Pharmaceutical composition having cardiovascular action

 

(57) Abstract:

The invention can be used for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension, and hypertensive crisis. The composition is made in the form of a solid dosage form coated, for example tablets. The core of the form contains, wt%: verapamil - 40,9-59,1, starch - 24-35, milk sugar - 13,5-24, talc and 0.1 - 3, calcium stearinovokisly - 0,1-1. The shell consists of the derived methyl cellulose, tween 80, titanium dioxide, dye and, optionally, a polishing agent of substances. The composition is stable during storage, quickly releases verapamil and can be obtained in a simple and technologically advanced way. 3 C.p. f-crystals, 1 table.

The invention relates to the field of medicine and is suitable for the treatment of acute and chronic coronary insufficiency, stable and unstable angina, supraventricular tachycardia and arrhythmia, arterial hypertension, and hypertensive crisis.

One of the most important cardiovascular drugs is verapamil (hydrochloride 5-[(3,4-dimethoxyphenethyl)methylamino]-2-(3,4 - acid) is by means so 1, ed. 13th, Kharkov, 1997, S. 407]. The mechanism of action of verapamil along with antagonism towards calcium ions also play an important role improving the content in the cells of potassium ions. The connection causes expansion of coronary arteries, increase coronary blood flow, reduces the need of the heart for oxygen, has antiarrhythmic action. In addition, by reducing tubular reabsorption shows a natriuretic and diuretic effect. Verapamil is effective in migraine and is considering its use for the treatment of diseases of the Central nervous system.

Among the variety of different pharmaceutical compositions based verapamil convenience and ease of use definitely produce solid dosage forms, and research and development of compounds in this series continues to the present time.

In the PCT application N 93/01803, class A 61 K 9/16, 9/26, publ. 1993, describes a composition containing verapamil and auxiliary substances and made in the form of tablets, wt.%:

Verapamil - 33,8

Dextrose - 44,5

Xanthan gum is 9.6

Resin carob - 9,6

Hydrogenomonas vegetable oil - 2,0

Magnesium stearate and 0.5

However, the lack of is. 988 described composition with slow release of the active substance of the following composition, wt.%:

Verapamil - 50,5

Sodium alginate is 28.5

Oksipropilmetiltselljuloza (Methocel E4M - 9,5

Microcrystalline cellulose - 7,0

Lactose - 1,7

Oksipropilmetiltselljuloza (Methocel E5) - 1,9

Magnesium stearate - 0,9

The tablet may have a shell comprising 2-15% by weight of the core, but its exact composition is not given.

Considering this song, it should be noted that for verapamil, as well as other lipophilic calcium channel blockers characterized by a high degree of metabolism at the first passage through the liver, i.e., before getting to the place of impact (the target organ). However it is noted that in the case of compositions with extended release verapamil is more intense metabolism and lower bioavailability than for drugs with a normal (fast) release. This causes a need to increase the daily dose of the active ingredient. The latter, in turn, increases the possibility of unwanted side effects.

Additive to the active component fatty acids (C12-C24) reduces the intensity of primary metabolism [Peosta introduces fluidization and/or thickener, for example Aerosil, combining these two functions, and thixotropic or thermoplastic substances, for example, di - or triglycerides. Another option for obtaining the solid phase consists of adding to the mixture of the main ingredients of oxypropylation or gums and subsequent granulation. The granules are covered with a shell of ethyl cellulose and is dispersed in the liquid phase, which concluded in the outer shell, covered with phthalate of oksipropilmetiltselljulozy.

For this composition preferably the application of the active ingredient in the form of a Foundation. However, the base verapamil unstable, and verapamil, which is a hydrochloride, does not form a homogeneous mixture with the abovementioned acids, which reduces the efficiency of the dosage form and causes significant technological difficulties. Using the shell of ethyl cellulose or phthalate of oksipropilmetiltselljulozy for new members is unacceptable because it does not give the required GF XI indicators raspadaemosti.

Most similar in essential characteristics to the present invention we consider the composition indicated in U.S. patent N 5132295, CL 514/54, publ. 1992, which is selected as a prototype. The pharmaceutical composition contains the including sodium alginate - 34,2

the rest of the ingredients - 28,5

To obtain core tablets in addition to the salt of alginic acid used these substances in the ratio, wt.%:

Microcrystalline cellulose - 40-55

Povidone - 25-35

Magnesium stearate is 0.2 - 2

Water - 15-25

Microcrystalline cellulose can be replaced with sugar or starch. As a binder may be applied to the starch paste. The tablet has a shell, which is 3% of the weight of the kernel and contains, wt%:

Oksipropilmetiltselljuloza - 22,3

Talc - 38,2

Titanium dioxide - 28,2

PEG-400 - 5,9

PEG-8000 - 3,6

Wax - 1,4

Dye - 0,5

The disadvantages of this composition should include the presence of a very large number of components in the film-forming composition and a relatively high content of solid phase (66,4%), which does not allow to reduce the weight of the protective shell. In addition, the presence of salt of alginic acid significantly increases the time of release of the active substance, which affects the bioavailability of the drug.

Thus, current technology involves the use in clinical practice, drugs verapamil made with. 408]. However, the trains slow release, as it was mentioned, along with the positive, have some significant drawbacks, due to their low bioavailability. In this regard, is still relevant is the problem of creating cardiovascular drug on the basis of verapamil quick release of the active principle (more than 75% within 45 min), which, of course, necessary to replenish the register of medicines.

The objective of the invention is to develop a composition with cardiovascular action on the basis of verapamil, which conforms to pharmacopoeial requirements, stable during storage, rapidly releases the active substance, easy to use and can be obtained in a simple and technologically advanced way.

This objective is achieved in that the proposed pharmaceutical composition comprises a core containing as active principle verapamil and as the target additives, starch, lactose, talc and calcium stearate, and has a shell that contains a derivative of methyl cellulose, tween 80, titanium dioxide, dye and, optionally, a polishing agent of the substance.

The ingredients contained in I is R> Talc and 0.1 - 3

Calcium stearinovokisly - 0,1 - 1.

The claimed ratio of ingredients is best found experimentally and provides the required quality of the composition.

The combined use of the composition of milk sugar and starch in the proportions provides the required GF XI indicators raspadaemosti and release verapamil for core tablets, and final dosage forms. Increasing the starch content of more than 24% allows to achieve core strength, sufficient for the subsequent deposition of the shell (4 kg, abrasion - 98%). In addition, the introduction of a starch composition having anti-friction properties, allows to reduce the content of used lubricant talc and calcium stearate to values not exceeding the allowed Pharmacopoeia GF XI (3% and 1% respectively), while maintaining the fluid properties of the granulate.

A new pharmaceutical composition is in the form of a solid dosage form coated, preferably in the form of tablets. The presence of shell gives, first, the stability of the composition during storage, second, reduces anesthetic effect of verapamil on the mucous membrane. The shell with the - -20

The dye is 0.1 to 2

Polishing agent substance - 0-15.

As the basis of the shell most acceptable was derived methyl cellulose (water-soluble methylcellulose or oksipropilmetiltselljuloza), and as fillers - tween 80 and titanium dioxide. The use of these ingredients in the stated amounts to produce a shell of a minimum weight (1-2% by weight of the core), and at the same time having the necessary strength and protecting the core from the external environment. In addition, they allow you to use as a carrier film-forming composition of the aqueous acetone instead of the commonly used mixture of organic solvents. The introduction of the membrane dye greatly improves its appearance, by giving a uniform and pleasing colors. Polishing agent substances enhance this effect, forming a glaze on the surface of the shell. The lower limit of the content of the dye is determined by the presence or absence of coloring effect, and the top, as and for the polishing agent substances, and economic feasibility. As the dye can be used tropeolin O, and as a polishing agent such as vaseline oil and wax in a ratio of 1 : 3-7.

The way procedmes sifted powders verapamil, milk sugar, and starch. The shepherd granularit, dried and milled. The granulate optivault the remainder of the starch, the talc and calcium stearate, the mixture is pressed and the resulting kernel is applied pre-prepared film-forming composition. If necessary, the tablets are treated polishing agent substances.

The obtained pharmaceutical composition complies with the requirements of the global Fund XI (in appearance, raspadaemosti, dissolution and other indicators), stable in storage and has a shelf life of over 3 years.

The invention is illustrated by the following examples:

Example 1. Mix the sifted powders verapamil (124,0 g), dry potato starch (69,5 d) and milk sugar (46,5 g) moisturize 73,3 g 5% starch paste, mix to a uniform distribution of moisture, wipe through the perforated grid pellet hole diameter of 3.0 mm, and dried. Dry granules grind, optivault the mixture of 2.44 g of talc, 1.22 g of calcium stearate and 0.61 g of potato starch and tabletirujut. The obtained kernel with an average weight 0,160 g sprayed film-forming composition containing 2.4% of water-soluble methylcellulose, 1% tween 80, 0.6% of titanium dioxide and 0.05% of tropeolin O in aqueous acetone, then obrabecim who satisfy the requirements of the pharmaceutical agent.

Examples 2 to 5 receive the same. The obtained tablets meet the requirements of the pharmaceutical agent. The results are presented in the table.

1. Pharmaceutical composition having cardiovascular action, including a core containing verapamil and pharmaceutically acceptable additives target, and a shell, wherein the target additives it contains starch, lactose, talc and stearinovokisly calcium in the following ratio of ingredients in the core, wt.%:

Verapamil - 40,9 - 59,1

Starch - 24 - 35

Milk sugar - 13,5 - 24,0

Talc - 0,1 - 3,0

Calcium stearinovokisly - 0,1 - 1,0

and the shell is derived from methyl cellulose, tween 80, titanium dioxide, dye and, optionally, a polishing agent of substances.

2. The pharmaceutical composition under item 1, characterized in that the shell contains components in the following ratio, wt.%:

The methylcellulose or oksipropilmetiltselljuloza - 50 - 70

Twin 10 - 30

Titanium dioxide - 5 - 20

Dye - 0,1 - 2,0

Polishing agent substances - 0 - 15

3. The pharmaceutical composition according to p. 2, characterized in that it contains in the shell as a dye, tropeolin About and as a polishing agent is p. 1 - 3, characterized in that it is made in the form of tablets.

 

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