Combined medication for treatment of arterial hypertension in patients with diabetes mellitus

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry and describes a peroral combined medication for the treatment of arterial hypertension in patients with diabetes mellitus. The medication is made in the form of a tablet. The combined tablet contains perindopril erbumine, amlodipine besylate, sorbitol, microcrystalline cellulose, sodium carboxymethyl starch, povidone, magnesium stearate in quantities, given in the invention formula.

EFFECT: combination of perindopril, amlodipine and sorbitol in the composition of one tablet provides enhancement of the therapeutic effect.

6 tbl

 

The present invention relates to the field of medicine, in particular to the pharmaceutical industry, and describes a method of manufacturing tablets with antihypertensive activity.

Arterial hypertension is the most common chronic disease that affects up to 20-30% of the adult population of the planet. According to the world health organization, this disease affects about 40% of the adult population of Russia, and among the causes of premature mortality of the population hypertension is the first place.

At the same time, according to official statistics, in Russia more than 2 million people suffer from diabetes. According to leading experts, this figure is significantly understated, and actually the number of diabetes patients in Russia is 2-3 times higher than the official statistics and may reach 7 million people.

Diabetes and hypertension - two interrelated pathologies that have a powerful synergistic damaging effect. Arterial hypertension in patients with diabetes mellitus occurs in approximately in 2 times more often than in the General population. The frequency of hypertension among diabetic patients ranges from 20 to 60% depending on the criteria used high blood pressure and type diabetes.

The choice �antigipertenzivny drugs is of particular importance, because diabetes imposes a number of restrictions to the use of a drug. You should consider the range of its side effects, the possible impact on carbohydrate and lipid metabolism, as well as the presence of associated vascular complications in the patient. Therefore, antihypertensive drugs in the treatment of diabetic patients must meet high requirements, namely:

- possess a high antihypertensive activity with minimum side effects;

- not to disturb carbohydrate and lipid metabolism;

- possess cardioprotective and renoprotective effect;

not to degrade for other (non-vascular) complications of diabetes.

The prior art known dosage form for the treatment of hypertension and cardiovascular disease, a composition comprising an inhibitor of angiotensin-converting enzyme and cardioselektivee beta-adrenoblocker, consisting of amlodipine and atenolol (Patent RF №2188636, the patentee f. Dr. Reddy from laboratories LTD.) in proportions: atenolol is 25 to 100 mg, amlodipine besylate - 3-15 mg.

Also known stable pharmaceutical composition having an antihypertensive effect (Patent RF №2341254, the patentee ZAO Medimex"), consisting of a composition comprising b�co-prolol or metoprolol, or atenolol (beta-blocker), indapamide (diuretic), enalapril maleate (angiotensin converting enzyme) and Vinpocetine.

The above-mentioned anti-hypertensive pharmaceutical compositions are not recommended for use by patients with diabetes mellitus. Current guidelines restrict the use of beta-blockers as first-line drugs in hypertensive patients with multiple metabolic risk factors including abdominal obesity, impaired glucose tolerance. Not recommended the use of beta-blockers for patients with insulin dependent diabetes mellitus with frequent Hypo - and hyperglicemia, as well as patients with impaired recognition of hypoglycaemia (due to the development of autonomic neuropathy). Subjective experience of developing hypoglycemia is often associated with activation of adrenergic receptors and the blockade of the latter may lead to the development of coma without subjective precursors (Shestakova M. V. Arterial hypertension and diabetes mellitus: mechanisms of development and treatment / diabetes mellitus. 1999. N3. P. 19-23).

Furthermore, the known pharmaceutical composition (European patent EP No. 2162434, the Russian Federation №2188636, publ. 17.03.2010 g) containing of 3.34 mg of perindopril and 5 mg of amlodipine.

In the compositions specified in the patent of Russian Federation №2188636 and patent� EP 2162434 as excipients present are lactose (anhydrous or monohydrate) in a significant amount by weight of the drug, what is undesirable when choosing medicines diabetics because the said substance has an effect on carbohydrate and lipid metabolism and blood sugar of the patient. In addition, restrictions in the use of lactose can be caused by intolerance to the latter. The frequency of constitutional lactose intolerance in Russia is 16-18% (Belmer S. V., Yu. G. Mukhina, Chubarova, A. I., Geras'kina, V. P., Gasilina T. B. lactose Intolerance in children and adults / Attending Physician, No. 1, 2005).

The technical object of the present invention is to provide a new combined pharmaceutical composition having hypotensive action, allowing its application for the treatment of patients with diabetes mellitus and decrease possible side effects for this group of patients.

About reducing the possible side effects of combination of perindopril and amlodipine according to the research "BREAKTHROUGH". It was found that strengthening actions that reduce blood pressure, when using this combination is accompanied by a decrease in the incidence of adverse reactions, in particular swelling of the legs, which is characteristic for dihydropyridine calcium antagonists. The study indicated a much lower incidence of swelling of the lower extremities in patients receiving fixie�agreed combination perindopril/amlodipine (about 10%) compared with the same indicator in these studies as "VALUE" or "PREVENT" (about 30 and 40%, respectively). Swelling were small and in most cases did not require not only the treatment, but dose adjustment of amlodipine. There is evidence that cough associated with taking an ACE inhibitor, also attenuated by calcium channel blockers, including amlodipine [Uncontrolled arterial hypertension - new opportunities in solving the problems of increasing the effectiveness of treatment / Y. A. Karpov, A. D. Deev; Cardiology. - 2012. - No. 2. - P. 34, para. 1. CARDIOLOGY, 2012, vol 2].

According to research by the United Kingdom Prospective Diabetes Study (6th report) blockers slow calcium channels are named among the drugs of choice for antihypertensive therapy in diabetic patients (UKPDS studies Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS studies 38) // Brit. Med. J. - 1998. - Vol. 317. - P. 703-713). The blocking slow calcium channel blockers (calcium antagonists) have no adverse effect on carbohydrate and lipid metabolism (metabolic neutral). They are widely used for the treatment of hypertension, so they are without fear and with great efficiency can be applied in patients with hypertension with diabetes mellitus. Besides other advantages of blocking slow calcium channels should mention their renal protective action mediated by normalization vnutriklubovskoe hemodynamics. Persons�NGOs effective in the treatment of hypertension in diabetes mellitus seem prolonged form dihydropyridine blocker of slow calcium channels as they do not cause an increase in the level of glucose in the blood in patients with diabetes mellitus and does not adversely effect on the lipid profile of blood plasma, while possessing good anti-hypertensive effect. The most lasting effect of all dihydropyridine blocker of slow calcium channels has amlodipine, its half-life reaches 35-45 h.

In 20-60% of patients with diabetes mellitus monotherapy even the most powerful drugs are not able to stabilize the blood pressure at the required level. In this case, to achieve this goal shows the assignment of the combination of several antihypertensive drugs of different groups. The most effective combinations of drugs for the treatment of hypertension in diabetes mellitus include the combination of angiotensin-converting enzyme and diuretic, angiotensin-converting enzyme and the blocker of slow calcium channels (D. V. Preobrazhensky, A. Sidorenko Arterial hypertension in diabetes mellitus / Russian honey. log. 340-344).

According to the present invention has been developed a solid pharmaceutical composition for oral use, which has the following composition:

- as a matter relating to the blocking slow calcium channel blockers class of dihydropyridines, used amlodipine besylate;

- in Kacha�TVE substances belonging to the angiotensin-converting enzyme perindopril is used albumin;

- as the target additives that represents at least one structure-forming agent, sorbitol is used.

Such a combination of drugs from the prior art could not be detected.

The inventive composition was found experimentally, is optimal and allows to obtain a technical result that is appropriate to the task: pharmaceutical composition in the form of dosage forms of tablets, containing at least two active substances to enhance therapeutic effect, with an expiry date not less than 3 years and suitable for the treatment of hypertension in patients with diabetes mellitus. The combination of angiotensin-converting enzyme (perindopril erbumine) with the blocking slow calcium channel blockers class of dihydropyridines (amlodipine besylate) causes a synergistic antihypertensive effect, and the content as structure-forming agent of sorbitol having a diuretic effect, enhances the hypotensive effect (Gumenyuk N. And., Dzublik J. A., Marine N. Etc., Agnize T. V. Background to the use of hyperosmolar infusion solution of sorbitol in patients with decompensatory chronic pulmonary heart / PU Ukrainian�monologically magazine. 2003. No. 1).

About strengthening therapeutic and synergistic effects of combination of perindopril and amlodipine according to the data of the above-mentioned study "BREAKTHROUGH", in which were noted the results of the secondary analysis study "EUROPA", which showed a synergistic enhancement of the protective effects of perindopril in reducing the risk of developing cardiovascular complications and cardiovascular mortality in patients with stable ischemic heart disease with concomitant use of calcium antagonists [Uncontrolled arterial hypertension - new opportunities in solving the problems of increasing the effectiveness of treatment / Y. A. Karpov, A. D. Deev; Cardiology. - 2012. - No. 2. - P. 34, para. 3. CARDIOLOGY, 2012, vol 2].

Additional agent used as a filler in the invention is sorbitol. Sorbitol is non-toxic and has a sweet taste masking, at the same time without causing rapid changes in blood sugar, and does not induce additional production of insulin by the pancreas. Being calorie-gene sweetener, sorbitol absorbed from the gastrointestinal tract, with virtually no impact on the content of glucose in the blood, which allows you to use the drug for the treatment of diabetic patients with combined pathology of the hepatobiliary system. Sorbitol has choleretic, des�ntoxication, laxative action (Register of medicines of Russia radar. Encyclopedia of medicines. - In the 14th vol. / edited by G. L. wyskowski. - M.: radar. - 2006, 2005). Additionally, this combination of sorbitol has a diuretic effect. Diuresis, as is well known to specialists in cardiology, is indicated for the treatment of arterial hypertension.

Most preferred is the following content of components in wt%:

Componentswt.%
Perindopril erbumine4,0
Amlodipine besylate3,47
(in terms of amlodipine base)2,5
Sorbitol75,03
Microcrystalline cellulose10,0
Carboxymethylcel sodium4,0
Povidone2,5
Magnesium stearate1,0
Total100,0

A specific variant of the formulation of the claimed composition is�I the following composition:

Componentsmg
Perindopril erbumine8,00
Amlodipine besylate6,94
(in terms of amlodipine base)5,0
Sorbitol150,06
Microcrystalline cellulose20,00
Carboxymethylcel sodium8,00
Povidone5,00
Magnesium stearate2,00
Total200,0

Additional diuretic effect in this combination, due to the inclusion of sorbitol as a filler, is confirmed by experimental data, is shown below.

Chronic experiments were conducted on 40 albino rats of both sexes, weighing 180-220 g, which method of drawing were divided into 4 groups each containing 10 animals:

Group 1 - control, treated once intraperitoneally with the help of specialists�professional device 3% water load relative to body weight of the animal;

Group 2 - experienced treated intragastrically once sorbitol in a dose of 21 mg/kg on the background of a 3% water load. The dose was taken as analogous to the content of sorbitol in the claimed drug products (hereinafter "Invention") sorbitol, namely 150 mg 1 tablet per 70 kg of body weight (the average weight of a person), therefore, 2.1 mg/kg; This dose was increased 10-fold due to the fact that rodents have a reduced sensitivity to the majority of pharmacological agents in comparison with people. Thus was obtained a dose of 21 mg/kg;

Group 3 - experienced treated intragastrically once claimed medicinal Invention of complex composition on the basis of sorbitol in a dose of 29 mg/kg on the background of a 3% water load. The dose calculation was made as follows. Took 1 tablet of 200 mg (perindopril 8 mg, amlodipine 7 mg, sorbitol 150 mg and excipients) for 70 kg of body weight (the average weight of a person), therefore, the 2.9 mg/kg. the dose was multiplied by 10, since rodents have a reduced sensitivity to the range of medicines in comparison with people. Thus was obtained a dose of 29 mg/kg And the dose of sorbitol in the composition of medicines amounted to 21 mg/kg;

Group 4 - experimental, treated intragastrically once a drug "Invention" on the lactose in a dose of 29 mg/kg on the background of a 3% aqueous n�of the burden. The dose calculation was made as follows. Took 1 tablet of 200 mg (perindopril 8 mg, amlodipine 7 mg lactose 150 mg and excipients) for 70 kg of body weight (the average weight of a person), therefore, the 2.9 mg/kg. the dose was multiplied by 10, since rodents have a reduced sensitivity to the range of medicines in comparison with people. Thus was obtained a dose of 29 mg/kg And the dose of lactose in the composition of medicines amounted to 21 mg/kg.

Before the introduction of the drugs were prepared working solutions in distilled water. So hitch weight of sorbitol 63 mg (equivalent to 3 kg of live animal weight) evenly stir in 90 ml of distilled water (corresponding to 3% of the water load 3 kg of animal weight). Tablet claimed a combined medicinal product "Invention" on the sorbitol weight of 200 mg (equivalent to 7 kg of live animal weight) were milled and evenly stir in 210 ml of distilled water (corresponding to 3% of the water load 7 kg of animal weight). Tablet claimed a combined medicinal product "Invention" on the lactose weight of 200 mg (equivalent to 7 kg of live animal weight) were milled and evenly stir in 210 ml of distilled water (corresponding to 3% of the water load 7 kg of animal weight). Working solutions �were carried out to the relevant groups of animals in the amount of 3% of body mass of animals, for example, 6 ml per 200 g of animal weight, 6,3 ml - 210 g, 6,6 ml - 220.

After the introduction of drugs and water load the animals were placed in metabolic cages for 4 h, after which it was determined diuresis, natriuresis and calibres (by flame photometry on a fiery fluid analyzer ASTL-1) and creatinine (colorimetric method on photocolorimeter CPK-3).

Experiments on animals were conducted in accordance with the requirements of the European Convention for the protection of vertebrate animals.

Statistical processing of the obtained experimental results was performed using Microsoft Excel 2010 and Statistica 8.0 by Mann-Whitney test.

In the experiment, it was found that sorbitol after a single intragastric dose of 21 mg/kg of animal weight on the background of a 3% water load effect on water-salt metabolism, increasing the allocation of water by the kidneys of experimental animals (2nd group) compared to the control with 2,84±0.10 ml/4 h before 3,70±0.16 ml/4 h (30%, p<0.01), sodium 297,80±14,76 µmol/4 h before 407,99±43,17 µmol/4 h (37%, p<0,05), potassium 94,60±4,14 µmol/4 h before 131,10±5,28 µmol/4 h (39%, p<0.01), creatinine 0.65±0.10 mg/4 h to 1.11±0.15 mg/4 h (71%, p<0.05) and 4 hours of the experiment (table 1). Which indirectly indicates that the urine output has increased due to the increase of glomerular filtration (authentic increase creatine�of nurese), and by reducing tubular reabsorption (significant increase in natriuresis). Consequently, sorbitol in the chosen dose of a diuretic effect.

After a single intragastric introduction of the claimed medicinal Invention on the manufacturer of sorbitol in a dose of 29 mg/kg (dose of sorbitol in the composition of this drug was 21 mg/kg) there was an increase of diuresis in the experimental animals (group 3) compared to the control with 2,84±0.10 ml/4 h to 3.41±0,13 ml/4 hours (20%, p<0.01), natriuresis with 297,80±14,76 µmol/4 h before 399,15±39,56 µmol/4 h (30%, p<0,05), creatures thus decreased from 0.65±0.10 mg/4 h to 0.28±0.07 mg/4 h (57%, p<0.05) and 4 hours of the experiment (tab. 1). These data indicate that the urine output has increased solely due to the reduction of tubular reabsorption (significant increase in natriuresis). Glomerular filtration rate was decreased (significant decrease of creatininase) - this can be explained by the fact that the claimed medicinal Invention of the sorbitol is mixed and contains not only a diuretic component sorbitol, and 2 hypotensive component, perindopril and amlodipine. And antihypertensives naturally lower glomerular filtration by reducing systemic and local blood pressure. Consequently, the claimed combined medication�Noah means "Invention" on the sorbitol has a diuretic effect.

At the same time, a single intragastric administration of the combined drug "Invention" on the lactose in a dose of 29 mg/kg (dose of lactose in the composition of this drug was 21 mg/kg) significant changes in renal excretion of water in the experimental animals (group 4) relative to the control did not cause, however, contributed to a significant decrease in natriuresis with 297,80±14,76 µmol/4 h before 82,05±of 9.89 µmol/4 h (72%, p<0.01), kaliuresis with 94,60±4,14 µmol/4 h before 50,74±5,31 µmol/4 h (47%, p<0.01), creatinuria from 0.65±0.10 mg/4 h to 0.32±0.07 mg/4 h (51%, p<0.05) and 4 hours of the experiment (Tab. 1). Therefore, this drug possesses diuretic activity.

It was interesting also to compare the effect on the excretory function of the kidneys of rats of two combined drugs: the claimed medicinal Invention of the sorbitol and drug "Invention" on the lactose. During the research it was found that "Invention" on the sorbitol in comparison with the "Invention" on the lactose significantly increases following indicators of renal excretory function: diuresis - 32%, natriuresis - 386%, kaliuresis 113% within 4 hours of the experiment (table 2).

The protocols of the chronic experiment are presented in tables 3-6. Thus, in the experiment it was found that W�approving drug "Invention" on the sorbitol in diuretic and salureticheskim activity close sorbitol in a similar dose and superior to drug Invention to lactose.

The claimed combined medicament for the treatment of hypertension in patients with diabetes mellitus may be manufactured as follows.

Weighted sorbitol, perindopril erbumine, amlodipine besylate, microcrystalline cellulose, part of carboxymethylcel sodium are mixed in a centrifugal impeller mixer. The resulting mixture was granulated in a fluidized bed dryer - granulator with an aqueous solution of povidone, then dried to the required residual moisture and calibrated. Calibrated granules are dusted with magnesium stearate and the remaining part of carboxymethylcel sodium. Powdered mixture is tableted on a rotary press.

The content of active substances in the tablet is 7.5%. The fillers are selected most frequently used in the manufacture of solid dosage forms microcrystalline cellulose, and, for the purpose of achieving a technical result of the invention, the filler used sorbitol, the combination of which gives a sturdy tablet with a small disintegration time. To improve bioavailability of active substances introduced disintegrant - carboxymethyl - starch sodium. For uniform distribution of relatively small quantities of substances across the volume of the mixture is blending, and n�seivane components in dry form. Then, to improve the flowability of the tablet weights and pressuremost, prevent stratification of multicomponent mixtures in tabletting, achieve the desired anti-friction properties, on the basis of the study was chosen as optimum for the preparation method of industrial production of the mixture is wet granulation with an aqueous solution of povidone in the dryer-granulator, followed by sizing, drying and dusting.

Studies have shown that the receipt of the product by the method of direct compression is not possible to obtain a stable result on the basic parameters of tablets: uniformity of dosage and strength. Tableting is conducted on a widely used in the pharmaceutical industry rotary tabletting machines in which the pressure gradually increases, which ensures smooth and uniform pressing of tablets.

Combined drug for the treatment of hypertension in patients with diabetes mellitus, comprising an effective amount of perindopril or its pharmaceutically acceptable salt of amlodipine or its pharmaceutically p�yimlamai salt, sorbitol, microcrystalline cellulose, carboxymethylcel sodium, povidone, magnesium stearate content of components in wt.% and number, mg:



 

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11 cl, 20 tbl, 3 ex, 13 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to microencapsulation, in particular, to microencapsulation of flavours. Carrageenan was used for the capsules, wherein an aromatic product portion was dissolved in dimethylsulfoxide, and the mixture was dispersed in a solution of carrageenan in ethanol in the presence of the preparation E472c, under stirring at the rate of 1300 rev/s, the aromatic product/carrageenan weight ratio was 1:3 respectively, after which mixture of butanol and distilled water taken in volume ratio 3:1 respectively was added, the resulted microcapsule suspension was filtered and dried, the process of production of "cherry" or "tomato" flavour microcapsules was carried out at 25°C.

EFFECT: simplified and fast process of aromatic product microencapsulation, with the reduced amount of waste.

3 ex, 7 dwg

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