Solid dosage form containing ramipril as angiotenzinkonvertiruyuschego enzyme inhibitor, and the connection of dihydropyridines

 

(57) Abstract:

Solid dosage form for oral administration contains 1 to 10 mg ramipril or its pharmaceutically acceptable salt and 1 to 70 mg of the compound of dihydropyridines. As compounds of dihydropyridines use felodipine, nitrendipin, nifedipine or lacidipine and their pharmaceutically acceptable salts. Release ramipril is instantaneous, and the release of the connection of dihydropyridines happens over a long period of time, which shall be at least 6 hours Dosage form may be in the form of pills combined pills or capsules. In the treatment of hypertension the patient takes a solid dosage form once a day in an effective amount. The combined action of the composition is continued for 24 h after one reception per day, which simplifies the design of drug treatment and facilitates the adherence of patients to treatment. The combined composition has an effective therapeutic effect when taken in low doses to reduce side effects of high doses. 5 C. and 18 h.p. f-crystals, 3 ill. 12 table.

The technical field to which the invention relates

The subject of this from the aqueous reception and the way this drug for the treatment of hypertension, diseases of the cardiovascular system and the resulting complications in mammals, including humans. This invention relates also to pharmaceutical compositions and methods for their preparation. This pharmaceutical product is a uniform dosage form, comprising instantly released ramipril as angiotenzinkonvertiruyuschego enzyme inhibitor prolonged action and a calcium antagonist of the dihydropyridine type, i.e. the inhibitor calcium channel (connection of dihydropyridines) with a long release.

The present invention relates also to hard drugs, which are permanent structures, including instantly released ramipril as angiotenzinkonvertiruyuschego enzyme inhibitor prolonged action and connection of dihydropyridines with a long release, such as felodipine, providing a selective effect on the vascular system, which lasts for 24 hours after one reception per day. The pharmaceutical preparations of the present invention have good terapeutiche pharmaceutical drugs can reduce side effects, associated with increasing doses, which arise when the individual taking higher doses of each of these drugs. The pharmaceutical preparations according to this invention simplify the scheme of medical treatment and facilitate compliance with the sick mode and regimens.

Prior art

The angiotenzinkonvertiruyuschego enzyme inhibitors are compounds that inhibit the conversion of angiotensin I to the active angiotensin II, as well as the breakdown of bradykinin, an active substance that causes blood vessels to dilate. Both of these mechanisms lead to vasodilation. Such compounds are described, for example, in European patents 158927 and 317878, U.S. patents 4743450 and 4857520. Ramipril (described in European patent 079022) is an inhibitor angiotensinconverting enzyme prolonged action. Its active metabolite is ramiprilat free acid, which is formed in vivo in the case of receiving ramipril. It is known that taking ramipril patients suffering from hypertension, reduces peripheral vascular resistance and hence reducing blood pressure without increasing heart rate. This substance is used to treat hype the TB among patients with clinical signs of congestive heart failure, after acute myocardial infarction. It is believed that ramipril has the additional advantage in comparison with many other angiotenzinkonvertiruyuschego enzyme inhibitors due to the pronounced inhibition angiotenzinkonvertiruyuschego enzyme in the tissues, resulting in protection of such organs as the heart, lungs, kidneys.

Ramipril sensitive to high temperatures, moisture and pressure, and therefore, when creating pharmaceutical products requires special attention to maintain its stability (U.S. patent 5151433).

Calcium antagonists are compounds that affect the inflow of calcium ions into cells, in particular smooth muscle cells. Such compounds dihydropyridine type are described, for example, in the United Kingdom patent 1358951 (nitrendipin), U.S. patent 3644627 (nifedipine), European patent 007293 (felodipine) and in the United Kingdom patent 2164336 (lacidipine).

The most frequent side effects observed during treatment with angiotenzinkonvertiruyuschego enzyme inhibitors and calcium antagonists according to this invention, are headache, cough, peripheral edema, hot flushes, dizziness, fatigue and the m light and therefore, when creating pharmaceutical products requires special attention to maintain their stability.

The use of compositions comprising angiotenzinkonvertiruyuschego enzyme inhibitors and calcium channel blockers dihydropyridine type, for the treatment of hypertension is described, for example, in European patents 488059, 180785 and 265685.

Bainbridge, A. D. and others (Br.j. lin. Pharmac. 1993, 36: 323-330) studied the possibility of using ramipril, which is an inhibitor angiotenzinkonvertiruyuschego enzyme, and felodipina with a long release, which is the inhibitor calcium channel, in the form of a free combination of individual dosage forms.

In U.S. patent 4703038 describes solid compositions for oral administration, including certain angiotenzinkonvertiruyuschego enzyme inhibitors and certain compounds of dihydropyridines, including nitrendipin and felodipine. This patent is also considered a method of treating hypertension in humans using such drugs. However, in U.S. patent 4703038 not specified ramipril as angiotenzinkonvertiruyuschego enzyme inhibitor. It also does not mention the use of dihydropyridines with a long release.

enta except ramipril and certain calcium antagonists except felodipina, for the prevention and/or treatment of proteinuria.

Description of the invention

The term "instant release" used in this patent application, means the release of the active drug component, according to the criteria of the U.S. Pharmacopoeia XXII in "<711> Dissolve, when Q=75%, the time is 60 minutes, and the solvent environment is the environment described in the following examples 5-8.

The term "extended release", as used in this patent application, means the dissolution of the active drug component from the dosage form over an extended period of time, i.e. for more than 6 hours, in accordance with the test method described in the below examples 5-8.

The term "uniform dosage form" as used in this patent application refers to a physical structure containing more than one active drug component and having a heterogeneous structure.

Quantitative values pharmaceutically acceptable salts of the active drug mentioned in this patent application, refer to the contents of the corresponding free base or acid.

This izopet the emer, tablets or capsules, which includes instantly released ramipril, which is an inhibitor angiotenzinkonvertiruyuschego enzyme prolonged action, or its pharmaceutically acceptable salt and dihydropyridines with a long release, selected from the group including felodipine, nitrendipin, nifedipine, lacidipine or their pharmaceutically acceptable salt. Specified solid, uniform dosage form provides effective and does not cause side effects after single receiving daily doses. The most preferred dihydropyridines is felodipine or its pharmaceutically acceptable salt. The composition comprising instantly released ramipril as angiotenzinkonvertiruyuschego enzyme inhibitor prolonged action and dihydropyridines with a long release, ensures optimal use of both drugs and minimizes side effects, allowing it to effectively reduce high blood pressure.

Molecule ramipril has five chiral centers and thus can accept 32 different enantiomeric forms. The preferred enantiomer called (2S, 3AS,6aS))-1[N-[1(S)-1-(ateno as ramipril.

Pharmaceutically acceptable salts of ramipril are, in particular, salts formed with pharmaceutically suitable amines and inorganic or organic acids, such as Hcl, NVG, N2SO4, maleic acid, fumaric acid, tartaric acid and citric acid.

Felodipine has one chiral center and, thus, can take two different enantiomeric forms. The vasodilator action of S-shape is stronger than a similar action of the R-form. However, you can use as S-form and the racemic mixture of S-form and R-form.

Pharmaceutically acceptable salts felodipina can be obtained from inorganic and organic acids such as acetic, benzolsulfonat, benzoic, camphorsulfonic, lemon, Tinsulanonda, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, satorova, lactic, maleic, malic, almond, methansulfonate, mucus, nitrogen, Mamonova, Pantothenic, phosphoric, succinic, sulfuric, tartaric and paratoluenesulfonyl.

Composition with prolonged release can be created on the basis of the structural frame hydrophilic gel, which is made active substance and which is division.

In order to prevent decomposition of ramipril under the influence of moisture during storage or extrusion during manufacture of medicinal products to the substance in the process of its incorporation into the compression portion of the dosage form is applied powder coating in accordance with the requirements of the present invention. Dihydropyridines are sensitive to light and therefore is protected by the surface layer.

The content of ramipril in combined uniform dosage form is 1-10 mg Content felodipina in this form is 1-10 mg of nitrendipine 2-40 mg, nifedipine - 5-70 mg and lacidipine - 1-8 mg.

The content of ramipril in combined uniform dosage form is preferably 1-5 mg, felodipina - 1-5 mg of nitrendipine - 5-20 mg, nifedipine - 10-60 mg and lacidipine - 2-6 mg

The preferred embodiment of the present invention is a solid uniform dosage form for oral administration, which is a composition containing 1-5 mg instantly released ramipril or its pharmaceutically acceptable salt as an inhibitor angiotenzinkonvertiruyuschego enzyme prolonged action and 5 mg Fe, selectively acting on the vascular system. Particularly preferred dosage form of the present invention contains 1-3 mg ramipril and 1-3 mg felodipina. The preferred ratio ramipril and felodipina in a preferred dosage form of the present invention is 1:1.

The pharmaceutical preparations of the present invention are intended for one use per day, subject to different mechanisms to reduce blood pressure, typical instantly released ramipril, which is an inhibitor angiotenzinkonvertiruyuschego enzyme, and the connection of dihydropyridines with a long release, selected from the group including felodipine, nitrendipin, nifedipine, lacidipine. The bioavailability of ramipril, which is included in the pharmaceutical preparation according natashia invention, variable depending on the concentration ramiprilata in plasma, the equivalent index of the same component, administered separately, see example 1. Bioavailability of dihydropyridines included in this pharmaceutical drug, also equivalent to the rate measured in the same way, see example 2. Tested zostanie of dihydropyridines, included in the pharmaceutical preparations of the present invention, taken once a day, lowers blood pressure, but does not increase the heart rate. This product provides effective in the treatment of systolic and diastolic hypertension. It is particularly effective in the treatment of systolic hypertension. Therefore, the reception of these drugs has a positive effect on States that are directly associated with high blood pressure (hypertension) in mammals, including humans. Examples 3 and 4 illustrate the effectiveness of the pharmaceutical preparations of the present invention in the results of comparative tests using separately ramipril or felodipina unified and solid dosage forms, comprising ramipril and felodipine. The data shown in these examples, indicate a significant reduction in systolic and diastolic blood pressure in the case of a drug with a low content of both components (2.5 mg ramipril + 2.5 mg felodipina) compared with separate application of each of these components and a combination drug containing higher doses of these components (5 mg + 5 mg). The most common pain, fatigue, nausea, and cough) are negligible and comparable to similar indicators specific to placebo. Side effects due to the introduction of calcium antagonists on the basis of dihydropyridines (increase heart rate, tides of blood, peripheral edema, headache, and dizziness), also were low and comparable to placebo.

Moreover, as follows from the examples 3 and 4, the most unpleasant side effects that occur when taking angiotenzinkonvertiruyuschego enzyme inhibitors, in particular cough, and calcium antagonists on the basis of dihydropyridines, namely, peripheral edema and tides of blood, less pronounced with the introduction of the composition with a low content of components compared to individual therapy each of these substances (F5 and R5).

The release of the respective components during the tests carried out in laboratory conditions shown in examples 5 to 8.

This pharmaceutical product is prepared in the form of a combined solid uniform dosage forms for oral administration, which in combination with one receiving a daily dose simplifies scheme of medical treatment and facilitates compliance with bloesem invention may be a capsule or coated tablets.

Ramipril concluded in capsules, can be used in the form of powder or granules, optionally associated with a carrier, and tablets. Dihydropyridines with a long release concluded in such capsules, used in the form of granules or tablets. Capsule, which ramipril associated with the media, and the dihydropyridines enclosed in the Central part of the tablet, represents a structural frame hydrophilic gel, and its preparation are discussed in example 9.

Examples of the manufacture of tablets, which is a normalized dosage form, containing ramipril and dihydropyridines with a long release, shown in Fig. 1, 2 and 3.

In Fig. 1 shows a tablet, in which the structural frame of dihydropyridines with a long release (D) is enclosed in a surrounding layer containing ramipril (R) with instant release. Such a tablet may be made using the appropriate teletrauma machine. Alternatively, the structural frame containing dihydropyridines can be compressed into tablets in teletrauma car, and then apply to them the coating containing ramipril. Tablet of this type is discussed in example 10.

In Fig. 2 the image is extended release (D). Ramipril with instant-release is in the lower part, which is enclosed in a large, separate part containing felodipine with prolonged release. Instant release ramipril is because he is not completely enclosed in a structural frame. Such a tablet can be made in the appropriate teletrauma machine.

In Fig. 3 depicts a tablet in which one layer consists of instantly released ramipril (R) and is connected with another layer containing dihydropyridines with a long release (D), with the formation of a multilayer tablet. Both layers of the tablet can be connected directly with each other or with one or more intermediate layers (L).

Example 1 (table 1)

The pharmacokinetics of ramipril in 18 healthy volunteers on a 7-day treatment drug of the present invention, taken once a day, which is described in example 12, and arbitrary treatment by tablets ramipril (B), in which the contents of the specified component was the same and was 5 mgmax- the maximum concentration in plasma, tmaxthe time to reach the maximum concentration after administration of the drug radio plasma, SD - standard deviation. Values of p greater than 0.05 to indicate a lack of statistical significance in the correlation or significant differences

Example 2 (table 2)

Pharmacokinetics felodipina in 18 healthy volunteers on a 7-day treatment drug of the present invention, taken once a day, which is described in example 12, and arbitrary treatment by tablets felodipina (B), in which the contents of the specified component was the same and was 5 mgmax- the maximum concentration in plasma, tmaxthe time to reach the maximum concentration after administration of the medicinal productmin- the lowest concentration in the plasma during this period, AUC - area under the curve of plasma concentration, SD - standard deviation. Values of p greater than 0.05 to indicate a lack of statistical significance in the correlation or significant differences.

Example 3

Antihypertensive efficacy and tolerance of a combination of uniform dosage form containing felodipine with long release and ramipril in quantities of 5+5 mg and 2.5+2.5 mg, was compared with similar indicators for individual tablets containing Aulnay studies using five parallel groups in several research centers. Patients with primary arterial hypertension in whom diastolic blood pressure in the supine position was equal 95-110 mm Od with two separate measurements made over a 4-6-week period of receiving placebo, were randomly divided into groups for treatment with preparations containing 5 mg felodipina with a long release and 5 mg ramipril (FR 5+5), drug 2.5 mg felodipina with a long release and 2.5 mg ramipril (FR 2,5+2,5), 5 mg felodipina with a long release (F5), 5 mg ramipril (R5), or a placebo.

Were surveyed one thousand three hundred man (1103) from which to participate in this study, randomly selected nine hundred thirty-nine (939) patients from six countries (Australia, Canada, Denmark, Italy, New Zealand and Sweden). Finished this study, eight hundred seventy (870) patients. The results of the analyses are given for 518 men and 421 women with an average age of 57 in the age interval from 24 to 86 years.

Diastolic and systolic blood pressure in the supine position was measured after 4 and 24 hours after administration of the medications ordered by the method of blind selection (raw data), and 11 and 12 weeks of treatment.

Average SMI data average for 11-12 weeks of treatment (statistically significant are the values of p less than 0.05) (table 3).

All circuits active treatment was possible to achieve a statistically significant reduction in diastolic blood pressure in the supine position (24 and 4 hours after administration of the medicinal product) in relation to the original data average for 11-12 weeks of treatment when compared with placebo.

The mean differences in the change (from the original data average for 11-12 weeks) blood pressure. Comparison of treatment methods combined drugs and placebo (table 4).

Both regimens combined uniform dosage forms taken once a day in patients suffering from hypertension, has achieved a statistically significant reduction in systolic and diastolic blood pressure in the supine position compared with placebo as with the maximum concentration (within 4 hours after taking the drug), and minimum concentration (24 hours after taking the drug).

The mean differences in the change (from the original data average for 11-12 weeks) blood pressure in the supine position. Comparison of treatment regimens (table 5).

Regimens combined uniform drug the pressure in the supine position, than in the treatment of individual drugs.

In addition, the drug with low contents the following components are equal (compared with felodipina) or more (compared to ramipril) effective to reduce diastolic and systolic blood pressure in the supine position than the separate components with a double dose.

Similar results were obtained in the standing position, indicating the absence of orthostatic effects in any treatment regimen.

The most common adverse events (% of patients) (table 6).

Both regimens combined standardized medical forms were characterized by very good tolerance to medicines. The number of patients who have had adverse events that required discontinuation of treatment in the group treated with uniform drug were comparable with similar results for placebo.

Side effects that occur during the reception of angiotenzinkonvertiruyuschego enzyme inhibitor (dizziness, headache, fatigue, nausea, and cough) and calcium antagonists on the basis of dihydropyridines (increase castorini in the treatment of combined uniform dosage forms, than individual therapy drugs. In addition, it is much more related to this unpleasant side effects like cough, which occurs when taking angiotenzinkonvertiruyuschego enzyme inhibitors, and peripheral edema and tides of blood, occurring when receiving calcium antagonists on the basis of dihydropyridines.

Example 4

The results of the clinical study to assess the efficacy and tolerance of a combination of uniform dosage form containing 2.5 mg felodipina with a long release and 2.5 mg ramipril (FR 2,5+2,5), compared with the individual drugs, containing 2.5 mg of ramipril (R 2.5), and 2.5 mg felodipina with a long release (F 2,5) taken once a day. This study was a double-control study with three parallel groups in several research centers. Applied the same criteria to create groups, as in the study of example 1, the duration of treatment was 12 weeks. This study was completed approximately 600 patients. Below are the results of measurements of blood pressure within 24 hours after administration of the drug (table 7).

Most Mipril on the media and 5.0 mg felodipina in Presolana. This drug is characterized by a rapid release of ramipril ("instant release") and prolonged release felodipina ("extended release").

The solubility of ramipril and felodipina in laboratory conditions experienced in 500 ml of 0.1 M phosphate buffer solution with a pH of 6.5 by adding 0.4% of bromide, cetyltrimethylammonium. This test was performed using the apparatus for dissolving 2 (mixer) used by the USP provided with a fixed baskets and having a rotation speed of 100 rpm. Data on the release of the active components in percent are shown as average values, and in parentheses are the minimum and maximum values (table 9). It was tested 6 capsules. The capsule shown in example 9.

Example 6

The solubility of ramipril and felodipina in the laboratory of coated tablets containing 2.5 and 5 mg of the active substances tested in 500 ml of 0.1 M phosphate buffer solution with a pH of 6.5 by adding 0.4% of bromide, cetyltrimethylammonium. This test was performed using the apparatus for dissolving 2 (mixer) used by the USP provided with a fixed baskets and speed of the rotation the days of magnitude, in parentheses are the minimum and maximum values (table 10). It was tested 6 tablets. The composition of the tablets shown in example 10.

Example 7

Solubility ramipril and felodipina in the laboratory of a multilayer tablet containing 2.5 mg of the active substances tested in 500 ml of 0.1 M phosphate buffer solution with a pH of 6.5 by adding 0.4% of bromide, cetyltrimethylammonium. This test was performed using the apparatus for dissolving 2 (mixer) used by the USP provided with a fixed baskets and having a rotation speed of 100 rpm. Data on the release of the active components in percent are shown as average values, and in parentheses are the minimum and maximum values (table 11). It was tested 6 tablets. The composition of the tablets shown in example 11.

Example 8

The solubility of ramipril and felodipina in the laboratory of a multilayer tablet containing 5 mg of active substances tested in 500 ml of 0.1 M phosphate buffer solution with a pH of 6.5 by adding 0.4% of bromide, cetyltrimethylammonium. This test was performed using the apparatus for dissolving 2 (mixer) used by the Pharmacopoeia With the order his active components in percent are shown as average values, in parentheses are the minimum and maximum values (table 12). It was tested 6 tablets. The composition of the tablets shown in example 12.

Example 9

Capsule containing 2.5 mg of ramipril on the media and 5.0 mg felodipina in Presolana. This drug is characterized by a rapid release of ramipril ("instant release") and prolonged release felodipina ("extended release").

The Central part of the tablet, consisting of felodipina was made to create a structural frame hydrophilic gel described Colin D. Melia in the article "System prolonged action with hydrophilic matrix based on polysaccharide carriers" ("Hydrophilic Matrix Sustained Release Systems Based on Polysaceharide Carriers"), published in the journal "Critical Reviewrs in Therapeutic Drug Carrier Systems", 8(4): 395-421 (1991), under which were prepared by two different granulating solution (I and II), after which they were used for granulating powdered material (III).

Solution I - mg/tablet

Felodipine - 5,00

Gidrirovannoe castor oil "polyoxyl 40" - 12,50

Propylgallate - to 0.060

Ethanol - 30,00

Solution II

Polyvinylpyrrolidone - 24,00

Ethanol - 300,0

Powders in the granulate III

The hypromellose - 30,00

Fumarate sodium - 8,60

The powder mixture was moistened with a solution of I, stirring until smooth. Then added to the solution II and continued mixing until smooth. The granulate was dried in a drying oven.

The dry granules were crushed in mixer granulator Prewitt (Frewitt). After grinding, the granulate was mixed until smooth with an additional amount of hydroxypropylmethylcellulose at the rate of 30 mg per tablet, and then treated with sodium fumarate. Stirring is continued for another 3 minutes. Pressing produced in a stamping press Korsh Pharmapress 100 using stamps size 713 (labeled). The hardness of the resulting tablets, measured along the largest axis was more than 20 kPa.

Media ramipril made in the following way:

The solution for coating

Ramipril - 3.33 g

The hypromellose - 10,00 g

0.01 M solution of acetic acid and 200 g

Ethyl alcohol 200 g

The Central part of

Inert substance that does not contain Pareil (in accordance with the monograph of the Pharmacopoeia of the United States "Sugar granules") - 210 g

Equipment

The device d is lo: Schlick.

The inserted tube diameter 50 mm, length 60 mm

In the coating were obtained granules containing 13.5 mg/g ramipril. In hard gelatin capsules size 00 was administered one tablet obtained in the above manner, together with 185 mg of granules containing ramipril.

Properties of the obtained capsules

Weight capsule - 747 mg

Content felodipina - 5,0

Content ramipril - 2.4 mg/capsule

Example 10

Tablet contains ramipril in coating and felodipine in the Central part. This drug is characterized by an instantaneous release of ramipril and prolonged release felodipina.

The Central part of the tablet containing felodipine, made on the principle of creating a structural framework hydrophilic gel (see reference example 7), according to which received two different granulating solution (I and II), after which they were used for granulating powdered material (III).

Solution I - mg/tablet

Felodipine - 5,00

Gidrirovannoe castor oil "polyoxyl 40" - 5,00

Propylgallate - to 0.060

Ethanol - 30,00

Solution II

Hydroxypropylcellulose - 10,00

Ethanol - 160,00

Powders III

Hydroxyproline - 3,00

Fumarate sodium - 4,20

The powder mixture was moistened with a solution of I, stirring until smooth. Then added to the solution II and continued mixing until smooth. The granulate was dried in a drying oven.

The dry granules were crushed in mixer granulator Prewitt (Frewitt). After grinding the granules were treated by sodium fumarate and produced the final stirring for 3 minutes, the Tablets were formed in teletrauma machine using 9 mm round concave punches. The hardness of the resulting tablets was approximately 7-8 kPa when measured using an instrument for determining the hardness of Lanigera (Schleuniger).

On tablets, containing felodipine, which were obtained in accordance with the above method, was applied a coating of ramipril, and as binders used the viscosity hypromellose 6 JV dissolved in a mixture of alcohol and water solution of acetic acid.

On the Central part of the tablet was coated as follows:

The solution for coating

0.01 M solution of acetic acid and 200 g

Ethanol - 200 grams

The viscosity hypromellose 6 SP - 10 g

R is a diameter of 9 mm (1000 tablets) - 206 g

Equipment

Apparatus for creating a fluidized bed (equipped with a device Wurster (Wurster)).

Spray nozzle: Schlick.

The inserted tube diameter 50 mm, length 60 mm

The hypromellose was dissolved in a mixture of an aqueous solution of acetic acid and ethanol, after which this solution was dissolved powder ramipril. The resulting solution was sprayed onto the tablets using the above equipment and in the presence of the above conditions. Alternatively, the coating can be applied using other known equipment, for example, apparatus Acceela Coata or baths for coating.

Properties of the obtained tablets:

weight tablets 216 mg/tablet;

content felodipina of 4.9 mg/tablet;

content ramipril 2.4 mg/tablet.

Example 11

Multi-layer tablets containing 2.5 mg of ramipril with an instant release and 2.5 mg felodipina with a long release.

The composition of

Component mg/tablet

Layer ramipril

Ramipril - 2,5

The hypromellose - 0,4

Lactose - 24,0

Maize starch 1500 - 48,8

Microcrystalline cellulose - 24,0

Fumarate natroalunite - 10,0

The hypromellose - 100

Lactose - 28,0

Microcrystalline cellulose - 3,0

Gidrirovannoe castor oil "polyoxyl 40" - 2,5

Propylgallate - 0,06

Silicate of sodium-aluminum - 47,0

Fumarate sodium - 6

Ethanol - demand

Floor

Colored iron oxide - 0.3

The hypromellose - 7,4

Paraffin - About 0,1

The glycol - 1,9

Titanium dioxide - 0,8

Distilled water - About 64

Ramipril was grained with hypromellose in distilled water. The dried material was classified and was mixed with lactose, maize starch and microcrystalline cellulose. Then mixed with sifted sodium fumarate. The granulate felodipina produced separately by the method described in example 8. Both granulate was then applied to press for layer-by-layer extrusion, equipped with two fillable compartments, and extruded into pellets.

On these tablets was applied outer coating using known equipment.

Example 12

Multi-layer tablets containing 5 mg of ramipril with immediate-release 5 mg felodipina long >The hypromellose - 0,9

Lactose - 23,5

Maize starch 1500 - 46,8

Microcrystalline cellulose - 23,5

Fumarate sodium - 1,0

Distilled water - On-demand

Layer felodipina

Felodipine - 5,0

Hydroxypropylcellulose - 10,0

The hypromellose - 100,0

Lactose - 28,0

Microcrystalline cellulose - 3,0

Gidrirovannoe castor oil "polyoxyl 40" - 5,0

Propylgallate - 0,06

Silicate of sodium-aluminum - 47,0

Fumarate sodium - 6

Ethanol - demand

Floor

Dyes, iron oxides - 0.3

The hypromellose is 7.5

Paraffin - About 0,1

The glycol - 1,9

Titanium dioxide - 0,8

Distilled water - About 64

The method of manufacture described in example 11.

1. Solid uniform dosage form for oral administration comprising a combination of an inhibitor angiotenzinkonvertiruyuschego enzyme, which is ramipril or its pharmaceutically acceptable salt, and a calcium antagonist which is a compound of dihydropyridines selected from the group including felodipine, nitrendipin, nifedipine, lacidipine and ski acceptable salts and 1 - 70 mg of the compounds of dihydropyridines or its pharmaceutically acceptable salts, with the release of ramipril is instantaneous, and the release of the connection of dihydropyridines happens over a long period of time, which shall be at least 6 hours

2. Dosage form under item 1, characterized in that the connection of dihydropyridines is felodipine.

3. Dosage form under item 1, characterized in that the connection of dihydropyridines is nitrendipin.

4. Dosage form under item 1, characterized in that the connection of dihydropyridines is nifedipine.

5. Dosage form under item 1, characterized in that the connection of dihydropyridines is lacidipine.

6. Dosage form according to any one of paragraphs. 1-5, characterized in that it contains 1 to 5 mg ramipril or its pharmaceutically acceptable salt and 1 to 60 mg of the compound of dihydropyridines or its pharmaceutically acceptable salt.

7. Dosage form under item 6, characterized in that it contains 1-5 mg ramipril or its pharmaceutically acceptable salt and 1-5 mg felodipina or its pharmaceutically acceptable salt.

8. Dosage form under item 6, characterized in that the Ki acceptable salt.

9. Dosage form under item 7 or 8, characterized in that the ratio of the components is 1: 1.

10. Dosage form according to any one of paragraphs. 1-9, characterized in that the connection of dihydropyridines with prolonged release were made in the structural frame hydrophilic gel.

11. Dosage form according to any one of paragraphs. 1-10, characterized in that it is made in the form of capsules.

12. Dosage form according to any one of paragraphs. 1-10, characterized in that it is made in the form of tablets.

13. Dosage form according to any one of paragraphs. 1-12, wherein the ramipril is included in the coating composition, which is applied to the dihydropyridines with a long release.

14. Dosage form under item 12 or 13, characterized in that the dihydropyridines with prolonged release is a layer of the tablet, which is connected with another layer containing ramipril, or, if necessary, dihydropyridines with prolonged release is a layer of the tablet, which is connected through one or more layers of non-active components with another layer containing ramipril.

15. Dosage form according to any one of paragraphs. 1-10, 12 or 13, characterized in that one of the components nah the ptx2">

16. Dosage form according to any one of paragraphs. 1-15, characterized in that it is intended for the prevention or treatment of diseases of the cardiovascular system, especially hypertension.

17. Dosage form according to any one of paragraphs. 1-15, characterized in that it is intended for the prevention or treatment of diseases of the cardiovascular system, especially hypertension in mammals, including humans.

18. A method of obtaining a solid uniform dosage forms described in any of paragraphs. 1-10, 12, 14, or 15, namely, that ramipril with an instant release and dihydropyridines with a long release pressed into a pill in teletrauma machine.

19. A method of obtaining a solid uniform dosage forms described in any of paragraphs. 1-10, 12, 14 or 15, which consists in the fact that the layer tablets containing ramipril with instant release, is connected to the layer containing dihydropyridines with a long release, with the formation of combined pills.

20. The method according to any of the p. 18 or 19, characterized in that on the pill cause a pharmaceutically acceptable coating.

21. A method of obtaining a solid Unificationism and dihydropyridines with a long release are enclosed in a capsule.

22. A method for preventing or treating hypertension in mammals, including humans, wherein the patient in need of such treatment, the drug takes the form described in any of paragraphs. 1-17, in an effective amount.

23. A method for preventing or treating hypertension in mammals, including humans, p. 22, wherein the patient in need of such treatment, take once a day dosage form, described in any of paragraphs. 1-17, in an effective amount.

Priority claims:

02.09.1994 - PP. 1-7, 10-23;

02.09.1994 - PP. 8 and 9.

 

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