Controlled release complex pharmaceutical composition containing angiotensin-ii receptor blockers and hydroximethylglutaryl-coa reductase inhibitors

FIELD: medicine.

SUBSTANCE: declared invention refers to medicine. What is declared is a delayed release complex pharmaceutical composition containing a delayed release part and an immediate release part. The delayed release part contains AII-receptor blocker as an 'active ingredient'. The immediate release part contains HMG-CoA reductase inhibitor as an active ingredient.

EFFECT: declared composition is effective for treating hypertension and preventing complications in the patients suffering metabolic syndromes, such as diabetes, obesity, hyperlipidemia, coronary vessel disease, etc.

10 dwg, 13 bl, 8 ex

 

The technical field

The invention relates to an integrated pharmaceutical compositions containing receptor blockers angiotensin-II (AII receptors) and the inhibitor hydroxymethylglutaryl-coenzyme a reductase (HMG-COA reductase), developed on the basis of theory of "diversity-chronotherapy", and the action of each component begins at different times, so each component can have its own special rate of release, as well as to a method for preparing such pharmaceutical compositions.

We offer comprehensive pharmaceutical composition with delayed release (here and below we mean the release of the active pharmaceutical ingredients) is effective in the treatment of hypertension with such complications as diabetes, cardiovascular (SS) disease, kidney disease, metabolic syndromes such as insulin resistance, or without complications.

The invention relates to a delivery system of drugs developed based on theory of "diversity-chronotherapy", and the dissolution of each component of the complex product occurs with a certain time of the release in the body, and its effect upon absorption in the body can be the most effective.

The invention proposes to develop the world's first technology of forming the composition effect and the pending release, based on the following three basic theories:

1) heterogeneity: an application of theory of drug metabolism enzymes

2) chronotherapy: applying theory of biorhythms in the conditions of the disease, and

3) a system for targeted drug delivery to tissues: application of theory of solubility and absorption depending on the time of receipt.

The level of technology

The need for a comprehensive product

Hypertension is often accompanied by coronary artery disease, and both of these disease are major risk factors for heart disease. The reason for this joint manifestations, risk factors, may be a common mechanism of their occurrence. Arteriosclerosis, followed by hypertension and hyperlipidemia, is exacerbated in the presence of both symptoms. When high blood pressure arteriosclerosis, acute, and when he becomes aggravated, blood pressure increases, leading to further aggravation of atherosclerosis. In addition, these pathological conditions are major risk factors for heart disease, such as hypercholesterolemia and hyperlipidemia are associated with early development of atherosclerosis, which is characterized by the formation within the arteries, including the coronary, carotid and peripheral arteries, lipid plaques. In addition, these lipid nl is the really characteristic of coronary heart disease (CHD) and SS diseases, on the severity of which is affected by the presence of diabetes, patient gender, Smoking, and left ventricular hypertrophy as a side effect hypertension (see Wilson et al., Am. J. Cardiol., vol.59 (14) (1987), p.91G-94G). Thus, it is known that in the treatment of such pathological conditions for the patient would be a good receiving adjuvant therapy, and comprehensive therapy becomes a recommended strategy.

It is known that the use of an inhibitor of HMG-COA reductase in complex with blocker AII receptors beneficial for the treatment of SS and renal diseases. However, there is no comprehensive medicinal product that combines both of these substances, in addition, yet offered a comprehensive pharmaceutical composition with delayed release from the point of view of pharmacological mechanisms, including the absorption, distribution and metabolism.

Information about active pharmaceutical ingredients

Most often for the treatment uses losartan, which is typical blocker AII receptors, and simvastatin, which is a typical inhibitor of HMG-COA reductase. The combined use of the components contained in the proposed pharmaceutical composition, justified, and pharmacological action of each component, as shown in Table 1, excellent.

[Table 1]
LosartanSimvastatin
1) Lower blood pressureSuppression system the renin-angiotensin* and vasodilator actionPrevention of atherosclerosis and vasodilator action
Combination therapy enhances the antihypertensive effect of losartan and lepidophyma effects of simvastatin
2) ChronotherapyExcellent antihypertensive activity after midnight, still active renin-angiotensinPharmacological effect is manifested in the evening, when the most active lipid synthesis
When taking both components around 19:00 optimal antihypertensive supported during that represents the risk of developing complications after waking up the patient with resistant hypertension**
3) AtherosclerosisSignificant lepidophyma action
4) Changes in tankah vessels (1) Inhibition of proliferation of diseased cells of the vessel wall, (2) Regeneration and maintenance functions of endothelial cells(1) anti-inflammatory effect, (2) regenerating effect on cells
Integrated reception components strengthens and supports the function of endothelial cells
5) Glomerular arteryRelaxation efferent arteryInhibition sclerosis generating and efferent arteries
Integrated reception components enhances kidney function
6) the Extension of the lumen of blood vesselsThe extension of the lumen of blood vesselsThe extension of the lumen of blood vessels
Integrated reception components leads to further expansion of blood vessels
7) Factors of inflammation-MDA-CRP
-MCP-1
ReductionReduction
Integrated reception components leads to a further reduction of the content of substances that cause inflammation
8) the Action of insulinIncreasesIncreased content Increases adiponectin
Integrated reception components leads to increased insulin sensitivity
Notes:
* The system renin-angiotensin - this is one of the mechanisms of regulation of blood pressure.
** Patients with resistant hypertension (non-dipper") is a patient who, unlike conventional hypertensive patients, blood pressure is not reduced during sleep, which increases the risk of stroke; most often in elderly patients, diabetics, patients with cardiac hypertrophy, etc.

1) Losartan as a blocker AII receptors and its pharmaceutical application

Losartan, the chemical name is 2-butyl-4-chloro-1-[2-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-methanol, is an antihypertensive substance is an antagonist of the binding of angiotensin-II (AII) with vascular receptor (AII-receptor). Angiotensin-II is a factor in high blood pressure, causing hypertrophy is avago ventricle, vascular hypertrophy, atherosclerosis, kidney failure, stroke and the like (see U.S. patent 5.138.069).

Blocker AII receptors is the drug, lowering blood pressure and at the same time manifesting a number of other effects, including the prevention and treatment of renal failure, prevention and treatment of myocardial infarction, arrhythmia and heart failure, prevention and treatment of complications associated with diabetes, prevention and treatment of stroke, antiplatelet action, the prevention of arteriosclerosis, suppression of the adverse effects of aldosterone, reducing the metabolic syndrome and prevention of exacerbation of cardiovascular disease (see Clin. Exp. Hypertens., vol.20 (1998), (p.205-221); J. Hypertens., vol.13 (8) (1995), (p.891-899); Kidney Int., vol.57 (2) (2000), (p.601-606); Am. J. Hypertens., vol.10 (12PT2) Suppl.(1997), (p.325-331); Circulation, vol.101 (14) (2000), (p.1653-1659); J. Hypertens., vol.17 (7) (1999), (p.907-716); Circulation, vol.101 (2000), p.2349).

Antihypertensive and renoprotektivnoe effect of losartan and other blockers AII receptors are described, for example, in the following publications: J. Wagner et al., Effects of AT1 receptor blockade on blood pressure and the rennin-angiotensin system in spontaneously hypertensive rats of the stroke prone strain, Clin. Exp. Hypertens., vol.20 (1998), (p.205-221); M.Bohm et al., Angiotensin-II-receptor blockade in TGR(mREN2)27: Effects of rennin-angiotensin system gene expression and cardiovascular functions, J. Hypertens., vol.13 (8) (1995), p.891-899.

Other renoprotektivnoe effects of blockers AII-receptor is in, detected at the first clinical trials are described in the following publications: S.Andersen et al., Renoprotective effects of angiotensin-II-receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int., vol.57 (2) (2000), p.601-606; L.M.Ruilope, Renoprotection and rennin-angiotensin blockade in diabetes mellitus, Am. J. Hypertens., vol.10 (12PT2) Suppl. (1997), p.325-331.

The action of blockers AII receptors on endothelial dysfunction is described in the following publications: E.L.Schiffrin et al., Correction of arterial structure and endothelial dysfunction in human essential hypertension by the angiotensin receptor antagonist losartan, Circulation, vol.101 (14) (2000), p.1653-1659; R.M.Touyz et al., Angiotensin-II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: role of increasing interest among signal-regulated kinases, J.Hypertension, vol.17 (7) (1999), p.907-716; E.L.Schiffrin, Vascular remodeling and endothelial function in hypertensive patients: Effect of antihypertensive therapy, Scand. Cardiovasc. J., vol.32, Suppl.47 (1998), p.15-21; Prasad, Acute and Chronic angiotensin-1 receptor reverses endothelial dysfunction in atherosclerosis, Circulation, vol.101 (2000), p.2349.

In addition, it is known that the AII blockers-receptor blocking AT receptors, but do not act on IT-receptors, which results in suppression of growth and Regencia tissues.

2) Simvastatin as an inhibitor of HMG-COA reductase and its pharmaceutical application

Simvastatin is a typical latinoam lipidemias tool used more often than other inhibitors of HMG-COA reductase.

Simvastatin is a strong inhibitor of HMG-COA reductase converted to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA) mevalonata, showing, that is they way the effect of inhibiting the production of cholesterol in the liver and lower levels of cholesterol low-density lipoprotein (LDL). Due to such effects simvastatin is an excellent tool for the treatment of mixed hyperlipidemia and prevention and treatment of atherosclerosis. In addition, studies have shown that its effect on lowering LDL levels is highly effective against diseases of the coronary vessels of the heart (see "Scandinavian Simvastatin Survival Study", Lancet, vol.344 (1994), p.1383-89).

It is known that stationby lipidology agent, for example, an inhibitor of HMG-COA reductase is the primary drug for the prevention and treatment of heart disease resulting from atherosclerosis, coronary artery disease, including angina or myocardial infarction (see Lancet 1995; 346: 750-753, Am. J. Cardiol. 1998; 82: T-T, Am. J. Cardiol. 1995; 76: 107C-112C, Hypertens. Res. 2003; 26: 699-704, Hypertens. Res. 2003; 26: 273-280, Br. Med. Bull. 2001; 59: 3-16, Am. J. Med. 1998; 104 (Suppl.1):6S-8S, Clin. Pharmacokinet. 2002; 41: 343-370).

In addition, simvastatin is the most commonly used inhibitor of HMG-COA reductase, and its effectiveness in the treatment of coronary artery atherosclerosis, manifested in the reduction of mortality, proven large-scale clinical trials (see Lancet, 1994; 344: 1383-1389).

This effect is because simvastatin is a strong inhibitor of HMG-COA reductase, which plays to uciuu role in the process of cholesterol synthesis in the liver, and simultaneously inhibitor of inflammatory factors (see "Scandinavian Simvastatin Survival Study", Lancet, 1994, 344: 1383-89).

Simvastatin is a combination class of lactones, inactive by itself, it initially enters the liver, where it takes the active form of β-hydroxy acid with lipidemias action. The remaining simvastatin is also metabolised in the liver in several steps by cytochrome P450 3A4, and some metabolites are powerful lipidology effect.

Simvastatin and its β-hydroxycitrate metabolized in the liver by the enzyme cytochrome P450 3A4 and act in the liver until they are partially released into the blood vessels (see Drug Metab. Dispos. 1990; 18: 138-145, Drug Metab. Dispos. 1990; 18: 476-483, Drug Metab. Dispos. 1997; 25: 1191-1199).

Thus, when simvastatin is used together with a medicinal substance that is metabolized by the enzyme cytochrome P450 3A4 metabolism of simvastatin in the liver is suppressed, and the content of simvastatin in the blood. This can cause serious side effects, such as MOLISA (see Clin. Pharmacol. Ther. 1998; 63:332-341; Clin. Pharmacol. Ther. 1998; 64: 177-182; Physicians Desk Reference 2006 (Zocor); J. Pharmacol. Exp. Ther. 1997; 282: 294-300; Pharmacol. Exp. Ther. 1999; 290: 1116-1125; Life Sci. 2004; 76: 281-292).

Thus, when receiving an inhibitor of HMG-COA reductase inhibitor such as simvastatin, simultaneously with the blocker AII receptors, metabolisable the enzyme cytochrome P450 3A4 which is required for inhibitor of HMG-COA reductase, you should think about other ways of medication.

Because the synthesis of lipids in the liver is activated after lunch, in the early evening, it was recommended to take statins in the early evening (see Arterioscler. Thromb. 11: 816-826, Clin. Pharmacol. Ther. 40: 338-343).

Problems simple combination therapy

It is known that the use and reception of the blocker AII receptors together with an inhibitor of HMG-COA reductase provides the advantage in the treatment of SS and renal diseases. However, when the inhibitor of HMG-COA reductase inhibitor such as simvastatin, is applied together with the medicinal substance, metabolisable the enzyme cytochrome P450 3A4 metabolism of simvastatin in the liver is inhibited, which leads to increased levels of simvastatin in the blood. This is the reason for the occurrence of such side effects, as miles. Know that not all, and it was not taken into account patients when taking this medication.

If co-administration of the two drugs increases the risk of adverse consequences from such combined therapy should fundamentally be abandoned. However, co-administration of the blocker AII receptors and an inhibitor of HMG-COA reductase, in particular of losartan and simvastatin was prescribed despite the risk of side effects, such as myopathy, the manifestation of which is due to the effect of suppression [metabolism] si is vastatin by losartan in competition for the same enzyme cytochrome P450 3A4, because each of these two drugs is contributing to the synergistic effect.

Simvastatin effectively suppresses transformation in the mevalonata HMG-COA reductase HMG-COA 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-COA) mevalonata, thus showing the effect of inhibiting the production of cholesterol in the liver and lowering the levels of LDL.

Because of this lipidemias effect of simvastatin should act in the liver. Meanwhile simvastatin medicine is "first pass", which after receiving absorbed in the small intestine, enters the liver and for the most part transformed there cytochrome P450 3A4 in the active type, operates in the liver, where it is metabolized and excreted from the liver. Simvastatin remaining nematerializiranih by cytochrome P450 3A4, enters the bloodstream, reaching all organs, and this accounts for approximately 5% of the originally received simvastatin. The elevated levels of simvastatin in the blood is not associated with therapeutic effect of inhibiting the production of cholesterol and increases the risk of myopathy, such as MOLISA, which is the side effect of simvastatin.

Losartan after absorption in the small intestine enters the liver. Part of it is released into the blood in the form of active molecules of losartan, the content of which in the blood reaches a peak value for real the hour. And the rest is metabolized in the liver by two enzymes: cytochrome P450 2S9 and 3A4, transforming into active carboxyl metabolite having a higher activity, which reaches its highest concentration in the blood after three to four hours. I.e. pharmacological action of losartan is the pharmacological action of a mixture of losartan and its active carboxyl metabolite. About 14% of losartan, taken orally, is transformed in the liver enzymes in the active carboxyl metabolite, which pharmacological activity superior to losartan more than 40 times. For losartan excretion rate of 600 ml/min, and for his active carboxyl metabolite 50 ml/min, it is therefore assumed that, having a lower rate of excretion of the active metabolite plays an important role in maintaining the duration of the action.

From this point of view with coadministration of simvastatin and losartan the following problems occur.

When the joint admission in the liver simvastatin and losartan to happen competitive inhibition, and part of simvastatin, is not metabolized by cytochrome P450, is released into the blood, resulting in a weakening of inhibition of HMG-COA reductase and increase risk of side effects. Meanwhile decreases the transformation of losartan to the active Carbo is a strong metabolite. Because of this mutual antagonism while taking these two drugs are not optimum effect (see Cytochrome P450 Drug Interaction Table, Department of Medicine, Indiana University, updated 2004, March 11).

Examples of prior art

As a combined therapy of various illnesses inhibitors of HMG-COA reductase inhibitors and antagonists of AII receptors suggested the following solutions.

Publication WO 95/26188 discloses a method of treating atherosclerosis and reducing cholesterol using an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors. As a suitable blocker AII receptors named losartan.

Publication WO 97/37688 discloses a combined therapy of many symptoms, including hypertension and atherosclerosis, an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors.

Publication WO 99/11260 discloses the combined use of atorvastatin, losartan, irbesartan and valsartan to reduce blood pressure and lipid levels, as well as the treatment of angina and atherosclerosis in mammals.

Publication WO 00/45818 discloses the combined use of an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors for the treatment of diabetic neuropathy, giving an increase in the speed of nerve conduction and blood flow in the nerves in patients suffering from diabetes.

PU is published WO 04/062729 discloses a combined therapy with simvastatin as an inhibitor of HMG-COA reductase and telmisartan as a blocker AII-receptor for the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary or renal diseases.

Publication WO 06/040085 discloses a two-layer tablet for the prevention or treatment of cardiovascular, cardiopulmonary, pulmonary or renal diseases, containing simvastatin as an inhibitor of HMG-COA reductase and telmisartan as a blocker AII receptors. This two-layer tablet is a combination in which simvastatin and telmisartan released at the same time, and her idea completely different from the ideas of the present invention, in which first released the inhibitor of HMG-COA reductase, so it is first metabolized in the liver. Logical or pharmacological point of view, this combination therapy is considered inappropriate for optimal synergistic effect of these two drugs. With such therapy, when the inhibitor of HMG-COA reductase inhibitor and blocker AII receptors enter the liver at the same time, their metabolism by cytochrome P450 3A4 is competitive, resulting in the release of an inhibitor of HMG-COA reductase in blood without metabolism in the liver. That is disclosed by the above publication inventions inherent in the disadvantage that an inhibitor of HMG-COA reductase, which must be metabolized in the liver to act in the liver, released into the blood without being sufficiently metabolized, resulting in unnecessary increased levels of simvastatin and its metabolites in the blood that can cause myopathy.

Such a simple combination product may be patentable due to the lack of inventive step. Korean patent application No. 2000-7002144 was rejected as related to simple combinations.

The proposed pharmaceutical composition that provides a delayed release and containing an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors, is a new development. The proposed combination product provides the possibility of the manifestation of the largest pharmaceutical effect of each component while reducing their side effects, which could occur with the simultaneous release of these two components.

Disclosure of inventions

Technical problem

The idea of combined drug

The authors present invention has developed a new medicinal composition capable of reducing side effects (such as miles), which occur when a joint simultaneous administration of the two active ingredients, which are fully shown pharmacological action due to metabolism, with synergistic clinical effect is due to the fact that each active ingredient you obojdetsya then when he manifests optimal pharmacological action. Up to this time any type of combined product containing blocker AII receptors and an inhibitor of HMG-COA reductase, in such a pharmaceutical composition that technology delay time release is applied to the same component, and the pharmacodynamics and pharmacokinetics of both drugs adjusted for synergistic effects without antagonism in the liver.

The invention provides an integrated pharmaceutical preparation containing an AII blocker receptors and an inhibitor of HMG-COA reductase and the most suitable for the prevention and treatment of SS, cardiopulmonary, pulmonary or renal diseases in patients with metabolic syndrome or insulin resistant patients and in patients with suspected diabetes or prediabetes.

The invention relates to a complex composition blocker AII receptors and an inhibitor of HMG-COA reductase. That is, the invention relates to a delivery system oral medications substances that best meets the full synergistic action of the active ingredients in the body of the patient. In other words, the invention relates to such a system, drug delivery, when each drug has its rate of release, and when p is and absorption by the body of their action is the ideal way.

If the inhibitor of HMG-COA reductase inhibitor and blocker AII receptors are released at different times, so inhibited by the simultaneous transfer of these drugs in the liver and competitive antagonism of enzymes in the liver, the activity as inhibitor of HMG-COA reductase inhibitor and blocker AII receptors can be maximized, and can be reduced the side effects of an inhibitor of HMG-COA reductase. Thus, the technology for the release of an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors at different times can be highly preferred.

In the clinical trials it was found that the application of the blocker AII receptors, showing the effect of reducing blood pressure, along with a inhibitor of HMG-COA reductase inhibitor as an agent for the treatment of coronary artery disease possible synergistic effect in the treatment of coronary artery disease. However, when these medicinal substances are taken at the same time, they can antagonistically to suppress each other, or may occur side effects the cause for metabolic liver enzymes competitive antagonism of AII blocker receptors and an inhibitor of HMG-COA reductase. Thus, developed a complex composition with delayed release preventing konkurentov the antagonism of drugs in the liver, it can meet therapeutic needs, as manifested clinical synergistic effect of the two ingredients combined product, the release of each of which is in due time to ensure absorption and metabolism in the liver so that it is possible to avoid antagonism between them. In addition, the release of the two drugs at different times allows you to take one pharmaceutical composition orally once a day, so these medicinal substance to the patient to take conveniently, thereby increasing compliance.

However, the complex composition that could address these clinical problems, still has not been developed. According to the invention problems that may occur in pharmacological mechanisms, can be solved by a complex composition that provides a predetermined time delay, only once a day, so the release of each drug substance occurs at the right time corresponding to the heterogeneity of these two ingredients.

Since the synthesis of cholesterol actively going on at night, it is most effectively to take an inhibitor of HMG-COA reductase in the evening. In addition, because the action of the blocker AII receptors lasts for 24 hours, it is most effectively to take the blocker AII receptors in the evening, so he de is felt in the morning, when blood pressure reaches its highest level. Therefore, both medicinal substance should be taken in the evening, and patients may take them together, although they are presented separately. However, patients prefer to take these two medicinal substances simultaneously as is usually required.

Such treatment can cause liver competition between drug substances by cytochrome P450 3A4, which weakens the action of medicinal substances and enhances their side effects.

Therefore, when you want to receive two such drugs, it is necessary first to take an inhibitor of HMG-COA reductase, and then, after some time, the blocker AII receptors, however, this understanding is not easy to implement in the minds of the patients.

In addition, patients who need to take these two drugs is in most older people, who are always poor and do not comply with the regimen of medicines.

The inventors have attempted to solve the above problems and in clinical trials compared the simultaneous administration of an inhibitor of HMG-COA reductase represented by simvastatin, and blocker AII receptors, represented by losartan, taking these two drugs at different times to develop such a system of drug delivery, and when released the e medicinal substances can be posted in time with regard to their absorption by the body, metabolism and mechanism of action of each drug substance reasons prevent antagonism between them, thereby preventing side effects, and ensuring that maximize the synergistic effect of drugs upon their joint receipt. In the result, it was found that the acceptance of an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors in different time performance and safety of drugs were significantly better than while receiving.

The inventors have found that oral offer a combined product can be achieved clinical synergistic effect of an inhibitor of HMG-COA reductase inhibitor and blocker AII receptors, and competitive antagonism between these two medicinal substances can be avoided by ensuring the diversity of their release in time, it is possible to maximize effectiveness and minimize side effects of drugs, and can also be improved compliance. In addition, the proposed combination product is a single pill that is taken once a day, in the evening.

The aim of the invention is the creation of a system of drug delivery in which the release of one of the two active ingredients with the provision of pharmacological advantage is of being delayed as well as the creation of a method of preparation of such system. The dissolution of the blocker AII receptors is delayed for three to four hours after the initial release, preferably more than four hours after the initial release. When first blocker AII receptor is released inhibitor of HMG-COA reductase, he is absorbed in the small intestine before the blocker AII receptors and binds in the liver by cytochrome P450 3A4, so that the inhibitor of HMG-COA reductase is metabolized in the liver and will inhibit the biosynthesis of cholesterol. Blocker AII receptors, released in three to four hours (preferably more than four hours after absorption of the inhibitor of HMG-COA reductase inhibitors metabolized regenerated by cytochrome P450 3A4 in becoming active metabolites blocker AII receptors, providing the effect of reducing blood pressure.

Another aim of the invention is to provide a dosage form for the treatment of hypertension, coronary artery disease and related diseases containing blocker AII receptor or its pharmaceutically acceptable salt and inhibitor of HMG-COA reductase and an inhibitor of HMG-COA reductase inhibitor is released immediately, and release blocker AII receptor is slow.

Technical solution

The invention prospect who needs to create compositions with delayed release, contains blocker AII receptors and an inhibitor of HMG-COA reductase inhibitor as an active ingredient and pharmaceutically acceptable excipient (medium), and this complex composition contains a component with a delayed-release formulation containing as an active ingredient blocker AII receptors, and part of the immediate-release formulation containing as an active ingredient an inhibitor of HMG-COA reductase.

In oral administration the proposed delivery system, an inhibitor of HMG-COA reductase inhibitor is released immediately, so that more than 80% of drug substance dissolves within one hour, and release in the gastrointestinal tract (GIT) blocker AII receptors on sufficient time is delayed, so that the rate of dissolution is that four hours after oral administration it is dissolved not more than 40%. Prefer this mode of release of an inhibitor of HMG-COA reductase, when within hours dissolves more than 90% of this substance, and a release blocker AII receptors in the digestive tract slows down so much that four hours after oral administration of dissolved not more than 30% of this substance. Seems to be more preferred is slow release, when the release blocker AII receptors occurs after the expiration of the fourth hour with mo is enta beginning of the dissolution inhibitor of HMG-COA reductase.

Hereinafter the invention is described in detail.

The invention relates to integrated drug developed on the basis of the so-called "chronotherapy" and "diversity"when medicinal substances are taken to be released at different times, so that the release of one drug component in a certain way late. We offer combined preparation contains as active ingredients blocker AII receptors and an inhibitor of HMG-COA reductase, which are both exposed to the same enzyme class P450, with the mentioned ingredients have different speed of release, so it is possible to avoid antagonism between them, as well as reduce the side effects of each ingredient to achieving a synergistic effect, increasing the convenience for the patient and his commitment.

Next is a detailed description of the proposed integrated product containing blocker AII receptors and an inhibitor of HMG-COA reductase.

We offer comprehensive preparation contains as active ingredients blocker AII receptors and an inhibitor of HMG-COA reductase. Blocker AII receptors may be selected from among substances, metabolisable enzymes-class P450, as specific examples of which can be named: losartan, valsartan, irbesartan, candesartan, tel is Sartan, eprosartan, olmesartan, as well as their pharmaceutically acceptable salts, however, the scope of the invention in the above blockers AII receptors is not limited. Preferable, the use of losartan or its pharmaceutically acceptable salts. A typical example of a pharmaceutically acceptable salt of losartan is losartan potassium. As the blocker AII-receptor is used in an amount 5-1200 mg per day for adults (adult male weighing 65-75 kg), it is used in an amount 5-1200 mg per day, preferably 8-600 mg in the proposed combined product, the total mass of which 200-1010 mg.

As an example of the blocker AII receptors, showing the effect of reducing blood pressure, hereinafter will be described losartan, however, the scope of invention is not limited to.

In addition, we offer comprehensive pharmaceutical composition comprises as an active ingredient of the inhibitor of HMG-COA reductase. Inhibitor of HMG-COA reductase is inactive, but it has lepidophyma action after becoming active 8-gidrokshikislotu using esterase and conversion to the active metabolite by the cytochrome P450 3A4 in the liver. As specific examples of inhibitors of HMG-COA reductase can be named the following substance: simvastatin, lovastatin, atorvastatin, as well as their Messiah. farmacevtichesky acceptable salt. Preferable, the use of simvastatin or its pharmaceutically acceptable salts. Although as an example of an inhibitor of HMG-COA reductase is described below simvastatin, the scope of the invention is not limited to them. As inhibitor of HMG-COA reductase is used in an amount 5-160 mg per day for adults, it is used in an amount 5-160 mg / day, preferably 5-80 mg, we offer a combined product, the total mass of which 200-1010 mg.

When simvastatin as an inhibitor of HMG-COA reductase inhibitor and losartan as a blocker AII receptors at the same time the liver, is a competitive inhibition between these substances in the liver. Thus, part of simvastatin, is not metabolized by cytochrome P450, is released into the blood, reducing the effect of an inhibitor of HMG-COA reductase and increasing the risk of side effects. In addition, the conversion of losartan to its active carboxylic metabolite inhibited, and its effect is reduced. So while receiving two such drugs is not achieved their optimal action, because they are antagonists.

To solve the above problems, i.e. to correct the interference blocker AII receptors and an inhibitor of HMG-COA reductase in the liver, the invention provides that the inhibitor of HMG-COA-R is ductase introduced in part with an intermediate release, so that it is dissolved and absorbed in the small intestine first and blocker AII receptor is introduced in part a delayed release so that it absorbed for three to four hours later, inhibitors of HMG-COA reductase.

Comparison between the proposed functional combination drug and simple simultaneous joint reception can be described as shown in Table 2 below.

[Table 2]
Simultaneous co-administrationWe offer functionally combined product
1) the Time of admissionMostly about 07:00Around 19:00
2) Dissolution and absorption componentsThe components were dissolved and absorbed at the same time in the morningSimvastatin was dissolved and absorbed at 19:00.
Losartan was dissolved and absorbed at 23:00.
3) the Best time of antihypertensive actionPeriod 10:00-22:00Between 23:00 and 10:00 the next day
4) Control of blood pressure in patients who non duperow" InappropriateEffective for patients-non-duperow", hypertensive patients with a high risk of complications.
5) Preventive effect in the period 05:00-11:00, when the risk of cardiovascular complications the most high(1) When taking losartan at 07:00 losartan shows the peak concentration in the blood 13:00, which is 13:00 is reduced. Thus, it is inconvenient for patients-non-duperow after 13:00 should be subject to stricter controls. In addition, in the period of higher risk of cardiovascular complications (05:00-11:00) antihypertensive effect of losartan is waning.
(2) Simvastatin fundamentally should be taken in the evening, when activated mainly lipid metabolism. Therefore, these two drugs should be taken in the evening than in the morning.
(1) When receiving a proposed functionally combined product at 19:00 first released simvastatin. Thus, simvastatin is effective during the active synthesis of lipids.
(2) Because the losartan is dissolved and released into the liver via three to four hours after metabolisation of simvastatin enzymes in the liver, losartan is also sufficiently metabolized in the liver and released into the blood so that it shows up is enough effect on lowering blood pressure in patients-non-duperow", whose blood pressure rises at dawn and during the period of high risk of complications (from dawn to 11:00).
6) the Interaction between the two componentsCompetitive bindingCompetitive binding
Since both components are released at the same time, they are metabolized in the liver the same cytochrome P450 3A4, competing with each other.Because the components are released at intervals of three to four hours, they do not compete for metabolism by cytochrome P450 3A4 and sufficiently metabolized in the liver.
Cytochrome P450 3A4: 1) converts inactive simvastatin in active and provides activated simvastatin able to act in the liver, 2) increases the activity of losartan more than 40 times and provides activated losartan to show antihypertensive activity in the blood.

Advantages of the invention

As noted above, the invention provides a pharmaceutical composition, developed on the basis of theory of "diversity-chronotherapy" to maximize therapeutic effects and prevent or mind is nisene side effects, which can take place after the joint reception of the two drugs. The proposed combination product contains as active ingredients blocker AII receptors and an inhibitor of HMG-COA reductase exposed to the same enzyme class P450. The product also contains various pharmaceutically acceptable excipients, is able to control the time of release of the active ingredients, provided that the release of active ingredients with passing time. Accordingly, compared with the simultaneous joint reception of the two components of the proposed combination product more useful in pharmacological, clinical, scientific and economic terms, from the point of view of prevention or treatment of hypertension, followed by complications such as cardiovascular, cardiopulmonary, pulmonary or renal disease, metabolic syndrome, including insulin resistance, diabetes or prediabetes.

In addition, the proposed arrangement is designed in such a way that medicinal substances differ in the rate of release. Thus, prevented or reduced antagonism between drug substances and their side effects, and provides the possibility of obtaining a synergistic effect.

In addition, offers the suggested composition can be taken once a day, that facilitates instructing patients and composition method.

The advantages of the proposed composition above simultaneous joint reception of the active ingredients set forth in Table 3 below.

[Table 3]
The proposed combination product has the following advantages:
1) excellent effect of reducing blood pressure,
2) excellent effect of reducing the synthesis of cholesterol,
3) excellent preventive effect against endothelial dysfunction,
4) optimal effect during the period of highest risk of cardiovascular complications
5) excellent efficacy of treatment of hypertension in patients-non-duperow",
6) a significant reduction of insulin resistance in hypertensive patients-diabetics
7) reduce the time of instructing patients and making predpisy is.

Description of the drawings

Figure 1 compares the profiles of dissolution of the active ingredient losartan/simvastatin delayed release of one component prepared in Example 1, and losartan and simvastatin separately in pills Cozaar® and Zocor®, used as a control.

Figure 2 compares the profiles of dissolution of the active ingredient losartan/lovastatin delayed release of one component prepared in Example 9, and losartan and lovastatin separately in pills Cozaar® and Mevacor®, used as a control.

Figure 3 shows the dissolution profiles relating to Examples 2-5.

Figure 4 shows the dissolution profiles relating to Examples 4 and 6-8.

Figure 5 compares the profiles of dissolution of the active ingredient losartan/atorvastatin delayed release of one component prepared in Example 10, and losartan and atorvastatin separately in pills Cozaar® and Lipitor®, used as a control.

Figure 6 compares the profiles of dissolution of the active ingredient losartan/simvastatin delayed release of one component prepared in each of Examples 14 and 19, and losartan and is of simvastatina separately in pills Cozaar® and Zocor®, used as a control.

Figure 7 compares the profiles of dissolution of the active ingredients of the composition irbesartan/simvastatin delayed release of one component prepared in Example 21, and irbesartan and simvastatin separately in the composition of drugs Aprovel® and Zocor®, used as a control.

On Fig graphically presents the results of clinical trials according to Example 8, shows the dynamics of systolic blood pressure for different reception modes.

Figure 9 graphically presents the results of clinical trials according to Example 8, shows the dynamics of diastolic blood pressure for different reception modes.

Figure 10 graphically presents the results of clinical trials according to Example 8, shows the dynamics of the average blood pressure for different reception modes.

Option of carrying out the invention

We offer comprehensive pharmaceutical composition contains a component with a delayed release containing blocker AII receptor or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients, and part of the immediate-release formulation containing an inhibitor of HMG-COA reductase inhibitor or its pharmaceutically acceptable salt, as well as the desired excipients, and mentioned physically Department is s from each other, so they can have a different speed of release. Mentioned part of the immediate-release and delayed release can be implemented in various forms.

That is part of a delayed release can be fitted with a shell of a known material, providing a controlled release, and is provided with a shell particles or granules together with particles or granules side immediate-release can be compressed into a tablet or loaded into the capsule.

We offer comprehensive pharmaceutical composition has the advantage in the period, 17:00-22:00 every day.

According to the invention the part with the pending release contains blocker AII receptors, represented by losartan, and the material providing controlled release blocker AII receptor selected from the following list: enteric polymer, a water-insoluble polymer, a hydrophobic compound, the hydrophilic polymer. Pursuant to part with a delayed release material which provides controlled release, can be used in an amount of 10-500 mass parts per 100 mass parts of the blocker AII receptors. If the amount of material that provides controlled release, is less than the lower limit, then the release will not be until the ciently controlled, and if greater than the upper limit, then the release will be delayed, and the clinical effect is small.

As the enteric polymer can be one or a mixture of two or more of the following substances: polyvinylacetate, copolymers of methacrylic acid, the phthalate of hydroxypropylmethylcellulose, shellac, acetated cellulose, Eudragit L, Eudragit s preferable to use phthalate of hydroxypropylmethylcellulose.

As the water-insoluble polymer can be one or a matrix of two or more of the following substances: polyvinyl acetate, such copolymers polymethacrylate as copolymers of poly(acrylate, methyl-methacrylate) and copolymers of poly(acrylate, methacrylate, trimethyl-aminoheterocycles), ethylcellulose, acetylcellulose, which are pharmaceutically acceptable salts.

The hydrophobic compound may be selected from the following list: fatty acids, esters of fatty acids, alcohols, fatty acids, waxes, inorganic materials. Specifically, it can be one or a mixture of two or more compounds from the following list: fatty acids or esters of fatty acids, including glycerylmonostearate, literallayout, glycerinated, cetylpalmitate, glycerylmonostearate and stearic acid, alcohols, fatty acids, including what I cetosteatil alcohol, cetyl alcohol and stearyl alcohol, waxes, including Carnauba wax, beeswax and microcrystalline wax, and inorganic materials including talc, precipitiously calcium carbonate, dibasic calcium phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and Wigan.

The hydrophilic polymer may be selected from the following list: sugars, cellulose derivatives, gums, proteins, derivatives of polyvinyl, copolymers of polymethacrylate, derivatives of polyethylene, polymers of carboxyvinyl. Specifically, it can be one or a mixture of compounds from the following list: sugars, including dextrin, polydextran, dextran, pectin and derivatives of pectin, alginate, polygalacturonase acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylmethyl, amylose and amylopectin, cellulose derivatives, including hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, methylcellulose, sodium carboxymethylcellulose, acetylsuccinate hydroxypropylmethylcellulose and hydroxyethylmethylcellulose, gums, including guar gum, gum beans carob, tragacanth gum, carrageenan, acacia gum, Arabic gum, Gellan gum and xanthan gum, proteins, including gelatin, casein, and Zein, derivatives of polyvinyl who, including polyvinyl alcohol, poly(vinyl pyrrolidone) and polyvinyltrimethylsilane, copolymers of polymethacrylate, including copolymers of poly(butylmethacrylate, (2-dimethylaminoethyl)methacrylat, methyl methacrylate), copolymers of poly(methacrylic acid, methyl methacrylate) and copolymers of poly(methacrylic acid, acrylate, derivatives of polyethylene, including polyethylene glycol and polyethylene oxide, and polymers of carboxyvinyl, including carbomer.

The invention also provides the use of pharmaceutically acceptable and does not impair the effectiveness of the invention diluents such as starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, salts of alkaline earth metals, clay, polyethylene glycol and dicalcium phosphate, and lubricants, including talc, alkaline earth metal stearates such as calcium stearate, magnesium stearate or zinc stearate, lauryl, hydrogenated vegetable oil, sodium benzoate, sodium fumarate, glycerylmonostearate and polyethylene glycol 4000, and this list of possible additives is not exhaustive.

The part with the pending release is a disperse phase containing particles or granules obtained by mixing, granulating or wrapping blocker AII receptor material, providing a counter is controlled delayed release, and well-known pharmaceutically acceptable excipient.

Part of the immediate-release formulation can be prepared in the form of particles or granules by applying an active ingredient of the inhibitor of HMG-COA reductase inhibitor (simvastatin) and pharmaceutically acceptable excipient such known processes for producing solid drug oral applications, such as mixing, plastilinovaya, drying and granulation. If the fluidity simvastatinum mixture satisfactory, so that may be pressed into pellets, the composition can be obtained by mixing, if the fluidity is unsatisfactory, then the composition may be obtained in the form of pellets by extrusion, granulation and sieving. This way you can get a dispersive medium, a part of immediate-release.

Dwuhfazno matrix composition for oral administration containing part of the delayed-release and immediate-release formulation can be prepared by adding to a composition containing the above-mentioned part of the delayed-release and immediate-release, pharmaceutically acceptable additives and then compressing the mixture into tablets or loaded into capsules.

For example, it is possible to prepare compositions in the form of two is asno matrix tablets, having two granular phase, multi-layered tablets, tablets with dry skin and capsules, pellets containing two phases, one of which is part of the pending release, and the other part with the immediate-release. You can also prepare a two-layer tablet in which the inner layer contains blocker AII receptors and provides a delayed release, and the outer layer contains an inhibitor of HMG-COA reductase and provides an immediate release.

However, the form of the composition, may be prepared according to the invention, is not limited to dwuhfazno-matrix tablet, which is a single object, where the dispersed phase, a component of the delayed release blocker AII receptors are distributed in the dispersion medium constituting a part of the immediate-release inhibitor of HMG-COA reductase.

Mixing of granules that are part of a pending release and immediate-release formulation with pharmaceutically acceptable excipients and further compressing the mixture with the help of a number of tablet machines in a two-layer or three-layer tablet with parallel layers to obtain a multilayer tablet for oral administration, the appropriate layers which provide delayed release and immediate release.

the moreover, tablet for oral administration, the core of which provides a slow release, and the outer layer covering the core, provides an immediate release, can be obtained by mixing the granules containing the part with the pending release and pharmaceutically acceptable excipient, pelletizing kernel, mixing granules containing part of the immediate-release and pharmaceutically acceptable excipient, and pressing the mixture onto the surface of the core to receive the outer layer.

In addition, mixing of granules containing part of the delayed-release and immediate-release, and pharmaceutically acceptable excipients and, if necessary, fill with a mixture of capsules can be obtained two-phase capsule composition with delayed release for oral use.

Pharmaceutically acceptable additives to the immediate release of the active ingredient include diluents, binders, disintegrating agents, lubricants, stabilizers, dyes and fragrances, and are preferably used in quantities of 100-3000 mass parts per 100 mass parts of an inhibitor of HMG-COA reductase. Without compromising the effectiveness of the invention as diluents can be used starch, microcrystalline cellulose, lactose, glucose, mA the Nitol, alginate, salts of alkaline earth metals, clay, polyethylene glycol and dicalcium phosphate. Examples of binders can be starch, microcrystalline cellulose, highly dispersed silicon dioxide, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone and gelatin. Examples of disintegrating agents can be such starches as nitroglycol starch, corn starch, potato starch, pregelatinized starch or modified starch, such clays like bentonite, montmorillonite or wigum, microcrystalline cellulose, nizkozameshhennoj hydroxypropylcellulose, hydroxypropylcellulose, sodium alginate, cellulose cross-links, such as crosscarmellose sodium, such gums like guar gum or xanthan gum, polymers with cross-links, such as crosspovidone, and materials such as sodium bicarbonate or citric acid. These leavening agents can be used both separately and in mixtures of two or more. Examples of lubricants can be talc, magnesium stearate, alkali metal stearates such as calcium stearate or zinc stearate, lauryl, hydrogenated vegetable oil, sodium benzoate, sodium fumarate, glycerion the stearate and polyethylene glycol 4000. Examples of stabilizers can be ascorbic acid and citric acid, bottled hydroxyanisol, bottled hydrocolor and derivatives of tocopherol. In addition, the invention can be used pharmaceutically acceptable dyes, fragrances, etc.

In amounts known in the art, Examples of the additives used microcrystalline cellulose, nitroglycol starch, colloidal silicon dioxide, magnesium stearate and the like, however, the invention is not limited.

On the surface of the tablets may optionally be obtained from the shell. That is, the proposed composition containing blocker AII receptors and an inhibitor of HMG-COA reductase, can also be used in the form of tablets, supplied by shell if the shell is formed on the surface of the tablets containing the aforementioned active ingredients, so that the obtained film-coated tablet, then this provides a further increase in the stability of these active ingredients. The shell can be obtained by any method providing a shell on the surface of the tablet, for example by treatment in the fluidized bed or drazhirovanie. The application shell drazhirovanie is preferred.

The shell can be obtained using the top substance, cover with whom estva or mixtures thereof. Specifically, as the coating substance to the shell, you can use any substance or mixture of substances from the following list: cellulose derivatives, derivatives of sugars, derivatives of polyvinyl, waxes, fats, gelatin, and as the cover means may be used any substance or mixture of substances from the following list: polyethylene glycol, ethylcellulose, glycerides, titanium dioxide, diethylphthalate.

When preparing tablets, sheathed, the share of the latter preferably is 0.5-15% by weight of the total tablet.

The proposed system drug delivery described above is a composition containing as active ingredients blocker AII receptors and an inhibitor of HMG-COA reductase. Accordingly, since it is taken only once in the evening, the reception is much easier than in case of simultaneous use of separate compositions containing the aforementioned active ingredients. In addition, because of the antagonism between drugs no side effects antagonism reduced or eliminated. In addition, medicinal substances exhibit a synergistic effect in controlling blood pressure and lipids at the same time.

The results of comparative clinical trials are described below.

The patients in the control group at the same time took whom archacki available blocker AII receptors (50 mg of losartan potassium) and an inhibitor of HMG-COA reductase (20 mg of simvastatin). Patients of the test group these medications are taken at different times, so the time of the release of medicinal substances were the same as in the composition obtained in the Example embodiment of the invention, and the effects of drugs, therefore, were the same as in the above-mentioned composition. Observations showed that in the treated group, the blocker AII receptors and an inhibitor of HMG-COA reductase at different times, the efficacy and safety of drugs were significantly higher than in the treated group, the blocker AII receptors and an inhibitor of HMG-COA reductase at the same time, and that changes in the concentration of drugs in blood corresponded to the change in their clinical efficacy and safety.

The authors studied pharmaceutical composition that uses a system of drug delivery, the finding that this pharmaceutical composition can exhibit the effects described above.

That is, the proposed system drug delivery can be properly used for the prevention or treatment of hypertension with complications such as cardiovascular, cardiopulmonary, pulmonary or renal diseases, including the metabolic syndrome, as insulin resistance, diabetes or prediabetes, or no complications.

Hereinafter the invention is described in more p is explored with reference to the following examples. However, the scope of the invention, these examples are not limited.

Examples 1-13: Preparation of core tablets

1) Preparation of core tablets of losartan delayed release

For the preparation of core tablets of losartan delayed release, as shown in Tables 4 and 5, losartan potassium, microcrystalline cellulose, pregelatinized starch, copovidone and Aerosil 200 were sieved through sieve No. 35 and mixed in a high speed mixer for 5 minutes. Then the mixture for 4 minutes, stirred magnesium stearate. The resulting mixture is extruded in the core tablets using a tabletting machine (MRC-33, Sejong Machinery Co., South Korea). The resulting core tablets were placed in the equipment Hi-coater (SFC-30N, Sejong Machinery Co., South Korea), which were prepared core tablets with delayed release, the composition of which is shown in Tables 4 and 5.

2) Preparation of the layer with the immediate-release inhibitor of HMG-COA reductase

In Example 1 for the preparation of the layer with the immediate-release inhibitor of HMG-COA reductase inhibitor of HMG-COA reductase inhibitor, simvastatin, and excipients, such as microcrystalline cellulose, lactose, corn starch and nitroglycol starch, proseware through sieve No. 35 and mixed in a high speed mixer. Meanwhile prepared binder solution by dissolving the water hydroxypropylcellulose and citric acid. The binder solution was poured in a high speed mixer where the mixture, and stirred. After mixing the resulting material was granulated by passing through a sieve No. 18, using the vibrator, and the granules were dried in the dryer with water heated at 60°C. after drying, the granules were sieved through sieve No. 20. With the sifted material in a double-cone mixer mixed bottled hydroxyanisol. With the mixture in the double-cone mixer mixed magnesium stearate.

In Examples 2-13 products with immediate-release formulation containing the composition and the components shown in Tables 4 and 5, prepared in the same way as described above.

3) Tableting and enveloping

For the preparation of tablets, equipped with a dry shell having losartanlosartan the core and simvastatin.steroid outer layer, used tablet press machine (RUD-1: Kilian). For the preparation of shell solution of 132 mg of ethanol and 33 mg of purified water was dissolved hydroxypropylcellulose 2910, titanium oxide and talc. The obtained tablets were placed in the equipment Hi-coater (SFC-30N, Sejong Machinery Co., South Korea), in which the tablets were covered with a shell solution, resulting in the acquisition of the tablets covered with a dry shell.

Examples 14-17

1) Preparation of granules with delayed release of l is of Sartana

In Example 15 for the preparation of granules with delayed release of losartan losartan potassium, microcrystalline cellulose, polyvinylpyrrolidone cross-links and sodium chloride were sieved through sieve No. 35 and mixed in a high speed mixer for 5 minutes. Meanwhile prepared binder solution by dissolving hydroxypropylcellulose in purified water. The binder solution was poured in a high speed mixer where the mixture, and stirred, after which he was assigned granulation and drying. The dried material was placed in a device for coating fluidized bed. Meanwhile prepared shell solution, dissolving and dispersive 220 mg of ethanol and 980 mg of methylene chloride cellulose acetate with 32% of acetyl groups, the cellulose acetate from 39.8% acetyl groups and hydroxypropylcellulose. The dried granules were coated shell solution in the device for coating fluidized bed (GPCG-1, Glatt, Germany), thus obtaining granules with delayed release of losartan.

In Examples 14, 16 and 17 of granules containing compositions and the components shown in Table 5, prepared in the same way as described above.

2) Preparation of granules with the immediate-release simvastatin

For the preparation of granules with immediate release simvastat is on, as shown in Table 5, simvastatin, microcrystalline cellulose and D-mannitol were sieved through sieve No. 35 and mixed in a high speed mixer. Meanwhile, dissolving in water hydroxypropylcellulose and citric acid, prepared binder solution, which is then mixed with the mixture. After mixing, the material was granulated, passing through sieve No. 18 and using a vibrator, then the obtained granules were dried in the dryer with water heated at 60°C. After drying, the granules were passed through sieve No. 20. The sifted material was mixed with butilirovannyh hydroxyanisole.

3) Subsequent mixing, tableting and enveloping

Prepared granules with delayed release of losartan and granules immediate-release simvastatin was stirred in a double-cone mixer. The resulting mixture was mixed with matriptase starch and, finally, with stearate. The resulting mixture was pressed into tablets using a rotary tablet machine (MRC-33, Sejong Machinery Co., South Korea). Meanwhile received a shell solution, dissolving and dispersive in 64.8 mg of ethanol and 16.2 mg of purified water a hypromellose 2910, hydroxypropylcellulose, titanium oxide and talc. The tablets covered with a shell hardware Hi-coater (SFC-30N, Sejong Machinery Co., South Korea), receiving shell SL is th, thus obtaining tablets with a two-phase matrix.

Examples 18-27

1) Preparation layer delayed release blocker AII receptors

In Example 18 to prepare the layer delayed release blocker AII-receptor losartan potassium, which is a blocker of AII receptors, and excipients, which included microcrystalline cellulose, polyvinylpyrrolidone cross-links and sodium chloride, were sieved through sieve No. 35 and mixed in a high speed mixer for 5 minutes. Meanwhile, dissolving in purified water hydroxypropylcellulose, received a binder solution. The binder solution was added to the mixture and stirred, the resulting material was granulated and dried. The dried granules were placed in a device for coating fluidized bed. Meanwhile prepared shell solution, dissolving and dispersive 220 mg of ethanol and 980 mg of methylene chloride acetate cellulose with 32% of acetyl groups, the cellulose acetate from 39.8% acetyl groups and hypromellose. The granules were coated shell solution in the device for coating fluidized bed (GPCG-1, Glatt, Germany). After encapsulating the granules were mixed with magnesium stearate for 4 minutes, thus obtaining the layer with the pending release of losartan.

In the Example the 19-27 layers with delayed release, containing compositions and the components listed in Tables 5 and 6, prepared in the same way as described above.

2) Preparation of the layer with the immediate-release inhibitor of HMG-COA reductase

In Example 9 for preparation of the layer with the immediate-release inhibitor of HMG-COA reductase simvastatin, which is an inhibitor of HMG-COA reductase, and excipients, which included single-crystalline cellulose, D-mannitol were sieved through sieve No. 35 and mixed in a high speed mixer. Meanwhile, dissolving in water hydroxypropylcellulose and citric acid, prepared binder solution. The binder solution was added to the mixture and stirred with it. The mixed material was granulated, passing through sieve No. 18 and using a vibrator, then the obtained granules were dried in the dryer with water heated at 60°C. After drying, the granules were passed through sieve No. 20. The sifted material was mixed with butilirovannyh hydroxyanisole and matriptase starch, and then mixed with magnesium stearate in a double-cone mixer.

In Examples 19-27 layers with the immediate-release formulation containing the composition and the components listed in Tables 5 and 6, prepared in the same way as described above.

3) Tableting and enveloping

Used machine for mogolo the aqueous tabletting (MRC-37T, Sejong Machinery Co., South Korea). Simvastatin-containing composition was placed in a first powder feeder, and composition with delayed release of active substance is placed in the second powder feeder. Compositions feeders extruded into pellets under conditions of minimized interlayer of incorporation. Meanwhile prepared shell solution, dissolving in 64.8 mg of ethanol and 16.2 mg of purified water a hypromellose 2910, hydroxypropylcellulose, titanium oxide and talc. The tablets covered with a shell hardware Hi-coater (SFC-30N, Sejong Machinery Co., S.Korea), thus obtaining a multilayer tablet extended release.

Examples 28 and 29: Cooking capsules

1) Preparation of granules with delayed release of losartan

In Example 28 for the preparation of granules with delayed release of losartan losartan potassium, microcrystalline cellulose, polyvinylpyrrolidone cross-links and sodium chloride were sieved through sieve No. 35 and mixed in a high speed mixer for 5 minutes. Meanwhile, dissolving in purified water hydroxypropylcellulose, received a binder solution, which was added to the mixture and stirred. The obtained mixed material was granulated and dried. The dried granules were placed in a device for coating fluidized bed. Meanwhile, p is igorously shell solution dissolving 220 mg of ethanol and 980 mg of methylene chloride cellulose acetate with 32% of acetyl groups, the cellulose acetate from 39.8% acetyl groups and hypromellose. The granules were coated shell solution in the device for coating fluidized bed (GPCG-1, Glatt, Germany), thus obtaining granules with delayed release of losartan.

In Example 29 granules with delayed release of active substance-containing composition and the components listed in Table 6, prepared in the same way as described above.

2) Preparation of granules with the immediate-release simvastatin

In Example 28 for the preparation of granules with the immediate-release simvastatin simvastatin, microcrystalline cellulose and D-mannitol were sieved through sieve No. 35 and mixed in a high speed mixer. Meanwhile, dissolving in water hydroxypropylcellulose and citric acid, prepared binder solution, which is then mixed with the mixture. After mixing, the material was granulated, passing through sieve No. 18 and using the vibrator, the obtained granules were dried in the dryer with water heated at 60°C. After drying, the granules were passed through sieve No. 20. The sifted material was mixed with butilirovannyh hydroxyanisole in a double-cone mixer.

In Example 29 granules with needle the major release of simvastatin, containing compositions and the components listed in Table 6, prepared in the same way as described above.

3) mixing of the components and filling capsules

The composition obtained in stages 1) and 2), were mixed in a double-cone mixer. To the mixture in the double-cone mixer mixed nitroglycol starch. The mixture was mixed with magnesium stearate. The resulting mixture was placed in a powder feeder and filled it capsules by using capsulopalpebral machine, thus obtaining a capsulated composition with delayed release.

Test example 1. Comparative test dissolution profile

Conducted testing of the dissolution profile of tablets containing two-phase combination of losartan/simvastatin, with a delayed-release formulation prepared in Example 1 and used in the quality control of drugs "zocor" (Zocor®) (tablet only contains simvastatin) and cozaar" (Cozaar®) (tablet containing only losartan). Test dissolution profiles simvastatinum component was performed according to the USP monograph (USP30), testing dissolution profile losartanage component occupied a period of 480 minutes, during which isteineeinbu 120 minutes solvent environment changed with artificial gastric juice artificial intestinal juice. Test dissolution profiles of each component was carried out as described below, and the test results are illustrated in figure 1.

As can be seen from figure 1, when performing tests of dissolution profile when the following conditions simvastatinbuy component of the tablet containing the proposed two-phase combination, showed a dissolution profile, essentially coinciding with the dissolution profile of the control drug "zocor", while lasertherapy component compared with the corresponding control drug "cozaar" showed a very slow dissolution. The test results revealed that for the first 120 minutes, which corresponds to the duration of artificial gastric juice, dissolved not more than 10% losartanage component of the tablet containing the proposed two-phase combination, whereas the corresponding control of the drug dissolved in approximately 60% of losartan. During the first 150 minutes losartan control of the drug dissolved in an environment of artificial intestinal juice 100%, whereas lasertherapy component of the tablet containing the proposed two-phase combination of losartan/simvastatin, after the first 240 minutes dissolved by approximately 20%, suggesting that this lasertherapy component was dissolved much more slowly than losartan control of Lenogo drug.

As indicated above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/simvastatin, is much slower than the release simvastatinum component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized simvastatin, provided sufficient time for regeneration.

Testing simvastatin

Test dissolution profiles was performed on the basis of paragraph "tablet simvastatin" United States Pharmacopeia (USP30).

Test condition: paddle stirring at 50 rpm

Dissolving medium: 900 ml buffer pH 7 (0.01 M solution of the secondary acid phosphate with the addition of as surfactant 0.5 wt.% lauryl sodium).

Analysis method: spectrophotometry using ultraviolet and visible spectra (wavelength range detection 247-257 nm).

Testing of losartan potassium

Test dissolution profiles was performed on the basis of a common test methods of dissolution according to the Pharmacopoeia of the Republic of Korea, eighth edition.

Test condition: paddle stirring at 50 rpm

Solvent environment: 750 ml of 0.01 M hydrochloric acid solution (artificial gastric juice); 1000 ml of phosphate buffer solution pH 6.8 (artificial intestinal juice).

Analysis method: spectrophotometry using ultraviolet and visible spectra (wavelengths of detection is less than 230 nm).

Test example 2. Comparative test dissolution profile

Conducted testing of the dissolution profile of tablets containing two-phase combination of losartan/lovastatin, with a delayed-release formulation prepared in Example 9 and used in the quality control of drugs "mevacor" (Mevacor®) (tablet only contains lovastatin) and cozaar". Test dissolution profiles lovastatinsee component was performed according to the USP monograph (USP30), testing dissolution profile losartanage component occupied a period of 480 minutes, during which after the first 120 minutes of the solvent medium was changed with artificial gastric juice artificial intestinal juice. Test dissolution profiles of each component was carried out as described below, and the test results are illustrated in figure 2. Analysis losartanage component was carried out as in Example 1.

As can be seen from figure 2, when performing tests of dissolution profile when nigersan the x terms lovastatinsee component tablets containing the proposed two-phase combination, showed a dissolution profile, essentially coinciding with the dissolution profile of the control drug "mevacor", while lasertherapy component compared with the corresponding control drug "cozaar" showed a very slow dissolution. The test results revealed that for the first 120 minutes, which corresponds to the duration of artificial gastric juice, dissolved not more than 10% losartanage component of the tablet containing the proposed two-phase combination, whereas in the corresponding test drug was dissolved in approximately 60% of losartan. During the first 150 minutes losartan control of the drug dissolved in an environment of artificial intestinal juice 100%, whereas lasertherapy component of the tablet containing the proposed two-phase combination of losartan/lovastatin after the first 240 minutes dissolved by approximately 20%, suggesting that this lasertherapy component was dissolved much more slowly than the control losartan drug.

As mentioned above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/lovastatin, is much slower than the release lovastatinsee component, in contrast to the profiles Rast is orenia, received while admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized lovastatin, provided sufficient time for regeneration.

Testing lovastatin

Test dissolution profiles was performed on the basis of paragraph "tablet lovastatin" United States Pharmacopeia (USP30).

Test condition: paddle stirring at 50 rpm

Dissolving medium: 900 ml buffer pH=7 (0.01 M solution of the secondary acid phosphate with the addition of as surfactant 2 wt.% lauryl sodium).

Analysis method: high performance liquid chromatography (HPLC).

Detected wavelength: 230 nm.

Mobile phase: acetonitrile: 0.02 M buffer solution secondary acid phosphate (pH=4): methanol = 5:3:1.

Column: stainless steel, inner diameter of 4.6 cm, length 250 mm, loaded octadecylsilyl-silica gel.

Flow rate: 1.5 ml/min

Test example 3. Comparative test dissolution profile

Conducted test dissolution profiles of the formulations prepared in Examples 2-5. Test dissolution profiles of each component was carried out as in Test example 1, the results shown in figure 3.

As can be seen from the Phi is .3, when performing tests dissolution profile under the conditions described in Test example 1, lasertherapy component offer tablets with dry shell showed a reduction in the percentage of dissolution with increasing number of applications. The compositions of Examples 2-5, covered with ethylcellulose showed dissolution of losartan less than 20% after the first 240 minutes.

As mentioned above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/simvastatin, is much slower than the release simvastatinum component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized simvastatin, provided sufficient time for regeneration.

Test example 4. Comparative test dissolution profile

Conducted test dissolution profiles of the formulations prepared in Examples 6-8. Test dissolution profiles of each component was carried out as in Test example 1, the results shown in figure 4.

As shown in figure 4, when performing tests of dissolution profile in terms of the, described in Test example 1, lasertherapy component offer tablets with dry shell showed rapid release after a specified time delay, with a layer delayed release coated ethylcellulose contained polyvinylpyrrolidone cross-links. The percentage of dissolution losartanage component was less than 20% after the first 240 minutes, and lasertherapy component showed a quick release with increasing amount of polyvinylpyrrolidone with cross-links.

As mentioned above, after a specified time delay quick release losartanage component of the proposed tablet of losartan/simvastatin may be provided by adjusting the amount of polyvinyl pyrrolidone with cross-ties used in the layer with the pending release.

As mentioned above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/simvastatin, is much slower than the release simvastatinum component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, after CA is in the liver is first metabolized simvastatin, provided sufficient time for regeneration.

Test example 5. Comparative test dissolution profile

Conducted testing of the dissolution profile of tablets containing two-phase combination of losartan/atorvastatin delayed release, prepared in Example 10, and used as a control drug "lipitor" (Lipitor®) (tablet containing only atorvastatin) and cozaar". Test dissolution profiles atorvastatina component was performed according to the testing method of dissolution set forth in the Pharmacopoeia of the Republic of Korea, eighth edition, test dissolution profiles losartanage component occupied a period of 480 minutes, during which after the first 120 minutes of the solvent medium was changed with artificial gastric juice artificial intestinal juice. Test dissolution profiles of each component was performed, as described below, the test results are illustrated in figure 5.

As can be seen from figure 5, when performing tests of dissolution profile when the following conditions atorvastatina component of the tablet containing the proposed two-phase combination, showed a dissolution profile, essentially coinciding with the dissolution profile of the control drug "lipitor", while lasertherapy component p is compared with the corresponding control drug "cozaar" showed a very slow dissolution. The test results revealed that for the first 120 minutes, which corresponds to the duration of artificial gastric juice, dissolved not more than 10% losartanage component of the tablet containing the proposed two-phase combination, whereas in the corresponding test drug was dissolved in approximately 60% of losartan. During the first 150 minutes losartan control of the drug dissolved in an environment of artificial intestinal juice 100%, whereas lasertherapy component of the tablet containing the proposed two-phase combination of losartan/atorvastatin after the first 240 minutes dissolved by approximately 20%, suggesting that this lasertherapy component was dissolved much more slowly than the control losartan drug.

As indicated above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/atorvastatin, is much slower than the release atorvastatina component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized atorvastatin, is sufficient lying is for regeneration.

Testing of atorvastatin

Test dissolution profiles was carried out according to the testing method of dissolution set forth in the Pharmacopoeia of the Republic of Korea, eighth edition.

Test condition: paddle stirring at 50 rpm

Dissolving medium: 900 ml buffer pH=7 (0.01 M solution of the secondary acid phosphate with the addition of as surfactant 2 wt.% lauryl sodium).

Analysis method: HPLC.

Detected wavelength: 247 nm.

Mobile phase: 0,02M buffer solution secondary acid phosphate (pH=4.0)is: methanol = 67:33.

Column: stainless steel, inner diameter of 4.6 cm, length 250 mm, loaded octadecylsilyl-silica gel.

Flow rate: 1.5 ml/min

Test example 6. Comparative test dissolution profile

Conducted testing of the dissolution profile of tablets containing two-phase combination of losartan/simvastatin, with a delayed-release formulation prepared in Examples 14 and 19, and used as control drugs "zocor and cozaar". Test dissolution profiles simvastatinum component was performed according to the USP monograph (USP30), testing dissolution profile losartanage component occupied a period of 480 minutes, during which after the first 120 minutes of the solvent medium was changed with artificial gastric with whom and in artificial intestinal juice. Test dissolution profiles of each component was carried out as described in Test example 1, the results of the tests are illustrated in Fig.6.

As can be seen from Fig.6, when performing tests of dissolution profile in the conditions of Test example 1 simvastatinbuy component of the tablet containing the proposed two-phase combination, showed a dissolution profile, essentially coinciding with the dissolution profile of the control drug "zocor", while lasertherapy component compared with the corresponding control drug "cozaar" showed a very slow dissolution. The test results revealed that for the first 120 minutes, which corresponds to the duration of artificial gastric juice, dissolved not more than 10% losartanage component of the tablet containing the proposed two-phase combination, whereas the corresponding control of the drug dissolved in approximately 60% of losartan. During the first 150 minutes losartan control of the drug dissolved in an environment of artificial intestinal juice 100%, whereas lasertherapy component of the tablet containing the proposed two-phase combination of losartan/simvastatin, after the first 240 minutes dissolved by approximately 20%, suggesting that this lasertherapy component was dissolved much slow is e, than losartan control of the drug.

As mentioned above, the initial release losartanage component of the tablet containing the proposed two-phase combination of losartan/simvastatin, is much slower than the release simvastatinum component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized simvastatin, provided sufficient time for regeneration.

Test example 7. Comparative test dissolution profile

Conducted testing of the dissolution profile of tablets containing two-phase combination of erbeten/simvastatin, with a delayed-release formulation prepared in Example 21, and used as control drugs "zocor" and "approval" (Aprovel®) (tablet containing only arbesman). Test dissolution profiles simvastatinum component was performed according to the USP monograph (USP30), testing dissolution profile ernestinovo component occupied a period of 480 minutes, during which after the first 120 minutes of the solvent medium was changed with artificial gastric juice artificial is th intestinal juice. Test dissolution profiles of each component was performed, as described below, the test results are illustrated in Fig.7. Analysis simvastatinum component was carried out as in Test example 1.

As can be seen from Fig.7, when performing tests of dissolution profile when the following conditions simvastatinbuy component of the tablet containing the proposed two-phase combination, showed a dissolution profile, essentially coinciding with the dissolution profile of the control drug "zocor", while yestaday component compared with the corresponding control drug "approval" showed a very slow dissolution. The test results revealed that for the first 120 minutes, which corresponds to the duration of artificial gastric juice, dissolved not more than 10% ernestinovo component of the tablet containing the proposed two-phase combination, whereas in the corresponding control drug dissolution Ernestina was almost 100%. During the first 150 minutes arbesman control of the drug dissolved in an environment of artificial intestinal juice 100%, whereas yestaday component of the tablet containing the proposed two-phase combination of erbeten/simvastatin, after the first 240 minutes dissolved by approximately 20%, which allows the assumption is arranged, this yestaday component was dissolved much more slowly than arbesman control of the drug.

As mentioned above, the initial release ernestinovo component of the tablet containing the proposed two-phase combination of erbeten/simvastatin, is much slower than the release simvastatinum component, unlike dissolution profiles obtained when simultaneous admission control component of the tablets. Thus, when taking the offered tablets are associated with metabolism enzymes-cytochrome P450, once in the liver is first metabolized simvastatin, provided sufficient time for regeneration.

Testing Ernestina

Test dissolution profiles was performed on the basis of a common test methods of dissolution according to the Pharmacopoeia of the Republic of Korea, eighth edition.

Test condition: paddle stirring at 50 rpm

Solvent environment: 750 ml of 0.01 M hydrochloric acid solution (artificial gastric juice); 1000 ml of phosphate buffer solution pH 6.8 (artificial intestinal juice).

Analysis method: HPLC.

Detected wavelength: 220 nm.

Mobile phase: acetonitrile: phosphate buffer (pH=3,7)=33:67. Column: stainless steel, inner diameter 4.0 cm, length 250 mm, loaded octadecylsilyl-silica gel.

Flow rate: 1.0 ml/min

Ispytatel the hydrated example 8. Animal studies

In this test example in order to confirm the validity of the proposed compositions were testing on animals in accordance with the following Table 7. Namely, the control group were given commercially available preparations "zocor" (tablet MSD containing only simvastatin) and cozaar" (tablet MSD containing only losartan), which were taken at the same time. The animals of the test group drugs were given at different times, so the time of the release was the same as for the composition prepared in the Example embodiment of the invention, and the effect of each drug was the same as in the case of the proposed composition.

In addition, these animal studies were designed to confirm the time of admission, showing the maximum antihypertensive effect.

[Table 7]
The name of the testAnimal studies to compare the antihypertensive action at the same time and are separated by time receiving losartan and simvastatin spontaneously hypertensive rats (SHR)
Objective testsP is izvesti comparative assessment of homeostatic pharmacokinetic properties, the antihypertensive actions and safety of simultaneous and separated by time receiving losartan and simvastatin and make a comparative assessment of homeostatic pharmacokinetic properties of antihypertensive action and security depending on the time of reception
Experimental animals25 8-week-old male SHR, distributed in five groups of five animals each, and four 9-week-old male rats of the Wistar-Kyoto (WKY)
The test planThe test plan consisted of the following.
As the test drugs were used losartan and simvastatin. All 29 animals were grouped into six groups of five animals each: control was used WKY, which received saline solution; as a screening was used SHR; one test took losartan and simvastatin at the same time in the morning (group SM) (without lighting); one test took losartan and simvastatin at the same time in the evening (group SN) (lighting); one test took losartan and simvastatin at different times in the morning (group DM) (without lighting); one test took losartan and simvastatin at different times in the evening (group DN) (lighting) (only three of most the group: control, screening and test). Medication was taken within five days of once per day. In these trials as experimental animals rats were used, so the tests were carried out with light and without light. The reception during testing on animals to man applied the opposite way, because biorhythm rats opposite to the biorhythm of people.
MethodTo estimate the effects medicines
evaluation resultsComparison values (measured using automatic meter blood pressure) systolic blood pressure, diastolic blood pressure average blood pressure and pulse rate in groups, taking medication in the morning or in the evening at the same time, and groups who took the medication in the morning or in the evening at different times.
Group nameMedications taken and methods (concentration of 5 ml/kg)The number of animals
Normal (WKY, saline)Hourly saline4
Media (saline)Hourly saline5
Subjects in groupCoadministration of losartan and simvastatin in the morning (group SM) (without lighting)Losartan and simvastatin was given at the same time at 9:305
Coadministration of losartan and simvastatin in the evening (group SN) (when illuminated)Losartan and simvastatin was given simultaneously at 19:005
Receive losartan and simvastatin at different times in the morning (group DM) (without lighting)Losartan at 9:30, simvastatin at 13:305
Receive losartan and simvastatin at different times in the evening (group DN) (when illuminated)Losartan at 19:00, simvastatin at 23:005

Pharmacokinetics/pharmacodynamics according to the results of clinical trials on animals made in this Test example, shown below in Table 8 and illustrated in Fig-10.

As experimental animals rats were used when lighting and no lighting. The reception during testing on animals to man applied the opposite way, because biorhythm rats opposite to the biorhythm of people.

1. The effect in reducing blood pressure: systolic blood pressure and diastolic blood pressure showed lower values compared to the screening group at day 5.

2. The effect in reducing blood pressure is illustrated in Fig-10. According to the observation group, taking medications at different times in the evening (when illuminated)found among the four groups with the greatest decrease in blood pressure.

Thus, it is possible to see that, unlike groups, taking medications at the same time, the proposed composition after admission has on reducing blood pressure optimal action for a period of time from morning till noon, when the average blood pressure reaches its peak value.

You can see that, in the case of medications that contain, as the proposed composition blocker AII receptors and an inhibitor of HMG-COA reductase, at different times occurred optimal antihypertensive effect, in contrast to the case when the blocker AII receptors and an inhibitor of HMG-COA reductase were taken at the same time.

The following Table 9 poisonality measurements of blood pressure and heart rate in the group taking losartan and simvastatin simultaneously, and in the group, taking them at different times in the morning according to the invention. As can be seen from Table 9, the test group taking losartan and simvastatin at different times according to the invention, showed a 0.3%increase in the mean systolic blood pressure compared with the group treated with medicines at the same time, but this increase is negligible. In addition, the group, which tested the invention, showed a 4.8%increase effect of reducing the average diastolic pressure, a 3.3%increase effect of reducing the average blood pressure and a 7.1%increase in the effect of reducing the pulse frequency compared with groups treated with medication at the same time. Thus, the group that tested the invention, showed a significant increase in the overall effect of reducing blood pressure.

[Table 9]
GroupSystolic blood pressure (mm Hg)Diastolic blood pressure (mm Hg)Mean blood pressure (mm Hg)Pulse rate (per min)
Normal1250±5,5 80,3±15,595,±10,6457,0±55,0
Screening168, 8mm±8,3106,8±22,8127,8±13,9439,0±18,6
Taking medications at different times in the eveningto 124.4±1,774,0±13,190,2±9,8463,6±58,6
Taking medications at the same time in the evening124,0±8,077,8±14,1to 93.3±8,4498,8±45,0
The difference in reduction of blood pressure between the groups, taking medications at the same time and at different times-0,3%+4,8%+3,3%+7,1%

As experimental animals rats were used when lighting and no lighting. The reception during testing on animals to man applied the opposite way, because biorhythm rats opposite to the biorhythm of people.

On losartan delayed release, taken four hours, as proposed by the invention for red eye reduction is of pressure, it was shown that the group taking medications at different times, showed the effect of reducing blood pressure, superior to that effect, which showed the group taking medication at the same time.

Test example 9. Preliminary clinical trials

To confirm the effect of the proposed combination was conducted clinical trials described in the following Table 10. Namely, the control group took or only commercially available tablets "zocor" (20 mg simvastatin, Merck), or tablet "zocor and cozaar" (50 mg of losartan potassium, MSD) at the same time. The subjects of the group took zocor and cozaar" at different times, so the time of the release was the same as in the case of the combination according to the Example embodiment of the invention.

[Table 10]
The name of the testMultiinstitutional clinical trials that compare the pharmacokinetic properties, effects, and safe administration of losartan and simvastatin simultaneously and at different times for patients with hypertension and hyperlipidemia (research, testing, initiated by the researcher)
Objective tests Comparative evaluation of pharmacokinetic properties, effects, and safety in patients with hypertension and hyperlipidemia who "zocor and cozaar" at the same time, and groups who took these drugs at different times after administration once a day for six weeks (42 days)
Subjects patients17 patients 30-60 years with hypertension and hyperlipidemia; eight patients drugs were given at the same time, nine patients at different times
The test planTests were planned as follows:
2-open and a single dose.
The test drug 1: "cozaar" (one tablet 50 mg)
The test drug 2: zocor" (one tablet (20 mg).
Group A: received "zocor and cozaar" at the same time in the evening.
Group B: received "zocor and cozaar" in the evening at different times.
Medications were taken six weeks (42 days), the results were compared.
The efficacy and safety1. Assessment of the effectiveness of
The starting point for the evaluation of the effectiveness of therapy: comparison of changes (before and after testing) average systolic blood pressure and LDL-X the two groups, i.e. groups who took the drugs the and at the same time, and groups, taking medications at different times.
The second paragraph of the evaluation of the effectiveness of therapy: comparison of changes (before and after testing) average diastolic blood pressure in the sitting position and pulse pressure, lipid profiles (total cholesterol (mg/DL), LDL-cholesterol (mg/DL), HDL-cholesterol (mg/DL)triglycerides (mg/DL), other risk factors (Apolipoprotein B, LDL-X/PVP-X) and the group risk SS-diseases between the two groups.
2. Safety assessment
Physical examination, vital signs, NYA, ECG, etc.
Subjects in groupGroup nameMedications taken and the methodThe number of patients
Took the evening at different times"Zocor" 20 mg was taken at 19:00, "cozaar" 50 mg took four hours to 23:00.9
Took an evening at the same time"Cozaar" 50 mg and zocor" 20 mg were taken simultaneously at 19:00.8

Studies confirm the effects of the invention and used to market drugs and were held is as small groups of patients according to ICH-GCP and KGCP.

Data on lipids obtained at day 42 (fasting) after you start taking in these clinical studies, are given in the following Table 11.

-79,1 (45,4%)
[Table 11]
Group A (drugs taken at the same time, eight patients)Group B (drugs taken at different times, nine patients)Results
Lipids
ScreeningD42Change (%)ScreeningD42Change (%)
Total cholesterol (120-230
mg/DL)
208,6151, 3mm-57,4 (27,5%)251,1172,3-78,8 (31,4%)The group B is better
LDL-cholesterol (0-120 mg/DL)139,682,6-57,00 (40,8%)174,295,1The group B is better
HDL/LDL0,3020,5190,217 (71,9%)0,3120,5380,226 (72,4%)In both groups a significant increase
Triglycerides (40-150)177,5175,9-1,6 (0,9%)172,4161,4-11,0 (6,4%)The group B is better

Blood pressure, pulse rate and pulse pressure measured at day 41 after the start of medication in these clinical trials, are shown in the following Table 12.

[Table 12]
Group A (drugs taken at the same time, eight patients)Group B (drugs taken at different times, nine patients)Results
ScreeningO41Change %) ScreeningO41Change (%)
Systolic blood pressure148,3141,3-7,0 (4,7%)145, 2mm132,4is-12.7 (8.7 per cent)The group B is better
Diastolic blood pressure99,490,0-9,4 (9,5%)94,880,9-13,9 (14,7)The group B is better
Pulse pressure53,151,3-1,8 (3,4%)50,851,50,7 (3,3%)Similar
Pulse rate76,5is 83.87,3 (9,5%)72,376,34,0 (5,5%)The group B is better

Biomarkers measured on day 41 after the beginning of reception Lek is rst in these clinical trials, shown in the following Table 13.

[Table 13]
Group A (drugs taken at the same time, eight patients)Group B (drugs taken at different times, nine patients)Results
ScreeningD42Change (%)ScreeningD42Change (%)
AST (0-50 IU/L)25,427,42,0 (7,9%)26,128,01,9 (7,3%)Similar
ALT (0-45 IU/L)40,441,41,0 (2,5%)37,134,7-2,44 (6,6%)The group B is better
r-GTP (4-50)63,168,0+4,9 (25,5%) 38,239,7+0,5 (1,3%)The group B is better
CPK (51-246 IU/L)157,8117,5-40,3 (25,5%)82,984,81,9 (2,3%)Maintained in the normal range (A>B)

The results of clinical trials in respect of the group who took simvastatin and losartan at different times, and groups taking these medicines at the same time, showed that for all evaluated parameters, including lowering blood pressure, lipid-lowering and biomarkers associated with side effects, the superiority belongs to the treated group, simvastatin and losartan at different times. In particular, in the tested group was not serious NYA, which usually occur after administration of each of these drugs.

In the clinical trials it was shown that when the blocker AII receptors and an inhibitor of HMG-COA reductase are taken at different times, as provided by the invention, the inhibitor of HMG-COA reductase shows without increasing dose shows a greater antihypertensive effect than while receiving monocomponent preparations blocker AII receptors and Inga is itora HMG-COA reductase. In addition, it was shown increased action of the blocker AII receptors on lowering blood pressure, and you can see that this increased action of the blocker AII receptors is due to the extension of time of release of this drug.

Industrial applicability

According to the above-described invention relates to the composition with delayed release containing blocker AII receptors and an inhibitor of HMG-COA reductase, and provides for a pharmaceutical combination containing blocker AII receptors and an inhibitor of HMG-COA reductase, which is most suitable for the prevention and treatment of hypertension, accompanied or not accompanied by complications such as cardiovascular, cardiopulmonary, pulmonary or renal disease, metabolic syndrome, including insulin resistance and diabetes or prediabetes.

Specifically, the invention provides a system for targeted drug delivery to tissues containing material with a delayed release material and immediate-release, so is control the rate of dissolution of the blocker AII receptors and an inhibitor of HMG-COA reductase in the body. The proposed system for targeted drug delivery to the tissues is a composition with delayed release, create the authorized taking into account absorption, metabolism and pharmacological actions of each of the drugs, so when taking it once a day in the evening and provided with optimal efficacy and safety.

In addition, the invention provides a method of making a combination with a delayed release.

1. Comprehensive pharmaceutical composition with delayed release, containing part of the delayed-release formulation comprising as an active ingredient blocker AII receptors, and part of the immediate-release formulation comprising as active ingredient an inhibitor of HMG-COA reductase.

2. The composition according to claim 1, in which within four hours after oral administration blocker AII receptors released less than 40 wt.%, when this absorption blocker AII receptors in the liver are provided at three to four hours later than the absorption inhibitor of HMG-COA reductase.

3. The composition according to claim 2, in which for four hours after oral administration blocker AII receptors released less than 30 wt.%, when this absorption blocker AII receptors in the liver are provided at three to four hours later than the absorption inhibitor of HMG-COA reductase.

4. The composition according to claim 1, in which the release blocker AII receptors in the liver is provided through four hours after the start of the dissolution inhibitor of HMG-COA reductase.

p> 5. The composition according to claim 1, in which the blocker AII receptor selected from the following list: losartan, valsartan, irbesartan, candesartan, telmisartan, eprosartan, olmesartan, and their pharmaceutically acceptable salts.

6. The composition according to claim 5, in which the blocker AII receptors is losartan or its pharmaceutically acceptable salt.

7. The composition according to claim 6, in which the blocker AII receptors is losartan potassium.

8. The composition according to claim 1, containing blocker AII receptors in the amount of 5-1200 mg.

9. The composition according to claim 1, in which the inhibitor of HMG-COA reductase inhibitor is one or a mixture of two or more substances from the following list: simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, fluvastatin, pravastatin, and their pharmaceutically acceptable salts.

10. The composition according to claim 9, in which the inhibitor of HMG-COA reductase inhibitor is one or a mixture of two or more substances from the following list: simvastatin, lovastatin, atorvastatin, and their pharmaceutically acceptable salts.

11. The composition according to claim 10, in which the inhibitor of HMG-COA reductase inhibitor is simvastatin.

12. The composition according to claim 1, containing an inhibitor of HMG-COA reductase in the number of 5-160 mg

13. The composition according to claim 1, in which the part with the pending release contains material that controls the release, selected from the following list: enteric-soluble polymer, water-insoluble polymer,a hydrophobic compound, hydrophilic polymer.

14. The composition according to item 13, containing the material, controlling the release, in the amount of 10-500 parts by weight per 100 parts by weight of the blocker AII receptors.

15. The composition according to item 13, in which the enteric-soluble polymer is one or a mixture of two or more substances from the following list: polyvinylacetate, copolymers of methacrylic acid, the phthalate of hydroxypropylmethylcellulose, shellac, acetated cellulose, propionate cellulose, Eudragit L, Eudragit s

16. The composition according to item 13, in which the water-insoluble polymer is one or a mixture of two or more substances from the following list: polyvinyl acetate, copolymers of polymethacrylate, such as copolymers of poly(ethyl acrylate, methyl methacrylate) and copolymers of poly(acrylate, methacrylate, trimethylaminoethyl), ethylcellulose, acetylcellulose.

17. The composition according to item 13, in which the hydrophobic compound is one or a mixture of two or more substances from the following list: fatty acids, esters of fatty acids, alcohols, fatty acids, waxes, inorganic materials.

18. The composition according to 17, in which the hydrophobic compound is one or a mixture of two or more substances from the following list: glycerylmonostearate, literallayout, glycerinated, cetylpalmitate, glycerylmonostearate and stearic acid as a fatty acid or a complex EPE is s fatty acids, cetosteatil alcohol, cetyl alcohol and stearyl alcohol as alcohols, fatty acids, Carnauba wax, beeswax and microcrystalline wax as a wax, talc, precipitiously calcium carbonate, dibasic calcium phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite and wigum as inorganic materials.

19. The composition according to item 13, in which the hydrophilic polymer is one or a mixture of two or more substances from the following list: sugars, cellulose derivatives, gums, proteins, derivatives of polyvinyl, copolymers of polymethacrylate, derivatives of polyethylene, polymers of carboxyvinyl.

20. The composition according to claim 19, in which the hydrophilic polymer is one or a mixture of two or more substances from the following list: dextrin, polydextran, dextran, pectin and derivatives of pectin, alginate, polygalacturonase acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylmethyl, amylose and amylopectin as sugars, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, sodium carboxymethylcellulose, acetylsuccinate hydroxypropylmethylcellulose and hydroxyethylmethylcellulose as cellulose derivatives, guar gum, gum beans carob, tragacanth gum, carrageenan, acacia gum, arabiska the gum, Gellan gum and xanthan gum like gum, gelatin, casein and Zein as proteins, polyvinyl alcohol, poly(vinyl pyrrolidone) and polyvinyltrimethylsilane as derivatives of polyvinyl, copolymers of poly(butylmethacrylate, (2-dimethyl-amino-ethyl)methacrylate, methyl methacrylate), poly(methacrylic acid, methyl methacrylate) and poly(methacrylic acid, ethyl acrylate) copolymers polymethacrylate, polyethylene glycol and polyethylene oxide derivatives as polyethylene, carbomer as a representative polymers of carboxyvinyl.

21. The composition according to claim 1, formed as a single tablet, representing two-phase matrix, in which the part with the pending release exists as a dispersed phase, providing slow release blocker AII receptors, as part of the immediate-release exists as a dispersion medium, providing an immediate release of an inhibitor of HMG-COA reductase.

22. The composition according to claim 1, in which a part of the delayed-release and immediate-release form a multilayer structure.

23. The composition according to claim 1, formed as a single tablet, representing a two-layer structure including an inner core containing the part with the pending release, and an outer layer deposited on the surface of the inner core.

24. The composition according to claim 1,formed as a capsule, containing granules, consisting of parts with delayed release, and granules which consists of immediate-release.

25. The composition according to claim 1, formed as bezobolochnoe tablet or coated tablet.

26. The composition according A.25, formed as a coated tablet comprising a layer containing coating agent, coating agent or a mixture.

27. The composition according to p, in which the layer contains one or a mixture of two or more substances from the following list: cellulose derivatives, derivatives of sugars, derivatives of polyvinyl, waxes, fats, gelatin, polyethylene glycol, ethylcellulose, titanium dioxide, diethylphthalate.

28. The composition according to p, in which the layer is 0.5-15 wt.% by weight of the total tablet shell.



 

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13 cl, 15 ex, 7 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a composition of microparticles or nanoparticles for local delivery and delivery to a mucous surface of an active ingredient containing 0.1-99.5 wt % of an inorganic element chosen from alkaline, earth or transition metal, lanthanide or silicon dioxide, alkoxide, oxide, oxalate, ureate, nitrate or acetate, 0.01-95 wt % of a pharmaceutical or cosmetically active ingredient, and 0.001-75 wt % of a release control agent chosen from natural, synthetic or semisynthetic polymers, polysaccharides, monosaccharides, salts, fibres or peptides. Also, the invention covers methods for making said composition which involve dissolving each ingredient in a solvent, mixing the prepared solutions, adding a solution of alkaline hydroxide and producing a dry powder composition or gel colloidal solution of nanoparticles. Besides, the invention refers to a kit comprising said composition, a delivery device and an application data sheet.

EFFECT: invention provides better fixation in an effective area, effective absorption and controlled release.

34 cl, 9 tbl, 2 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: vitamin dosage form contains a combination of biologically active substances chosen, first of all, from a group of vitamins, mineral substances and microelements, and also their mixtures and at least partially included or introduced in a swellable matrix providing controlled or time shift release of biologically active substances after intake of such composition.

EFFECT: higher bioavailability of the biologically active substances, optimised absorbtion in a gastrointestinal tract, preferentially with avoided time overdose of the relevant biologically active substances and prevented excessive load on involved absorption systems.

22 cl, 3 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: pellet-form pharmaceutical composition for treating vertigo containing cinnarizine and dimenhydrinate wherein the release of active ingredients is slowed down, and the composition also contains a binding agent, a slow-release agent, an excipient and a pharmaceutical aid taken in a certain ratio. The application of the pharmaceutical composition for treating vertigo of any genesis.

EFFECT: slow-release composition is effective in treating vertigo.

6 cl, 4 dwg, 3 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form contains a physiologically active substance (A), with the exception of tramadol hydrochloride and oxycodone hydrochloride, optionally one or more physiologically compatible pharmaceutical aids (B), synthetic or natural polymer (C) and optionally natural, semisynthetic or synthetic wax (D). Polymer (C) is chosen from the group including polyalkylene oxide, polyethylene, polypropylene, polyvinylchloride, polycarbonate, polystyrene, polyacrylate, their copolymers and mixtures. The dosage form according to the invention, exhibits breaking strength at least 400 H and under the physiologic conditions after 5 h, release maximum 99% of the physiologically active substance (A).

EFFECT: dosage form is mechanically stabilised; it reduces overdose risk invoked by the abuse and inadequate application, particularly chewing, grinding and pestling.

30 cl, 7 dwg, 17ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is application of a 1-aminoalkyltcyclohexane derivative specified in neramexane or its pharmaceutically acceptable salt for preparing a drug for preventing and/or treating hearing loss, except for drug-induced hearing loss, application thereof for preventing and/or treating hearing loss, except for drug-induced hearing loss and a pharmaceutical composition for the same application.

EFFECT: auditory threshold extension after 4 months of the therapy with neramexane 50 mg a day is shown.

27 cl, 1 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and may be used for treating patients with hypertension and lipid storage disease. There is applied a combined drug containing dihydropyridine, calcium canal blockers, and statin, a hypolipidemic agent. The drug is prepared in such a manner that release rate of said ingredients can be controlled with respect to each other.

EFFECT: method allows higher clinical effectiveness and compliance, prevented antagonist and side effects of the combined therapy.

27 cl, 12 tbl, 10 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry and discloses a pharmaceutical composition containing phenylephrine in a prolonged release dosage form, either alone, or in a combination with another active ingredient, such as an antihistamine, an analgesic, a febrifuge, a non-steroid anti-inflammatory drug or a mixture of two or more other active ingredients. In a preferential version of the invention, the composition contains a solid dosage form with hydroxypropyl methylcellulose and sodium-carboxymethyl cellulose as a prolonged release phenylephrine matrix. Phenylephrine is released from the solid dosage form during a long period of time, substantially irrespectively of pH.

EFFECT: development of the pharmaceutical composition containing phenylephrine in the prolonged release dosage form.

18 cl, 1 ex, 1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, and deals with diuretic composition with delayed release, in which torasemide is an active substance.

EFFECT: compositions, corresponding to invention, are used to obtain possibility to avoid trouble-causing pressing urge to urinate, caused by conventional compositions with immediate release.

9 cl, 11 ex, 2 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to coated pharmaceutical formulations with a controlled-release active substance and to the use thereof for treating benign prostatic hyperplasia. The formulation contains a therapeutically effective amount of the active substance representing tamsulosin or its pharmaceutically acceptable salt encapsulated in a granulated core, and an insoluble permeable polymer found both in the granulated core and in the coating. Said pharmaceutical formulations may also contain a surfactant and other optional excipients. Besides, the invention refers to a method for preparing the pharmaceutical formulations which involves mixing core ingredients, granulating, pressing and shaping in a sphere, drying and coating.

EFFECT: invention provides the formulations with pH-independent release of the active substance, low inter-individual variability and low biological variability.

14 cl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmaceutics, more specifically to a controlled-release preparative form of a compound of formula I representing an oral cytokine inhibitor of an interleukin-1 beta-converting enzyme. A method for producing said preparative form involves granulation of the compound of formula (I) in the presence of an organic solvent - isopropyl alcohol. Stability of the compound of formula (I) in the organic solvent is such that the solvent preserves more than 5% of the compound of formula (I) unsolved over 24 hours at room temperature or lower. A material produced by wet granulation has a density from approximately 0.40 g/cm3 to approximately 0.90 g/cm3. There are offered versions of the controlled-release preparative form containing the compound of formula (I) granulated with isopropyl alcohol.

EFFECT: due to wet granulation of the compound of formula (I) before thoroughly mixed with all auxiliary substances, the group of inventions provides making granules of improved density and flowability.

90 cl, 2 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics, and concerns a method for producing a carrier for biologically active compounds of an interpolyelectrolyte complex by mixing copolymer of a cationic nature of dimethylaminoethylmetacrylate, butylmetacrylate and methylmetacrylate in proportions 2:1:1 reduced to pH 2.0-7.0 and gel of lightly crosslinked polyacrylic acid with pH 2.0-7.0; as a solvent, water is used with both solutions have the equal pre-mixing pH values; for copolymer of dimethylaminoethylmetacrylate and neutral methacrylic esters, and for crosslinked polyacrylic acid, acetic acid 0.1 M and sodium hydroxide 0.1 M taken in certain proportions, and recovering the end product.

EFFECT: ensured improvement of the pharmaceutical characteristics and creation of the release profile of various drug preparations.

4 cl, 4 dwg, 2 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: dosage form for pain management and controlled release of 3-(2-dimethylaminomethylcyclohexyl)phenol or one of its pharmaceutically acceptable salts contains said active substance and a polymer matrix of cellulose ether, which has a viscosity ranging within 3000 to 150000 mPa·s in the concentration of 2.0 wt % in a water solution at 20°C. Cellulose ether is selected from a group consisting of methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose and hydroxypropyl methylcellulose. The dosage form ensures in vivo a maximum plasma level of the active substance in 2-10 h.

EFFECT: dosage form under the invention provides maintaining the plasma concentration of the active substance 3-(2-dimethylaminomethylcyclohexyl)phenol at a pharmacologically effective level for at least 12 h and shows minimum spectrum of side effects including nausea and/or vomiting.

35 cl, 1 dwg, 8 ex

FIELD: pharmaceutical industry.

SUBSTANCE: pharmaceutical composition represents a minitablet or pellet, covered with an isolating layer and enteric cover. The minitablet or pellet contains a pH-dependent medical product, preferably, dipiridamol, and the рН modifier, chosen of the group consisting the following components: lemon acid, fumaric acid, amber acid, adipic acid and maleic acid. The isolating layer includes polymer, softener and the agent reducing stickiness, and separates a minitablet or pellet from enteric covering. The рН modifier ratio to the pH-dependent medical product is from 0,2:1 to 2:1. The full liberation of the medical product from the pharmaceutical composition occurs simultaneously with the рН modifier liberation during the time periodfrom 1 till 4 hours.

EFFECT: invented pharmaceutical compositions are characterized by decrease in variability and bioavailability increase in the body of one patient or more patients.

7cl, 3 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers namely to pharmaceutical industry, and concerns tablets with the slowed down liberation, containing alfuzosin hydrochloride. The tablet includes: the top layer including 0,2 weight parts of alfuzosin HC1, 90 weight. parts of hypromellose, 29. 6 weight parts of polyethylene oxide, 1 weight part of stearyl alcohol, 0.4 weight parts of easy waterless silicon acid and 1 weight part of ethyl cellulose; and the bottom layer including 9.8 weight parts alfuzosin HC1, 36-62 weight parts of microcrystalline cellulose, 24-60 weight parts of polyethylene oxide, 20 weight parts low substituted hydroxypropyl cellulose, 1-6 weight parts of stearyl alcohol and 99 weights parts of hydroxypropyl cellulose.

EFFECT: received tablet is characterized by the liberation of the medicine with the curve of the zero order.

3 cl, 2 tbl, 10 ex, 6 dwg

FIELD: medicine.

SUBSTANCE: present invention refers to medicine and describes a method for preparing a tablet exhibiting antihypertensive activity containing a) an active substance containing valsartan 80 or 160 mg or its pharmaceutically acceptable salt, and hydrochlorothiazide (HCTZ) 12.5 or 25 mg; b) pharmaceutical acceptable additives suitable for preparing tablets by compression wherein said method involves the stages, I) grinding of the active substance which contains said valsartan and said hydrochlorothiazide, and pharmaceutically acceptable additives; II) compression of a mixture of the grinded active substance and additives with making a comprimate with said compression for making the comprimate requires compaction of the dry mixture of the grinded ingredients; III) transformation of the comprimate into a granulate having a particle size distribution 9 to 340 micron; and IV) compression of the granulate with preparing the tablet.

EFFECT: method provides preparing the tablet possessing intensified antihypertensive activity.

4 cl, 3 ex

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