4.24.11; enkephalinase; tripeptides; NEP) is a zinc-containing by metalloproteases, which breaks down the various peptide substrates on aminobenzene side of aromatic amino acids. See Biochem. J., 241, (1987), 237-247. Substrates of this enzyme include, but without limitation, atriale natriuretic factors (ANF, also known as ANP), brain naturethese peptide (BNP), methionine - and leucine-enkephalin, bradykinin, neurokinin and substance P.

ANPs is a family vasodilator, diuretic and antihypertensive peptides, which have been the subject of many recent messages in the literature, for example, Annu. Rev.Pharm. Tox., 29, (1989), 23-54. In one form, ANF 99-126, is circulating in the blood is onoy system peptide hormone, which is released from the heart in conditions of cardiac enlargement. Function ANF is to maintain salt and water homeostasis and blood pressure regulation. ANF quickly deactivated in the circulatory system at least two ways: receptor-mediated clearance, reported in Am. J. Physiol., 256 (1989), R469-R475, and enzymatic deactivation through NEP reported in Biochem. J., 243 (1987), 183-187. Previously it was demonstrated that NEP inhibitors potentiate hypotensive, diuretic, naturethese and contained in plasma ANF responses in experimental animals for pharmacological injection ANF. Potentiation ANF using two specific inhibitors of NEP reported Sybertz, and others, in J. Pharmacol. Exp. Ther. 250, 2 (1989), 624-631 and Hypertension, 15, 2 (1990), 152-161, whereas the potentiation ANF generally disclosed in US patent 4749688. In the patent US 4740499 Olins discloses the use of Tirana and calahorrano for potentiation trialing peptides. Moreover, NEP inhibitors reduce blood pressure and show ANF-like effects, such as diuresis, and increased allocation of cyclic guanosine-3',5'-monophosphate (cGMP) in some forms of experimental hypertension. Antihypertensive activity of NEP inhibitors is mediated through the ANF, because the ANF antibody will neutralize the decrease in blood pressure.

Long and controler is radiated hypertensive vascular disease eventually leads to various pathological changes in the target organs, such as the heart and kidneys. Stable hypertension can also lead to increased cases of paralysis. Therefore, there is a great need to assess the effectiveness of antihypertensive therapy, the study of cardiovascular endpoints defeat after lower blood pressure, to obtain further evidence on the benefits of combination therapy.

Nature hypertensive vascular diseases is multifactorial. Under certain circumstances combine drugs with different mechanisms of action. However, only a theoretical consideration of any combination of drugs with different mode of action does not necessarily lead to combinations with pre-emptive effects. Accordingly, there is a need for more effective combination therapy, which gives less harmful side effects.

In one aspect the present invention relates to pharmaceutical combinations comprising valsartan or its pharmaceutically acceptable salt and inhibitor of neutral endopeptidase (NEP) or its pharmaceutically effective salt, optionally in the presence of a pharmaceutically acceptable carrier, and to pharmaceutical compositions comprising them.

In another variant embodiment of the present invention relates to methods therapiezentrum and related renal conditions by introducing a pharmaceutical composition, includes valsartan plus NEP inhibitor, or relates to pharmaceutical compositions comprising valsartan or its pharmaceutically acceptable salt and inhibitor of neutral endopeptidase (NEP) or its pharmaceutically effective salts.

In another variant embodiment of the invention the present invention relates to pharmaceutical compositions comprising valsartan or its pharmaceutically acceptable salt and inhibitor of neutral endopeptidase (NEP) or its pharmaceutically effective salts and diuretic, especially hydrochlorothiazide.

Valsartan is an antagonist of the receptor AT 1, (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl] the amine of formula (I)

and disclosed in the patent EP 0443983 AND patent US 5399578, disclosure of which is included in the context in their entirety as if they were placed later in the context.

The NEP inhibitor, applicable in the above-mentioned combination, means a compound of the formula (II)

and its pharmaceutically acceptable salt,

where

R2means alkyl of 1-7 carbon atoms, trifluoromethyl, phenyl, substituted phenyl, -(CH2)1-4-phenyl, or -(CH2)1-4-substituted phenyl;

R3means hydrogen, alkyl of 1-7 carbon atoms, phenyl, substituted phenyl,

-(CH2)1-4-Fe is silt or -(CH 2)1-4-substituted phenyl;

R1means hydroxy, alkoxy of 1-7 carbon atoms, or amino;

n means the number of 1-15; and

the term "substituted" refers to phenyl Deputy selected from (ness.)of alkyl of 1-4 carbon atoms, (ness.)alkoxy of 1-4 carbon atoms, (ness.)alkylthio of 1-4 carbon atoms, hydroxy, chlorine, bromine or fluorine.

Preferred selective inhibitors of neutral endopeptidase formula II include compounds

where

R2means benzyl;

R3means hydrogen;

n denotes a number from 1 to 9; and

R1means hydroxy.

Even more preferred is a selective inhibitor of neutral endopeptidase formula II is described in the literature as SQ 28603, which means the compound of formula II,

where

R2means benzyl;

R3means hydrogen;

n is 1; and

R1means hydroxy.

Getting selective inhibitors of neutral endopeptidase formula II, where R2other than trifluoromethyl, revealed Delaney and others in the patent US 4722810. Getting selective inhibitors of neutral endopeptidase formula II, where R2means trifluoromethyl, revealed Delaney and others in the patent US 5223516.

Inhibitors of NEP in the scope of the present invention include compounds disclosed in US patent 4610816, inserted in the context, by citation, the key especially N-[N-[1(S)-carboxyl-3-phenylpropyl]-(S)-i.e. phenylalanyl]-(S)-isomeren and N-N-[((1S)-carboxy-2-phenyl)ethyl]-(S)-i.e. phenylalanyl]-β -alanine; compounds disclosed in US patent 4929641, in particular N-[2(S)-mercaptomethyl-3-(2-were-propionyl]methionine; SQ 28603, (N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine), disclosed in the application 84/0670; UK 69578 reveals CIS-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonyl]amino]cyclohexanecarbonyl acid and its active enantiomer(s); thiorphan and its enantiomers; recreatiohal; phosphoramidon; and SQ 29072, (7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]-heptane acid). Also useful for applying are any depot-forms above NEP inhibitors, such as compounds in which one or more carboxyl groups tarifitsirovana.

Inhibitors of NEP in the scope of the present invention also include compounds disclosed in US patent 5217996, in particular the ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid and N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate-4-amino-2R-methylbutanoyl acid or in each case its or its pharmaceutically acceptable salt; compounds disclosed in the patent EP 00342850, especially (S)-CIS-4-[1-[2-(5-intenrational)-3-(2-methoxyethoxy)propyl]-1-cyclopentanecarboxylic]-1-cyclohexanecarbonyl acid; the compounds disclosed in the patent GB 02218983, in particular 3-(1-[6-endoperoxides[2,2,1]heptane-2-ectocarpales]cyclopent the l)-2-(2-methoxyethoxy)propanoic acid; compounds disclosed in the application WO 92/14706, in particular the methyl ester of N-(1-(3-(N-tert-butoxycarbonyl-(S)-propylamino)-2(S)-tert-butoxycarbonylmethyl)cyclopentanecarbonyl)-O-benzyl-(S)-serine; compounds disclosed in the patent EP 00343911; compounds disclosed in JP patent 06234754; compounds disclosed in the patent EP 00361365, especially 4-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]benzoic acid; the compounds disclosed in the application WO 90/09374, in particular 3-[1-(CIS-4-carboxyterminal-CIS-3-butylcyclohexyl-1-carbarnoyl)cyclopentyl]-2S-(2-methoxyethoxymethyl)propanoic acid; the compounds disclosed in JP patent 07157459, in particular N-((2S)-2-(4-biphenylyl)-4-carboxy-5-phenoxyphenyl)glycine; compounds disclosed in the application WO 94/15908, in particular N-(1-(N-hydroxycarbonylmethyl)-1-cyclopentanecarbonyl)-L-phenylalanine; compounds disclosed in US patent 5273990, particularly (S)-(2-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)ethylamino)methylphosphonous acid; the compounds disclosed in the patent US 5294632, particularly (S)-5-(N-(2-(phosphonomethyl)-3-(4-biphenyl)propionyl)-2-amino-ethyl)tetrazol; compounds disclosed in patent US 5250522, especially β-alanine, 3-[1,1'-biphenyl]-4-yl-N-[diphenoxyethane)methyl]-L-alanine; compounds disclosed in the patent EP 00636621, in particular N-(2-carboxy-4-thienyl)-3-mercapto-2-benzoylpropionic; compounds disclosed in the application WO 93/09101, in particular 2-(2-mercap the o-methyl 3-phenylpropionamide)thiazole-4-inkarbaeva acid; compounds disclosed in the patent EP 00590442, especially (L)-(1-((2,2-dimethyl-1,3-dioxolane-4-yl)-methoxy)carbonyl)-2-phenylethyl)-L-i.e. phenylalanyl)-β-alanine, N-[N-[(L)-[1-[(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy]carbonyl] -2-phenylethyl]-L-i.e. phenylalanyl]-(R)-alanine, N-[N-[(L)-1-carboxy-2-phenylethyl]-L-i.e. phenylalanyl]-(R)- alanine, ethyl ester of N-[2-acetyltributyl-3-(2-were)propionyl]methionine, N-[2-mercaptomethyl-3-(2-were)propionyl]methionine, N-[2(S)-mercaptomethyl-3-(2-were)propanol]-(S)-isomeren, N-(S)-[3-mercapto-2-(2-were)propionyl]-(S)-2-methoxy-(R)-alanine, N-[1-[[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino]cyclopentanecarbonyl]-(S)-isomeren, N-[1-[[1(S)-carbonyl-3-phenylpropyl]amino]cyclopentanecarbonyl]-(S)-isomeren, 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-isomeren, 1,1'-[dithiobis-[2(S)-(2-methylbenzyl)-1-oxo-3,1-propanediyl]]-bis-(S)-methionine, N-(3-phenyl-2-(mercaptomethyl)propionyl)-(S)-4-(methylmercapto)methionine, N-[2-acetyltributyl-3-phenylpropionyl]-3-aminobenzoic acid, N-[2-mercaptomethyl-3-phenylpropionyl]-3-aminobenzoic acid, N-[1-(2-carboxy-4-phenylbutyl)cyclopentanecarbonyl]-(S)-isomeren, ethyl ester of N-[1-(acetyltributyl)cyclopentanecarbonyl]-(S)-methionine, 3(S)-[2-(acetyltributyl)-3-phenylpropionyl]amino-c-caprolactam; and the compounds disclosed in the application WO 93/10773, in particular the ethyl ester of N-(2-acetyltributyl-3-(2-were)propionyl)methionine.

Di is retik means, for example, the derived thiazide selected from the group consisting of chlorothiazide, hydrochlorothiazide, methylclothiazide and chlorthalidone. Most preferred is hydrochlorothiazide. Connections that need to be combined can be present in the form of pharmaceutically acceptable salts. If these compounds contain, for example, at least one basic center, they can form acid additive salt. The corresponding acid additive salts may also be formed having optionally present basically the center. Compounds containing at least one acid group (for example COOH)can also form salts with bases. In addition, can be formed corresponding internal salts, if the compound contains, for example, as carboxypropyl and the amino group.

As for the ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid, the preferred salts include sodium salt disclosed in patent US 5217996, salt and triethanolamine salt and with Tris(hydroxymethyl)aminomethane. Getting salt triethanolamine and salts with Tris(hydroxymethyl)aminomethane can be carried out as follows.

Triethanolamine: ethyl ether, N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic sour is you (349 mg, 0,848 mmol) was added 5 ml of ethyl ether and 0,113 ml (0,848 mmol) of triethanolamine in 1 ml of ethyl acetate. The solid is collected and dried, melting at 69-71°C.

Tris(hydroxymethyl)aminomethan: ethyl ether, N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid (3.2 g, 7,78 mmole) was added 32 ml of ethyl acetate and 940 mg (7,78 mmole) of Tris(hydroxymethyl)aminomethane. The suspension was diluted with 45 ml of ethyl acetate and heated at boiling during the night (about 20 hours). The reaction mixture was cooled to 0°C, filtered, the solid washed with ethyl acetate and dried, melting at 114-115°C.

Salt of the ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid with triethanolamine and Tris(hydroxymethyl)aminomethane are new and can be used as inhibitors of NEP. Another alternative embodiment of the present invention are referred to new salts, their use as inhibitors of NEP, especially for the prevention and treatment of conditions and disorders associated with inhibition of NEP, the pharmaceutical composition comprising these salts and their combination with valsartan, in particular for treating conditions and diseases, as disclosed for combinations of the present invention above and beyond.

Suddenly it was ideno, the combination of valsartan and NEP inhibitor gives a greater therapeutic effect than the introduction of valsartan, ACE inhibitors, or inhibitors of NEP separately, and promotes the formation of angioedema less than observed with the introduction of a single inhibitor vasopeptidase. Higher efficiency can also be justified as increased duration of action. The duration can be controlled or time to return to baseline before the next dose, or as the area under the curve (AUC) and Express as a result of changes in blood pressure in mm Hg (change in mm Hg) and duration (minutes, hours or days).

Further advantages are that can be used lower doses of the individual drugs to be combined according to the present invention, to reduce the dosage, for example, requires that in most cases, doses were not only smaller, but also applied less frequently, or could be used to reduce the frequency of side effects. The combined introduction of valsartan or its pharmaceutically acceptable salt and NEP inhibitor or its pharmaceutically acceptable salt leads to a significant response in a large percentage exposed in the treatment of patients, i.e. leads to greater speed feedback or suggestions is as responsible body, regardless of the underlying etiology of the condition. This corresponds to the wishes and needs of patients, which must be subjected to therapy.

It can be shown that combination therapy with valsartan and NEP inhibitor leads to more effective antihypertensive therapy (malignant, primary arterial, renovascular, diabetic, isolated systolic, or other symptomatic of the type of hypertension) through improved efficiency and greater responsiveness of the responding organism. The combination is also useful in the treatment or prevention of heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter or harmful vascular reconstruction. In addition, it was shown that treatment with valsartan and NEP inhibitor has proved that it is useful in the treatment and prevention of myocardial infarction and its consequences. The combination of valsartan plus a NEP inhibitor useful in the treatment of atherosclerosis, angina (stable or unstable) and renal insufficiency (diabetic and nediabeticescoy). Moreover, combiner the bathroom therapy, using valsartan and a NEP inhibitor, can improve endothelial dysfunction, thereby providing an advantage in diseases in which normal endothelial function is impaired, such as heart failure, angina and diabetes. In addition, the combination of the present invention can be used for the treatment and prevention of secondary aldosteron, primary and secondary pulmonary hypertension, States renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's), glaucoma and stroke.

The structure of the active agents identified by generic or trade names or code numbers can be obtained from the current edition of the standard guide "The Merck Index" or from databases, e.g. Life Cycle Patents International (e.g. IMS World Publications). Corresponding to the content that is included by citation. Any expert in this area are fully able to identify active agents and, based on this Ref is Oh, able thus to receive and investigate pharmaceutical indications and properties in standard experimental models both in vitro and in vivo.

The subject of NEP inhibitors, include, for example, US patents, EP, GB, JP, or applications WO hereby incorporated by citation, especially relevant inhibitors of NEP and their pharmaceutically acceptable salts and pharmaceutical compositions that are described in the claims or disclosed in the working examples.

The person skilled in the art are fully capable of selecting relevant experimental model to prove the effectiveness of the combination of the present invention in therapeutic indications above and beyond.

Representative research was carried out with the combination of valsartan and ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid, for example, using the following methodology.

The effectiveness of the drug has been evaluated in various animal models, including the rat treated with acetate hypertension and salt (DOGA-salt), and a rat with spontaneous hypertension (SHR) or supported on a normal salt diet, or with a salt load (4-8% of salt in the diet of rats or 1% sodium chloride in drinking water).

Experimental model of DOCA-salt uses a Protocol or acute, or XP the technical studies. Methods acute study includes an assessment of the effects of different studied species in the six-hour experimental period, using rats with constantly femoral arterial and venous catheters. Methods acute study evaluates the analyte on their ability to lower blood pressure during the established phase of DOCA-salt hypertension. In contrast, the method of the chronic study evaluates the ability of the investigated substances to prevent or delay the rise in blood pressure during the evolutionary phase of DOCA-salt hypertension. Therefore, the blood pressure in the method of the chronic studies will be controlled by radio. The radio surgically implanted in the abdominal aorta of the rat before beginning processing DOCA-salt and, thus, before the induction of hypertension. Blood pressure is constantly monitored for periods up to 6 weeks (approximately one week before the introduction of DOCA-salt and within 5 weeks after).

Rats were given General anesthesia with 2-3% isoflurane in oxygen inhalation, then use amytal sodium (amobarbital) at a dose of 100 mg/kg intraperitoneally. The level of anesthesia was assessed by using features relaxed rhythmic breathing.

Methods acute studies

Rats subjected is whether unilateral nephrectomy during implantation of the DOCA. The coat is fastened by clamps on the left side and the back side of the neck and was treated with sterile swabs with alcohol and povidone/iodine. During the surgery the rats were placed on a heating pad to maintain the temperature at 37°C.

Did a 20 mm incision through the skin and under it the muscle to select the left kidney. The kidney was freed from the surrounding tissue, taken out temporarily on the surface of the body, and two ligatures (3-0 silk) is securely fastened around the renal artery and vein, located proximally to their connection to the aorta. Then the renal artery and vein was cut and the kidney was removed. Muscle and skin wound was closed with surgical suture (4-0 silk) and clips for wounds stainless steel, respectively. At the same time did a 15 mm incision on the back of the neck and implanted subcutaneously into pellets with the release of the active ingredient within 3 weeks (Innovative Research of America, Florida)containing acetate hypertension (100 mg/kg). The wound was then closed with stainless steel clamps, and both wounds were treated with povidone/iodine; rats performed surgical intramuscular injection of penicillin G (100,000 UNITS) against the background of procaine and subcutaneously was taking buprenorphine (0.05-0.1 mg/kg). Rats immediately put drinking water containing 1% sodium chloride and 0.2% potassium chloride; this processing etc which was doliolus at least 3 weeks during this time the animals became hypertensive and available for experimentation.

For forty-eight hours before the experiments, animals were given General anesthesia with isoflurane and implanted catheters in the femoral artery and vein for measurement of pressure, blood collection and injection of the investigated compounds. The rats were allowed to recover for 48 h when kept them bound in a cage for habitation made of organic glass, which also served as the experimental chamber.

Methods chronic studies

This technique such as described above, except that rats implanted the microwave for 7-10 days prior to unilateral nephrectomy and start processing DOCA and salt. In addition, rats were subjected to surgical intervention for the installation of femoral arterial and venous catheters. Radio sensors implanted, as described ..Bazil, .Krulan and R.L.Webb. Telemetric monitoring of cardiovascular parameters in conscious spontaneously hypertensive rats. J.Cardiovasc.Pharmacol. 22:897-905, 1993.

Then the protocols were entered into a computer for measuring blood pressure, speed, heart rate, etc. at predetermined time points. Data baseline was collected at various time points and for different time intervals. For example, the base line values prior dose usually consists of a set of data and averaging in t the value of 3 consecutive 24-hour periods before the introduction of the drug.

Blood pressure, speed, heart rate and activity were determined in different pre-selected time points before, during and after drug administration. All measurements were performed on unlimited and intact animals. The biggest time of the study, as determined by a combination of several criteria of life, could be up to nine months. For studies of this duration, the rats were given oral (1-3 ml/kg of filler) not more than twice a day or injected drug in the water for drinking or mixed with food. For studies with shorter duration, i.e. up to 8 weeks, the drugs were injected via subcutaneously implanted osmotic mini-pumps. Osmotic mini-pumps were chosen based on the speed and time of delivery of the drug. Dose valsartan ranged from 1 to 10 mg/kg/day, and doses of ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid was changed in the range from 10 to 50 mg/kg/day.

In addition, rats with spontaneous hypertension (SHR) were used to study the effects of valsartan in combination with the ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid. Hypertensive background SHR modified or with chronic salt loading in an attempt to suppress the system the renin-angiotensin (RAS), or chronic salt depletion to activate RAS in rats with spontaneous hypertension. These manipulations will be carried out to more broadly evaluate the effectiveness of various of the compounds under investigation. The experiments were conducted on rats with spontaneous hypertension (SHR), supplied by Taconic Farms, Germantown, New York (Tac:N(SHR)fBR). Radiotelemetric device (Data Sciences International, Inc. St. Paul, Minnesota) implanted in the lower abdominal aorta in all studied animals aged between 14 and 16 weeks. All SHR were allowed to recover from the surgical procedure of implantation for at least 2 weeks before experiments. Cardiovascular parameters were continuously monitored using radio and transmitted to a receiving device, where the converted digital signal is then located and stored using the computerized system of collected data. Blood pressure (mean arterial, systolic and diastolic pressure) and the rate of heart contractions controlled from being conscious, freely moving and intact SHR, which are in the cells for habitation. Arterial blood pressure and rate of heart contractions was measured every 10 min for 10 s and recorded. Data reported for each rat, represent average values, renandya within 24-hour period and is composed of 144 ten-minute measurements, collect every day. The baseline values for blood pressure and rate of heart contractions consists of the average value of three consecutive 24-hour measurements obtained before beginning treatment with the drug. All rats individually housed in a room with controlled temperature and humidity and were kept under a 12-hour cycle of light / dark.

In addition to cardiovascular parameters in all rats recorded measurement data of body weight. The drugs were injected in the water for drinking orally via a stomach tube or by using osmotic mini-pumps, as described above. In the case of the introduction of water for drinking water consumption was measured five times per week. Doses of valsartan and ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid was then calculated based on water consumption for each rat, the drug concentration in drinking water and individual body masses. All solutions of drugs were prepared fresh every 3-4 days. In combination use lower doses of each drug, and accordingly valsartan is introduced in the range of 1-30 mg/kg/day and ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid in doses below 50 mg/kg/day. However, when combination therapy increases Corot response of the human body, doses identical to those used in monotherapy.

When drugs are administered orally using a stomach probe, the dose of valsartan varies from 1 to 50 mg/kg/day, and ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid does not exceed 100 mg/kg/day.

Upon completion of the chronic studies SHR and treated DOCA-salt rats were given anesthesia and quickly removed the heart. After separation and removal of the ear auricle left ventricle and the left plus right ventricle (total) was weighed and recorded. Left ventricular and total ventricular mass was then led to body weight and described. All values reported for blood pressure and the mass of the heart, represent group average ± the standard deviation.

Vascular function and structure were assessed after treatment to determine the beneficial effect of the combination. SHR investigated in accordance with the techniques described Intengan H.D., Thibault G., Li J.S., Schiffrin E.L., Circulation 1999, 100 (22): 2267-2275. Similarly, the methodology for the assessment of vascular function in rats treated with DOCA-salt described Intengan H.D., Park, J.B., Schiffrin, E.L., Hypertension, 1999, 34(4 part 2): 907-913.

The results indicate an unexpected therapeutic effect of the combination according to the invention.

In one aspect the object of this invention is the I provision of a pharmaceutical combination compositions for example, for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental to the health of the reconstruction of blood vessels, myocardial infarction and its consequences, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nediabeticescoy), heart failure, angina pectoris, diabetes, secondary aldosteron, primary and secondary pulmonary hypertension, States renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's), glaucoma and stroke, the composition that includes (i) receptor antagonist at-1 valsartan or its pharmaceutically acceptable salt and (ii) a NEP inhibitor or it is pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. Additional active ingredient can be a diuretic, especially hydrochlorothiazide.

In this composition, the components (i) and (ii) can be obtained and put together, one after the other or separately in one combined standard dosage form or in two separate standard dosage forms. Standard dosage form may also be defined by a combination.

An additional aspect of the present invention is a method of treating or preventing the condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental to the health of the reconstruction of blood vessels, myocardial infarction and its consequences, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nediabeticescoy), heart failure, angina pectoris, diabetes, secondary aldosteron, primary and secondary pulmonary hypertension, States renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, the protein is AI with primary renal disease, and also renal vascular hypertension, diabetic retinopathy, the management of other vascular disorders, such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's), glaucoma and stroke, including the introduction of a therapeutically effective amount of the combination (i) receptor antagonist at-1 valsartan or its pharmaceutically acceptable salt and (ii) a NEP inhibitor or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier to a mammal in need of such treatment.

A therapeutically effective amount of each component of the combination according to the present invention can be introduced simultaneously or sequentially and in any order.

Corresponding active ingredient or its pharmaceutically acceptable salt can also be used in the form of hydrates or include other solvents used for crystallization.

The pharmaceutical compositions according to the invention can be obtained well-known, in fact, the way and ways suitable for enteral, such as oral or rectal, and parenteral administration mammals (warm-blooded mammals), covering human, comprising a therapeutically effective amount of pharmacologically active compounds, one or in combination with one or bore alkemi pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. Conventional oral formulations include tablets, capsules, syrups, elixirs and suspensions. Conventional injectable forms include solutions or suspensions.

Examples of typical pharmaceutically acceptable carriers for use in the combinations described above are: sugars such as lactose, sucrose, mannitol and sorbitol; starches such as corn starch, the starch from tapioca and potato starch; cellulose and its derivatives, such as carboxymethylcellulose sodium form, ethylcellulose and methylcellulose, calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone; polyvinyl alcohol; stearic acid, stearates alkaline-earth metals such as magnesium stearate and calcium stearate; stearic acid; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; polymers of ethylene glycol; β-cyclodextrin; fatty alcohols; and hydrolyzed solids cereals, as well as other non-toxic compatible fillers, binders, disintegrators, buffers, preservatives, antioxidants, lubricity agents, flavouring agents and the fact is such, commonly used in pharmaceutical compositions.

The invention also relates to combining separate pharmaceutical compositions in the form of a set. That is, the set that combines two separate units: the pharmaceutical composition of valsartan and pharmaceutical composition of the NEP inhibitor. The set is particularly useful when two separate components must be entered in different dosage forms (e.g., parenteral form of valsartan and oral form NEP inhibitor) or introduced with different dose intervals.

These pharmaceutical preparations are preparations for enteral, such as oral, and also rectal, or parenteral administration of warm-blooded animals, drugs, containing a pharmacologically active compound, or one, or together with customary pharmaceutical excipients. For example, pharmaceutical preparations comprise from about 0.1% to 90%, preferably from about 1% to about 80% active compounds.

Pharmaceutical preparations for enteral or parenteral administration are, for example, in standard dosage forms, such as tablets, coated tablets, capsules or suppositories, and also ampoules. Get them in a manner which is known in fact, for example, using conventional methods of mixing, g is nusli, coating, solubilization, or lyophilization. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, if required, by granulation of the mixture, which was received, and if required or necessary, after the addition of appropriate excipients - processing the mixture or granulate into tablets or cores tablets coated.

The dose of the active compounds may depend on various factors such as the type of introduction, warm-blooded species, age and/or individual condition.

The preferred dose of the active ingredients for the pharmaceutical combination of the present invention are therapeutically effective dose, especially those that are commercially available.

Usually in the case of oral administration the approximate daily dose from about 1 mg to about 360 mg must be installed, for example, for a patient weighing about 75 kg

Valsartan comes in the form of a corresponding standard dosage forms, such as capsules or tablets containing a therapeutically effective amount, for example, from about 20 to about 320 mg of valsartan, which can be applied by the patients. The use of active ingredient may occur up to three times a day, starting for example, with daily doses of 20 mg or 40 mg of valsartan, increasing from 80 mg daily and further to 160 mg daily up to 320 mg daily. It is preferable in patients with heart failure valsartan apply once daily or twice daily dose of 80 mg or 160 mg, respectively, each. The appropriate dose can be, for example, morning, noon or evening. Preferred in heart failure is the introduction of four or two times a day.

In the case of NEP inhibitors preferred standard dosage forms are, for example, tablets or capsules comprising, e.g., from about 20 mg to about 800 mg, preferably from about 50 mg to about 700 mg, even more preferably from about 100 mg to about 600 mg, and more preferably from about 100 mg to about 300 mg, entered once a day.

In the case of diuretics preferred standard dosage forms are, for example, tablets or capsules comprising, e.g., from about 5 mg to about 50 mg, preferably from about 6.25 mg to about 25 mg Daily dose of 6.25 mg, 12.5 mg or 25 mg of hydrochlorothiazide preferably is injected once a day.

The above doses comprise a therapeutically effective amount of the active ingredients of the present invention.

The following examples and lusterous described above the invention; however, this does not imply in any way limiting the scope of the invention.

Example 1 obtaining dosage forms

Tablets coated

ComponentsComposition per (mg)Standards
Granulation
Valsartan (active ingredient)80,00
Microcrystalline cellulose/ avicel PH 10254,00NF, USP Europe
Crosspovidone20,00NF, USP Europe
Anhydrous colloidal SiO2/colloidal SiO2/Aerosil 2000,75The European Pharmacopoeia/NF
Magnesium stearate2,5NF, USP Europe
Mixing
Anhydrous colloidal SiO2/colloidal SiO2/Aerosil 2000,75The European Pharmacopoeia/NF
Magnesium stearate2,00NF, USP Europe
Coating
Purified water*-
DILAK pale red 00F348997,00
The total mass that is yrs 167,00
* Removed during processing

The tablet with the coating is made, for example, as follows.

A mixture of valsartan, microcrystalline cellulose, crosspovidone, part of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 200, silicon dioxide and magnesium stearate are pre-mixed in a diffusion mixer and then sift through the sorting shredder. The resulting mixture was again mixed in a diffusion mixer, compacted in a roller press, and then sift through the sorting shredder. To the resulting mixture add the remainder of the colloidal anhydrous silica/colloidal silicon dioxide/Aerosil 200, and the final mixture is treated in a diffusion mixer. The entire mixture is pressed in a rotary tablet press machine and the tablets are coated using dilak pale red in the perforated container.

Example 2 obtain the dosage forms

Tablets coated

tr>
ComponentsComposition per (mg)Standards
Granulation
Valsartan (active ingredient)160,00
Microcrystalline cellulose/ avicel PH 102108,00NF, USP Europe
Crosspovidone40,00NF, USP Europe
Anhydrous colloidal SiO2/colloidal SiO2/Aerosil 2001,5The European Pharmacopoeia/NF
Magnesium stearate5,0NF, USP Europe
Mixing
Anhydrous colloidal SiO2/colloidal SiO2/Aerosil 2001,5The European Pharmacopoeia/NF
Magnesium stearate4,00NF, USP Europe
Coating
Opadry® pale brown OOF331727,00
Total weight pills330,00

The tablet with the coating is made, for example, as described in example 1, obtaining the medicinal form.

Example 3 obtaining dosage forms

Tablets coated

ComponentsComposition per (mg)Standards
Core: the inner phase
Valsartan (active ingredient) 40,00
Silica, colloidal anhydrous (colloidal silicon dioxide) (slip agent)1,00The European Pharmacopoeia, USP/NF
Magnesium stearate (lubricant)2,00USP/NF
Crosspovidone (disintegrator)20,00The European Pharmacopoeia
Microcrystalline cellulose (binder)124,00USP/NF
External phase
Silica, colloidal anhydrous (colloidal silicon dioxide) (slip agent)1,00Pharmacopoeia Europe, USA/NF
Magnesium stearate (lubricant)2,00USP/NF
Coating
Opadry® brown OOF 16711*9,40
Purified water**-
Total weight pills199,44
* The composition of the coloring agent Opadry® brown OOF 16711 listed in the following table.

** Removed during processing.

The composition of Opadry®

IngredientApproximate % of songs
Iron oxide black (C.I. No. 77499, E 172)0,50
Iron oxide brown (C.I. No. 77499, E 172)0,50
Iron oxide red (C.I. No. 77491, E 172)0,50
Iron oxide yellow (C.I. No. 77492, E 172)0,50
Macropomum (European Pharmacopoeia)4,00
Titanium dioxide (C.I. No. 77891, E 171)14,00
Hypromellose (USP Europe)80,00

The tablet with the coating is made, for example, as described in example 1, obtaining the medicinal form.

Example 4 obtaining dosage forms

Capsules

ComponentsComposition per unit (mg)
Valsartan (active ingredient)80,00
Microcrystalline cellulose25,10
Crosspovidone13,00
Povidone12,50
Magnesium stearate1,30
Sodium lauryl sulfate0,60
The shell
Iron oxide red (C.I. No. 77491, EU No. E 172)0,123
Iron oxide yellow (C.I. No. 77492,EU No. 72 El) 0,123
Iron oxide black (C.I. No. 77499, EU No. E 172)0,245
Titanium dioxide1,540
Gelatin74,969
Total tablet weight209,50

The tablet produced, for example, as follows.

Granulation/drying

Valsartan and microcrystalline cellulose was granulated by spraying in a fluidized bed granulator with coating, granulating solution consisting of povidone and sodium lauryl dissolved in purified water. The obtained granulate was dried in the drying device fluidized bed.

Grinding/mixing

The dried granules were crushed together with crosspovidone and magnesium stearate. Then the mass was mixed in a conical screw mixer type for about 10 minutes

Encapsulation

Empty hard gelatin capsules were filled with mixed bulk granules under conditions of controlled temperature and humidity. Filled capsules were freed from dust, visually examined, tested the weight and insulated until with the help of the Department of quality assurance.

Example 5 obtaining dosage forms

Capsules

ComponentsComposition per unit (mg)
160,00
Microcrystalline cellulose50, 20mm
Crosspovidone26,00
Povidone25
Magnesium stearate2,60
Sodium lauryl sulfate1,20
The shell
Iron oxide red (C.I. No. 77491, EU No. E 172)0,123
Iron oxide yellow (C.I. No. 77492, EU No. 72 El)0,123
Iron oxide black (C.I. No. 77499, EU No. E 172)0,245
Titanium dioxide1,540
Gelatin74,969
Total tablet weight342,00

Dosage form produced, for example, as described in example 4 to obtain the dosage form.

Example 6 obtaining dosage forms

Hard gelatin capsule

ComponentsComposition per unit (mg)
Valsartan (active ingredient)80,00
Sodium lauryl sulfate0,60
Magnesium stearate1,30
Povidone12,50
Crosspovidone13,00
Microcrystal the ical pulp 21,10
Total tablet weight130,00

Example 7 get dosage forms

Hard gelatin capsule, containing as the active ingredient, for example, (S)-N-(1-carboxy-2-methylprop-1-yl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine may be prepared, for example, as follows.

Composition:

(1) valsartan80.0 mg
(2) microcrystalline cellulose110,0 mg
(3) polyvidone K-3045,2 mg
(4) sodium lauryl sulfate1.2 mg
(5) crosspovidone26,0 mg
(6) magnesium stearate2.6 mg

Components (1) and (2) was granulated with a solution of components (3) and (4) in the water. Added components (5) and (6) to the dry granulate and the mixture was filled in hard gelatin capsules of size 1.

All publications and patents mentioned in the context, in their entirety incorporated by citing, as if they were set forth in the context completely.

1. Pharmaceutical combination

(i) the antagonist at-1 valsartan or its pharmaceutically acceptable salt in a single daily dose of from about 20 mg to about 320 mg, and

(ii) and hibitor NEP representing the ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid or N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoyl acid or its pharmaceutically acceptable salt in a single daily dose of from about 20 mg to about 800 mg

and pharmaceutically acceptable carrier

for the treatment or prevention of a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental to the health of the reconstruction of blood vessels, myocardial infarction and its consequences, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nediabeticescoy), heart failure, angina pectoris, diabetes, secondary aldosteron, primary and secondary pulmonary hypertension, States renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease, and also renal vascular hypertension, di is piticescu retinopathy, ability to cope with other vascular disorders such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's), glaucoma and stroke.

2. The pharmaceutical combination according to claim 1, including a NEP inhibitor, which represents an ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid or its salt with triethanolamine or Tris(hydroxymethyl)aminomethane.

3. The pharmaceutical combination according to claim 1, additionally containing a diuretic.

4. Kit for treating or preventing the condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental to the health of the reconstruction of blood vessels, myocardial infarction and its consequences, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nediabeticescoy), heart failure, angina pectoris, diabetes, secondary aldosteron, primary and secondary pulmonary hypertension, States renal is inadequate the STI, such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease, and also renal vascular hypertension, diabetic retinopathy, ability to cope with other vascular disorders such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's), glaucoma and stroke, containing in one package in separate tanks pharmaceutical combination, comprising in one container a pharmaceutical composition comprising ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid or N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoyl acid or their pharmaceutically acceptable salt and in a second container a pharmaceutical composition comprising valsartan.

5. A method of treating or preventing a condition or disease selected from the group consisting of hypertension, heart failure such as (acute and chronic) congestive heart failure, left ventricular dysfunction and hypertrophic cardiomyopathy, diabetic cardiac myopathy, supraventricular and ventricular arrhythmias, atrial fibrillation, atrial flutter, detrimental to health reconstruction the AI vessels, myocardial infarction and its consequences, atherosclerosis, angina (unstable or stable), renal insufficiency (diabetic and nediabeticescoy), heart failure, angina pectoris, diabetes, secondary aldosteron, primary and secondary pulmonary hypertension, States renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria in primary renal disease, and also renal vascular hypertension, diabetic retinopathy, ability to cope with other vascular disorders such as migraine, disease, peripheral vascular disease, Raynaud's disease, luminal hyperplasia, dysfunction of consciousness (such as Alzheimer's disease), glaucoma and stroke, including the introduction of a therapeutically effective amount of the combination (i) receptor antagonist at-1 valsartan or pharmaceutically acceptable salts in a single daily dose of from about 20 mg to about 320 mg and (ii) ethyl ester of N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoic acid or N-(3-carboxy-1-oxopropyl)-(4S)-n-phenylphenolate)-4-amino-2R-methylbutanoyl acid or its pharmaceutically acceptable salt in a single daily dose of from about 20 mg to about 800 mg



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns valsartan pill obtained by pressing. A pill contains pharmacologically effective valsartan quantity, filler and fluffer. Weight ratio of valsartan to filler is 2:1 to 0.3:1. Weight ratio of valsartan to fluffer is 2.9:1 to 1:1. The pill includes over 30 mass % of filler. Preferable filler is monocrystallic cellulose. Preferable fluffer is crospovidone. The claimed pill has at least 1.2 times higher biological accessibility in comparison to the known valsartan-containing composition.

EFFECT: increased biological accessibility of valsartan-containing composition.

9 cl, 2 dwg, 4 tbl, 8 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention proposes a lipid compound with formula (I): , where PHG is a polar head group, obtained from one of the following: phospholipid, lysophospholipid, ceramides, monoacylglycerine, diacylglycerine and triacylglycerine, or -W-Linker-HG, p is a number from 1 to 3, X is independently chosen from C6-24alkenyl, containing one or more double bonds and, possibly, one or more triple bonds, or C6-24alkyl, which are can be substituted with at least one of the following: F, hydroxy, C1-C4alkoxy, C1-C4alkylthio, C2-C5acyloxy and C1-C4alkyl; Y chosen from at least one of S, Se, SO2, SO, O and CH2; and Z is a C1-C10alkyl residue, where each of the X, Y and Z groups is chosen independently, when p is 2 or 3, under the condition that, at least one Y does not represent CH2. Description is also given of the use of formula (I) compound or its pharmaceutical salt in the production of medicinal preparations for curing and/prevention of different conditions, pharmaceutical composition, containing formula (I) compound and the method of obtaining a lipid compound with formula (I).

EFFECT: obtaining sulphur containing phospholipid compounds, with useful biological properties.

58 cl, 8 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to processing of reindeer products, specifically to method of biologically active product making of antler reindeer tails. Method implies that raw material is milled to make particles 150-400 mcm, extracted with followed filtration of end product, at that distilled water is used as extracting agent; extraction is performed at temperature 120-126°C during 1.5-2.5 hours at ratio water - raw material 5:1-6:1.

EFFECT: production of aqueous extract having high biological activity and applicable for patients with contraindication to alcohol-containing medicinal agents.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 represents (C1-C4)-alkyl with branched or linear chain; R2 represents hydrogen atom (H); R3 represents (C1-C4)-alkyl with branched or linear chain; R4 represents (C1-C4)-alkyl with branched or linear chain, (C2-C4)-alkenyl; R5 represents -SO2NR10R11; R8 represents (C1-C4)-alkyl with branched or linear chain; each R10 and R11 represents independently H or (C1-C12)-alkyl with branched or linear chain; or R10 and R11 in common with nitrogen atom to which they are bound form pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl that are substituted optionally with (C1-C4)-alkyl with branched or linear chain, -NR14R15, phenyl group substituted optionally with -OH or phenyl group bound in common with other substituted phenyl group by carbonyl group; R13 represents (C1-C4)-alkyl with branched or linear chain, (C2-C6)-alkyl with branched or linear chain and substituted with hydroxyl; (C2-C6)-alkyl with branched or linear chain substituted with phenyl; (C2-C6)-hydrocarbon with branched or linear chain substituted with -CO2R8; wherein each radical among R14 and R15 represents independently H; (C1-C4)-alkyl with branched or linear chain, or its pharmaceutically acceptable salt. The claimed compounds possess inhibitory effect on activity of phosphodiesterase-5 and can be used for production of drug for treatment or prophylaxis of diseases associated with phospholipase and its function. Also, invention relates to pharmaceutical composition, medicinal composition for veterinary science, and intermediate compounds IA-IG used for synthesis of compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

8 cl, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, biochemistry pharmacy.

SUBSTANCE: invention relates to using the known 2-phenyl-substituted imidazotriazinone of the formula (I): (vardenafil) possessing improved properties as compared with other known inhibitors of phosphodiesterase-5 (PDE-5), such as sildenafil and tadalafil. Proposed compound is used for preparing drugs used in treatment of cardiac insufficiency.

EFFECT: valuable medicinal and biochemical properties of compound.

1 tbl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to 1,4,5,6-tetrahydro-6-oxo-5-(2-piperazinoethyl)-4-phenyl-3-(4-chlorophenyl)pyrrolo[3.4]pyrazole dihydrochloride of the formula (I): . This compound is synthesized by interaction of 1-(2-piperazinoethyl)-5-phenyl-4-(4-chlorobenzoyl)-3-hydroxy-3-pyrrolin-2-one dihydrochloride with hydrazine hydrate. Synthesized compound can be used in medicine as agent decreasing arterial blood pressure and blood coagulation. Invention provides synthesis of a novel compound not described early that possesses hypotensive and anti-coagulant effect simultaneously.

EFFECT: valuable medicinal properties of compound.

3 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical compositions containing inhibitor of cholesterol esters-transporting protein (CETP) and a water-insoluble additive increasing its concentration. As CETP inhibitor invention uses S-{2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl}-2-methylpropanethioate or a prodrug that forms in vivo S-{2-([[1-(2-ethylbutyl)cyclohexyl]carbonyl]amino)phenyl}-thiol. A water-insoluble additive increasing the concentration of CETP inhibitor represents crospovidon. Indicated compositions show improved bioavailability in medium wherein they are used that allows using in methods for treatment of cardiovascular disorders.

EFFECT: improved and valuable pharmaceutical properties of compositions.

13 cl, 11 tbl, 5 dwg, 9 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes a hypotensive medicinal agent as tablet that comprises captopril, mixture of lactose of particles size above 0.2 mm and microcrystalline cellulose in the ratio from 73:1 to 49:25, respectively, and lubricating agent. Agent is made as a tablet of mass from 0.1 to 0.3 g with the content of captopril 25 or 50 mg. Invention provides making captopril tablets decomposing for 15 min and satisfying Pharmacopoeia requirements by all indices and showing stability in production and storage for 5 years.

EFFECT: improved and valuable pharmaceutical properties of agent.

3 cl, 1 dwg, 4 tbl, 6 ex

FIELD: pharmaceutical industry and technology, pharmacy, medicine, phytotherapy.

SUBSTANCE: method involves three-times extraction of milled coriander herb with 40% ethyl alcohol taken in the ratio raw : extractant = 1:5 for 1 h in each extraction step. Extracts are combined, filtered, ethyl alcohol is removed and prepared aqueous residue is kept at temperature +10°C, not above, for 5 h, not less. Deposit is separated, aqueous extract is dried and the end product is prepared. Invention provides realizing the indicated designation.

EFFECT: improved preparing method.

5 tbl, 2 dwg, 1 ex

FIELD: chemical-pharmaceutical industry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents of prolonged effect used in treatment of arterial hypertension. Medicinal agent of prolonged effect used in treatment of arterial hypertension comprises indapamide, accessory substance represented by interpolymeric complex of polymethacrylic acid with polyethylene glycol or polypropylene glycol. The claimed invention provides preparing a stable and easily dosed medicinal formulation of prolonged effect.

EFFECT: improved and valuable medicinal properties of agent.

1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemical pharmaceutical industry, particularly a combination including selective cyclooxygenase-2 (COX-2) inhibitor and epothilone. COX-2 inhibitor can be 5-methyl-2-(2'-chlor-6'-fluoranilino)phenylacetic acid or its pharmaceutically acceptable salt. The combination can be applied in treatment of precancerous colon lesions or colon cancer as well as other malignant diseases. The invention also claims consumer package including cyclooxygenase-2 inhibitor and epothilone with manual for simultaneous, separate or alternating application of the medications for proliferative disease treatment.

EFFECT: reduction of side effects during epothilone treatment.

12 cl, 8 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns chemical pharmaceutical industry, particularly pharmaceutical administration forms with delayed liberation, containing at least one active peptide. The invention also concerns method for obtaining such forms, a kit containing liophilised peptide and water non-organic salt or acetate solution, and application of water non-organic salt or acetate solution in obtaining a pharmaceutical administration form sustaining continuous peptide liberation for a prolonged time.

EFFECT: prolonged liberation of active peptide due to the depot effect.

42 cl, 7 ex, 4 tbl

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to applying alpha-2-delta ligand to producing medicinal means for lower urinary tract symptoms treatment, except for urinary incontinence caused by HUB (hyperactive urinary bladder) and/or BHPG (benignant hyperplasia of prostate gland).

EFFECT: medicinal means has increased efficiency.

12 cl, 2 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to pharmaceutical composition for senile osteoporosis, post-menopausal osteoporosis, bone fractures, bone transplant, and osteopenia or male osteoporosis treatment, that include effective therapeutic quantity, in amount 0.01 mcg/kg/day to 10 mcg/kg/day of compound 2-methylene-19-nor-20(S)-1α,25-dihydroxyvitamin D3, and effective therapeutic quantity, in amount 0.01 mcg/kg/day to 200 mcg/kg/day of selective estrogen receptor modulator, which bounds to estrogen receptor; the selective estrogen receptor modulator mentioned being chosen from the group comprising estrogen agonist, estrogen antagonist, or its pharmaceutically acceptable salt.

EFFECT: efficiency of medication is increased.

6 cl, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmacology and medicine, particularly: the set applied to treatment for thrombosis, which includes compound with formula and aspirin; pharmaceutical composition, which includes compound with formula (1) and aspirin; and application of pharmaceutical composition, which includes compound with formula (1), and pharmaceutical composition, which includes aspirin to treatment for thrombosis.

EFFECT: providing of increased thrombosis therapy efficacy.

6 cl, 1 dwg, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to method of residual lipoproteins producing inhibition by inhibition of HDL cholesteryl aether transport to chylomicron and/or VLDL, including introduction of composition with SeTr-inhibiting activity to patient for treatment of hyperlipidemia, arteriosclerosis or hyper(residual lipoprotein)emy where composition represents S-8{2-([[1-(2-ethylbutyl) cyclohexyl] carbonyl] amino) phenyl}-2-methylpropanethioat or methane sulfonate trans-(4-{[N-(2-{[N'-[3,5-bis(trifluoromethyl)benzyl]-N'-(2-methyl-2H-tetrazolum-5-yl)amino]-methyl}-5-methyl-4-trifluoromethylphenyl)-N-ethylamino] methyl} cyclohexyl) acetic acid, as active component.

EFFECT: improved efficiency of treatment.

8 cl, 2 ex, 10 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns a combination for proliferative disease treatment which contains antidiarrheal agent and epothylon derivative of formula (1) or epothylon derivative, method of diarrhoeia management, associated with epothylon introduction of formula (1), pharmaceutical composition, trade packing and medical product, including antidiarrheal agent and epothylon derivative.

EFFECT: compositions have improved efficiency.

9 cl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to methods and compositions for treatment and/or prevention maintenance of infectious condition in liquid-containing organ or organ with natural external aperture. Composition includes antibacterial agent, and also, probably, other active agents, amphipathic oil which is soluble in water and insoluble in ethanol, microcrystalline wax and pharmaceutically acceptable nonaqueous carrier. The method of treatment is realised by introduction of a pharmaceutical composition in body through natural external aperture.

EFFECT: regarding composition, invention provides stability of the active agent against oxidising decomposition, low interfacial tension of composition, easy solubility in liquids, and short time of excretion; invention provides effective treatment and reduction of by-effects and toxicity.

61 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention concerns method of pain relief by introduction of pharmaceutical composition containing effective amount of α-adrenergic antagonist and pharmaceutical composition, containing effective amount of the selective α-2A-antagonist.

EFFECT: method provides prolonged relief of chronic pain.

104 cl, 12 dwg, 4 tbl, 7 ex

FIELD: medicine; pharmacology.

SUBSTANCE: compositions under this invention are used as treatment or prevention agents for immune diseases including not steroid immunophylin-dependent immunosuppressant (NsIDI) and intensifier NsIDI (NsIDIE), chosen of selective serotonin recapture inhibitor (SSRI), tricyclic antidepressant (TCA), phenoxy phenol, antihistaminic agent, phenothiazine or mu-opioid receptor antagonist.

EFFECT: increased efficiency of immune disease treatment.

38 cl, 26 tbl, 22 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to method of thrombocyte aggregation inhibition. Method consists in that therapeutically efficient amount of valsartan metabolite, valeryl-4-hydroxyvalsartan, is introduced to patient who needs it. Invention also relates to pharmaceutical composition including valeryl-4-hydroxyvalsartan, and to its application for prevention, slowing-down development or treatment of disease and disorder mediated by thrombocyte aggregation.

EFFECT: reduction of thrombocyte ability to aggregate.

3 cl, 4 tbl, 1 ex

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