Solid pharmaceutical form prolonged action for the treatment of cardiovascular diseases

 

(57) Abstract:

Use: medicine for the treatment of disorders of the cardiovascular system. The essence of the invention: solid pharmaceutical form prolonged action, continuously releasing the active principle at least 15 hours almost regardless of the pH of the gastrointestinal tract, contains the nucleus, containing metoprolol, and shell. Consists of a set of balls the size of 0.25 - 2 mm, the core of which not less than 95 wt.% contain metoprolol in the form of a salt, the solubility of which in water at 25oWith less than 600 mg/ml of Active principle is released with a speed of 3 to 7 wt. % ch. On each ball applied polymer shell. Preferably the size of the balls 0,35 - 1,0 mm Salt of metoprolol may be benzoate or sorbate S-enantiomer of metoprolol. The contents of the balls may include a salt of metoprolol printed on the insoluble core of silicon dioxide. Insoluble core of silicon dioxide may have a size of 0.1 to 1.0 mm, preferably 0.15 to 0.3 mm or to be 0.15 - 0.3 mm and to be covered with a salt of metoprolol with formation of balls the size of 0.35 - 1.0 mm, coated with a polymer shell. The polymer shell may be made of ethyl cellulose or military balls, coated with a polymer shell, or in the form of a tablet of compacted with pharmaceutical additives balls. 14 C.p. f-crystals, 3 ill., table 1.

The subject invention is a new pharmaceutical preparation with controlled release of metoprolol for treating disorders of the cardiovascular system.

Metoprolol having the structural formula

< / BR>
known, for example, from the patent DE-2 106209. This drug that is an antagonist of adrenoceptor, preferably used in the form of a salt, for example tartrate.

Metoprolol blocks adrenergic stimulation of the heart and thus reduces the oxygen demand of the heart tissue. Obviously this explains the beneficial effect in the case of angina and cardiotoxin action in the case of myocardial infarction. In addition, metoprolol normalizes blood pressure in a large proportion of patients suffering from arterial hypertension, which is probably a consequence of the additional steps for the regulation of peripheral resistance to blood flow.

Patients suffering from disorders of the cardiovascular system, it is desirable to have a constant concentration of an introd what their medication over a long period of time. In accordance with the usual course of treatment patients were prescribed one instant pill twice a day. This leads to the change of concentration with high peak values and downs throughout the day.

With the aim of introducing once daily metoprolol made in tablets insoluble matrix type controlled release, for example, durules.. However, the release of drug from matrix tablets is unsatisfactory, because about 50% of the dose is released within a few hours after injection. Therefore there was a requirement to find a way to obtain the drug, characterized by a more permanent controlled release of the active ingredient within about 20 to 24 hours, thus achieving a more uniform concentration in the blood and the effective profiles of exposure throughout the period of exposure of the administered dose.

To achieve controlled release, for example, metoprolol, administered once daily, can be used bearing system for a drug called Oros. Oros. is a singleton system consisting of osmotically active core, including core is nicoe hole. The release of drug from this system remains constant up until the membrane effect of constant osmotic pressure. 50 to 60% of the total content of the drug is released at a constant speed (1).

In patent application SE-A-840085 has been proposed a method of obtaining a product with an enteric coating containing, for example, metoprolol, and with a slow release of the active compound near the colon. This drug does not provide a continuous and slow release of metoprolol regardless of the pH, which is typical of the preparation in accordance with this invention.

Preparations in the form of a depot containing a large number of smaller elements are also known, for example, from the patent EP 13263. This patent describes a neutral in the pharmaceutical respect to the core, covered with an active connection. These cores are made of a soluble material, such as lactose.

The drug is in the form of a depot, including a large number of small elements, has advantages in the sense that each element releases the drug with variable speed, which is not characteristic of the drug in the form of a depot consisting of one lekarstvennogo of the drug. For example, it is possible to obtain a reproduced output elements from the stomach, when used particles less than 1 to 2 mm. Cm. Bogetoft K., and others, "the Impact of food on the absorption of acetylsalicylic acid from the dosage form with an enteric coating", "Eropean of jernelov clinical pharmacology", 1978, S. 351 355. Dispersion over a large area of the gastrointestinal tract provides a more reproducible total time taken to travel that creates an advantage for absorption. In addition, multi-drug preferred compared to singleton drug, as this dose is distributed in the intestine. The risk of local irritation and accumulation of multiple doses due to narrowing of the digestive tract are also much lower.

Another advantage of multiple drug is that it can be divided into smaller portions, with the same absorption properties. This allows more flexibility when choosing the size of the dose.

The subject of the invention is a preparation containing metoprolol as an active ingredient and which is characterized by a controlled rate of release of the drug for at least 15 hours In the creation of the main soluble component and coated with a polymer membrane, including derivatives of cellulose without protoliterate groups, it was possible to obtain the drug, with adjustable speed release metoprolol, virtually independent of the pH, for 16 to 24 hours

Small particles, beads, containing metoprolol, have a size of 0.25 to 2 mm, preferably of 0.35 to 1.0 mm

These balls can consist of a single metoprolol or may include insoluble core, covered with metoprolol. These beads are characterized by a very high content of metoprolol, preferably 95 to 100 wt. the soluble part of the balls. Insoluble cores have a size of 0.1 to 1.0 mm, preferably of 0.15 to 0.3 mm Examples of insoluble cores in accordance with this invention can be silicon dioxide and small particles of glass.

Balls in accordance with this invention are dense, which means that their porosity is less than 15%

As can be seen from Fig. 1, a new drug is characterized by the fact that at least 75% of the metoprolol is released within 20 hours and at least 50% of the dose of metoprolol is released with a speed of 3 to 7 wt. in 1 hour

Metoprolol used in this preparation may be in the form of the racemate or one of the enantiomers, and the Orme).

Acceptable soluble salt of metoprolol are characterized by a solubility of less than 600 mg/ml in water at a temperature of 25oWith, preferably 30 to 600 mg/ml in water at a temperature of 25oC. Examples of acceptable salts are salts formed from organic carboxylic acid, preferably a low molecular weight. Particular preference is given to succinate, fumarate or benzoate racemic metoprolol and benzoate or sorbate s-enantiomer of metoprolol.

Highly soluble salts, for example tartrate, hydrochloride, are less acceptable for implementing the present invention.

Examples of acceptable polymeric materials are ethylcellulose or a mixture of ethyl cellulose with oksipropilmetiltselljulozy, oxypropylated, Eudragit RL or Eudragit RS.

Ethylcellulose available in the form of variants with different degrees of viscosity. In accordance with this invention it is necessary to use ethyl cellulose having a viscosity in the range of 10 to 50 JV, but also can be applied to other types of applications.

Eudragit is the brand name of a number of planapochromat substances on the basis of polyacrylate produced by the firm "REM Pharma. Eudragit RL and RS before the m groups of the Quaternary ammonium. The molar ratio of these ammonium groups to the remaining neutral esters meta/acrylic acid is 1:20 for Eudragit RL and 1:40 for Eudragit RS, which leads to different permeability characteristics.

In the polymer layer can be added plasticizers and/or pigments to improve the technical properties of the layer or change the permeability of the coating. Examples of acceptable plasticizers can serve esters of citric acid, acetylated monoglycerides, and glycerol triacetate, particular preference is given to acetyltributyl.

The polymer membrane is made of one or more polymers and has virtually independent of the pH characteristics of permeability in the range of pH of 1.8 to 8.0.

Each coated bead metoprolol in accordance with this invention forms a separate element with adjustable release that releases the drug with a predetermined speed. So the balls coated in accordance with this invention make possible the production and introduction of the drug in different dosage forms. They can be enclosed, for example, in solid gelatino is Tracii in plasma and duration of exposure.

In cases where small coated particles metoprolol pelletized, they are mixed with additives, such as microcrystalline cellulose, such as avicel, which improves the tabletting properties and facilitates the process of splitting the pill, which released some balls.

This invention makes possible the manufacture of pharmaceutical dosage forms, which may be administered once a day and create a nearly constant concentration of drug in the blood over the whole interval of the dose until the next dose.

The manufacturing method of preparation with controlled release represents another aspect of this invention. After the initial forming of beads containing metoprolol obtained beads cover a polymer layer, as described in the examples. The polymer mixture is dissolved in such an organic solvent as ethanol, isopropyl alcohol and/or methylene chloride. The spraying can be done in the bath for coating, but preferably the process is carried out in the fluidized bed. Ethylcellulose also can be applied from aqueous dispersion (latex).

Of preparation the activities of the cardiovascular system, and treatment of such conditions is another aspect of this invention (weight components in examples 1 to 5 is given in grams).

Example 1.

Fumarate of metoprolol 1440

Methylene chloride 9618

Ethanol 95% 3888

SiO2(0.15 to 0.25 mm) 375

Polymer layer

Ethylcellulose with a viscosity of 10 SP 265,6

Oksipropilmetiltselljuloza 58,4

Acetyltributyl 36,0

Methylene chloride 6141

Isopropyl alcohol 1544

In the granulator, fluidized bed metoprolol fumarate deposited on a core of silicon dioxide from a solution of 95% methanol. 40 g of the thus obtained beads (granules) (fraction 0,4 0,63 mm) were covered with a polymer layer containing ethyl cellulose with a viscosity of 10 SP, oksipropilmetiltselljuloza and acetyltributyl, by spraying a solution of the indicated substances in methylene chloride and isopropyl alcohol. Beads coated is then placed in hard gelatin capsules.

Example 2.

Succinate metoprolol 1440

Methylene chloride 9618

Ethanol 95% 3888

SiO2(0.15 to 0.25 mm) 375

Polymer layer

Ethylcellulose with a viscosity of 50 JV 168,1

Oksipropilmetiltselljuloza 36,9

Acetyltributyl 22,8

Methylene chloride kurosky starch 117,6

Potato starch is 10.6

Purified water 342,2

Magnesium stearate 1,2

Succinate metoprolol deposited on a core of silicon dioxide in accordance with the method described in example 1. 400 g formed so pellets were covered with a polymer film containing ethyl cellulose having a viscosity of 50 JV, oksipropilmetiltselljuloza and acetyltributyl. Additional mass for tablets was obtained by wet granulation of the dry mixture of microcrystalline cellulose and corn starch with an aqueous solution of potato starch in a planetary mixer. Equal amounts (600 g) active and additional granules ultimately mixed with magnesium stearate 0.1% and extruded into pellets.

Example 3. 100% of metoprolol succinate in the form of solid spherical granules with an average particle size of 0.42 mm 400 g of the above granules succinate metoprolol with particles less 0,63 mm was coated with a mixture of the following substances:

Ethylcellulose with a viscosity of 10 SP 177,1

Oksipropilmetiltselljuloza 38,9

Acetyltributyl 24,0

Methylene chloride 4094

Isopropyl alcohol 1029

From the obtained beads were molded pharmaceutical preparations in accordance with the above described methods.

Example 5. s-enantiomeric sorbate metoprolol in the form of solid spherical granules fraction 0,4 0,63 idealnych granules with a particle size in the range of 0.75 to 1.0 mm was coated with a mixture of the following substances:

Ethylcellulose with a viscosity of 10 SP 51,7

Oksipropilmetiltselljuloza 11,3

Acetyltributyl 7,0

Methylene chloride 1194

Isopropyl alcohol 300

From the obtained beads were molded pharmaceutical preparations in accordance with the above described methods.

Biopharmaceutical research

The concentration of metoprolol in plasma after a single dose of the drug with controlled release, containing 190 mg of metoprolol succinate in accordance with example 4 description of the invention, and plasma concentrations after a single dose of the drug durules containing 200 mg of metoprolol tartrate, shown in the accompanying Fig. 2. 190 mg of the salt of succinic acid is equivalent to 200 ml of metoprolol tartrate. The comparison was made at 10. Each result represents the average data obtained from 10 subjects. As can be seen, the drug in accordance with this invention allows to obtain an almost constant concentration of metoprolol for over 20 h, while the insoluble matrix, the drug creates undesirable high concentration in plasma during the first hours after drug administration.

Reducing the frequency of heart beats during exercise.

The best embodiment of this invention at the present time is the example 4.

The table illustrates the release of metoprolol from compositions of examples 1 to 4 under laboratory conditions. The table shows that at least 50% of the dose of metoprolol is released with a speed component 3 to 7 wt. in 1 hour

1. Solid dosage form with controlled release of active principle continuously releasing the active principle at least 15 hours almost regardless of the pH of the gastrointestinal tract, including the nucleus, containing metoprolol and shell, characterized in that the form consists of a set of spheres with a size of 0.25 to 2 mm, the core of which not less than 95 wt. contain metoprolol in the form of a salt, the solubility of which in water at 25oWith less than 600 mg/ml, at least 75% of the dose of metoprolol, is on each ball applied polymer shell.

2. Dosage form under item 1, characterized in that the size of the balls is 0.35 to 1.0 mm

3. Dosage form under item 1, characterized in that the porosity of the beads is less than 15%

4. Dosage form under item 1, characterized in that the salt of metoprolol has a solubility in water of 30 to 600 mg/ml.

5. Dosage form under item 4, characterized in that the salt of metoprolol formed of an organic carboxylic acid.

6. Dosage form under item 5, wherein the salt of metoprolol is a succinate or fumarate racemic metoprolol.

7. Dosage form under item 5, wherein the salt of metoprolol is a benzoate or sorbate S-enantiomer of metoprolol.

8. Dosage form under item 1, wherein the uncoated beads contain a salt of metoprolol printed on the insoluble core of silicon dioxide.

9. Dosage form under item 8, characterized in that the insoluble core of silicon oxide have a size of 0.1 to 1.0 mm, preferably of 0.15 to 0.3 mm

10. Dosage form under item 8, characterized in that the insoluble core of silicon oxide have a size of 0.15 to 0.3 mm and covered with salt is fair form on p. 1, wherein the uncoated beads have a size of 0.35 to 1.0 mm, contain a salt of metoprolol and coated with a polymer shell.

12. Dosage form under item 1, wherein the polymer membrane comprises ethyl cellulose.

13. Dosage form under item 1, characterized in that the polymer shell consists of a mixture of ethyl cellulose with hypromellose.

14. Dosage form under item 1, characterized in that the balls are coated contained in hard gelatin capsules.

15. Dosage form under item 1, characterized in that the coated beads together with pharmaceutical additives are contained in compressed tablets, disintegrating the coated balls in contact with the fluid of the gastrointestinal tract.

 

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