EA035073B1 - Pharmaceutical composition having nootropic activity in the form of a rapidly dissolving effervescent tablet, and method for preparation thereof - Google Patents

Abstract

The invention relates to pharmaceutical industry and medicine and concerns the preparation of a pyracetam pharmaceutical composition having nootropic activity, namely, a drug in the form of effervescent tablets used to prepare a solution for internal use. The invention consists in that the provided pharmaceutical composition comprises an active ingredient pyracetam (2-(2-oxo-1-pyrrolidinyl)acetamide), a filler, a gas-forming mixture, a binder, a lubricant, and, if required, substances which improve water permeability, taste and odour correctives, and provides a method for the preparation of a pharmaceutical formulation. The pharmaceutical composition is made in the form of rapidly dissolving effervescent tablets and is prepared using a direct compression method or wet granulation method.

Description

The invention relates to medicine, specifically to the pharmaceutical industry, and relates to the creation of a pharmaceutical composition based on a substance having nootropic activity, and a method for its preparation and use.

Nootropic drugs (Greek noos - thinking, reason; tropos - direction) are drugs that have a specific positive effect on the higher integrative functions of the brain. They improve mental activity, stimulate cognitive functions, learning and memory, increase brain resistance to various damaging factors, including extreme stress and hypoxia. In addition, they have the ability to reduce neurological deficits and improve corticosubcortical connections.

In the mid-1960s, UCB pharmaceutical in Belgium developed piracetam, which was originally used to treat motion sickness. Between 1968 and 1972, thanks to extensive research on piracetam, its ability to facilitate learning, prevent amnesia caused by hypoxia and electric shock, and accelerate the return of EEG to normal in animals undergoing hypoxia was discovered. By 1972, 700 articles on piracetam were published. In 1972, its pharmacological uniqueness led Giurgea, the leader of the piracetam research team and research coordinator at UCB, to formulate a completely new category of nootropic drugs. Piracetam is still the reference nootronic drug and has wide clinical use.

Dosage forms are known containing piracetam as an active substance, such as a solution for intravenous and intramuscular administration, a solution for infusion, a solution for oral administration, capsules, tablets, film-coated (RU 2205631 C1, RU 2224514 C2, RU 2203660 C1, etc. .).

All of these dosage forms are used in medicine for the symptomatic treatment of intellectual-mnestic disorders in the absence of an established diagnosis of dementia, a decrease in the manifestations of cortical myoclonia in patients sensitive to piracetam, both as monotherapy and as part of complex therapy (http://grls.rosminzdrav.ru / GRLS. Aspx? RegNumber = & MnnR =% d0% 9f% d0% b8% d1% 80% d0% b 0% d1% 86% dO% b5% d1% 82% dO% bO% dO% bc & lf = & TradeNmR = & OwnerName = & MnfOrg = & Mnf OrgCountry = & isfs = 0 & isND = 1 & regtype = & pageSize = 10 & order = RegDate & orderType = desc & pageNum = 1).

A disadvantage of the known dosage forms of piracetam in the form of injections is pain, the risk of infection, the risk of embolism due to the ingress of solid particles or air bubbles, the need to attract qualified personnel.

A disadvantage of the known dosage forms of piracetam in the form of coated tablets is that with prolonged course use of high doses of the drug (a single dose is 400-1200 mg, a daily dose is 1200-6000 mg), the patient has to take inside a large tablet with a size of 12 or more mm (dose of 400 mg) to 21 mm (dose of 1200 mg) up to 5 times a day.

Currently, one of the most popular pharmaceutical forms for the administration of drugs, vitamins and minerals is the so-called effervescent tablet. In addition to commercial reasons, the spread of this form from the point of view of pharmaceutical action is facilitated by a number of factors: reduction of gastric irritation, improved absorption, etc. When such tablets are dissolved in water, an effervescent (or carbonated) drink is obtained.

In particular, a drug in the form of effervescent tablets is known, described in CN 102018683, publ. 2011.04.20. The tablets contain piracetam, citric acid, sodium bicarbonate, oligosaccharides and other edible sugars. This source can be indicated as the closest analogue (prototype) of the claimed invention.

The tablets according to the prototype have good stability, easy adsorption, good taste, and they can be easily dissolved in water without stirring. However, the inclusion of sugars leads to technological difficulties during pressing, namely increased stickiness and then instability and caking during storage.

The purpose of the present invention is a radical solution to the problem of frequent intake of high daily doses of piracetam by creating an effective pharmaceutical composition in dosage form effervescent tablets used to prepare a solution for internal use.

According to the claimed invention, a pharmaceutical composition is provided in the form of instant effervescent tablets for the preparation of a solution for internal use, comprising the active substance piracetam (2- (2-oxo-1-pyrrolidinyl) acetamide), a filler, a gas-forming mixture, a binder, a lubricant, and, if necessary, substances, improving water permeability, flavor and odor flavoring, as well as a method for producing a composition by direct compression or separate wet granulation.

The technical result to which the invention is directed is to develop a composition and method for producing a drug in the form of instant effervescent tablets,

- 1 035073 used for the preparation of a solution for internal use, containing piracetam as the active substance, soluble in water at room temperature for less than 5 minutes, stable when stored for at least 2 years.

The inventive composition allows to overcome technological difficulties associated with the pressing of effervescent tablets.

The invention provides a composition that is stable during storage and has optimal bioavailability, high nootropic activity of the active substance and its accompanying pharmacological effects.

The specified technical result is achieved by the fact that the developed pharmaceutical composition in the form of effervescent tablets used for the preparation of a solution for internal use contains piracetam and pharmaceutically acceptable excipients as an active substance: a filler, a gas-forming mixture, a binder selected from polyvinylpyrrolidone K-25, K -30 or copovidone, a lubricant, which is a polyethylene glycol 4000-20000, if necessary, a substance that improves water permeability, flavor and odor flavorings in the following ratio of components, in wt.%:

piracetam - 20.0-50.0;

filler - 7.5-38.0;

gas-forming mixture 36.2-55.8;

a substance that improves water permeability - 0,0-0,05;

lubricant - 3.0-5.6;

binder - 1.0-1.3;

flavor flavoring - 0.0-1.5;

flavor odor - 0.0-0.5.

The indicated technical result is also achieved by the fact that the method for producing a drug having nootropic activity in the form of instant effervescent tablets used for preparing a solution for internal use includes the following stages: preliminary grinding of components with an average particle size of more than 60 mesh; mixing the components or granulating a mixture of piracetam, filler and a gas-forming mixture with a solution of a binder in ethyl or isopropyl alcohol; when applying the wet granulation method, additionally drying the granulate at a temperature of 40-85 ° C to a residual moisture content of not more than 0.3%; granulate calibration up to 0.8-1.4 mm; dusting the mass for tabletting with a lubricant; tableting with relative humidity in the room no more than 25%. As a rule, the resulting tablets have a weight of 1200-3000 mg.

The drug is made in a convenient form in the form of instant effervescent tablets that meet the requirements of the 13th edition of the State Pharmacopoeia.

The pharmaceutical substance piracetam has nootropic activity, it is used in medicine for the symptomatic treatment of intellectual and mnestic disorders in the absence of an established diagnosis of dementia, and for the reduction of manifestations of cortical myoclonus in patients sensitive to piracetam, both as monotherapy and as part of complex therapy.

The gas-forming mixture consists of edible organic acid (such as tartaric, citric, or known analogs, or a mixture thereof, or a mixture of their stereoisomers) and a base, such as an inorganic carbonate, for example potassium carbonate, magnesium carbonate, sodium bicarbonate. Preferably, citric, tartaric, fumaric or adipic acid and sodium bicarbonate are used, which provide rapid disintegration of the tablet in water, increased stability over the entire shelf life. Even more preferably, stereoisomers of tartaric acid and sodium bicarbonate are used as the gas-forming mixture.

In the composition, mannitol, sorbitol, hydrated dextran and the like can be used as filler.

If a water permeability improving agent is used, it may be sodium lauryl sulfate or an emulsion of simethicone. As an example, sodium saccharinate or aspartame may be selected as flavoring agents for flavor, lemon flavoring may be used as flavoring agents for odor.

The use of a filler in the composition provides the necessary profile for the dissolution of piracetam in water, improves the technological parameters of the mass for tabletting and tablets.

The introduction into the composition of the tablet of substances that improve water permeability, contributes to a more rapid penetration of water into the tablet, thereby accelerating its disintegration.

Since the manufacture of effervescent tablets requires avoiding the interaction of gas-forming components, a number of technological difficulties arise. In particular, preferential direct compression is difficult due to the large difference between the bulk densities of the materials used, which can lead to desegregation of the tablet powder; the need to grind the active substance leads to a problem associated with the uniformity of the composition, and the use of sugars leads to stickiness and the need to use lubricants. In the technology of effervescent tablets using granulation, it is necessary to ensure the stability of both the gas-forming mixture and the active substance.

- 2 035073

The traditional lubrication of an effervescent tablet is problematic due to the lipophilicity of known lubricants. Insoluble particles appear on the surface of the water after disintegration in the form of a foamy thin layer.

According to the invention, high molecular weight polyethylene glycol is used as a lubricant in the composition, which unexpectedly in the proposed composition avoided all of these drawbacks for tablets with piracetam. The use of polyethylene glycol 4000-20000 as a lubricant reduces the adhesion of the tablet mass to the press tool and helps to produce tablets with a satisfactory appearance without chips and sticks, and also improves the technological properties of the tablet mass, which makes it possible to obtain effervescent tablets on high-speed industrial rotary presses.

The use of polyvinylpyrrolidone K-25, or K-30, or copovidone as a binder provides plastic granules, which makes it possible to obtain tablets with satisfactory indicators of strength, appearance, namely tablets are obtained without chips and external defects. In addition, it was found that when using polyvinylpyrrolidone K-25, or K-30, or copovidone together with the acid and main components of the gas-forming mixture in the claimed quantitative ratio, it increases the shelf life and stability of the quality indicators of the drug.

The invention is characterized by the following examples.

Example No. 1.

The weight of the tablets is 1200 mg in the following ratio of components, in wt.% (Preferred composition):

piracetam - 50.0;

mannitol - 9.8;

gas-forming mixture - 36.2, including citric acid - 16.9;

sodium bicarbonate - 19.3;

polyethylene glycol 4000 - 3.0; polyvinylpyrrolidone K-25 - 1.0.

Piracetam, mannitol, citric acid, sodium bicarbonate, polyvinylpyrrolidone K-25, polyethylene glycol 4000 are sieved and mixed. The resulting tablet mass is pressed onto a tablet press using a chrome plated press tool into tablets with a diameter of 15 mm and a height of 4 mm. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 2 minutes, the pH of the solution is 5.7.

Example No. 2.

The weight of the tablets is 1800 mg in the following ratio of components, in wt.%:

piracetam - 33.3;

sorbitol - 21.4;

gas-forming mixture - 38.0, including citric acid - 24.0;

sodium bicarbonate - 14.0;

aspartame - 1.0;

polyethylene glycol 6000 - 4.0;

polyvinylpyrrolidone K-30 - 1.3;

Flavor Lemon - 1.0.

Piracetam, sorbitol, citric acid, sodium bicarbonate, polyvinylpyrrolidone K-30, polyethylene glycol 6000, aspartame and lemon flavor are sieved and mixed. The resulting tabletting mass is pressed onto a tablet press using a chrome-plated press tool into tablets with a diameter of 20 mm and a height of 3.8 mm. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 3 minutes, the pH of the solution is 5.2.

Example No. 3.

The mass of the tablet is 1400 mg in the following ratio of components, in wt.%:

piracetam - 42.9;

mannitol - 10.7;

gas-forming mixture - 40.7, including citric acid - 19.3;

sodium bicarbonate - 21.4;

polyethylene glycol 20,000 - 4.7; polyvinylpyrrolidone K-25 - 1.0.

- 3 035073

Preliminarily, citric acid is ground, sodium bicarbonate and piracetam are sieved and mixed. Granulated with a 15% solution of polyvinylpyrrolidone K-25 in ethanol. The obtained granulate is dried in a shelf dryer at 40 ° C to a residual moisture content of 0.2%. The tablet mass was dusted with pre-sieved mannitol, polyethylene glycol 20,000. The resulting tablet mass was pressed on a tablet press using a chrome-plated press tool into tablets with a diameter of 17 mm and a height of 3.9 mm. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 4 minutes, the pH of the solution is 5.9.

Example No. 4.

The weight of the tablets is 1920 mg in the following ratio of components, in wt.%:

piracetam - 31.2;

sorbitol - 7.8;

gas-forming mixture - 55.8, including tartaric acid - 24.6;

sodium bicarbonate - 31.2;

polyethylene glycol 20,000 - 3.3;

copovidone - 1.3;

flavoring Lemon - 0.5;

sodium lauryl sulfate - 0.05.

Pre-tartaric acid is crushed, sodium bicarbonate, sorbitol and piracetam are sieved and mixed. Granulated with a 17% solution of copovidone in ethyl alcohol. The resulting granulate is dried in a shelf dryer at 50 ° C to a residual moisture content of 0.1%. The powder for tabletting is pre-dusted with pre-sieved sodium lauryl sulfate, polyethylene glycol 20,000 and Lemon flavoring. The resulting tabletting mass is pressed onto a tablet press using a chrome plated press tool into tablets with a diameter of 23 mm and a height of 3.4 mm. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 2.5 minutes, the pH of the solution is 5.5.

Example No. 5.

The weight of the tablet is 3000 mg in the following ratio of components, in wt.%:

piracetam - 20.0;

hydrated dextrate - 38.0;

gas-forming mixture - 38.0, including tartaric acid - 24.0;

sodium bicarbonate - 14.0; polyethylene glycol 4000 - 3.0; polyvinylpyrrolidone K-30 - 1.0.

Piracetam, hydrated dextrate, tartaric acid, sodium bicarbonate, polyvinylpyrrolidone K-30, polyethylene glycol 4000 are sieved and mixed. The resulting tabletting mass is pressed onto a tablet press using a chrome plated press tool into tablets with a diameter of 25 mm and a height of 4 mm. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 3 minutes, the pH of the solution is 6.0.

Example No. 6.

The weight of the tablet is 2000 mg in the following ratio of components, in wt.%: Piracetam - 30.0;

sorbitol - 7.5;

gas-forming mixture - 53.6, including tartaric acid - 23.6;

sodium bicarbonate - 30.0; polyethylene glycol 6000 - 5.6; polyvinylpyrrolidone K-25 - 1.25; flavoring Lemon - 0.5; Simethicone emulsion - 0.05; aspartame - 1.5.

Pre-tartaric acid is crushed, sodium bicarbonate, sorbitol, aspartame and piracetam are sieved and mixed. Granulated with a 15% solution of polyvinylpyrrolidone K-25 and simethicone emulsion in isopropyl alcohol. The resulting granulate is dried in a shelf dryer at 50 ° C to a residual moisture content of 0.1%. The powder for tabletting is dusted with pre-sieved polyethylene glycol 6000 and lemon flavoring. The resulting tabletting mass is pressed onto a tablet press using a chrome-plated press tool into tablets with a diameter of 20 mm and

- 4 035073 4.5 mm high. The whole process is carried out in rooms with a relative humidity of not more than 25%. The disintegration of the tablets is 3.5 minutes, the pH of the solution is 5.6.

Example No. 7.

A study of the nootropic effects of the new form was carried out on human volunteers, aged 34-45 years. The following cognitive function research methods were used in the experiment: short-term memory was studied by the method of memorizing ten simple words proposed by A.R. Luria, the study of switching attention in an active choice of useful information was carried out using Schulte tables. The volunteers were offered five squares with numbers from one to twenty-five; in each square, it was necessary to cross out the numbers in increasing order. The processing time of each square and the average time to search for numbers in a square were fixed.

The experiments showed that the introduction of 1 tablet 1 time per day for 4 weeks significantly increased the attention and short-term memory of the subjects when testing both at the beginning and at the end of the working day. There was an increase in the speed of mental reactions, a reduction in the time taken to complete the task, a decrease in the number of errors, and a decrease in fatigue.

Example No. 8.

The tablets of examples No. 1-6 were put into storage. The study was carried out in accordance with GF XII, part 1 Shelf life of drugs. LF samples were stored in propylene tubes with a snap-on stopper cap made of low density polyethylene containing a drying agent. The test samples were stored in a dry, dark place at a temperature of no higher than 25 ° C.

On the day of manufacture and during storage (every 6 months of storage under natural conditions), the LF samples were analyzed by the following indicators: appearance, authenticity, quantitative content of JIB, disintegration, pH value of the aqueous solution and, in addition, for granules, the determination of bulk density, flowability, angle natural slope, residual moisture. The table discloses a number of these characteristics.

The samples were characterized by the constancy of the basic characteristics throughout the entire shelf life of 2 years. As for the tablets of the prototype, the indicators for flowability, disintegration and pH deteriorated by an average of 10%.

In addition, during storage, the loss of carbon dioxide in the case of the prototype after 6 months amounted to 1% of the weight of the tablet, in the case of example 1 - not more than 0.2%.

Thus, the proposed drug is stable, effective and convenient and can be obtained on an industrial scale and is widely used in medical practice.

The stability of the quality of the drug Piracetam effervescent tablets, 600 mg for 2 years

Series No. Expiration date, year Analysis Date Quality indicators Description Authenticity Average tablet weight (2000 mg ± 5%) Disintegration, min. (no more than 5 min.) ! Description of the drug solution pH (4.0 - 6.0) Related impurities Dosing uniformity Microbiological purity Quantitative determination, mg (from 570 to 630 mg.) Any single unidentified impurity (not more than 0.5%) The amount of impurities (not more than 1%) 1 2 3 4 5 6 7 8 9 10 eleven 12 thirteen 14 E010215 (release date 02/20/2015) 0 02/20/2015 Round, flat-cylindrical tablets, white or almost white, interspersed, chamfered on both sides. Grungy. With a characteristic smell of lemon. Acc. Acc. 2 Acc. 5.72 0.04 0.051 Acc. Acc. 621.4 0.2 5 05/19/2015 Acc. Acc. 3 Acc. 5.65 0,041 0,052 Acc. Acc. 622.7 0.5 08/19/2015 Acc. Acc. 2 Acc. 5.57 0,043 0.050 Acc. Acc. 614.5 0.7 5 11/19/2015 Acc. Acc. 2 Acc. 5.81 0.04 0,049 Acc. Acc. 615.8 1 02/18/2016 Acc. Acc. 3 Acc. 5.65 0,038 0,053 Acc. Acc. 618.4 1,5 08/20/2016 Acc. Acc. 3 Acc. 5.46 0,039 0,054 Acc. Acc. 617.3 2 02/19/2017 Acc. Acc. 3 Acc. 5.19 0,042 0,052 Acc. Acc. 616.9 2.2 5 05/20/2017 Acc. Acc. 2 Acc. 5.34 0,043 0,052 Acc. Acc. 617.2

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1 2 3 4 5 6 7 8 9 10 eleven 12 thirteen 14 E020215 (release date 02/20/2015) 0 02/20/2015 Round, flat-cylindrical tablets, white or almost white, interspersed, chamfered on both sides. Grungy. With a characteristic smell of lemon. Acc. Acc. 3 Acc. 5.47 0,038 0,050 Acc. Acc. 618.4 0.2 5 05/19/2015 Acc. Acc. 2 Acc. 5.44 0,039 0.051 Acc. Acc. 615.8 0.5 08/19/2015 Acc. Acc. 2 Acc. 5.81 0,041 0,049 Acc. Acc. 618.4 0.7 5 11/19/2015 Acc. Acc. 3 Acc. 5.65 0,040 0,053 Acc. Acc. 617.3 1 02/18/2016 Acc. Acc. 3 Acc. 5.46 0,043 0,054 Acc. Acc. 616.9 1,5 08/20/2016 Acc. Acc. 3 Acc. 5.19 0,041 0,052 Acc. Acc. 617.2 2 02/19/2017 Acc. Acc. 2 Acc. 5.34 0,042 0,052 Acc. Acc. 617.3 2.2 5 05/20/2017 Acc. Acc. 3 Acc. 5.47 0,042 0,050 Acc. Acc. 616.9 E030215 (release date 02/20/2015) 0 02/20/2015 Round, flat-cylindrical tablets, white or almost white, interspersed, chamfered on both sides. Grungy. With a characteristic smell of lemon. Acc. Acc. 2 Acc. 5.77 0,039 0,049 Acc. Acc. 618.4 0.2 5 05/19/2015 Acc. Acc. 2 Acc. 5.81 0,038 0,053 Acc. Acc. 617.3 0.5 08/19/2015 Acc. Acc. 3 Acc. 5.65 0,039 0,054 Acc. Acc. 616.9 0.7 5 11/19/2015 Acc. Acc. 2 Acc. 5.46 0,041 0,052 Acc. Acc. 617.2 1 02/18/2016 Acc. Acc. 2 Acc. 5.19 0,042 0,052 Acc. Acc. 618.4 1,5 08/20/2016 Acc. Acc. 2 Acc. 5.34 0,040 0,050 Acc. Acc. 615.8 2 02/19/2017 Acc. Acc. 3 Acc. 5.47 0,042 0,054 Acc. Acc. 618.4 2.2 5 05/20/2017 Acc. Acc. 3 Acc. 5.88 0,041 0,052 Acc. Acc. 617.3

CLAIM

Claims (5)

CLAIM 1. The pharmaceutical composition in the form of an effervescent tablet for the preparation of a solution for internal use, containing piracetam and pharmaceutically acceptable excipients as the active ingredient, characterized in that it contains excipients not containing sugar, gas-forming mixture, a binder selected from polyvinylpyrrolidone K -25, K-30 or copovidone, a lubricant representing polyethylene glycol 4000-20000, with the following components, in wt.%: piracetam - 20.0-50.0; sugar free filler - 7.5-38.0; gas-forming mixture 36.2-55.8; lubricant - 3.0-5.6; the binder is 1.0-1.3. 2. The pharmaceutical composition according to claim 1, characterized in that it further comprises a substance that improves water permeability in an amount of up to 0.05 wt.%, Flavor flavor in an amount of up to 1.5 wt.% And odor flavor in an amount of up to 0.5 wt. .% of the total weight of the tablets. 3. The pharmaceutical composition according to claim 2, characterized in that it contains sodium lauryl sulfate or a simethicone emulsion as a substance that improves water permeability 4. A method of obtaining a pharmaceutical composition in the form of effervescent tablets used to prepare a solution for internal use according to claim 1, characterized in that it includes the following stages: preliminary grinding of components, the average particle size of which exceeds 60 mesh; mixing components; tableting with relative humidity in the room no more than 25%. 5. A method of obtaining a pharmaceutical composition in the form of effervescent tablets used to prepare a solution for internal use according to claim 1, characterized in that it includes the following stages: preliminary grinding of components, the average particle size of which exceeds 60 mesh; granulating a mixture of piracetam, a sugar-free filler and a gas-forming mixture with a solution of a binder in ethyl or isopropyl alcohol; drying the granulate at a temperature of 40-85 ° C to a residual moisture content of not more than 0.3%; granulate calibration up to 0.8-1.4 mm; dusting the mass for tabletting with a lubricant; tableting with relative humidity in the room no more than 25%.