Pharmaceutical solid composition having anti-arrhythmic activity, and how you can get

 

(57) Abstract:

The pharmaceutical composition contains, as active compounds potassium Asparaginate and magnesium Asparaginate. As an auxiliary inert substances it contains lactose, starch, magnesium stearate and talc in amounts to 32.4 32.8 per cent by weight of these active compounds. Pharmaceutical solid composition with antiarrhythmic activity produced by the method of granulation. Preferably the composition is made in the form of tablets. New composition and method provide quality tablets in accordance with the requirements of the State Pharmacopoeia strength, solubility and raspadaemosti. 2 S. and 2 C.p. f-crystals.

The invention relates to medicine, more precisely to the pharmacy, and can be used for the preparation of solid pharmaceutical compositions, the active compound which is asparagine.

Assume that asparagine is the carrier of potassium and magnesium ions and facilitates their penetration into the intracellular space. Proceeding in the cell, Asparaginate included in the processes of metabolism, improves blood circulation and metabolic processes in the heart muscle. Magnesium ion contributes shows the tract through the mouth (ros). The advantage of this way is easy to use as it does not require the help of medical staff, as well as comparative safety and absence of complications specific for parenteral administration.

When administered orally, the drug must pass through a series of biological cell membranes (mucous membrane of the stomach, liver and so on) and only part of it gets into the blood system. The effect of the drug depends largely on how big this part. This indicator characterizes the bioavailability of the drug. The bioavailability of a drug is influenced not only by the route of administration of the drug, but biopharmaceutical factors (dosage form, its composition, characteristics of the production technology of the drug).

Mostly solid dosage forms for oral administration comprise one or more pharmaceutically active compounds and auxiliary inert substances, which include solvents. fillers, diluents, preservatives and stabilizers, binders and sliding substances, which largely determine the rate of release of pharmaceutically active compounds, speed and Panangin", containing potassium Asparaginate and magnesium Asparaginate produced in the form of pills and capsules (Mashkovsky M Doctor of medicine, Manual for doctors. 14th edition, revised, corrected and augmented. Moscow: New wave., 2000, so 2, S. 149).

Known domestic product "Asparkam" containing 0,175 g potassium Asparaginate and magnesium Asparaginate produced in the form of tablets (Mashkovsky M D Drugs. Manual for doctors. 14th edition, revised, corrected and augmented. Moscow: New wave, 2000, so 2, S. 149).

Known solid dosage form (solid pharmaceutical composition "Asparkam, containing potassium Asparaginate 0,175 g and magnesium Asparaginate 0,175, the Drug "Asparkam", selected as a prototype, produced by JSC "uralbiopharm", , Ekaterinburg. The form of the product is made in the form of tablets.

Analyze known solid dosage form is not possible, because information about pharmaceutical composition in the patent and scientific literature is not found.

A method of obtaining tablets "Asparkam" by pressing the finished tablet weight (TU 84-08628424-686-97), produced by the NGO Pornololitasc composition and as a consequence the problem of formiruemoi and the average weight of the tablets. When this tablet was fragile, such at packing, collapsing in the package during storage.

The most common ways of obtaining tablets are three technological scheme: wet granulation, dry granulation and direct pressing (Technology of medicinal forms./Edited by Ivanova L. A. Medicine, 1991, so 2, S. 142).

The closest but the technical nature of the proposed facility is a method of wet granulation, comprising the following steps: mixing ingredients, moisturizing, granulating, drying, apadravya, tableting, which is selected as a prototype.

The objective of the proposed technical solution is the creation of a solid pharmaceutical composition having anti-arrhythmic activity, containing as active compound of potassium and magnesium Asparaginate that would satisfy all the requirements of the standard pharmaceutical agent.

Problem solving and advantages of the invention ensue from the subsequent detailed description of the solid pharmaceutical compositions on the basis of Asparaginate, method of producing solid dosage forms of the salts kaliam, that solid pharmaceutical composition having anti-arrhythmic activity, containing as active compound of potassium and magnesium Asparaginate and auxiliary inert substances according to the invention as an auxiliary inert substances it contains lactose, starch, magnesium stearate, talc, taken in an amount to 32.4 32.8 per cent by weight of active compounds, in the following ratio, wt.%:

Magnesium Asparaginate - 33,6-33,8

Potassium Asparaginate - 33,6-33,8

Lactose - 10,0-20,0

Starch - 8,0-15,0

Magnesium stearate - 0,5-1,0

Talc - 0,5-3,0

In addition, the problem is solved due to the fact that in a method of producing solid pharmaceutical composition having anti-arrhythmic activity, containing as active compound of potassium and magnesium Asparaginate and auxiliary inert substances, including the preparation of raw materials, obtaining mass for tabletting, tableting, according to the invention, the receiving weight for tabletting carried out sequentially by mixing magnesium Asparaginate with lactose and starch, moistening the mixture with a humidifier, mostly 10-15% solution of starch paste at a mass ratio of the humidifier to wvu, containing potassium Asparaginate, starch, magnesium stearate and talc.

To solve the problem in the method according to the invention in the process of getting mass for tabletting spend the dry starch in the following amounts, wt.%:

- when mixing 50,3 with 52.0%;

- when cooking 10-15% solution of starch paste 14,7-9,8;

when dusting 35-38,2%.

The task is also solved by a method according to the invention the solid pharmaceutical composition is made in the form of tablets.

The claimed pharmaceutical solid composition is a drug coronelismo and antihypoxic action and can be used in the treatment of hypokalemia. As adjunctive therapy for the claimed pharmaceutical solid composition can be used for angina, myocardial infarction, heart failure, and arrhythmias.

The active compounds in the inventive pharmaceutical solid composition is potassium Asparaginate and magnesium Asparaginate.

Properties and quality of the finished dosage form - pill largely depends on an auxiliary inert substances, so magatelli inert substances contains lactose, starch, magnesium stearate, talc. The composition and quantity of the inert auxiliary substances are optimal and identified experimentally.

In addition, the proposed ratio connection is active and inert auxiliary substances also is best found experimentally and provided quality tablets with high therapeutic effect of the active compounds that meet the requirements of the State Pharmacopoeia XI strength, solubility, raspadaemosti etc.

Failure to comply with the limit of the ratio of one of the components of the composition in compliance with the proposed limits of the ratios of all other components of the composition does not allow to achieve a positive effect.

The claimed pharmaceutical solid composition structurally is compressed between the granules mainly from 0.6 to 1.5 mm; obtained as follows: magnesium Asparaginate - active component is mixed with the lactose and starch as a filler in the amount of 50,3% by weight of the total starch present in the claimed composition. As the humidifier use 10-15% solution of starch paste (14,7 mA is magnesium stearate, talc, starch, taken mainly in the amount of 35% by weight of the total starch present in the claimed composition.

The obtained granules are pressed to each other by formation of a solid pharmaceutical composition, having a form of tablets.

Introduction magnesium Asparaginate inside the granules, and potassium Asparaginate on stage dusting eliminates the appearance of "marbling" of tablets for the production and storage process, i.e., to meet the requirements of FS.

The inventive composition includes additives that facilitate the pressing of powder materials and give the tablets strength. As such fillers in the inventive compositions use a combination of lactose and starch. Lactose is a disaccharide that is suitable for pressing, in particular from the viewpoint of flowability preferred anhydrous lactose, although you can apply water lystrosaurus lactose. The presence in the claimed composition specified number lactose largely determines the speed of granulometry, and the introduction of the granules of starch, preferably corn, significantly increases the rate of release of active compounds.

The presence in the claimed composition specified number of starch largely determines the rate of release (the rate of acceleration of the disintegration of the tablet after swallowing to ensure rapid release of the active compound), the speed and completeness of absorption of the active compounds (bioavailability), as well as its stability. In addition, the starch provides the conditions for the penetration of liquid (water and/or digestive juices) into solid pharmaceutical composition. The reduction of starch (less than 8.0% by weight of the tablet) leads to an increase in time raspadaemosti tablets, and the increase in starch (more than 15,0% by weight of the tablet) to reduce the strength, stability and increase the abrasion of the tablets.

As moving substances in the inventive compositions use an auxiliary inert substances that improve the process of formation of solid pharmaceutical composition, reduce the friction between the particles inside the tablet, reducing the reaction forces that appear on the walls of the matrix. In predlagaet in the inventive composition reinforce the slide and provide a uniform filling of the space in the matrix, while receiving the tablets with a constant weight.

The presence in the inventive composition stearate provides the effect of slip required at the stage of pressing, as it is the effect of slip causes the uniformity of the mechanical and physical properties in the volume of the dosage form, thereby facilitating the formation of the smooth surface of the tablet. However, since magnesium stearate hinders the penetration of digestive fluids in the porous structure of the dosage form and worsens raspadaemost, granules claimed composition Audrey mixture of stearate, taken in an amount of not more than 1 wt.h. starch, taken in an amount of 11.4% of the total mass contained starch, and talc, taken not more than 3 wt.h.

In addition, talc provides not only the effect of the sliding, but also gives the finished tablets Shine.

In this case a reduction stearate (less than 0.5% by weight of the tablet) and talc (less than 0.5% by weight of the tablet) leads to ethnological tabletting process, i.e. to the deterioration of the sliding properties of the granulate in the tabletting process, and increasing the amount of lubricating substances: magnesium stearate (more than 1.0% by weight tabla is to mass for tabletting and in addition, prohibited by the requirements of the State Pharmacopoeia XI release 2.

As can be seen from the above, only the proposed intervals of the ratios of components are optimal and can achieve a non-toxic drug in tablet form that meets the requirements of normative-technical documentation on all counts.

New in the proposed method is that getting mass for tabletting carried out sequentially by mixing the active ingredient magnesium Asparaginate with lactose and starch, moistening the mixture 10-15% solution of starch paste, wet granulation, drying, dry granulation and powder tablet mass of the mixture containing the second active ingredient potassium Asparaginate, starch, magnesium stearate and talc.

The specified concentration of the starch paste is essential. Increasing the concentration increases the viscosity of the solution and the threat of nephromas humidifier in irrigated mass and, therefore, stains PA surface tablets. The decrease in concentration is impractical, because the paste loses its astringent properties, which impairs subsequent granulation and strength of the La and irrigated mass provides good adhesion of the active compound and the inert auxiliary substances, which contributes to a significant increase in the durability of tablets and thereby reduces their rejection in the process of packing.

The introduction of the active ingredient potassium Asparaginate part apadravya mixture allows to eliminate the influence of moisture starch paste on the stage of humidity and temperature on the stage of drying the wet granulate, which increases the stability of potassium Asparaginate.

Thus, the combination of these features in the claimed composition was allowed to achieve its raspadaemosti when administered for 7-10 minutes. The solubility of the claimed composition has considerably increased and as a consequence improved bioavailability of the active compounds. It was found experimentally that for 30 minutes in the solution passes 90-100% of asparaginates contained in the tablet.

While the claimed composition has good mechanical strength is not destroyed when the load reaches 4 kg.

The claimed technical solution and the method of its execution have differences from the prototype, therefore, meet the criteria of "novelty", do not follow explicitly studied the prior art, that is, have an inventive step.

Tablemodel "industrial applicability".

An example of a specific implementation.

Preparation of solid pharmaceutical compositions on the basis of Asparaginate carried out by preparation of raw materials, preparation of the humidifier, mixing, wetting, wet granulation, drying of the granulate, dry granulation and dusting with subsequent pelletizing.

1. Preparation of raw materials. Sift magnesium Asparaginate, potassium Asparaginate, lactose, starch, magnesium stearate, talc and dried starch 0.05 kg (5% by weight of the tablet) to 5% moisture content used for dusting.

2. Preparation of the humidifier. Prepare a 15% solution of starch paste. On the scales weigh the corn starch in the amount 0,021 kg, add water 0.05 l, and the resulting suspension is poured into 0,07 l of boiling water.

3. The mixing. On the scales weigh 0,352 kg magnesium Asparaginate, 0,082 kg of starch (18% moisture) and 0,115 kg of lactose. In the mixer load balanced components and mixed for at least 5 minutes. After mixing in the mixer serves humidifier and stirred tablets weight for 15-20 minutes to achieve uniform wetting.

4. Wet granulation. The wetted tablet cash passed through the granulator is

5. Drying of the granulate. Drying of the granulate produced in shelf vacuum dryer at a temperature of 45-50oC. During drying, an optimum residual moisture (2-3%) tablet mass.

6. Dry granulating and dusting. Outrivals the mixture is prepared as follows: in the balance weighed potassium Asparaginate in the amount of 0.36 kg, starch 5% humidity in the amount of 0.05 kg, magnesium stearate in an amount of 0.01 kg and talc in the amount of 0.02 kg of the Dried pellet mass is passed through a granulator with a diameter of grid cells of 2 mm, Then the dry granules are loaded into the mixer, add to it outrivals mixture and stirred for 15-20 minutes to evenly distribute apadravya mixture and potassium Asparaginate on the surface of the granules.

7. Tableting. The prepared tablets weight tabletirujut on a tablet press, after adjusting the average weight of the tablets and selecting the optimal pressure. During pressing of the granules starch and lactose to form the matrix, providing a quick raspadaemosti and release the body to the active compound and a sufficient strength of the tablets.

Then tablets dedust and guides on packaging.

Tablets based on cal and mark.

The average weight of the tablets 500 mg, a diameter of 11 mm and height 4 mm

Tablets of geometric shape and size meet industrial standard (OST 67-7-170-75), but the appearance, strength, dissolution, raspadaemosti and other indicators meet the requirements of the State Pharmacopoeia XI and FS 42-1701-97.

Tablets are stable in storage and have a shelf life of over 3 years.

Thus, compared with the prototype of the proposed technical solution implemented by obtaining the solid pharmaceutical composition of the salts of potassium and magnesium Asparaginate, more stable during storage, easily releases the active compound, which ensures its high bioavailability. Active ingredients: potassium and magnesium Asparaginate be introduced at different stages of the technological process to preserve their medicinal properties.

The sequence of operations and their technological options allow you to produce a solid pharmaceutical composition on the basis of Asparaginate, the quality of which meets all of the requirements for qualitative and quantitative indicators standard pharmaceutical agent.

1. Pharmaceutical firm HDMI and magnesium Asparaginate and auxiliary inert substances, characterized in that as an auxiliary inert substances it contains lactose, starch, magnesium stearate, talc, taken in an amount to 32.4 32.8 per cent by weight of active compounds, in the following ratio, wt.%:

Magnesium Asparaginate - 33,6-33,8

Potassium Asparaginate - 33,6-33,8

Lactose - 10,0-20,0

Starch - 8,0-15,0

Magnesium stearate - 0,5-1,0

Talc - 0,5-3,0

2. A method of obtaining a solid pharmaceutical composition having anti-arrhythmic activity, containing as active compounds potassium Asparaginate and magnesium Asparaginate and auxiliary inert substances, including the preparation of raw materials, obtaining mass for tabletting, tableting, characterized in that the receiving weight for tabletting carried out sequentially by mixing magnesium Asparaginate with lactose and starch, moistening the mixture 10-15% solution of starch paste, when the mass ratio of the specified humidifier to irrigated mass(20,7-21,7): (79,3-78,3), wet granulation, drying, dry granulation and powder tablet mass mixture, containing potassium Asparaginate, starch, magnesium stearate and talc, and the components are taken in the following ratio, wt.%:

Magnesium Aspar who -1,0

Talc - 0,5-3,0

3. The method according to p. 2, characterized in that in the process of getting mass for tabletting spend the dry starch in the following amounts, wt.%: when mixed 50,3-52,3, in the preparation of 10-15% solution of starch paste 14,7-13,7, when dusting 33-36.

4. The method according to p. 2, wherein the solid pharmaceutical composition is made in the form of tablets.

 

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