RU2464018C1 - Sustained-action pharmaceutical composition for treating heart diseases - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition for treating cardiovascular diseases which contains a therapeutically effective amount of metoprolol succinate as an active substance, and excipients - a combination of hypromellose type 2910 and hypromellose type 2208 taken in the relation of 1:(0.18-472.5), a filler, a glidant, a lubricant. Said pharmaceutical composition is presented in the form of a coated tablet.

EFFECT: said composition is characterised by modified release of the active substance; it is storage-stable and has high mechanical strength.

4 cl, 2 tbl, 12 ex

Description

The invention relates to medicine, specifically to a pharmaceutical composition comprising a cardioselective β-blocker, metoprolol, as an active ingredient, and can be used to treat arterial hypertension (mono-and combination therapy with other antihypertensive drugs), compensated chronic heart failure, functional disorders cardiac activity, accompanied by tachycardia, coronary heart disease: myocardial infarction, angina pectoris prevention of supraventricular tachycardia and ventricular extrasystole, in Rank-dependent adrenergic mechanisms elongation Q-T interval, migraine (prevention of attacks).

Metoprolol (chemical name - (R, S) -1- (isopropylamino) -3- [p- (2-methoxyethyl) phenoxy] propan-2-ol) is one of the most effective β _1- blockers and is successfully used in medical practice with hypertension, angina pectoris, arrhythmias, hyperthyroidism, for the prevention of repeated myocardial infarction [Mashkovsky M.D. Medicines, t.1, ed. 13th, Kharkov: Torsing, 1997, p.267].

The literature describes various pharmaceutical compositions with beta-adrenergic blocking action based on metoprolol. The latter, as a rule, is contained in these preparations in the form of a salt with acids, preferably in the form of a salt with tartaric acid, i.e. tartrate.

In USSR patent No. 1326180, 1987, a pharmaceutical composition of the following composition is described, wt.%:

Metoprolol tartrate - 62.1,

Talc - 4.2,

Silicic acid (finely divided) - 1.1,

Cetanol - 32.6.

The known composition is made in the form of granules with an average size of 0.75-1.0 mm However, to obtain a tablet dosage form, it is necessary to additionally introduce targeted additives into the composition.

In the patent of the Russian Federation No. 2072840, 1997, a pharmaceutical composition is proposed containing a large number of small dense particles, including metoprolol (in the form of salt) as an active ingredient and coated with a polymer membrane based on cellulose derivatives without protolizable groups.

To obtain a tablet form, the particles having a shell are mixed with microcrystalline cellulose and other excipients. For example, wt.%:

Coated balls, including:

The core (SiO ₂ ) - 7.0,

Metoprolol succinate - 26.8,

The polymer layer (ethyl cellulose, hydroxypropyl methyl cellulose, acetyl tributyl citrate) - 16.2,

Microcrystalline cellulose - 36.2,

Corn starch - 5.6,

Milk sugar - 3.4,

Polyvinylpyrrolidone - 4.7,

Magnesium stearate - 0.1.

A method of manufacturing this drug is as follows. Metoprolol salt is sprayed onto the cores of silicon dioxide, after which a polymer coating is applied. The resulting balls are mixed in equal parts with auxiliary ingredients (with the exception of magnesium stearate) and after adding magnesium stearate, the dry mixture is pressed into tablets, which are coated with a coating comprising hydroxypropyl methylcellulose, PEG 6000, colored titanium dioxide and special paraffin.

Significant disadvantages of the known composition include a limitation on the solubility of the active ingredient in water. In addition, it is characterized by sophisticated manufacturing technology.

In the patent of the Russian Federation No. 2190397 a pharmaceutical composition is described comprising a metoprolol salt, starch, a multifunctional filler (lactose, polyvinylpyrrolidone), a lubricant. The composition has high mechanical strength and rapid release of the active substance, which is not always acceptable, and when using metoprolol in the form of succinate, the stability of the composition is significantly reduced.

It should be noted that the beta-blocker metoprolol widely used in clinical practice exists in the form of two dosage forms - metoprolol tartrate and metoprolol succinate. Between them, there are significant differences both in pharmacokinetics and in clinical aspects of the application (primarily, efficacy and safety). Clinical studies have shown higher antihypertensive efficacy and antianginal activity of metoprolol succinate compared to metoprolol tartrate (CONSILIUM medicum, Volume 09 / N5 / 2007).

The present invention was to create a cardiovascular preparation based on metoprolol succinate in the form of a solid dosage form — coated tablets with a modified release profile that have a shelf life of more than 2 years and high mechanical strength.

To solve this problem, a pharmaceutical composition is proposed in the form of a tablet that contains metoprolol succinate in a therapeutically effective amount, and excipients - filler, glidant, lubricant, characterized in that it additionally contains hypromellose and has a shell

Preferably, the composition comprises hypromellose type 2208 and hypromellose type 2910 as hypromellose, more preferably a combination thereof. Preferably, hypromellose 2208 and 2910 are used in a ratio of (0.18-472.5): 1, respectively

The inventive composition of the ingredients is found experimentally and allows you to get a technical result that is consistent with the task. As an active ingredient, the new composition contains metoprolol in the form of succinate. Hypromellose, multifunctional filler, glidant and lubricant were selected as auxiliary substances in the preparation of the tablet core. As the glidant, preferably colloidal silicon dioxide, methylated silicon dioxide, talc or a combination thereof, more preferably colloidal silicon dioxide, are used. As the lubricant, stearic acid or salts of stearic acid, preferably magnesium stearate or calcium stearate, are preferably used. As a filler, a combination of lactose and povidone, for example Ludipress, is preferably used.

Preferably, the shell is made based on a cellulose derivative, more preferably based on hydroxypropyl methyl cellulose, even more preferably based on type 2910 hydroxypropyl methyl cellulose

The claimed composition is characterized by a modified release of the active ingredient - metoprolol succinate. Not more than 25% of the active substance passes into the dissolution medium (phosphate buffer solution with pH = 6.8) after 1 hour, from 20 to 50% after 4 hours, from 40 to 70% after 8 hours, not after 20 hours less than 80%

Thanks to the invention, the efficiency and safety of treating patients is increased, since side effects on the body are reduced by controlling the rate of release of the active substance and maintaining a uniform concentration in the blood. The usability of the drug is increased, since a lower number of doses per day is required compared with the usual dosage form. The claimed composition is stable during storage and has a satisfactory strength

The preferred ratio of the ingredients of the claimed composition is, parts by weight:

Metoprolol succinate - 1,

Hypromellose - 0.9-20.0,

Filler - 0.26-14.75,

Glidant - 0.003-0.2,

Lubricant - 0.003-0.2.

The new pharmaceutical composition is prepared in the form of a solid dosage form, preferably in the form of a coated tablet. The invention makes it possible to manufacture a pharmaceutical dosage form that can be administered once a day and at the same time create an almost constant concentration of the drug in the blood throughout the entire dose range until the next dose is administered.

A typical example (example 1). The pre-sifted powder of the substance of metoprolol succinate is granulated with a solution of hypromellose (type 2910), then the obtained granulate is mixed with the sifted powders of hypromellose (type 2208), filler, glidant and lubricant and the prepared mass is tabletted. Get tablets with an average weight of 0.300 g (for dosages of 25 mg and 50 mg) and 0.700 g (for dosages of 100 mg and 200 mg), strength 170 ÷ 185 N (for dosages of 25 mg and 50 mg) and 160 ÷ 190 N (for dosages of 100 mg and 200 mg) - Table 1.

If necessary, the core tablets are coated with a film-forming suspension obtained from a ready-made film-forming mixture based on hypromellose type 2910, orange or green, until the mass of the gastro-soluble coating increases in weight by no more than 5% of the weight of the tablet core (to obtain coated tablets with an average weighing 0.315 g for dosages of 25 mg and 50 mg, and 0.735 g for dosages of 100 mg and 200 mg).

The resulting tablets satisfy the regulatory requirements for a pharmaceutical agent. Dissolution (table 2),% release of metoprolol succinate in terms of metoprolol tartrate into the dissolution medium - phosphate buffer solution with pH = 6.8 - after 1 hour (UV spectrophotometry) - not more than 25%, after 4 hours - from 20 to 50%, after 8 hours - from 40 to 70%, after 20 hours - at least 80%, the content of metoprolol succinate in terms of metoprolol tartrate in one tablet (HPLC) - 25.0 mg (dosage 25 mg), 50.0 mg (dosage 50 mg), 100.0 mg (dosage 100 mg) and 200.0 mg (dosage 200 mg). The resulting tablets have a shelf life of more than 2 years.

This invention makes it possible to manufacture a pharmaceutical dosage form, which is characterized by a constant controlled release of the active component over a period of 20 hours, as a result of which a constant concentration of the drug in the blood will be achieved throughout the entire dose range until the next dose is administered.

Table 1 Ingredients Content, parts by weight Examples Dosage 25 mg Dosage 50 mg one 2 3 four 5 6 Metoprolol succinate one one one one one one Hypromellose (ratio type 2910 / type 2208) 6.55 18.94 1.80 3.35 9.44 1.27 1 / 25.2 1 / 472.5 1 / 1.4 1 / 12.4 1/235 1 / 0.69 Filler 4.9 0.8 14.75 1.8 0.3 5.5 Glidant 0.06 0.01 0.2 0,03 0.005 0.09 Lubricant 0.06 0.01 0.2 0,03 0.005 0.09 Ingredients Dosage 100 mg Dosage 200 mg 7 8 9 10 eleven 12 Metoprolol succinate one one one one one one Hypromellose (ratio type 2910 / type 2208) 1.95 5.04 1,03 1.09 2,57 0.89 1 / 6.8 1/125 1 / 0.37 1 / 3.36 1 / 63.25 0.18 Filler 4.3 0.72 13 2.17 0.26 4.6 Glidant 0.04 0.1 0.006 0.02 0,055 0.003 Lubricant 0.04 0.006 0.1 0.02 0.003 0,055

table 2 Time hour Metoprolol Release,% Examples one 2 3 four 6 7 9 10 12 one 13 fifteen eleven 13 16 fifteen 16 fourteen eleven four 40 45 41 40 37 35 44 43 43 8 60 64 60 65 62 60 65 63 637 twenty 91 90 88 90 93 89 91 90 89

Claims (4)

1. A pharmaceutical composition for the treatment of the cardiovascular system in the form of a solid coated dosage form, which includes a therapeutically effective amount of metoprolol succinate and excipients — hypromellose, filler, glidant, lubricant, characterized in that it contains hypromellose a combination of hypromellose type 2910 and hypromellose type 2208, taken in the ratio 1: (0.18-472.5). 2. The pharmaceutical composition according to claim 1, characterized in that it contains the active substance and auxiliary ingredients in the following ratio, parts by weight:
Metoprolol succinate one Hypromellose 0.9-20.0 Filler 0.26-14.75 Glidant 0.003-0.2 Lubricant 0.003-0.2 3. The pharmaceutical composition according to claim 2, characterized in that it is made in the form of a coated tablet. 4. The pharmaceutical composition according to claim 3, characterized in that the shell is made on the basis of hypromellose.