Combined controlled-release pharmaceutical agent containing dihydropyridine calcium canal blockers and hmg-coa-reductase inhibitors

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

 

The technical field to which the invention relates

The present invention relates to chronotherapeutics combined pharmaceutical drug controlled release, containing a dihydropyridine calcium channel blocker, and a statin, lipid-lowering agent. The drug of the present invention is designed so that the release of each ingredient can be controlled at a preset speed using the so-called chronotherapy, when drugs are introduced so that they showed their pharmacological activity at specific time intervals, providing due to this improved therapeutic effects while minimizing side effects.

Prior art

Atherosclerosis and hypertension are mutually worsen the symptoms of these conditions, and this can be prevented only by the treatment of patients suffering from hyperlipidemia and hypertension, and atherosclerosis and hypertension at the same time [Hypertens Res. 2001; 24: 3-11, Hypertens Res. 2003; 26: 1-36, Hypertens Res. 2003; 26: 979-990].

Thus, the obtained clinical results, which reported a synergistic effect of the joint introduction of lipid-lowering means statin and calcium channel blocker as a tool against the ISU is ransei. According to Kramsch et al., the combination of amlodipine and lipid-lowering means is characterized by a better therapeutic effect for the treatment of atherosclerosis [Journal of Human Hypertension (1995) (Suppl.1), 53-59]. Jukema et al. also shows a synergistic effect of the combination of calcium channel blockers and lipid-lowering means [Circulation, 1995 (Suppl.1), 1-197]: Arterioscler. Thromb. Vasc. Biol. 1996; 16: 425-430.

The most widely assigned to the combination of amlodipine as a representative of the calcium channel blocker, in particular, of dihydropyridine calcium channel blocker, with simvastatin as a statin, lipid-lowering means.

It is well known that amlodipine is used as a drug for the treatment of angina and hypertension. Simvastatin is known to have hypolipidemic activity and anti-inflammatory activity against blood vessel walls. Data security of medicines known, and they are available in pharmacies in the UK as over-the-counter (OTC) medications that do not require writing a prescription [Cardiology 1992; 80 (Suppl. 1): S31-S36, J. Cardiovasc. Pharmacol. 1988; 12 (Suppl. 7): S110-S113, Lancet 2000; 356: 359-365, Hypertens Res. 2002; 25: 717-725, Hypertens Res. 2002; 25: 329-333].

Meanwhile, amlodipine is used as an antihypertensive and also increases the hypolipidemic activity of simvastatin by synergic what about the action with the given lipid-lowering agent. Simvastatin is used as lipid-lowering means and also actively reduces blood pressure due to a synergistic effect with amlodipine. Two of the above medicines are introduced both once a day, and the introduction of both medicines is preferably carried out at lunch.

As a representative statin, lipid-lowering drug, simvastatin has the following characteristics. So, it is well known that the inhibitor of HMG-CoA reductase inhibitor, a statin, lipid-lowering agent, is a tool of first choice for the prevention and treatment of heart disease caused by coronary atherosclerosis, angina or myocardial infarction [Lancet 1995; 346: 750-753, Am. J. Cardiol. 1998; 82: 57T-59T, 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, among other statins, lipid, simvastatin most often applied and, as we know, reduces the frequency of coronary atherosclerosis and mortality in large-scale clinical test [Lancet 1994; 344: 1383-1389].

The above mentioned types of activity occur as a consequence of the fact that simvastatin strongly inhibits HMG-CoA-reductase, which plays a key role in the synthesis of cholesterol in the liver, and also inhibits factor, inducing inflammation ["Scandinavian Simvastatin Surival Study", published in the Lancet, 1994, 344, 1383-89].

Patients suffering from atherosclerosis or diabetes, are characterized by an abnormal level of NO-synthase (eNOs) in the wall of blood vessels, and blood pressure increases due to the reduction of NO formation. Statin, lipid-lowering means, including simvastatin, increases e-NOS to a normal level, which is the combined effect of destination, at which lipid-lowering activity contributes to the antihypertensive activity [Am. J. Physiol. Renal. Physiol. Vol. 281 Issue 5: F802-F809, 2001].

Simvastatin is an inactive lactone, which after entering the liver is transformed into an active form simvastatinum acid, lipid-lowering activity. The remaining simvastatin is also metabolized in the liver at different stages of cytochrome P450 3A4, and some of its metabolites are characterized by a high lipid-lowering activity.

Simvastatin and simvastatina acid are metabolized by cytochrome P450 3A4, are functioning in the liver and excretiruyutza from the liver [Drug Metab Dispos 1990; 18: 138-145, Drug Metab Dispos 1990; 18: 476-483, Drug Metab Dispos 1997; 25: 1191-1199].

Thus, when used in combination with a drug inhibiting the enzyme cytochrome P450 3A4, simvastatin weaker metabolized in the liver, and the concentration of simvastatin in plasma increased, which can lead to serious for the full effects such as rhabdomyolysis. [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].

Therefore, when the introduction of drugs such as amlodipine, which inhibits the induction of the enzyme cytochrome P450 3A4, together with such medication as simvastatin, which must be metabolized into an active form of the same enzyme cytochrome P450 3A4 should be used very specific chosen mode of administration. In addition, based on the statin drugs recommended for introduction early in the evening, because by evening, the synthesis of lipids in the liver is very active [Arterioscler. Thromb. 11: 816-826].

Representative calcium channel blocker amlodipine known as.

The calcium channel blocker is an antihypertensive agent that is most often prescribed in combination with simvastatin. In particular, amlodipine most widely in the world is assigned as an antihypertensive and funds from coronary heart disease, such as angina [Cardiology 1992; 80 (Suppl. 1): S31-S36, J. Cardiovasc. Pharmacol. 1988; 12 (Suppl. 7): S110-S113, Lancet 2000; 356: 359-365, Hypertens Res. 2002; 25: 717-725, Hypertens Res. 2002; 25: 329-333].

Amlodipine is used in the present invention in combination with a statin, lipid-lowering agent, presents simvastat the nom, is a medicine of long-term action that belongs to the dihydropyridine calcium channel blockers [Clin. Pharmacokinet. 1992; 22: 22-31, Am. Heart. J 1989; 118: 1100-1103, Hypertens Res. 2003; 26: 201-208].

Amlodipine, which has the chemical name 3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate is very widely used calcium channel blocker, characterized by a half-life equal to 30-50 hours, and activity over a relatively long period of time [publication of the European patent # 89167 and U.S. patent No. 4572909]. Amlodipine is also a tool for the treatment of hypertension, which prevents the flow of calcium into vascular smooth muscle and induces relaxation of peripheral arteries, reducing due to this blood pressure. Also amlodipine is a widely used drug for the treatment of ischemic diseases caused by spasmodic contraction of the walls of the coronary arteries.

When administered orally in pill amlodipine absorbed in the small intestine. Then over 40% of the drug is metabolized in the liver, and only the remaining 60% are present in the blood, showing, thus, sufficient anti-hypertensive activity.

Activity amlodipine lasts for 24 hours, and which shows the maximum hypotensive activity during the time from morning until noon, with the introduction of the previous evening.

From a pathophysiological point of view, a large pressure increase in the daytime caused by spasm of the vascular wall due to a stressful stimulus. Amlodipine operates, causing relaxation spasmodic contractions of the vascular wall, and shows great anti-hypertensive activity in the daytime. Thus, amlodipine, introduced the evening, reaches maximum plasma concentration early in the morning and shows great hypotensive activity during the morning stress [Hypertens 10 (Suppl.4): S136].

In the presence of the enzyme cytochrome P450 3A4 some molecules amlodipine oxidized by the enzyme and are metabolized in the form of inactive material. However, amlodipine immediately active on the inhibition of receipt of the enzyme cytochrome P450 3A4.

Due to the above characteristics of amlodipine should be entered at certain intervals of time, together with a statin, lipid-lowering means, such as simvastatin, since amlodipine inhibits the enzyme cytochrome P450 3A4, which is required for the action of simvastatin. [Med. Chem. 1991; 34: 1838-1844, Eur. J. Clin. Pharmacol. 2000; 55: 843-852].

The simultaneous introduction of amlodipine and simvastatin inherent in the above specific flaws, but still it was very difficult to get data combined products without these disadvantages. Sovremennaia is what is the purpose of doctors joint administration of amlodipine and simvastatin have been practiced for a long time, but rarely can be detected so that appropriate instructions for introducing brought to patients. Therefore, most patients do not know that simvastatin, at least, should be taken in the evening, and amlodipine should take a few hours.

However, co-administration of the above drugs may increase the concentration of simvastatinum acids in plasma by approximately 30%, thus, leading to side effects. It is also difficult to expect synergistic effects of the two drugs lowering blood pressure and lipid levels.

Shinichiro Nishio et al. report the results of experiments comparing two groups of patients suffering from hypertension with hyperlipidemia. One group was administered one tablet of amlodipine and one tablet of simvastatin at the same time, and the other group was injected only one tablet of simvastatin [Hypertens Res., 2005, Vol. 28, No.3].

According to the experiments, co-administration of simvastatin and amlodipine inhibits the enzyme cytochrome P450 3A4 due to the action of amlodipine and increases the concentration of simvastatin in plasma by 30%, which leads to the possibility of side effects.

Table 1
Daily dosingCmax(ng/ml)AUC (ng·h/ml)
Simvastatin 5 mg9,6±3,734,3±16,5
Simvastatin 5 mg + amlodipine 5 mg13,7±4,743,9±16,6
Hypertension Research, Vol.25 (2005). No.3 March 223-227

As shown in table 1, compared with the introduction of a single simvastatin combined purpose was increased by 30% concentration of lipid-lowering ingredient in the plasma. However, lipid-lowering activity was not increased. At plasma concentrations above a certain level simvastatin reduces activity by inhibition of the biosynthesis of cholesterol and could cause serious side effects, such as rhabdomyolysis.

In Korea patent No. 582347 described combined drug, in which amlodipine is dissolved and absorbed at the same time, when based on the statin component simultaneously released within 24 hours. The concept of this patent is completely the opposite of the concept of the present invention. However, this medicine (Korea patent No. 582347) is definitely the essence is : the defect, two of the medicinal component simultaneously mixed in the liver from the first moment of dissolution, and is antagonistic drug interactions; i.e., amlodipine inhibits the induction of the enzyme cytochrome P450 3A4 for simvastatin. As a result, some simvastatine acids are released from the liver into the blood to complete metabolism by cytochrome P450 3A4. Increasing the concentration of simvastatin in plasma brings unwanted side effects such as rhabdomyolysis.

In Korea patent No. 742432 described combination drug containing Camelot amlodipine and simvastatin, and the method of its production. In this patent two ingredients are released and metabolized in the liver at the same time. This drug is a simple combination, in which two of the medicinal component simultaneously dissolved, absorbed and penetrate into the liver. So, amlodipine inhibits the induction of cytochrome P450 3A4 required to activate and complete metabolism of simvastatin in the liver. As a result, approximately 30% of the simvastatin is released into the blood, without activity and metabolism in the liver. Such excessively high concentration of simvastatin not contributing to the lipid-lowering effect, but increases side effects. This defect is a simple combination of the clarification is in pre-clinical test, described in this invention.

Furthermore, patent publication Korea No. 2000-7002144 from Pfizer also rejected the Korean Intellectual Property Office, because it describes a simple medicinal product containing amlodipine and atorvastatin.

Thus, there is a need to develop a new treatment or a new pharmaceutical drug that can prevent the disadvantages of conventional methods, i.e. properties of such conventional composite products comprising amlodipine and based on statin drugs, lies in the fact that these two components are absorbed simultaneously, or amlodipine absorbed before simvastatin.

Description of the invention

The technical problem

Thus, there has long been a need for a new medical method or a new pharmaceutical drugs, which can prevent the disadvantages of the combined product of the two drug components, i.e. antagonistic effects between the drugs.

As a result, in the present invention developed a special combined pharmaceutical drug, which can overcome the antagonistic effects between drugs, using advantages of pharmacy is practical concepts namely, that drugs can be dissolved with a pre-established time intervals.

The authors of the present invention conducted intensive studies to develop solutions to the above problems and improve therapeutic effect of the combined destination that you want from a clinical point of view, with a reduction in side effects.

Held here clinical test shows that chronotherapeutics introduction statin, lipid-lowering means, represented by simvastatin, and dihydropyridines, calcium channel blocker, presents amlodipine, has a significantly improved therapeutic effect and safety compared with those with the simultaneous introduction of medicines.

According to the present invention discovered that the time interval between absorption statin, lipid-lowering means, and dihydropyridines, calcium channel blocker, in the gastrointestinal tract, can inhibit the increase in the concentration of the statin, lipid-lowering means, in plasma than necessary and to prevent associated with various side effects, and developed a combination drug that completely ends the present invention.

In the case of complex systems this is the overarching invention statin lipid-lowering agent, absorbed the first immediately after the introduction of drugs and transformed into an activated form of the enzyme cytochrome P450 3A4 and is valid in the liver, and then further metabolized by cytochrome P450 3A4 for elimination through the bile duct. After sufficient time, during which simvastatin is exposed to the enzyme cytochrome P450 3A4 in the liver, amlodipine absorbed in the gastrointestinal tract. Therefore, simvastatin may not be subjected to the inhibitory effect of amlodipine on the induction of cytochrome P450 3A4.

Considering the fact that simvastatin enters the liver first and metabolized to the active form for the inhibition of cholesterol synthesis in the liver, the present invention relates to the production of composite products so that simvastatin may be sufficient time to remain in the liver for its full hypolipidemic activity, but not released into the blood to high plasma concentrations above a certain level. For this purpose, the present invention relates to a specially designed drug controlled release.

I.e. the present invention relates to the control of ingredients for controlled release by preparing a medicinal product containing the part with medlennym release, containing dihydropyridines, calcium channel blocker, and a part of the immediate-release formulation containing a statin, lipid-lowering agent, as active ingredients, thus allowing the dihydropyridines, calcium channel blocker, can be dissolved or absorbed in the small intestine for 3-4 hours later statin.

Compared to just compiled a combined product of the two drug components (tablet calcium channel blocker/statin) chronotherapeutics combined pharmaceutical drug of the present invention, containing dihydropyridines, calcium channel blocker, and a statin, lipid-lowering agent, as expected, characterized by a far superior clinical effects and safety.

When administered orally combined products of the present invention provide clinical effect and safety synergistic effect of the two drug components (calcium channel blocker/statin) by maximizing the pharmaceutical activity of each active ingredient, by minimizing the antagonistic effects of the two drugs in the liver and by controlling the release of each drug component to maintain suction over time. For this purpose a combined the consistent product of the present invention should be introduced in the form of one tablet daily in the evening, preferably from 17 to 22 hours.

In principle, the drug should not be administered in combination with another drug, if the simultaneous introduction can disrupt their beneficial effects.

On balance synergistic clinical effects of combined administration of dihydropyridines, calcium channel blocker, and a statin, lipid-lowering means, in particular amlodipine and simvastatin, the present invention relates to maintaining synergistic effects and also to eliminate side effects by lifting the side effect of simvastatin, such as myopathy, which may occur when two drugs simply enter together. Such antagonistic relationship between amlodipine and simvastatin is based on the simple fact that every drug has to do the same cytochrome P450 3A4 in such an antagonistic manner that the blood appears excessive simvastatinum acids.

Therefore, the present invention relates to providing functional chronotherapeutics combined pharmaceutical medicines containing dihydropyridines, calcium channel blocker, controlled release and a statin, lipid-lowering agent.

Technical solution

This is the invention relates to a combined pharmaceutical drug, containing dihydropyridines, calcium channel blocker, and a statin, lipid-lowering agent, as an active ingredient and a pharmaceutically acceptable carrier, and the combined pharmaceutical drug is part of the controlled release containing dihydropyridines, calcium channel blocker, and a part of the immediate-release formulation containing a statin, lipid-lowering agent, as active ingredients.

Preferred effects

As indicated above, the present invention relates to the application of theory of chronotherapy and theory of xenobiotics in drug controlled release to maximize the pharmacokinetic and pharmacodynamic effects and minimize side effects that can occur when two drugs simply enter together.

The drug of the present invention contains as active ingredients a statin, lipid-lowering agent, and dihydropyridines, calcium channel blocker, and both ingredients are related to the same enzyme cytochrome P450, so that one acts on this enzyme, while the other is subjected to its influence, and this drug is characterized by the fact that the speed of release of the above in which of Reventon different, and the dissolution and absorption of each drug begins at specific points in time in a controlled way.

In the drug of the present invention can better be used in the treatment of chronic disorders of blood circulation in the pharmacological, clinical, scientific and economic terms, compared with the simultaneous introduction of two medicines.

In addition, the combined pharmaceutical drug of the present invention provides for the release of drugs with different speeds and prevents antagonistic effects and side effects, while maintaining the synergistic action of drugs.

Further, the combined pharmaceutical drug of the present invention is administered as a single dose once daily in the evening, and it has the advantage of convenience in the treatment and indications for use.

Description of the drawings

Figure 1 shows a graph of the comparison of dissolution rates of covered pressing tablets amlodipine/simvastatin obtained in example 1, and control drugs (Zocor®: a separate tablet of simvastatin, By®: a separate tablet of amlodipine).

Figure 2 shows a graph of the comparison of dissolution rates of combined pharmaceutical is th drug amlodipine/simvastatin, obtained in examples 4 and 10, and control drugs (Zocor®: a separate tablet of simvastatin, By®: a separate tablet of amlodipine).

Figure 3 shows a graph of the comparison of dissolution rates of combined pharmaceutical drugs amlodipine/lovastatin obtained in example 11, and control drugs (Mevacor®: a separate tablet lovastatin, By®: a separate tablet of amlodipine).

Figure 4 shows a graph of the comparison of dissolution rates of combined pharmaceutical drugs amlodipine/atorvastatin obtained in example 13, and control drugs (Lipitor®: a separate tablet of atorvastatin By®: a separate tablet of amlodipine).

Figure 5 shows a graph of the comparison of dissolution rates of combined pharmaceutical drug lercanidipine/simvastatin obtained in example 16, and control drugs (Zocor®: a separate tablet of simvastatin, Zanidip®: a separate tablet lercanidipine).

Figure 6 shows a graph of the comparison of dissolution rates of combined pharmaceutical drugs lacidipine/simvastatin obtained in example 18, and control drugs (Zocor®: a separate tablet of simvastatin, Vaxar®: a separate tablet lacidipine).

The piano is g shows the results of a clinical test in experimental example 7, in which compares the concentration simvastatinum acid in plasma among experimental groups.

On Fig shows the results of a clinical test in experimental example 7, which compares the concentration simvastatinum acid in plasma among experimental groups.

Figure 9 shows the results of a clinical test in experimental example 7, which compares the concentration of simvastatin and simvastatinum acid in plasma among experimental groups.

Figure 10 shows the results of a clinical test in experimental example 7, which compares the concentration of amlodipine in plasma among experimental groups.

The best option of carrying out the invention

Below is a detailed description of the present invention.

The present invention relates to chronotherapeutics combined pharmaceutical drug, which is designed so that the release of each ingredient can be controlled, and the rate of release is determined in advance, due to the application of the principles of the so-called chronotherapy and the doctrine of xenobiotics, where the medicinal product is administered in such a way that the action of medicines is implemented chronotherapeutics without any antagonistic interaction between them. The drug of the present invention includes the active ingredients, a statin, lipid-lowering agent, and dihydropyridines, calcium channel blocker, and they both relate to the same enzyme cytochrome P450, so that one acts on this enzyme, while the other is subjected to its influence, and this drug is characterized by the fact that the speed of release of the above ingredients are different, and the dissolution and absorption of each drug begins at specific points in time in a controlled way, by preventing it antagonistic effects and side effects, while maintaining the synergistic action and the provision of facilities for the treatment.

Here below is a detailed description of the combined pharmaceutical drug of the present invention, which contains the dihydropyridines, calcium channel blocker, and a statin, lipid-lowering agent.

Combined pharmaceutical drug of the present invention contains the dihydropyridines, calcium channel blocker, and a statin, lipid-lowering agent, as active ingredients. This dihydropyridines, calcium channel blocker, is known as a substance inhibiting the induction of cytochrome P450 airy of dihydropyridines, of calcium channel blockers include amlodipine, lercanidipine, lacidipine and their pharmaceutically acceptable salt. Preferably, amlodipine or its pharmaceutically acceptable salt, or its isomer, specifically, maleate amlodipine, besylate amlodipine, can be used as the dihydropyridines, a calcium channel blocker. Preferably, a daily dosage of dihydropyridines, a calcium channel blocker of the present invention contained in the tablet (total mass: 200-500 mg)is 1-20 mg (for an adult male weighing 65-75 kg), preferably 5-10 mg

As the dihydropyridines, calcium channel blocker, with lipid-lowering efficacy in this application specifically described amlodipine. However, the present invention is not limited to amlodipine.

At least one compound selected from the group consisting of simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, fluvastatin, pravastatin and their pharmaceutically acceptable salts can be used as a statin, lipid-lowering means. The daily dosage of the statin, lipid-lowering means of the present invention contained in the tablet (total mass: 200-500 mg)is 5-160 mg, preferably 5-80 mg for an adult.

A representative example of a statin, hypolipidemics the CSO funds is simvastatin, and in the present invention simvastatin described as a specific example. However, the present invention is in no way limited to simvastatin. Although simvastatin is an inactive substance, it can be transformed into active simvastatinum acid esterase and then be transformed into an activated form by cytochrome P450 3A4 in the liver, showing due to this hypolipidemic activity.

Meanwhile, amlodipine inhibits the induction of the enzyme cytochrome P450 3A4. Therefore, when amlodipine and simvastatin is administered simultaneously, amlodipine, which is rapidly absorbed in the small intestine reaches the liver earlier than simvastatin, and thus inhibits the induction of cytochrome P450 3A4. Thus, a significant part of simvastatin, which reaches the liver later or at the same time, does not undergo metabolic activity of cytochrome P450 3A4, and approximately 30% of simvastatin (simvastatin, simvastatine acid, etc. can penetrate into the blood system to complete metabolism by cytochrome P450 3A4 to active status in the liver and excretion through the bile duct. The result is an excessively high concentration of simvastatin or simvastatinum acid in the blood can cause muscle violation, such as rhabdomyolysis.

As solutions to the above problems and prevention and is generowania amlodipine complete enzymatic pathway of metabolism of simvastatin in the liver according to the present invention is made part of the medicines immediate-release, which first releases simvastatin and causes earlier absorption of simvastatin in the small intestine, with education, however, part of the controlled release amlodipine for absorption in the liver 3-4 hours later simvastatin.

The new composition of the present invention includes a composition of controlled release, containing amlodipine, its pharmaceutically acceptable salt and additives required, and the composition of the immediate-release formulation containing simvastatin and required additives that are physically separated and distributed so that two different drugs are characterized by different rates of release. In addition, part of the immediate-release and controlled-release may be issued in various forms.

I.e. a new pharmaceutical composition can be coated with the conventional method using a substance that controls the release selected from the group containing part of the controlled release, and thus obtained coated particles or pellets and multi-component particles with a composition of simvastatin immediate-release can be pressed into tablets or placed in capsules.

Part of the controlled-release of the present invention contains the dihydropyridines, blocat the R calcium channel, such as amlodipine, and enteric polymer, a water insoluble polymer, a hydrophobic compound, the hydrophilic polimernoe compound and a hydrophilic polymer as agents to control release of the drug. Substance to control the release in part controlled release can be contained in the amount of 10-500 mass parts relative to 100 mass parts of the dihydropyridines, a calcium channel blocker. If this amount is below the above range, the control release may be insufficient. If this number is above the specified interval, the release of drug is delayed, and a statistically significant clinical effect may not be achieved.

Enteric polymers that can be used include as non-limiting examples of the polyvinyl acetate-phthalate, methacrylic acid copolymer, phthalate of hydroxypropylmethylcellulose, shellac, acetate-phthalate cellulose propionate-cellulose phthalate, Eudragit L, Eudragit S, and their mixture.

Water-insoluble polymers that can be used include as non-limiting examples of pharmaceutically acceptable polyvinyl acetate, methacrylic acid copolymer, such as copolymer of poly(acrylate-co-methyl methacrylate) or a copolymer of poly(etelecare the-methacrylate-trimethylaminoethyl), ethylcellulose, cellulose acetate, and a mixture thereof.

Hydrophobic organic compounds that can be used include as non-limiting examples of fatty acid and an ester of a fatty acid, alcohol, fatty acid, wax, inorganic substance and a mixture. Specifically, fatty acids and esters of fatty acids, which can be used include as non-limiting examples glycerylmonostearate, literallayout, glycerinated, cetylpalmitate, glycerylmonostearate, stearic acid, and their mixture; fatty alcohols include as non-limiting examples cetosteatil alcohol, cetyl alcohol, stearyl alcohol and their mixture; waxes include as non-limiting examples of Carnauba wax, beeswax, microcrystalline wax and a mixture thereof; and inorganic substances include as non-limiting examples of talc, precipitated calcium carbonate, dibasic calcium phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, Wigan and their mixture.

Hydrophilic polymers include as non-limiting examples of the saccharide derivative of cellulose, a gum, a protein, a derivative of polyvinyl copolymer of polymethacrylate derived polyethylene, polymer carboxyvinyl and their mixture. Specifically, the saccharides include as non-limiting examples of de is Stryn, polydextran, dextran, pectin and derived pectin, alginate, poly(galacturonic acid), xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylmethyl, amylase, amylopectin and their mixture; derivatives of cellulose include as non-limiting examples of the hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxymethylcellulose sodium, acetate-succinate of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose and their mixture; gums include as non-limiting examples of guar gum, gum carob, tragakant, carragenan, Arabian gum, gum Arabic, Gellan gum, xanthan gum and a mixture thereof; proteins include as non-limiting examples of gelatin, casein, Zein and their mixture; derivatives of polyvinyl include as non-limiting examples of polyvinyl alcohol, polyvinylpyrrolidone, polyvinyltrimethylsilane and their mixture; copolymers of polymethacrylate include as non-limiting examples of poly(butylmethacrylate copolymer (2-dimethylaminoethyl)methacrylate, methyl methacrylate), a copolymer of poly(methacrylic acid, methyl methacrylate), a copolymer of poly(methacrylic acid, acrylate and a mixture thereof; a derivative of polyethylene include as non-limiting p is Kerov polyethylene glycol, the polyethylene oxide and a mixture thereof; and carboxyquinolone include as non-limiting examples of carbomer.

The drug of the present invention may optionally contain such quantities of other additives, to the effect of the present invention is not deteriorated. Examples of pharmaceutically acceptable diluents as the above additives include, without limitation, starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, salt, alkaline earth metal, clay, polyethylene glycol and calcium diphosphate. Examples of lubricants as the above additives include, without limitation, talc, magnesium stearate stearate and alkaline earth metal-type calcium, zinc, etc., dodecyl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium fumarate, glycerylmonostearate and polyethylene glycol 4000.

Part of the controlled-release of the present invention consists of a dispersed phase of particles or granules obtained by mixing, granulating or coating of dihydropyridines as calcium channel blocker, substance controlled release and commonly used pharmaceutical additives.

Part of the immediate-release formulation of the present invention can be obtained in the particles or granules by the OS shall implement the conventional methods of producing oral solid forms, such as mixing, combining, drying, and granulation using a statin, lipid-lowering means, such as simvastatin, as an active ingredient and pharmaceutically acceptable additives. If the fluidity of the mixture simvastatin good enough for direct extrusion, to provide compositions can be obtained mixture, whereas if the flow is not sufficient, the composition can be obtained by extrusion, pelleting and grinding, thus providing a homogeneous phase containing part of the immediate-release.

Drug for oral administration, comprising part of the controlled release and the matrix part of the immediate-release in two phases, receive subsequent mixing of the composition contained in part controlled-release and part of the immediate-release formulation with pharmaceutically acceptable additives for extrusion or by filling capsules composition.

For example, the drug of the present invention can be obtained in two-phase matrix, distributed in one tablet by obtaining a granular phase, multi-layered tablets, tablets with an inner layer or capsules filled with granules parts controlled-release and part with immediate wisweb the vision. In addition, the drug can also be obtained in tablet comprising a tablet with an inner layer of controlled release, containing amlodipine, and covered in pressed tablet of immediate-release containing simvastatin.

However, the drug of the present invention is not limited only tablet with a two-phase matrix, where the dispersed phase amlodipine controlled release exists in a homogeneous phase simvastatin immediate-release.

I.e. a tablet for oral administration having layers for immediate release or controlled release, prepared by mixing granules contained in part controlled-release and immediate-release formulation with pharmaceutically acceptable additives, followed by pressing in the two-layer or three-layer tablet in which the layers are parallel to each other with use of a press for the production of multilayer tablets.

Moreover, a tablet for oral administration, having a structure layer controlled release as the inner layer and the layer with the immediate-release covering the inner layer, is obtained by mixing and pressing of the granules contained in part controlled release, with f rmaceuticals acceptable additive to provide tablets with an inner layer and by mixing and pressing of the granules, contained in part with immediate-release formulation with a pharmaceutically acceptable additive.

Further, capsule drug for oral administration, in which there may be two-phase control release can be obtained by mixing the granules contained in part controlled-release and immediate-release formulation with a pharmaceutically acceptable additive, and filling the mixture in capsules.

Examples of pharmaceutical additives, which form part of the controlled release of a medicinal product according to the invention include a diluent, binder, dezintegriruetsja substance, a lubricant, a stabilizer, a dye and flavoring. The preferred amount of these supplements is 100-3000 mass parts relative to 100 mass parts of the statin, lipid-lowering means. In addition to the active ingredient and substance controlled release drug, the compound of the present invention may optionally contain such other additional ingredients to the effect of the present invention could not be reduced. Examples of pharmaceutically acceptable diluent as above additives include, without limitation, starch, microcrystalline cellulose, lactose, glucose, Mann is t, alginate, salt, alkaline earth metal, clay, polyethylene glycol and calcium diphosphate. Examples of the binder as mentioned above additives include, without limitation, starch, microcrystalline cellulose, highly dispersed silicon dioxide, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hypromellose, hydroxypropylcellulose, natural gum, synthetic gum, copovidone and gelatin. Examples dezintegriruetsja means as the above additives include, without limitation, starch or denatured starch such as sodium starch glycolate, corn starch, potato starch, and pre-gelatinizing starch; clays, such as bentonite, montmorillonite and veegum; cellulose, such as microcrystalline cellulose, hydroxypropylcellulose and carboxymethylcellulose; alginates such as sodium alginate or alginic acid; cross-linked cellulose, such as croscarmellose sodium; gums, such as guar gum and xanthan gum; cross-linked polymer such as crosspovidone; and fizzy drug, such as sodium bicarbonate and citric acid. Examples of lubricants as the above additives include, without limitation, talc, magnesium stearate stearate and selecetion the aqueous metal type calcium zinc, etc., dodecyl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium fumarate, glycerylmonostearate and polyethylene glycol 4000. You can use other pharmaceutically acceptable additives, such as dyes or perfumes.

Although as additives in the examples described here are used as additives microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, etc., the present invention is in no way limited to the above additives, and the use of these additives can easily determine a specialist in this field.

The drug may optionally include a coating layer on the surface of the tablet. I.e. combined pharmaceutical drug amlodipine/simvastatin according to the present invention can be form without coating or tablet, coated for better stability of the active ingredients.

The coating layer may be formed on the surface of the tablet using the above ingredients by using common methods such as the method of coating in the fluidized bed, and, preferably, the lubrication method of the form.

The coating layer can be obtained by using a film-forming agent, adjuvant, film formation, or a mixture thereof. In particular, the coating layer can be p in order to obtain using the derived cellulose, such as hypromellose and hydroxypropylcellulose, derived saccharide derivative of polyvinyl, waxes, lipids, gelatin and mixtures of film-forming agents; polyethylene glycol, ethyl cellulose, glycerides, titanium oxide, diethylphthalate and mixtures thereof as an adjuvant of film formation.

The coating layer is preferably contained in the amount of 0.5-15 wt%. by weight of the total coated tablets.

Combined pharmaceutical drug of the present invention receive in the form of a single combined pharmaceutical medicines containing amlodipine and simvastatin as active ingredients, and it can be administered once daily in the evening.

Thus, compared to the case with the introduction of two medicines at the same time or with the case of injection of each drug separately with time intervals combined pharmaceutical drug of the present invention has advantages in simplifying the assignment to treatment, provides the advantage of minimizing side effects and a decrease in the efficiency caused by the antagonistic effects between the drugs.

When administered orally combined pharmaceutical drug of the present invention the characteristic is cherished immediate-release simvastatin and releases more than 80% of the original amount of simvastatin in the course of one hour. Release amlodipine sufficiently controlled in the small intestine, and it starts 2 hours after injection, and the amount released after 3 hours after injection, do not exceed 40% of the initial amount of amlodipine. Preferably, simvastatin revealed more than 90% of the initial amount within one hour and that the released amount of amlodipine did not exceed 30% of the initial amount after 3 hours after injection.

Further, the present invention relates to the results of the clinical test, which compared therapeutic effects of (i) the introduction of the only commercially available statin, lipid-lowering agents (simvastatin 20mg), (ii) simultaneous administration of commercially available statin, lipid-lowering means, and commercially available dihydropyridines, calcium channel blocker (besylate amlodipine 5 mg) and, as the experimental group, (iii) chronotherapeutics the introduction of commercially available statin, lipid-lowering means, and dihydropyridines, a calcium channel blocker. Chronotherapeutics introduction planned in such a way that the rate of release of drugs corresponded to that of the combined medicinal product in the present invention.

It was established that chronotherapeutic the Kai group is characterized by a marked increase therapeutic efficacy and safety compared with a group of simultaneous administration, and that such therapeutic efficacy and safety, apparently, there has been partly due to changes in the concentration of drugs in plasma and partially due to the complete synergistic effects of the two drugs.

The authors of the present invention conducted intensive studies to find effective ways of obtaining a combined product of the present invention.

Combined pharmaceutical drug of the present invention can be used for the prevention and treatment of hypertension, atherosclerosis, hyperlipidemia, ischemic brain diseases and cardiovascular, stroke, ischemic kidney disease, etc.

Option of carrying out the invention

The present invention is described more specifically in the following examples. The examples given here, is meant to serve only to illustrate the present invention but they should not be construed as limiting the scope of the present invention.

Example 1. Obtaining tablets amlodipine-simvastatin with inner layer

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed with used the eat double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt) and sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules, and dried. Granules were combined with powders carbomer 71G, and mixed with the magnesium stearate through a double-cone mixer. The resulting mixture was extruded using a rotary compressor (MRC-33: Sejong) with a speed of 30 revolutions per minute (rpm), providing tablets with a hardness of 7-9 kp, a thickness of 3.0 mm and a diameter of 5.5 mm

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combined with a mixture containing the main ingredient. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and sieved through sieve No. 20. The resulting mixture was mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide, and finally mixed with magnesium stearate using a double-cone mixer.

3) PR is Sovana and floor

A composition including an inner layer containing amlodipine, and an outer layer containing simvastatin, extruded using a compressor for products covered by the pressing of tablets (RUD-1: Kilian) with a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 2. Obtaining tablets with a two-phase matrix amlodipine-simvastatin

1) Obtaining granules amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed. The mixture was obtained using Kollicoat SR30D in high-speed mixer. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and selected by size using a sieve No. 20.

2) Obtaining granules of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high the local mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combined with a mixture containing the main ingredient. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites, sieved through sieve No. 20 and mixed with butilirovannyh hydroxyanisole.

3) Subsequent mixing, pressing and coating

The resulting composition was mixed using a double-cone mixer, was added sodium starch glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate.

The final composition was extruded using a rotary compressor (MRC-33: Sejong) at a speed of 30 revolutions per minute (rpm) to produce tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, the tablet with two-phase matrix.

Example 3. Obtaining tablets with a two-phase matrix amlodipine-simvastatin

1) Obtaining granules amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, sift through the sea is about 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt) and sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules. After drying, the granules were coated by spraying with 20% of the mass. solution of Eudragit RS PO in 1:1-mixture of ethanol and methylene chloride.

2) Obtaining granules of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combined with a mixture containing the main ingredient. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites, sieved through sieve No. 20 and mixed with butilirovannyh hydroxyanisole.

3) Subsequent mixing, pressing and coating

The resulting composition was mixed using a double-cone mixer, was added sodium starch glycolate and colloidal silicon dioxide and mixed with magnesium stearate using a high speed mixer.

The final composition was extruded using a rotary compressor (MRC-33: Sejong) at a speed of 30 revolutions per minute (rpm the Institute) to produce tablets with a hardness of 7-9 kp, the thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, the tablet with two-phase matrix.

Example 4. Obtaining a multilayer tablets amlodipine-simvastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules. After drying, the granules were coated by spraying with 10% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride. The coated granules were mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combining with the mixture of the main ingredi now. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and sieved through sieve No. 20. The resulting mixture was mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

The composition can be pressurized using a compressor for the production of multi-layer tablets (MRC-37: Sejong). More, the composition comprising simvastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 5. Obtaining tablets amlodipine-simvastatin with two-phase matrix

1) Obtaining granules amlodipine controlled release

Predefined number and lodipine and microcrystalline cellulose, shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt) and sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules. After drying, the granules were coated by spraying with 10% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride.

2) Obtaining granules of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combined with a mixture containing the main ingredient. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites, sieved through sieve No. 20 and mixed with butilirovannyh hydroxyanisole.

3) Subsequent mixing, pressing and coating

The resulting composition was mixed using a double-cone mixer was added sodium starch glycolate and colloidal silicon dioxide and mixed with magnesium stearate using vysokoskorostnogo the mixer.

The final composition was extruded using a rotary compressor (MRC-33: Sejong) at a speed of 30 revolutions per minute (rpm) to produce tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, the tablet with two-phase matrix.

Example 6. Obtaining a multilayer tablets amlodipine-simvastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules. After drying, the granules were coated by spraying with 20% of the mass. solution of Eudragit RS PO in 1:1-mixture of ethanol and methylene chloride. The coated granules were mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder in the society was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combining with a mixture of basic ingredients. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and sieved through sieve No. 20. The granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

The composition can be pressurized using a compressor for the production of multi-layer tablets (MRC-37: Sejong). More, the composition comprising simvastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 7. Obtaining tablets amlodipine-simvastatin with inner layer

1) receiving the tablets of the inner layer amlodipine

Predefined quantity of amlodipine and microcrystalline Zell is eskers, shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt) and sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules. After drying, the granules were coated by spraying with 10% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride. The coated granules were mixed with magnesium stearate using a double-cone mixer and extruded using a rotary compressor (MRC-33; Sejong) with a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 3.0 mm and a diameter of 5.5 mm, which was used as the inner layer tablets.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combining with a mixture of basic ingredients. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and sift cerussite No. 20. The granules were mixed with butilirovannyh hydroxyanisole using a double-cone mixer.

3) Pressing and coating

Pressing was carried out in the compressor to obtain tablets with an inner layer (KUD-1: Kilian) with a speed of 30 revolutions per minute (rpm) using tablets amlodipine for the inner layer and the composition comprising simvastatin, an inner layer and outer layer, respectively, to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm, By setting the coating Hi-coater (SFC-30N, Sejong mechanics, Korea) were received, therefore, the tablets with the inner layer.

Example 8. Obtaining tablets amlodipine-simvastatin with inner layer

1) receiving the tablets of the inner layer amlodipine

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and was mixed in a high speed mixer. The mixture was introduced into a high-speed mixer, combined with Kollicoat SR30D and was granulated using an oscillator with sieve No. 20. After drying, the granules were selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with magnesium stearate using a double-cone mixer and extruded using a rotary compressor (MRC-33; Sejong) when the IC is grow to 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, thickness of 3.0 mm and a diameter of 5.5 mm, which was used as the tablets of the inner layer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of the binder was obtained by dissolution in water hydroxypropylmethylcellulose and citric acid and combining with the mixture of the main ingredients in a high speed mixer. Thus obtained mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and sieved through sieve No. 20. The granules were mixed with butilirovannyh hydroxyanisole using a double-cone mixer.

3) Pressing and coating

Pressing was carried out in the compressor to obtain tablets with an inner layer (KUD-1: Kilian) with a speed of 30 revolutions per minute (rpm) using tablets amlodipine for the inner layer and the composition comprising simvastatin, an inner layer and outer layer, respectively, to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm, By setting the coating Hi-coater (SFC-30N, Sejong mechanics, Korea), were received, therefore, the tablets with internal with the OEM.

Example 9. Obtaining a two-phase capsules amlodipine-simvastatin

1) Obtaining granules amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying a solution of a binder (an aqueous solution of hydroxypropylmethylcellulose) and dried. After drying, the granules were coated by spraying with 20% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride.

2) Obtaining granules of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. To the selected size of the granules was added butile is consistent of hydroxyanisol and at the end I mixed the drug with the use of double-cone mixer.

3) Pressing and coating

Resulting from the above methods 1) and 2) the composition was mixed using a double-cone mixer and to it was added sodium starch glycolate. The mixture was stirred using a double-cone mixer, then mixed with colloidal silicon dioxide using a double-cone mixer and finally mixed with magnesium stearate. The resulting mixture was introduced into the inlet of the powder and filled it capsules by using a machine for filling capsules.

Example 10. Obtaining a two-phase capsules amlodipine-simvastatin

1) Obtaining granules amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 2, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying Kollicoat SR30D and dried.

2) Obtaining granules of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 2, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylcellulose and lim is authorized acid, combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules was added at the end of mixing with butilirovannyh hydroxyanisole.

3) Pressing and coating

Resulting from the above methods 1) and 2) the composition was mixed using a double-cone mixer and to it was added sodium starch glycolate. The mixture was stirred using a double-cone mixer, then mixed with colloidal silicon dioxide using a double-cone mixer and finally mixed with magnesium stearate. The resulting mixture was introduced into the inlet of the powder and filled it capsules by using a machine for filling capsules.

Example 11. Obtaining a multilayer tablets amlodipine-lovastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying the solution swazoo is his agent (aqueous solution of hydroxypropylmethylcellulose) and dried. The granules were coated by spraying with 10% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride and finally mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer lovastatin

Predefined number of lovastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. To the selected size of the granules was added bottled hydroxyanisole, sodium starch glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition containing lovastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second input re rsta. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 12. Obtaining a multilayer tablets amlodipine-lovastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was introduced into a high-speed mixer, combined with Kollicoat SR30D and was granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and sieved through sieve No. 20. Selected based on the size of the granules in the end was mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer lovastatin

Predefined number of lovastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mix is and. A solution of a binder obtained by dissolving in an aqueous solution of hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition containing lovastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

When is EP 13. Obtaining a multilayer tablets amlodipine-lovastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying a solution of a binder (an aqueous solution of hydroxypropylmethylcellulose) and dried. The granules were coated by spraying with 10% of the mass. solution of phthalate hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride and finally mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of atorvastatin

Predefined quantity of atorvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Sobranie sized granules were mixed with butilirovannyh hydroxyanisole, the sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition comprising atorvastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 14. Obtaining a multilayer tablets of amlodipine-atorvastatin

1) the Receiving layer amlodipine controlled release

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was introduced into a high-speed mixer, combined with Kollicoat SR30D and was grained using a generator Coleman the th with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of atorvastatin

Predefined quantity of atorvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition comprising atorvastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed in vtora the inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 15. Obtaining tablets of amlodipine-atorvastatin inner layer

1) receiving the tablets of the inner layer amlodipine

Predefined quantity of amlodipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying a solution of a binder (an aqueous solution of hydroxypropylmethylcellulose) and dried. To the pellet was added to the powder carbomer 71G and mixed with magnesium stearate using a double-cone mixer. The resulting mixture was extruded using a rotary compressor (MRC-33; Sejong) with a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 3.0 mm and a diameter of 5.5 mm, these tablets are used in the tablets of the inner layer.

2) P is the receiving layer of atorvastatin

Predefined quantity of atorvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing was carried out in the compressor to obtain tablets with an inner layer (RUD-1: Kilian) with a speed of 30 revolutions per minute (rpm) using tablets amlodipine for the inner layer and the composition comprising atorvastatin, an inner layer and outer layer, respectively, to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm, By setting the coating Hi-coater (SFC-30N, Sejong mechanics, Korea) on the compressed tablets were formed layer planon the th coverage.

Example 16. Obtaining a multilayer tablets lercanidipine-simvastatin

1) Receiving layer lercanidipine controlled release

Predefined number of lercanidipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt) and sprayed with a solution of binding agent (aqueous solution of hydroxypropylmethylcellulose) to obtain granules, and dried. The granules were coated by spraying 6% of the mass. solution obtained by dissolving phthalate of hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride. Coated granules at the end was mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C and use the reattaching of parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition comprising simvastatin, is placed in a first inlet for powder, and the composition containing lercanidipine, placed second inlet for powder. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 17. Obtaining a multilayer tablets lercanidipine-simvastatin

1) Receiving layer lercanidipine controlled release

Predefined number of lercanidipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was introduced vysokoskorostnoi mixer, combined with Kollicoat SR30D and was granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end I mixed the drug with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition containing syngas is Athyn, placed in a first inlet for powder, and the composition containing lacidipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), thus obtaining a multilayer tablet.

Example 18. Obtaining a multilayer tablets lacidipine-simvastatin

1) the Receiving layer lacidipine controlled release

Predefined number lacidipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed using a double-cone mixer. The mixture was placed in a granulator, fluidized bed (GPCG 1: Glatt)was granulated by spraying a solution of a binder (an aqueous solution of hydroxypropylmethylcellulose) and dried. The granules were coated by spraying with 10% of the mass. solution obtained by dissolving phthalate of hydroxypropylmethylcellulose in 1:1-mixture of ethanol and methylene chloride and finally mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer when Muscatine

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of main ingredients in a high speed mixer and granulated using an oscillator with sieve No. 20. The granules were dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition comprising simvastatin, is placed in a first inlet for powder, and the composition containing lacidipine, placed second inlet for powder. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and diameter is ω 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Example 19. Obtaining a multilayer tablets lacidipine-simvastatin

1) the Receiving layer lacidipine controlled release

Predefined number lacidipine and microcrystalline cellulose as shown in table 3, were sieved through sieve No. 35 and mixed with the use of double-cone mixer. The mixture was stirred using Kollicoat SR30D in high-speed mixer. The resulting mixture was granulated using an oscillator with sieve No. 20, was dried at 60°C using parasites and selected by size using a sieve No. 20. Selected based on the size of the granules were mixed with magnesium stearate using a double-cone mixer.

2) the Receiving layer of simvastatin

Predefined number of simvastatin, microcrystalline cellulose and mannitol, are shown in table 3, were sieved through sieve No. 35 and mixed using a high speed mixer. A solution of a binder obtained by dissolving in water hydroxypropylmethylcellulose and citric acid, were combined with a mixture of basic ingredients. This mixture was combined granules is listed using the oscillation generator with sieve No. 20, was dried at 60°C using parasites and selected by size using a sieve No. 20. These granules were mixed with butilirovannyh hydroxyanisole, sodium glycolate and colloidal silicon dioxide and in the end was mixed with magnesium stearate using a double-cone mixer.

3) Pressing and coating

Pressing is carried out with the use of the compressor for the production of multi-layer tablets (MRC-37T: Sejong). More, the composition comprising simvastatin, is placed in a first inlet for powder, and the composition containing amlodipine, placed second inlet. The pressing is carried out under such conditions that the interpenetration of the layers could be minimized, at a speed of 30 revolutions per minute (rpm) to provide tablets with a hardness of 7-9 kp, a thickness of 6.0 mm and a diameter of 9.5 mm On compressed tablet formed of the layer film coating using installation for coating a Hi-coater (SFC-30N, Sejong mechanics, Korea), and thus, a multilayer tablet.

Table 2
IngredientsQuantity (mg/tablet)
Examples
12345678910
Layer controlled releaseMaleate amlodipine6.42 per6.42 per6.42 per6.42 per6.42 per6.42 per6.42 per6.42 per6.42 per6.42 per
Lercanidipine HCl----------
Lacidipine--------- -
Microcrystalline cellulose70,8373,58of 71.5880,8381,5870,8380,8372,8381,5873,58
Kollicoat SR30D1)-20-----20-20
Eudragit RS PO2)--20--20----
Carbomer 71G3)10------- --
The hypromellose2-22222-2-
Phthalate hydroxypropyl-methylcellulose10--1010-10-10-
Magnesium stearate0,75--0,75-0,750,750,75--
Total100100100100100100100 100100100
Layer with the immediate-releaseSimvastatin20202020202020202020
Lovastatin----------
Atorvastatin----------
Microcrystalline cellulose5757575757 5757575757
D-mannitol112,46112,46112,46112,46112,46112,46112,46112,46112,46112,46
The glycolate sodium1111111111
Bottled hydroxyanisol0,040,040,040,040,040,040,040,040,040,04
The hypromellose555 5555555
Aerosil 2004)1111111111
Citric acid2222222222
Magnesium stearate1,51,51,51,51,51,51,51,51,51,5
The covering layerThe hypromellose 29102,6 2,62,62,62,62,62,62,6--
Hydroxypropylcellulose2,62,62,62,62,62,62,62,6--
The titanium oxide2,32,32,32,32,32,32,32,3--
Talc1,51,51,51,51,51,51,51,5--
Ethanol64,8 64,864,864,864,864,864,864,8--
Distilled water16,216,216,216,216,216,216,216,2--
Total309309309309309309309309300300
1)Kollicoat SR30D - Main ingredient: 30% suspension polyacetate (BASF).
2)Eudragit RS PO - Main ingredient: copolymer of polymethacrylate (BASF).
3)Carbomer 71G - Main ingredient: carboxyvinyl polymer (Lubrizol).
4)Aerosil 200 is a Main ingredient: colloidal silicon dioxide (Degussa).

112,46
Table 3
IngredientsQuantity (mg/tablet)
Examples
111213141516171819
Layer controlled releaseMaleate amlodipine6.42 per6.42 per6.42 per6.42 per6.42 per----
Lercanidipine HCl-----1010--
Lacidipine--- ----44
Microcrystalline cellulose80,8372,8380,8372,8370,8379,2564,2578,2575,25
Kollicoat SR30D1)-20-20--25-20
Eudragit RS PO2)---------
Carbomer 71G3)----10- ---
The hypromellose2-2-24-7-
Phthalate hydroxypropyl-methylcellulose10-10-106-10-
Magnesium stearate0,750,750,750,750,750,750,750,750,75
Total100100100100100100100100100
Layer with the immediate-releaseSimvastatin-----20202020
Lovastatin2020-------
Atorvastatin--202020----
Microcrystalline cellulose575757575757575757
D-mannitol112,46112,46112,46112,46112,46112,46112,46112,46
The glycolate sodium111111111
Bottled hydroxyanisol0,040,040,040,040,040,040,040,040,04
The hypromellose555555555
Aerosil 2004)11 1111111
Citric acid222222222
Magnesium stearate1,51,51,51,51,51,51,51,51,5
The covering layerThe hypromellose 29102,62,62,62,62,62,62,62,62,6
Hydroxypropylcellulose2,62,62,6 2,62,62,62,62,62,6
The titanium oxide2,32,32,32,32,32,32,32,32,3
Talc1,51,51,51,51,51,51,51,51,5
Ethanol64,864,864,864,864,864,864,864,864,8
Distilled water16,216,216,216,216,216,2 16,216,216,2
Total309309309309309309309309309
1)Kollicoat SR30D - Main ingredient: 30% suspension polyacetate (BASF).
2)Eudragit RS PO - Main ingredient: copolymer of polymethacrylate (BASF).
3)Carbomer 71G - Main ingredient: carboxyvinyl polymer (Lubrizol).
4)Aerosil 200 is a Main ingredient: colloidal silicon dioxide (Degussa).

Experimental example 1: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using a covered pressing tablets amlodipine/simvastatin obtained in example 1, and control drugs (Zocor®: a separate tablet of simvastatin, MSD, By: a separate tablet of amlodipine, Pfizer). If the test profile of dissolution of an ingredient of amlodipine solution for dissolution in artificial gastric juice after 2 hours was changed to artificial intestinal juice. A specific method for testing the dissolution profile of each Jn is radiant described below, and the results are presented in figure 1.

When testing dissolution profile was performed under the conditions described below, covered in pressed tablets of the present invention ingredient simvastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drugs (Zocor®), while the ingredient amlodipine was characterized by a very low dissolution rate as compared to that of the control drug (By®). In the case covered by the pressing of tablets amlodipine/simvastatin according to the present invention, the degree of dissolution of an ingredient of amlodipine everywhere was within 50% one hour after the start of the test, which is much lower than the control drugs (approximately 99%).

As described above, covered in pressed pill amlodipine/simvastatin according to the present invention amlodipine is characterized by a substantially lower initial rate of dissolution than simvastatin, in contrast to the control drugs (i.e., the individual tablets of amlodipine), and, thus, the tablet amlodipine/simvastatin with two-phase matrix of the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of simvastatin.

The way to test amlodipine

snowin on a common way of testing for solubility, described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 240 nm).

The way to test simvastatin

Based on part of the USP X X IX "Tablet simvastatin".

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium lauryl sulfate 0.5% wt./mass. as surface-active substances), 900 ml

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 247 nm and a minimum 257 nm).

Experimental example 2: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using a combined pharmaceutical drugs amlodipine/simvastatin obtained in examples 4 and 10, and control drugs (Zocor®: a separate tablet of simvastatin, By®: a separate tablet of amlodipine). The behavior of simvastatin and amlodipine when dissolution was observed, as described below, and in the case of test dissolution profiles ingredient amlod the Pina solution for dissolution in artificial gastric juice after 2 hours was changed to artificial intestinal juice. The specific method of testing dissolution profile of each ingredient is described below, and the results are presented in figure 2.

When testing dissolution profile was performed in the conditions described below in examples 4 and 10, the ingredient simvastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drugs (Zocor®), while the ingredient amlodipine was characterized by a very low dissolution rate as compared to that of the control drug (By®). In the case of tablets amlodipine/simvastatin with two-phase matrix according to the present invention, the degree of dissolution of an ingredient of amlodipine everywhere was within 50% one hour after the start of the test, which is much lower than the control drugs (approximately 99%).

As described above, in the multilayer tablet of amlodipine/simvastatin according to the present invention amlodipine is characterized by a substantially lower initial rate of dissolution than simvastatin, in contrast to the control drugs (i.e., the individual tablets of amlodipine), and thus, the multilayer tablet of amlodipine/simvastatin according to the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of simvastatin.

The method tested is I amlodipine

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 240 nm).

The way to test simvastatin

Based on part of the USP X X IX "Tablet simvastatin".

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium lauryl sulfate 0.5% wt./mass. as surface-active substances), 900 ml

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 247 nm and a minimum 257 nm).

Experimental example 3: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using a combined pharmaceutical drugs amlodipine/lovastatin obtained in example 11, and control drugs (Mevacor®: a separate tablet lovastatin, By®: a separate tablet of amlodipine, Pfizer). If the test profile of dissolution of an ingredient of amlodipine solution for Rast is orenia in the form of artificial gastric juice after 2 hours was changed to artificial intestinal juice. The specific method of testing dissolution profile of each ingredient is described below, and the results are presented in figure 3.

When testing dissolution profile was performed in the conditions described below in example 11, the ingredient lovastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drugs (Mevacor®), while the ingredient amlodipine was characterized by a very low dissolution rate as compared to that of the control drug (By®). In the case of multilayer tablets amlodipine/lovastatina of the present invention the rate of dissolution of an ingredient of amlodipine everywhere were within 50% one hour after the start of the test, which is much lower than the control drugs (approximately 99%).

As described above, in the multilayer tablet of amlodipine/lovastatina of the present invention amlodipine is characterized by a substantially lower initial rate of dissolution than lovastatin, in contrast to the control drugs (i.e., the individual tablets of amlodipine), and thus, the multilayer tablet of amlodipine/lovastatina of the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of lovastatin.

The way to test amlodipine

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 240 nm).

The testing method lovastatin

Based on part of the USP X X IX "Tablet lovastatin".

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium dodecyl sulfate and 2.0% wt./mass. as surface-active substances), 900 ml

Method of analysis: high performance liquid chromatography.

Recorded wavelength: 230 nm.

Mobile phase: Acetonitrile : 0,02 M monobasic sodium phosphate buffer solution (pH=4.0) is : methanol = 5:3:1.

Column: octadecylsilyl, Packed in a stainless steel tube size 4.6 mm (inner diameter) and 250 mm (length).

Flow rate: 1.5 ml/min

Experimental example 4: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using a combined pharmaceutical drugs AML is dipina/atorvastatin, obtained in example 13, and control drugs (Lipitor®: a separate tablet of atorvastatin, By: a separate tablet of amlodipine, Pfizer). If the test profile of dissolution of an ingredient of amlodipine solution for dissolution in artificial gastric juice after 2 hours was changed to artificial intestinal juice. The specific method of testing dissolution profile of each ingredient is described below, and the results are presented in figure 4.

When testing dissolution profile was performed in the conditions described below in example 13, the ingredient atorvastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drug (Lipitor®), while the ingredient amlodipine was characterized by a very low dissolution rate as compared to that of the control drug (Lipitor®). In the case of multilayer tablets of amlodipine/atorvastatin according to the present invention the rate of dissolution of an ingredient of amlodipine everywhere were within 50% one hour after the start of the test, which is much lower than the control drugs (approximately 99%).

As described above, in the multilayer tablet of amlodipine/atorvastatin according to the present invention amlodipine is characterized by a substantially lower initial speed rest is rhenium, than atorvastatin, in contrast to the control drugs (i.e., the individual tablets of amlodipine), and thus, the multilayer tablet of amlodipine/atorvastatin according to the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of atorvastatin.

The way to test amlodipine

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 240 nm).

The method of testing of atorvastatin

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium lauryl sulphate 2% wt./mass. as surface-active substances), 900 ml

Method of analysis: high performance liquid chromatography.

Recorded wavelength: 240 nm.

Mobile phase: Methanol: buffer solution of 0.005 M monobasic phosphate (pH=5,2) : methanol= 37:63 (pH=4,0).

Column: octadecylsilyl, Packed in a stainless steel tube size 4.6 mm (inner diameter) and 250 mm (length).

Flow rate: 1.5 ml/min

Experimental example 5: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using a combined drug lercanidipine/simvastatin obtained in example 16, and control drugs (Zocor®: a separate tablet of simvastatin, Merck, Zanidip®: a separate tablet lercanidipine, LG Life Sciences Ltd.). In the case of test dissolution profile of the ingredient lercanidipine solution for dissolution in artificial gastric juice after 2 hours was changed to artificial intestinal juice. The specific method of testing dissolution profile of each ingredient is described below, and the results are presented in figure 5.

When testing dissolution profile was performed as described below in example 16 conditions, ingredient simvastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drugs (Zocor®), while the ingredient lercanidipine was characterized by a very low dissolution rate as compared to that of the control drug (Zanidip®). In the case of a multilayer tablet lercanidipine/simvastatin p the present invention the rate of dissolution of an ingredient of lercanidipine everywhere were within 50% one hour after the beginning of the test which is much lower than the control drugs (approximately 99%).

As described above, in the multilayer tablet of lercanidipine/simvastatin according to the present invention lercanidipine characterized by a significantly lower initial rate of dissolution than simvastatin, in contrast to the control drugs (i.e., the individual tablet lercanidipine), and, thus, the tablet lercanidipine/simvastatin with two-phase matrix of the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of simvastatin.

The method of testing lercanidipine

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: high performance liquid chromatography.

Recorded wave length: 356 nm.

Mobile phase: Acetonitrile : 0.01 M phosphate buffer solution = 45:55 (pH=4,0).

Column: octadecylsilyl, Packed in a stainless steel tube size 4.6 mm (inner diameter) and 250 mm (length).

Flow rate: 1.0 ml/min

The way to test simvastatin

Based on part of the USP X XIX "Tablet simvastatin".

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium lauryl sulfate 0.5% wt./mass. as surface-active substances), 900 ml

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 247 nm and a minimum 257 nm).

Experimental example 6: test for comparison of dissolution profiles

Test comparison of dissolution profiles was performed using the combined drugs lacidipine/simvastatin obtained in example 18, and control drugs (Zocor®: a separate tablet of simvastatin, Merck, Vaxar®: a separate tablet lacidipine, GlaxoSmithkline Plc.). In the case of test dissolution profiles ingredient lacidipine solution for dissolution in artificial gastric juice after 2 hours was changed to artificial intestinal juice. The specific method of testing dissolution profile of each ingredient is described below, and the results are shown in Fig.6.

When testing dissolution profile was performed as described below in example 18 conditions, ingredient simvastatin was characterized by a roughly equivalent behavior dissolution compared with that of the control drugs (Zocor®), while Ingrid the UNT, lacidipine was characterized by a very low dissolution rate as compared to that of the control drug (Vaxar®). In the case of multilayer tablets lacidipine/simvastatin according to the present invention, the degree of dissolution of the ingredient lacidipine everywhere was within 50% one hour after the start of the test, which is much lower than the control drugs (approximately 99%).

As described above, in the multilayer tablet lacidipine/simvastatin according to the present invention lacidipine characterized by a significantly lower initial rate of dissolution than simvastatin, in contrast to the control drugs (i.e., the individual tablets lacidipine), and thus, a multilayer tablet lacidipine/simvastatin according to the present invention is less likely undergoes metabolism in the liver, ahead of the metabolism of simvastatin.

The way to test lacidipine

Based on the General method of testing the solubility described in Korea Pharmacopoeia (8th edition).

Method of testing: the way a paddle stirrer, 75 rpm

The solution for dissolution: 0.01 M hydrochloric acid, 750 ml, 0-2 h, artificial intestinal fluid at pH 6.8, 1000 ml (after 2 hours).

Method of analysis: high performance liquid chromatography.

Recorded wave length: 282 nm.

Mobile phase: Acetonitrile : buffer solution 0.05 M ammonium acetate = 80:20.

Column: octadecylsilyl, Packed in a tube of stainless steel is eUSA steel size 4.6 mm (inner diameter) and 250 mm (length).

Flow rate: 1.0 ml/min

The way to test simvastatin

Based on part of the USP X X IX "Tablet simvastatin".

Method of testing: the way a paddle stirrer, 50 rpm

The solution for dissolution: buffer solution with pH=7.0 (0.01 M solution of monobasic sodium phosphate containing sodium lauryl sulfate 0.5% wt./mass. as surface-active substances), 900 ml

Method of analysis: spectrophotometry in the UV-visible range (measured wavelength = max 247 nm and a minimum 257 nm).

Experimental example 7: preliminary clinical test

Preliminary clinical test conducted as described in table 4 for comparison of therapeutic effects of (i) separate the introduction of commercially available 'tablets Zocor®' (simvastatin 20 mg, Merck), (ii) simultaneous administration of tablets Zocor® and 'tablets By®' (besylate amlodipine 5 mg, Pfizer) and, as the experimental group, (iii) chronotherapeutics the introduction of tablets Zocor® tablets By®. Chronotherapeutics introduction planned so that the time of the release of drugs was similar to the one in the combined drug of the present invention.

The test was carried out to identify the effect of the present invention using standard who s local and foreign clinical test for permissions drugs and by reducing the number of experimental groups. However, the test subjects were strictly controlled during the test was strictly follow the standards of clinical testing. Comparative results of the clinical test are presented in table 5 and figure 7-10.

Table 5
Pharmacokinetic/pharmacodynamic results of a clinical test
Clinical test for comparison chronotherapeutics introduction and simultaneous introduction (Korea University Medical Center)
1DiseaseHypertension with hyperlipidemiaHypertension with hyperlipidemiaHyperlipidemia
2GroupGroup chronotherapy-critical introduction (EC)Group simultaneous introduction (ENC)Group introduction one of simvastatin (SS)
3The number of subjects797
After daily injection within 41 days
4Systolic blood pressure121 mm Hg127 mm Hg-
5Diastolic blood pressure80 mm Hg82 mm Hg-
6Average blood pressure94 mm Hg97 mm Hg-
7Pulse pressure40 mm Hg45 mm Hg-
8Total cholesterol158 mg/DL164 mg/DL170 mg/DL
9LDL88 mg/DL94 mg/DL95 mg/DL
10Neutral fats107 mg/DL143 mg/DL 134 mg/DL
11HDL61 mg/DL46 mg/DL49 mg/DL
12S-GPT23 IU/l39 IU/l31 IU/l
13S-GOT23 IU/l38 IU/l33 IU/l
14CPK71 IU/l85 IU/l117 IU/l
15r-GPT38 IU/l46 IU/l28 IU/l
16Alkaline phosphatase70 IU/l
(No significant changes)
57 IU/l
(No significant changes)
59 IU/l
(No significant changes)
17Clinical side effectOne case (diarrhea)One case (fatigue)
One case (cold)
-
18AUC simvastatinum acid (ng·h/ml)14,2123,424,59
19AUC of simvastatin (ng·h/ml)24,2920,2921,62
20AUC of simvastatin + simvastatinum acid (ng·h/ml)38,5043,7346,21
21AUC0-15amlodipine (ng·h/ml)111,38107,11-

1. Group chronotherapeutics injection was characterized by lower systolic and diastolic blood pressure at 41 days of daily administration.

2. Group chronotherapeutics injection was characterized by lower levels of total cholesterol and cholesterol low-density lipoprotein (LDL) at 41 days of daily injection, compared with a group of simultaneous introduction and group introduction one of the simvastatin.

3. Group chronotherapeutics injection was characterized by a higher activity level reduction triglycer is s, pathogenetic important lipids, and the group introduction one of the simvastatin was in second place to reduce the level of triglycerides, and a group of simultaneous administration had no activity for the reduction of triglycerides. Although based on statin tool is a tool that inhibits the synthesis of cholesterol, it is known that it inhibits the synthesis of triglycerides on 8-25%, since cholesterol synthesis is the stage of synthesis of lipoproteins, which determines the reaction rate. Group chronotherapeutics introduction and group introduction only simvastatin reduces the synthesis of triglycerides by 20% and 10%, respectively, and a group of simultaneous administration had no activity for the reduction of the synthesis of neutral lipids. One reason may be that undesirable increase in group simultaneous administration of the concentration of simvastatin in the blood by about 30% due to the antagonistic effect of amlodipine on liver enzymes, it seems that also leads to reduction of control of the synthesis of triglycerides. Meanwhile, the group chronotherapeutics injection was characterized by a lower level of lipid synthesis than group introduction one of the simvastatin. This may be due to the activity of amlodipine to decrease the level of lipids.

4. It is well known that to improve the condition when bol is the June, related to lipid metabolism should increase the level of HDL. Group chronotherapeutics injection was characterized by the highest increase HDL.

5. The safety of medications was assessed by monitoring changes in levels of biomarkers at 41 days of daily injection, and the results were as follows.

1) Chronotherapeutics introduction was characterized by the most appropriate values of biomarkers such as levels of S-GPT, S-GOT, CPK, γ-GPT and alkaline phosphatase.

2) under the simultaneous introduction of simvastatin in plasma was higher than that in group chronotherapeutics the introduction of more than 30%, which caused unwanted inflammation associated with simvastatin.

6. Only two subjects from all three groups were characterized by three cases of side effects. Only one case of diarrhoea was observed in the group chronotherapeutics introduction, and two cases (fatigue and cough) were observed in group simultaneous administration. The concentration of drug in plasma was changed as follows.

1) the Concentration of plasma simvastatinum acid

When chronotherapeutics introduction plasma concentration simvastatinum acid was 40% lower than with the simultaneous introduction and the introduction of a single simvastatin (table 6 and 7). These pharmacokinetic data (table 6) shows the t, what chronotherapeutics introduction outperforms the simultaneous introduction reduction of lipid levels. (This means that the liver is absorbed by the higher concentration of active simvastatinum acids than inactive simvastatin, for the inhibition of cholesterol synthesis, and these acids are more fully metabolized in the liver excretion through the bile duct, but without getting into the blood.)

2) the Concentration of simvastatin in plasma: as shown in table 7 and Fig, three groups were similar in terms of the concentration of simvastatin.

3) Values of the total concentration of simvastatin and simvastatinum acids are presented in table 8, show that chronotherapeutics introduction is characterized by the low total concentration of simvastatin in the blood, and this means that the maximum concentration is consumed in the liver, and therefore achieved in the most effective curves decrease lipid and the best performance of biomarkers for evaluation of possible side effects).

Table 8
The increase in total concentration simvastatinum acid and simvastatin
Simvastatin +
simvastatina the I acid
AUCINF(ng·h/ml)The increase in plasma concentrations (%)
AverageDeviation
The introduction of a single simvastatin (SS)46,2130,58-
Simultaneous introduction (ENC)43,7422,92-5,36
Chronotherapeutics introduction (EC)38,5013,40-16,68

4) the Concentration of amlodipine in plasma (table 9)

The concentration of amlodipine in plasma is closely connected with its activity in reducing blood pressure, and also with its hypolipidemic activity, since amlodipine is an indirect activity to reduce the level of lipids by improvement in atherosclerosis.

Table 9
The concentration of amlodipine in plasma
AmlodipineAUC0-15(ng·h/ml)
AverageDeviation
Simultaneous introduction (ENC)107,1120,38
Chronotherapeutics introduction (EC)111,3817,73

As shown in Fig.7-9, chronotherapeutics introduction with the time interval (simvastatin initially dissolved and absorbed in the liver, and after 3-4 hours amlodipine follows the same path) allows simvastatinum acids in the form of active forms of the fully formed from the inactive simvastatin by the hepatic enzyme cytochrome P450 3A4 and is fully disposed in the liver and is then further metabolized by the same liver enzymes with excretion via the bile duct.

Therefore, it is undesirable higher concentration simvastatinum acids in the blood is not achieved, as it is in the group of simultaneous introduction, where the same liver enzyme cytochrome P450 3A4 amlodipine inhibited in the presence of simvastatin in the liver, therefore, the metabolism of simvastatin is a partial, some of the educated simvastatinum acids are not further metabolized after their operation. And they get into the bloodstream with the occurrence of undesirable high concentration simvastatinum acid is t in the blood, that may be the source of adverse effects, such as muscle violation, such as rhabdomyolysis.

Next, as shown in figure 10, Tmax(the time to reach maximum plasma concentration) of dihydropyridines, calcium channel blocker represented by the amlodipine group chronotherapeutics introduction was delayed by approximately 4-5 hours, and dihydropyridines, calcium channel blocker, is characterized by slow activity in reducing blood pressure, because it is provided in 24 hours (night). As a result, in contrast to the group's normal simultaneous introduction chronotherapeutics combined drug can have maximum activity for the reduction of blood pressure during the time from morning until noon the next day, when the mean blood pressure is the highest.

As described above, chronotherapeutics introduction, planned here through the combined drug of dihydropyridines, calcium channel blocker, and a statin, lipid-lowering means inhibits the side effects of the statin, lipid-lowering means, compared with the simultaneous introduction. Here chronotherapeutics introduction also provides maximum hypotensive clinical effect of dihydropyridines, blocker calcium Cana is offering.

Table 10 compares chronotherapeutics introduction with the simultaneous introduction in terms of lipid-lowering efficacy. In the group chronotherapeutics the introduction of tablets By (besylate amlodipine 5 mg and tablets Zocor (simvastatin 20 mg), taken in the evening with a time interval between meals, more significantly reduced the concentration of LDL-cholesterol and total cholesterol in the plasma than in the simultaneous injection.

As shown in Fig.7-9, combined products of the present invention, as can be expected, show the same results because of the medicinal component simvastatin transformed into an activated form in the liver by the enzyme cytochrome P450 and fully exerts its pharmacological action in the liver, and completely metabolized by the same enzyme in the liver for excretion through the bile duct, without the antagonistic effects of amlodipine.

Table 10
Total cholesterol, HDL, LDL and neutral lipid (*p<0,05, **p<0,01 compared with screening)
GroupGroup chronotherapy-critical introduction (EC)Group simultaneous introduction (ENC) Group introduction one Zocor (SS)
Total cholesterolScreening225±28,0239±52,9260±50,7
D41158±25,1164±32,9170±18,9
HDLScreening61±18,048±13,652±12,7
D4161±20,546±7,649±7,3
LDLScreening153±14,6161±43,1180±44,2
D4188±11,894±31,095±24,6
TriglyceridesScreening135±69,3150±57,3160±72,4
D41107±29,1143±65,2134±39,0

In tables 11 and 12 shows the result of the ATA, related to blood pressure and pulse blood pressure, respectively, for a group of simultaneous introduction and group chronotherapeutics introduction. Established that the average systolic blood pressure in the sitting position and the average diastolic blood pressure in the sitting position significantly reduced in the group chronotherapeutics introduction. This is most likely a consequence of high concentrations of amlodipine in the blood (figure 10) in the group chronotherapeutics introduction.

Consequently, the group chronotherapeutics introduction characterized by superiority in terms of the antihypertensive effect compared with a group of simultaneous introduction due to the delay of the release of amlodipine approximately 4 hours.

Table 11
Blood pressure (*p<0,05, **p<0,01
compared with screening)
GroupGroup chronotherapeutics introduction (EC)Group simultaneous introduction (ENC)
Systolic blood pressure (mm Hg)Screening148±6,3150±5,9
D41121±8,8127±7,1
D42117±10,2125±8,8
Diastolic blood pressure (mm Hg)Screening95±4,095±2,8
D4180±5,482±8,1
D4274±8,279±7,3
Mean blood pressure (mm Hg)Screening113±4,5113±3,6
D4194±5,897±7,1
D4288±8,694±7,5

Table 12
Pulse blood pressure and pulse rate (*p<0,05, **p<0,01 compared with screening)
GroupGroup chronotherapeutics introduction (EC)Group one is a temporary introduction (ENC)
Pulse blood pressure (mm Hg)Screening53±4,355±4,2
D4140±7,145±7,0
D4243±4,646±4,6
Heart rate (tank/min)Screening75±16,263±10,1
D4173±14,872±11,5
D4276±12,568±10,5

In conclusion, in the above clinical test found that chronotherapeutics combined drug of dihydropyridines, calcium channel blocker, and a statin, lipid-lowering means, the present invention is characterized by a significantly improved synergistic effect in inhibiting high-cholesterol-statin, lipid-lowering means, and lower blood pressure by dihydropyridines, a calcium channel blocker, in the same dosage as compared with the simultaneous introduction of two drug the funds due to the effects of controlling the time of release of each drug component.

Industrial applicability

As indicated above, the present invention relates to the combined product of the two drugs, which demonstrates chronotherapeutics effects and synergistic effects, increasing in more efficiency and less security. Thus, drug controlled release of the present invention is based on theory of xenobiotics and chronotherapy.

The drug of the present invention comprises as active ingredients a statin, lipid-lowering agent, and dihydropyridines, calcium channel blocker, and they both relate to the same enzyme cytochrome P450, so that one acts on this enzyme, while the other is subjected to its influence, and is characterized by the fact that the speed of release of the above ingredients are different, and the dissolution and absorption of each drug is initiated at certain intervals of time in a controlled way. In the drug of the present invention can better be used in the treatment of chronic disorders of blood circulation in the pharmacological, clinical, scientific and economic terms, compared with the simultaneous introduction of two medicinal environments the TV without a certain interval of time without consideration of the profile chronotherapeutics rhythm.

Combined pharmaceutical drug of the present invention provides for the release of drugs with different speeds than prevents antagonistic effects and reduce side effects while maintaining the synergistic action of drugs. In addition, the combined pharmaceutical drug of the present invention is administered as a single dose once a day, which provides convenience in the treatment and time saving doctors when instructing patients.

1. Combined pharmaceutical drug controlled release, including controlled release, containing dihydropyridines, calcium channel blocker, and a part of the immediate-release formulation containing a statin, lipid-lowering agent, as active ingredients.

2. Combined pharmaceutical drug according to claim 1, where the characteristics of the release of dihydropyridines, calcium channel blocker, and a statin, lipid-lowering means are controlled so that the dihydropyridines, calcium channel blocker, may dissolve for absorption in the liver for 3-4 h later than the statin, lipid-lowering agent.

3. Combined pharmaceutical drug n is 1, where the characteristics of the release of dihydropyridines, calcium channel blocker, and a statin, lipid-lowering means are controlled to reduce the interaction between the two medicinal ingredients, metabolisable at the same time in the liver by cytochrome P450, so dihydropyridines, calcium channel blocker, may be released in 2 hours after initial release of the statin, lipid-lowering means.

4. Combined pharmaceutical drug according to claim 1, where the dihydropyridines, a calcium channel blocker selected from the group consisting of amlodipine, lercanidipine, lacidipine and their pharmaceutically acceptable salts.

5. Combined pharmaceutical drug according to claim 4, where the dihydropyridines, a calcium-channel blocker is amlodipine and its pharmaceutically acceptable salt or isomer.

6. Combined pharmaceutical drug according to claim 5, where the dihydropyridines, a calcium-channel blocker is amlodipine maleate or besylate amlodipine.

7. Combined pharmaceutical drug according to claim 1, where the medicinal product contains 1-20 mg of dihydropyridines, a calcium channel blocker.

8. Combined pharmaceutical drug according to claim 1, where the portion controlled wisweb the vision contains the substance of supervised release, selected from the group consisting of enteric-soluble polymer, the water-insoluble polymer, a hydrophobic compound, the hydrophilic polimernogo compound and a hydrophilic polymer.

9. Combined pharmaceutical drug of claim 8, where the substance is a controlled release in part controlled release is contained in an amount of 10-500 mass parts relative to 100 mass parts of the dihydropyridines, a calcium channel blocker.

10. Combined pharmaceutical drug of claim 8, where the enteric-soluble polymer selected from the group consisting of polyvinyl acetate phthalate, methacrylic acid copolymer, phthalate of hydroxypropylmethylcellulose, shellac, acetate-phthalate cellulose propionate-cellulose phthalate, Eudragit L, Eudragit S, and mixtures thereof.

11. Combined pharmaceutical drug of claim 8, where the water-insoluble polymer is a polyvinyl acetate, a copolymer of methacrylic acid selected from the group consisting of a copolymer of poly(acrylate-co-methyl methacrylate) or a copolymer of poly(acrylate-methyl methacrylate-trimethylenetrinitramine), ethylcellulose, cellulose acetate, and a mixture thereof.

12. Combined pharmaceutical drug of claim 8, where the hydrophobic compound selected from the group Castiadas fatty acids and complex fatty acid ester, fatty alcohol, wax, inorganic substances and their mixtures.

13. Combined pharmaceutical drug indicated in paragraph 12, where fatty acid and esters of fatty acids selected from the group consisting of glycerylmonostearate, glycerylmonostearate, glyceraldehyde, cetylpalmitate, glycerylmonostearate, stearic acid and mixtures thereof; fatty alcohol selected from the group consisting of cetosteatil alcohol, cetyl alcohol, stearyl alcohol and mixtures thereof; a wax selected from the group consisting of Carnauba wax, beeswax, microcrystalline wax and mixtures thereof; inorganic substance selected from the group consisting of talc, precipitated calcium carbonate, dibasic calcium phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, Vigoda and mixtures thereof.

14. Combined pharmaceutical drug of claim 8, where each of the hydrophilic polimernogo compound and a hydrophilic polymer selected from the group consisting of a saccharide-derived cellulose, gums, protein, derived polyvinyl, a copolymer of polymethacrylate derived polyethylene, polymer carboxyvinyl and their mixture.

15. Combined pharmaceutical drug for 14, where the saccharide is selected from the group consisting of dextrin, Polydextrose, dextran, pectin spools and the aqueous pectin, alginate, poly(galacturonic acid), xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylmethyl, amylose, amylopectin, and mixtures thereof;
derivative of cellulose selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethylcellulose sodium, acetate-succinate of hydroxypropylmethylcellulose, hydroxyethylmethylcellulose and their mixtures/gum selected from the group consisting of the guar gum, gum carob, tragakant, carrageenan, Arabian gum, gum Arabic, Gellan gum, xanthan gum and mixtures thereof;
protein is selected from the group consisting of gelatin, casein, Zein and mixtures thereof;
a derivative of polyvinyl selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, poly(vinylchloridevinylacetate) and their blend/copolymer of polymethacrylate selected from the group consisting of a copolymer of poly(butylmethacrylate-(2-dimethylaminoethyl)methacrylate-methyl methacrylate), a copolymer of poly(methacrylic acid-methyl methacrylate), a copolymer of poly(methacrylic acid-ethyl acrylate) and mixtures thereof; and
derived polyethylene selected from the group consisting of polyethylene glycol, polyethylene oxide and mixtures thereof; the polymer carboxyvinyl is a carbomer.

Non pharmaceutical drug according to claim 1, where a statin, lipid-lowering agent, selected from the group consisting of simvastatin, lovastatin, atorvastatin, pitavastatin, rosuvastatin, fluvastatin, pravastatin, and mixtures thereof.

17. Combined pharmaceutical drug according to item 16, where the statin, lipid-lowering agent, selected from the group consisting of simvastatin, lovastatin, atorvastatin, and mixtures thereof.

18. Combined pharmaceutical drug according to claim 1, where the statin, lipid-lowering agent, is contained in the amount of 5-160 mg

19. Combined pharmaceutical drug according to claim 1, which represents a single tablet with the structure of two-phase matrix, where part of the controlled release provides controlled release of dihydropyridines, calcium channel blocker, and a part of the immediate-release formulation provides an immediate release of the statin, lipid-lowering means.

20. Combined pharmaceutical drug according to claim 1, where the portion of the controlled-release and immediate-release form a multilayer structure.

21. Combined pharmaceutical drug according to claim 1, which comprises a tablet with dual-layer structure containing an inner layer part with the controls which has been created by the release and the outer layer with the immediate-release, which surrounds the inner layer.

22. Combined pharmaceutical drug according to claim 1, which is a capsule containing pellets are part of controlled release and the pellet side immediate-release.

23. Combined pharmaceutical drug according to claim 1, which represents the uncoated tablet or tablet is coated.

24. Combined pharmaceutical drug according to item 23, where the tablet with the coating includes a coating layer of a film-forming agent, adjuvant film-forming agent, or a mixture thereof.

25. Combined pharmaceutical drug according to paragraph 24, where the coating layer contains at least one substance selected from the group consisting of a derivative of cellulose, a derivative of a saccharide derivative of polyvinyl, wax, fat, gelatin, polyethylene glycol, ethyl cellulose, titanium oxide, diethylphthalate and mixtures thereof.

26. Combined pharmaceutical drug according to paragraph 24, where the coating layer is contained in the amount of 0.5-15 wt.% from the total mass of the coated tablets.

27. Combined pharmaceutical drug according to claims 1 to 26, where the statin, lipid-lowering agent, is released first, and dihydropyridines, calcium channel blocker, is gradually released after 2 h after introduction the Oia, thereby reducing the interaction between statin, lipid-lowering means, and dihydropyridines, a calcium channel blocker.



 

Same patents:

Gsk-3 inhibitors // 2449998

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns applying urea derivatives or their pharmaceutically acceptable salts characterised by formula , wherein RB is specified in: while R3, R4, R'2, R'3, R'4, R'5, and R'6 represent hydrogen as GSK-3 inhibitors, pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

EFFECT: preparing the pharmaceutical compositions containing them, and using them for treating and/or preventing disorders the development of which involves GSK-3.

14 cl, 2 ex, 1 tbl, 4 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) which is selected from gentisate, maleate, citrate, fumarate and semitartrate salts, which possess improved properties in their application, in particular higher stability.

EFFECT: invention also relates to method of obtaining acid-additive salts of pyrrolopyrimidinone derivative, represented by formula (1) and to pharmaceutical composition, containing them, for treatment and prevention of erectile dysfunction, pulmonary arterial hypertension, chronic obstructive lung disease, benign prostate gland hypertrophy and diseases of lower urinary tract.

11 cl, 30 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a pharmaceutical composition for treating and/or preventing arterial hypertension containing an angiotensin converting enzyme (ACE) inhibitor and N-acetyl-5-methoxytriptamine (melatonin) in the following proportions: ACE inhibitor - 2-4; N-acetyl-5-methoxytriptamine (melatonin) - 2-8; excipients - up to 100 mg with the ACE inhibitor being presented by the compounds specified in a group of enalapril, captopril, perindopril, lisinopril, fozinopril, quinapril, spirapril. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a softgel capsule, a solid gel capsule, by a soft dosage form - a rectal suppositorium.

EFFECT: providing a therapeutically significant effect (stable night-time blood pressure profile) and a lower risk of side effects due to using the doses low for the ACE inhibitors specified above have been shown.

3 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, where Ar denotes a phenyl group substituted with piperazine or benzo[d]thiazole, with a phenyl part bonded to B, where the piperazine or benzo[d]thiazole can be unsubstituted or substituted with substitutes selected from alkyl or acetyl; B denotes -O-; R1 denotes hydrogen; R2 denotes S(O)2R4 or C(O)(CH2)n-C(O)OR5; R3 denotes halogen; R4 denotes an aryl which can be unsubstituted or substituted with substitutes selected from a group comprising halogen, alkyl, fluoroalkyl, alkoxy and trifluoromethoxy; R5 denotes hydrogen; n is a whole number from 1 to 3. The invention also relates to a method of producing said compounds and a pharmaceutical composition for treating metabolic disorders associated with insulin resistance or hyperglycaemia, based on said compounds.

EFFECT: novel compounds are obtained, which can be used in medicine to treat type 2 diabetes, obesity, glucose intolerance, dyslipidaemia, hyperinsulinaemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension or non-alcoholic fatty liver disease.

28 cl, 3 dwg, 4 tbl, 22 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to - physiotherapy, balneology. A method involves basic drug-induced therapy, transcranial electrical stimulation and balneotherapy. The transcranial electrical stimulation is performed within the period from 11.00 to 15.00. The exposure is enabled by a frontooccipital technique with using pulse bipolar current with gradually increased current intensity from 0.8 to 1.2 mA to make evident painless vibration observed under electrode. Duration of a procedure is 30-40 minutes. The procedures are daily; the therapeutic course is 10-12 procedures. Within the period from 14.00 to 18.00, balneotherapy is prescribed with iodine-bromine baths at the concentration of sodium chloride 10 g/l, potassium bromide 25 g/l, potassium iodide 25 g/l. The procedures are daily; the therapeutic course is 9-10 procedures.

EFFECT: method provides higher therapeutic effectiveness ensured by improved psychological status, central and intracardial hemodynamic parameters, values of lipid exchange and antioxidant protection, intensified hypotension effect and improved microcirculation in reducing drug-induced load on patient's body.

2 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to combined drugs, and can be used for treating arterial hypertension. The drug is prepared by direct compression. A preparation with low residual humidity is more storage stable, shows high processibility and biological availability. The combined hypotensive drug contains a combination of enalapril maleate and hydrochlorthiazide as an agent, and lactose anhydride, microcrystalline cellulose, povidone, colloidal silicon dioxide, croscarmellose sodium and stearic acid salt as excipients. The optimum proportions of the components makes, wt %: The agent 11.0-18.0; Lactose anhydride 56.0-78.0; Microcrystalline cellulose 5.0-15.0; Povidone 2.0-4.0; Colloidal silicon dioxide 0.5-1.0; Magnesium stearate 0.5-1.0; Croscarmellose sodium 3.0-5.0.

EFFECT: making the drug preparation for treating arterial hypertension.

12 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is referred to the area of medicine, namely to hematology and cardiology and can be used for optimization of spontaneous RBC aggregation in patients with arterial hypertension and disrupted glucose tolerance. To do that the dosed static and dynamic physical exercises are given including the combination of morning hygiene gymnastics, therapeutic gymnastics and single physical exercises during the day. Additionally the fozinopril is given in the dose 10 mg once a day at 6 AM. The treatment shall be performed for 6 months.

EFFECT: increased effectiveness of correction of spontaneous RBC aggregation putting it on the level close to that of healthy people due to selected components of complex treatment and developed treatment regime.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to arylamines of formula (I) and their pharmaceutically acceptable salts which are active in relation to 5HT receptors, particularly show 5-HT6 modulating activity, and can be used for treating a number of diseases, such as obesity, or the other diseases, for treating 5-HT-associated condition selected from a group containing Alzheimer's disease, Hundington's disease, obesity, obesity-related disorder, insulin-independent diabetes, Alzheimer's disease related cognitive disorders, schizophrenia related cognitive disorders, reflux gastroesophagitis, non-ulcer dyspepsia, depression, anxiety, migraine, gastritis, gastric emptying disorder, eating disorders, gastrointestinal disorders, constipations, panic attacks, memory impairment, disturbed sleep, alcohol-use disorders, anorexia, bulimia, obsessive-compulsive disorders, psychosis, Parkinson's disease, Hundington's chorea, and/or schizophrenia, drug abuse and attention deficit/hyperactivity disorder (ADHD). In the compound of formula (I) n means 1; A means C1-C3alkylene; R1 means hydrogen or C1-C10alkyl; R2 means C1-C10alkoxy, C(O)CF3 or SO2R6, where R6 can be C1-C4 alkyl R3 and R4 independently means hydrogen, substituted or unsubstituted C1-C7alkyl, where a substituted is selected from dihydrobenzodioxidine or benzodioxole, probably substituted by halogen; phenyl, probably substituted by C1-C4alkyl, C1-C4alkoxy, halogen, trifluoromethyl; aryl selected form naphthyl or tetrahydronaphthyl, optionally substituted by C1-C4alkyl, C1-C4alkoxy; heteroaryl, 5-members heteroaryl condensed with the benzoic ring with sulphur atom as a heteroatom, chromanyl probably substituted by halogen; B means a bound; and X and Y means -CH-.

EFFECT: preparing pharmaceutically acceptable salts which are active in relation to 5HT receptors.

59 cl, 9 dwg, 1 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: compounds can be used to treat such diseases as hypertension, congestive heart failure, cardiac hypertrophy and others. In formula I R1 denotes a) cyclohexyl or trifluoromethyl; or b) phenyl, 2-thienyl, 3-thienyl, 2-pyridyl, 2-imidazolyl, 2-thiazolyl, 2-benzothienyl, 4-benzofuryl, 4-benzothienyl, 7-benzofuryl, 2,3-dihydro-7-benzofuryl, 7-benzothienyl, 1,3-benzodioxol-4-yl, 7-indazolyl, or 8-quinolinyl, optionally substituted with 1-3 substitutes, and X and Y each denotes a single bond; R2 denotes methyl, ethyl, propyl, butyl, pentyl, hexyl, 5-pentenyloxy, 3,33-trifluoropropyl, 4,4-difluoropentyl, 3-(cyclopropyl)propyl, 4-(cyclopropyl)butyl, 3-hydroxypropyl, 4-hydroxybutyl, 4-hydroxypentyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 2-hydroxyethoxy etc, given in the claim; R3 denotes H, F, OH, methoxy, ethoxy, 3-hydroxypropoxy, acetylamino, propionylamino, (2-methylpropionyl)amino, or butanoylamino; A denotes 2,4-disubstituted morpholine with R1XCR2R3Y, bonded on the second position and Q bonded on the fourth position, 1,3-disubstituted piperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-dibustituted-3-methylpiperidine with R1XCR2R3Y bonded on the third position and Q bonded on the first position, 1,3-disubstituted benzene or 1,3-disubstituted cyclohexane; Q denotes Q1, Q2, Q4, Q5, Q9, or Q10 given in the claim, to which A and N are bonded on cut-off bonds, R4 denotes H or methyl.

EFFECT: obtaining novel compounds having aspartic protease inhibitor properties, particularly renin inhibitor.

10 cl, 1 tbl, 166 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or formula (I') where values of the substitutes are disclosed in the patent claim. The present compounds are able to inhibit Rho-kinase.

EFFECT: making the compounds effective for treating and/or preventing the Rho-kinase-associated and/or Rho-kinase-mediated diseases by phosphorylation of myosin light chain phosphatise.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, and concerns a composition and a technology of finished dosage forms of phospholipid nanoparticles of the size of 25 nm. The preparation is intended for oral administration for the purpose of therapy of lipid storage disease as a hypocholesterolemic agent. An infusion form is presented to be applied in injections in therapy of toxic and pre-comatose states. The phospholipid therapeutic composition for lipid storage disease and hepatic comatose and pre-comatose state in the form of the phospholipid nanoparticles of the size of 15-25 nm contains phosphatidyl choline, phosphatidyl ethanolamine and maltose. A method for making said phospholipid therapeutic composition consists in the fact that phospholipid, phosphatidyl ethanolamine and maltose are suspended in water, and the prepared suspension is exposed to a number of microfluidisation cycles at pressure 1700-1900+10% bar, temperature 40-55°C to be lyophilised.

EFFECT: preparations represent long stored lyophilised powders.

4 cl, 3 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutical industry, and concerns a method for preparing a dosage form of a hypolipidemic, hypoglycemic agent of thioctic (α-lipoic) acid. A mixture of thioctic acid, microcrystalline cellulose and lactose is wetted with hydroxypropyl methyl cellulose in the mixture of water and ethanol; the wetted mass is mixed, dried, granulated; the granulate is added with magnesium alumomethasilicate, primojel, magnesium and/or calcium stearate, sodium stearylfumarate, aerosil and/or talc; the tablets are pressed and coated with the film Opadry II. As a result, there are produced the coated tablets containing thioctic acid 300 mg and 600 mg as the active substance.

EFFECT: prepared drug preparation provides effective daily dosage - 600 mg/day for 1 - 2 intakes; the preparation is storage stable.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and pharmaceutically acceptable salts thereof, where Ar denotes a phenyl group substituted with piperazine or benzo[d]thiazole, with a phenyl part bonded to B, where the piperazine or benzo[d]thiazole can be unsubstituted or substituted with substitutes selected from alkyl or acetyl; B denotes -O-; R1 denotes hydrogen; R2 denotes S(O)2R4 or C(O)(CH2)n-C(O)OR5; R3 denotes halogen; R4 denotes an aryl which can be unsubstituted or substituted with substitutes selected from a group comprising halogen, alkyl, fluoroalkyl, alkoxy and trifluoromethoxy; R5 denotes hydrogen; n is a whole number from 1 to 3. The invention also relates to a method of producing said compounds and a pharmaceutical composition for treating metabolic disorders associated with insulin resistance or hyperglycaemia, based on said compounds.

EFFECT: novel compounds are obtained, which can be used in medicine to treat type 2 diabetes, obesity, glucose intolerance, dyslipidaemia, hyperinsulinaemia, atherosclerotic disease, polycystic ovary syndrome, coronary artery disease, hypertension or non-alcoholic fatty liver disease.

28 cl, 3 dwg, 4 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely endocrinology, cardiology and can be used for treating dislipidemia. That is ensured by introducing a pharmaceutical composition containing a thiazolidinedione analogue of formula

EFFECT: introducing the compound of formula 1 having decreased binding and activation of PPAR-gamma nuclear transcription factor, enables effective treatment of dislipidemia with no adverse side effects typical for PPAR-gamma agonists.

2 dwg, 5 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a thiazole derivative of formula 1

,

as an activator of peroxisome proliferator activated receptor δ (PPARδ), or to its pharmaceutically acceptable salts.

EFFECT: production of the pharmaceutical composition for preventing and treating arteriosclerosis or hyperlipidemia, for providing higher level of high-density protein (HDP), for preventing and treating diabetes, obesity, for strengthening muscles or endurance, for improving memory or preventing and treating dementia or Alzheimer's disease or Parkinson's disease containing such thiazole derivative.

7 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted methyl-amines of general formula 1, having serotonin 5-HT6 receptor antagonist properties. In formula 1 , W is naphthalene, indolysin or quinoline; R1 is hydrogen, fluorine, chlorine, methyl; R2 is hydrogen, fluorine, methyl, phenyl, thiophen-2-yl, furan-2-yl, pyridyl, piperazin-1-yl or 4-methylpiperazin-1-yl; R3 is methyl; or W is benzene, R3 assumes the value given above; R1 is 3-Cl, R2 is 3-piperazin-1-yl or 3-(4-methylpiperazin-1-yl); or R1 is hydrogen, R2 is phenyl or pyridyl; or R1 is hydrogen, fluorine, chlorine, methyl; R2 is 4-piperazin-1-yl or 4-(4-methylpiperazin-1-yl); or W is oxazole, R3 is optionally substituted methyl; R1 is chlorine or fluorine, R2 is methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is piperazin-1-yl, 4-methylpiperazin-1-yl, or R1 is chlorine, fluorine or methyl; R2 is furan-2-yl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is furan-2-yl, R3 is (tetrahydrofuran-2-yl)methyl, or R1 is hydrogen, fluorine, chlorine, methyl; R2 is thiophen-2-yl, R3 is 2-methoxyethyl, or R1 is chlorine or fluorine, R2 is thiophen-2-yl, R3 is methyl.

EFFECT: compounds can be used to treat central nervous system (CNS) diseases, such as psychiatric disorders, schizophrenia, anxiety disorders, as well as for improving mental capacity, for treating obesity or for studying the molecular mechanism of inhibiting serotonin 5-HT6 receptors.

15 cl, 27 dwg, 2 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: compounds activate glucokinase and can be used to prepare medicine for treating of metabolic disorders, for lowering blood glucose level, for treating hyperglycemia, for treating IGT, for treating Syndrome X, for treating impaired fasting glucose (IFG), for treating type 2 diabetes, for treating type 1 diabetes, for delaying the progression of impaired glucose tolerance (IGT) to type 2 diabetes, for delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, for treating dyslipidemia, for treating hyperlipidemia, for treating hypertension, for lowering food intake, for appetite regulation, for for treating obesity, for regulating feeding behaviour, or for enhancing the secretion of enteroincretins. In compounds of formula , A denotes , R3 is selected from a group consisting of phenoxy and benzyloxy, each possibly substituted with one or more substitutes independently selected from R12; R12 is F, CI, Br, -CF3, -CN methyl, ethyl, isopropyl, tert-butyl, methoxy, methylthio, ethoxy, cyclopropyl-methoxy, -NHC(O)CH3 or -S(O)2-CH3; R30 is methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, benzyloxy or cyclopropyl-methoxy, each possibly substituted with one or more substitutes independently selected from R12; R8 is methylthio, isopropylthio, ethylthio or 2-methylpropylthio, each substituted with one or more substitutes independently selected from R34; R34 is carboxy.

EFFECT: improved properties of the compound.

13 cl, 1 tbl, 242 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical oral compositions having anti-obesity activity and peripheral action include the premix with low adhesion manufactured from pure orlistat as an active ingredient and excipients that give stability to the premix. Pharmaceutical compositions for the invention preferably include microcrystalline cellulose, lactose monohydrate, sodium laurilsulfate, anhydrous colloidal silicon dioxide, carboxymethyl starch and sodium stearilfumarate. The method for production of said compositions is also proposed. Orlistat content in the premix is less than 20% from total mass of composition, preferably from 12% to 17%. Pharmaceutical compositions may be manufactured from the premix both in form of tablets with marks and in form of powder for suspension making. The invention provides the possibility to take different orlistat doses depending on the patient needs.

EFFECT: simple and economic method of orlistat composition manufacturing without losses caused by degradation of active compound - orlistat.

19 cl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to arylamines of formula (I) and their pharmaceutically acceptable salts which are active in relation to 5HT receptors, particularly show 5-HT6 modulating activity, and can be used for treating a number of diseases, such as obesity, or the other diseases, for treating 5-HT-associated condition selected from a group containing Alzheimer's disease, Hundington's disease, obesity, obesity-related disorder, insulin-independent diabetes, Alzheimer's disease related cognitive disorders, schizophrenia related cognitive disorders, reflux gastroesophagitis, non-ulcer dyspepsia, depression, anxiety, migraine, gastritis, gastric emptying disorder, eating disorders, gastrointestinal disorders, constipations, panic attacks, memory impairment, disturbed sleep, alcohol-use disorders, anorexia, bulimia, obsessive-compulsive disorders, psychosis, Parkinson's disease, Hundington's chorea, and/or schizophrenia, drug abuse and attention deficit/hyperactivity disorder (ADHD). In the compound of formula (I) n means 1; A means C1-C3alkylene; R1 means hydrogen or C1-C10alkyl; R2 means C1-C10alkoxy, C(O)CF3 or SO2R6, where R6 can be C1-C4 alkyl R3 and R4 independently means hydrogen, substituted or unsubstituted C1-C7alkyl, where a substituted is selected from dihydrobenzodioxidine or benzodioxole, probably substituted by halogen; phenyl, probably substituted by C1-C4alkyl, C1-C4alkoxy, halogen, trifluoromethyl; aryl selected form naphthyl or tetrahydronaphthyl, optionally substituted by C1-C4alkyl, C1-C4alkoxy; heteroaryl, 5-members heteroaryl condensed with the benzoic ring with sulphur atom as a heteroatom, chromanyl probably substituted by halogen; B means a bound; and X and Y means -CH-.

EFFECT: preparing pharmaceutically acceptable salts which are active in relation to 5HT receptors.

59 cl, 9 dwg, 1 tbl, 57 ex

FIELD: medicine.

SUBSTANCE: there are offered an oral pharmaceutical composition containing a) a testosterone ester and a fatty acid ester of a medium chain size; and b) two or more lipid ingredients, at least first of which contains a hydrophilic surfactant and at least second of which contains a lipophilic surfactant; said lipid ingredients together provide solubilisation of said testosterone ester in amount 10-20 % of weight of a pharmaceutical composition; a method for prevention or release of testosterone deficiency symptoms in mammal subjects and a method for maintenance of prolonged oral testosterone release.

EFFECT: invention provides medium-size testosterone and fatty acid ester delivery of intensified and prolonged adsorption, desired testosterone levels which are detected in people who do not suffer testosterone deficiency.

30 cl, 15 dwg, 4 tbl

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