RS52027B - ENTEROSOLVENT ACETYLSALICYLIC ACID TABLETS - Google Patents

Abstract

Pharmaceutical formulation of acetylsalicylic acid in the form of a controlled release enterosolvent film tablet, comprising at the core of the tablet an active ingredient - acetylsalicylic acid and a surfactant - hydrogenated castor oil, which is included in the film coating of the tablet, in addition to the carrier agents (hydrophilic nose) , binding, decomposition, sliding, lubricant, filmogenic substance, plasticizer and pigment. The application contains 1 more independent and 9 dependent claims.

Description

1.Technical field

The invention belongs to the field of pharmacy, more precisely to the field of manufacturing a pharmaceutical preparation in the form of enterosolvent film tablets for human medicine.

According to the International Classification of Patents, the invention belongs to class A 61 K.

2. Technical problem

This invention protects a new pharmaceutical form, enterosolvent film tablets, with acetylsalicylic acid as an active substance, which has a specific release in a certain part of the gastrointestinal tract (proximal part of the small intestine). In this way, its irritating action on the stomach lining is prevented.

The specificity of the formulation is the presence of a surfactant (hydrogenated castor oil) in the core and coating of the tablet, which ensures better dissolution of the active substance in the part of the gastro-intestinal tract (GIT) where it will be absorbed.

3. State of the art

Preparations with acetylsalicylic acid belong to the group of analgoantipyretics, antirheumatic drugs and aggregation inhibitors. It is used in the treatment of rheumatic diseases, rheumatic and non-rheumatic inflammatory diseases of soft tissues, as an analgesic for the elimination and reduction of moderate pain, as an antipyretic for the reduction of increased body temperature of various etiologies, as an antiplatelet drug for the prevention of morbidity and mortality in certain cardiovascular and cerebrovascular diseases and disorders.

Pharmaceutical dosage forms with acetylsalicylic acid irritate the stomach due to their chemical properties, undergo chemical changes in gastric acid and enzyme action, and thus become less effective. The following therapeutic goals for the production of enteric-solvent dosage forms arise from the above-mentioned reasons:

- gastric tolerability

- time controlled release

- optimization of the length of action

- release at a specific place.

Dosage forms are exposed to different influences. Therefore, the technical objectives are as follows:

- high mechanical stability

- long shelf life

- protection of active substances sensitive to gastric fluid

- isolation of mutually incompatible active substances.

Tablet coating is one of the oldest skills in the pharmaceutical industry. It is an additional process in the production of tablets that is carried out for various reasons, with the aim of masking the unpleasant taste, smell or color of the active substance, ensuring its protection from physical and chemical influences. controls the place of its release in the body, protects the active substance from the negative impact of stomach acid, prevents incompatibilities and improves the aesthetic appearance of tablets. Filming is defined as the application of a relatively thin coating to the surface of solid pharmaceutical forms. In this way, coated tablets with essentially the same mass can be obtained. shape and size as the uncoated tablet.

Patent GB 951418 refers to the process of making tablets with extended release containing: active substance (acetylsalicylic acid, chlorporomazine, aminophylline, secobarbital, tetracycline, etc.). gelatin, acacia or PVP in the form of a solution (volatile solvents, such as methyl, ethyl or isopropyl alcohol, etc.), lipid substances in an organic solvent that condition the prolonged release of the medicinal substance (hydrogenated castor oil, glyceryl monostearate, glyceryl stearate, 12-hydroxy stearyl alcohol and microcrystalline wax).

EP 0377439 patent describes an aqueous film coating for coating granules of acetylsalicylic acid, which consists of acrylate copolymer Eudragit NE 30D-30% aqueous dispersion. PEG, HPMC. sodium um chloride. talc and water.

In patent US 3755537, the formulation of the film coating is given, consisting of a mixture of at least one hydroxyalkyl ester of α,P-unsaturated mono- or dicarboxylic acids (most often esters of acrylic or methacrylic acid) and at least one monomer that can be polymerized forming a water-insoluble homopolymer. As solvents, 2-propanol, acetone and ethyl acetate are recommended.

The process of making matrix tablets with delayed release of the active substance is covered by patent US 4351825. The active substance is mixed with other auxiliary substances and granulated with an organic solution of polymethacrylate or its aqueous dispersion. The following polymethacrylates are most often used: Fudragit<®>RS, RL. And 30D. S or L. In order to control the degree of release of the medicinal substance from the tablets, Crnina<®>HR, which is basically hydrogenated castor oil, and SteroteK<®> are most often added. hydrogenated cottonseed oil.

Granules with acetylsalicylic acid made by the classic granulation process with standard auxiliary substances (lactose, microcrystalline cellulose, pregelatinized starch, etc.) are also covered by US patent 4970081. In order to achieve zero-order kinetics and prolonged release of acetylsalicylic acid (in a dose of 40 to 100 mg) within 5 to 8 hours, the acetylsalicylic acid granules are coated dispersion composed of methylmethacrylate-ethylacrylate copolymer (Eudragit NF 30D). HPMC, sodium chloride and talc.

The preparation in the form of capsules is covered by patent US 4507276. Acetylsalicylic acid is granulated with a suitable agent for granulation (ethanol solution of PVP or ethanol-water solution of HPMC), and then the obtained granules are coated with an enterosolvcnt coating, the composition of which includes substances e.g. CAP, ethylcellulose, hydroxypropylmethylcellulose phthalate. Aquacoat and others).

Patent US 3954959 mentions the use of acrylate polymers (proprietary name Fudragit) for the production of oral preparations in the form of dragees.

Coated preparations with controlled release are covered by the patent

GB 2253348. The sc formulation consists of a core with an active substance (idazoxan, mebeverine. paracetamol, acetylsalicylic acid or betahistine) and a diameter of up to 5 mm. The tablet core is coated with a mixture consisting of a) film-forming agent poly ethyl acrylate. methyl methacrylate, triethylaminoethyl methacrylate chloride. most often Fudragit<®>RS or RF and b) at least one anionic surfactant in different ratios (100:1 to 10:1 wt./wt.). Alkylaryl sulfonate, sodium lauryl sulfate, and sulfosuccinate can be used as anionic surfactants. sulfosuccinamate. sarcosinate or taurate. The film coating makes up 15 to 60% of the mass of the tablet core.

Enteric-solvent tablets are covered by the patent JP 4346930. Acetylsalicylic acid, which is compressed into tablets, is mentioned as a model substance. The tablets are then coated with an enterosolvent film, the composition of which includes hydroxypropylmethylcellulose phthalate or methyl methacrylate-methyl acrylate copolymer and a plasticizer.

Patent US 6284268 protects the process of making a microemulsion, which involves dissolving omega-3 fatty acids and selected active substances in water, with the addition of a surfactant and under certain conditions. The resulting microemulsion is filled into soft or hard gelatin capsules. Our technological solution involves the preparation of a solution (not a microemulsion) of a binding agent (polyvinylpyrrolidone, cellulose derivatives, gelatin, tragacanth, starch paste, polyethylene glycol, alginates - which do not belong to the group of omega-3 fatty acids) and Cremophora RH 40 in an organic solvent (isopropanol, ethanol methylene chloride, acetone). This solution does not contain an active substance. The process of wet granulation does not produce microemulsions, but granules, which are then, through further processing, "embedded" into tablets. Cremophor RH 40 is also used for the production of film dispersion, which is also not a microemulsion. nor does the active substance dissolve in it. The most important difference compared to our solution is that the patent in question describes the use of surface-active substances (including Cremophor RH 40) for the production of liquid and semi-solid pharmaceutical dosage forms, while our technical solution, for the first time, describes their application in a solid pharmaceutical dosage form, tablets.

US patent 63881 12B1 describes the process of purifying a nonionic surfactant using ion exchange resins and their use for the preparation of a pharmaceutical composition, a solution of a selected active substance, from the following pharmacological groups: antineoplastics. immunosuppressants. antimycotics, liposoluble vitamins or their mixtures. The patent does not protect the pharmaceutical composition, but only mentions the possibility of incorporating the obtained solution of the active substance in the surfactant into the pharmaceutical formulation. Our patent application does not describe the process of purifying the nonionic surfactant. As an active substance, acetylsalicylic acid was used, which belongs to the group of analgoantipyretics, antirheumatics and aggregation inhibitors, and does not include any active substance from the pharmacological groups listed in patent US 6388112B1. Our solution protects the pharmaceutical form of the tablet, which is not the case with the mentioned patent.

Patent JP 59193825 describes the use of magnesium carbonate and synthetic hydrotalcite to stabilize the formulation and achieve resistance to gastric juices, rather than surface-active hydrogenated castor oil, which is the subject of our technical solution.

4. Description of the solution to the technical problem

This invention protects a new pharmaceutical form, enterosolvent film tablets, with acetylsalicylic acid as an active substance. which has a specific release in a certain part of the gastrointestinal tract (proximal part of the small intestine). In this way, its irritating action on the stomach lining is prevented.

The specificity of the formulation is the presence of a surfactant (hydrogenated castor oil) in the core and coating of the tablet, which ensures better dissolution of the active substance in the part of the gastro-intestinal tract (GIT) where it will be absorbed.

The main ingredient of the proposed formulation is acetylsalicylic acid. The lowest dose of acetylsalicylic acid is lOOmg, and the upper limit is lg. The layer with the active substance also contains other auxiliary substances compatible with acetylsalicylic acid. The amounts of auxiliary substances may vary depending on the desired dose of acetylsalicylic acid. Usually these amounts range from 50% to 90%.

Surfactants or surfactants (PAM). as solubilizers. detergents. emulsifiers, antifoaming agents, are represented in all pharmaceutical forms: liquid (injections, infusions), semi-solid (dispersion systems) and solid (tablets, capsules). These substances lower the surface tension in small amounts by absorption at the interface that forms between the two phases. In addition to the above-mentioned properties, surface-active substances increase the ability to stretch (expand) the film during application. The development of our technical solution included tests with the most commonly used surfactants: sodium lauryl sulfate, surfactants from the group of hydrogenated castor oil, such as Cremophor RH 40, Cremophor RH 60, Cremophor EL. Mechanism of action of surfactants. as wetting agents, is based on lowering the contact angle between the surface to be wetted and the liquid. The angle between a drop of liquid and the surface over which it spreads (contact angle) can have a value of 0°, when the liquid completely wets the solid surface, to 180°, when it does not wet it at all. Values between 0° and 180° indicate partial wetting. The property of surfactants to be in solution in the form of particles of colloidal size or micelles. which are formed by the association of molecules and ions, is the most significant for the solubilization process.

In solid pharmaceutical forms, tablets, surfactants can have the following functions:

1) facilitate the granulation process by increasing the wettability of hydrophobic substances.

2) accelerate the processes of decomposition, dissolution and resorption of active components, i

3) facilitate tablet coating.

The role of surfactants in the processes of tablet disintegration, dissolution and resorption of the medicinal substance is the result of numerous variable factors such as the chemical nature and concentration of surfactants. possible interaction with the active substance, potential pharmacological and effect on biological membranes.

We found that by incorporating a hydrophobic active substance in a molecular state into a filler (hydrophilic carrier), it conditions an increase in the rate of dissolution of the substance itself. A limiting factor may be the solubility of the carrier. This is explained by the fact that the hydrophobicity of the substance affects the overall wetting, and thus the dissolution of the carrier. For this reason, a hydrophilic carrier that easily wets and dissolves in the intended medium was selected in our product, and the whole process is potentiated by the presence of a long-chain non-ionic surfactant - hydrogenated castor oil. The greater the length of the surfactant's hydrophobic chain, the greater the ability to solubilize, because there is an increase in the total volume of the inner part of the micelle. From all tested tablets that have surfactants in their composition, a larger amount of acetylsalicylic acid is released (almost 100%) compared to tablets that do not contain them (about 60%). This confirms earlier statements that surfactants incorporated in solid dosage form affect the increase in the amount of released difficult-to-dissolve substance from the tablet. A concentrated surfactant solution is formed around the particles of the medicinal substance after the dissolution medium has penetrated into the interior of the tablet. Facilitated wetting, which probably occurs due to the lowering of the surface tension of the surrounding medium, potentiates the process of releasing the active substance due to the formation of a molecular solution of the active substance. Due to the prevented aggregation of particles, there is an increase in the effective (boundary) surface area of the highly hydrophobic active substance. The surfactants present reduce the contact angle between the acetylsalicylic acid particles and the solvent, thus facilitating the wetting of this substance. Wetted particles are more difficult to connect with each other, which also leads to an increase in surface area by preventing the formation of larger aggregates.

When performing the dissolution rate monitoring test. it was observed that tablets containing surfactant, when disintegrating, form a suspension of fine particles in the dissolution medium, which achieves a good dispersion of the active substance, a larger effective surface and thus a faster dissolution of acetylsalicylic acid. However, in the absence of surfactant, the tablets disintegrate into larger fragments, forming a suspension of coarse particles that settle easily.

By comparing the pharmaceutical-technological characteristics of the cores of tablets made with sodium lauryl sulfate and hydrogenated castor oil, a pronounced tendency to "fall" of tablets with sodium lauryl sulfate was observed. These tablets are less resistant to wear, which later reflects on the properties of the film tablet, and also indicates the possibility of damage during the packaging and transportation process. Considering the liquid or semi-solid consistency, hydrogenated castor oil was added during the granulation phase to the binder solution, in concentrations of 0.01 to 1.0%.

During the development of the formulation, the influence of the following factors on the pharmaceutical-technological characteristics of the tablets (variation in weight, firmness, disintegration time, friability and active substance content) was examined: the tablet manufacturing process, types and concentrations of binders, disintegrants, surfactants and lubricants.

The physical and chemical properties of the active substance play a significant role in controlling the process of its dissolution from a certain dosage form. There is a direct relationship between the surface area of the particle in contact with the dissolution medium and the dissolution rate. As the surface area increases with decreasing particle size, faster dissolution can be expected if the particles are smaller, especially when dealing with poorly soluble active substances. Micronization as one of the procedures for increasing the dissolution rate of hardly soluble substances has been known for many years. In this way, sc not only increases the interface, but also decreases the strength of the hydrodynamic binding layer surrounding the dissolved particles. It seems that the hydrodynamic microenvironment is very sensitive to changes in size and geometric shape, which is especially true for particles smaller than 5 µm. Excessive crushing of particles leads to their electrification, whereby attractive forces come to the fore, which conditions the formation of aggregates of particles. Therefore, the particle size of the active substance is defined first: particles with a size of 200 to 500 pm are represented at most 50%. and particles larger than 700 pm maximum 10%.

The significance of the influence of various factors and manufacturing procedures on the dissolution rate of the active substance must be determined individually for each substance and must be taken into account when formulating a specific dosage form. The dissolution rate of the active substance can be significantly changed when other excipients are added to it, such as fillers, binders, disintegrants, surfactants, lubricants, etc.

Most substances in the form of powder do not have a sufficiently good flowability or compressibility necessary to obtain a high-quality dosage form without prior processing, i.e. granulation. By adding some liquid for granulation or a solution of binding material (adhesive, sticky) to the powder mixture and turning it into granulate, the aforementioned difficulties are eliminated. Therefore, the wet granulation procedure was used for the production of tablets. Considering the sensitivity of active substances to the presence of water (hydrolysis, etc.), isopropanol was used as a solvent in the granulation process. Other organic solvents (ethanol, methylene chloride, acetone) can also be considered.

The formulation made by the direct compression process shows little wear resistance. It is observed that the binding agent is more effective if it is applied in the form of a solution (wet granulation). The reason why the same amount of binder is much more active in solution than in dry form is that the powder binder is not as finely divided as in solution, and therefore not every particle of the granulating powder mixture can be coated and bonded. Polymers used as binders (polyvinylpyrrolidones, gelatin, tragacanth, glucose syrup, starch, cellulose derivatives, polyethylene glycols of molecular weight 1000-6000 mg/mol - Macrogol 6000 and alginates) are also used to increase the dissolution rate of difficult-to-dissolve substances. and are used in concentrations of 0.5 to 5%.

Polymers from the polyvinylpyrrolidone group are used as binders in the production of powders, granules and

tablets (in direct compression and wet granulation procedures). Due to their good solubility in water, they do not significantly affect the time of tablet disintegration in the mentioned amounts.

Thanks to their chemical structure, they have the ability to build chemical complexes with numerous substances, including pharmacologically active substances. The complexes obtained in this way generally ensure faster dissolution of the active substance and are far more stable than the active substance itself. Two basic types of bonding play a significant role in the complexation of ligand molecules to PVP: hydrogen bonding and hydrophobic bonding by Van der Waals bonds. These other, hydrophobic bonds are relatively weak and reversible, and therefore the molecules of the active substance easily disperse from the complex in contact with the dissolution medium.

The choice of filler (hydrophilic carrier) depends on the characteristics of the active substance. Additives can have a positive or negative effect on the decomposition process, depending on their solubility. For example, the hydrophobic nature of dibasic calcium phosphate slows the penetration of liquid through the tablets, and as a result, their disintegration time is prolonged compared to tablets in which lactose was used as an easily soluble filler (hydrophilic carrier).

Lactose monohydrate, anhydrous lactose, various types of starch, various types of modified starch, cellulose, cellulose powder, sugars - sucrose are most often used as fillers, in concentrations of 5 to 30%. dextrose. and sugar alcohols - mannitol or sorbitol. The disintegration process of tablets obtained by compressing the active substance and excipients is usually promoted by adding a small amount of disintegrant. Disintegrants are usually cross-linked polymeric substances. Disintegration is a consequence of the following two processes: convective transport, in which water penetrates and fills the pores of the tablet, and diffusion process, in which the polymer swells, developing additional force.

During the decomposition process, water enters the tablet in two ways: a) most of the water enters the pores

tablets by capillary or other forces and creates pressure inside; b) the remaining water leads to the swelling of the disintegrant and other components of the tablet. It can be concluded that rapid disintegration is necessary for rapid release and dissolution of the active substance from the dosage form. Such a general attitude led some manufacturers to draw conclusions about the dissolution rate based on the dissolution test. However, the works of individual researchers have shown that this is not always true and that a correlation cannot always be established between the decomposition time and the dissolution rate. However, most researchers point to the fact that there is a correlation between the mentioned processes. In order to achieve the desired disintegration of tablets, one of the most commonly used agents for disintegration is used, such as microcrystalline cellulose, various types of starch, various types of modified starch, cellulose, cellulose derivatives, cross-linked PVP, sodium alginate. one part was added to the granulate in concentrations of 3 to 15%, while the rest was incorporated extragranularly (5-15%).

The basic purpose of using lubricants in tablets is to ensure the flow of granules or powder into the matrix of the tablet machine, to reduce the friction between the granules and the walls of the matrix during compression and when ejecting the tablet from the matrix.

However, lubricants can contribute to increase the hydrophobicity of the tablet and thus prevent the penetration of the disintegration medium. Most effective lubricants are insoluble in water. and even some water-soluble lubricants are waxy in nature and dissolve slowly, and their lubricating ability is significantly weaker compared to insoluble lubricants. In order to ensure the fluidity of the granules, colloidal silicon dioxide (0.1-1.0%) is used as a sliding agent, while stearic acid or magnesium stearate, calcium stearate is added as a lubricant. stearic acid, paraffin, talc. vegetable and animal fats, oils and waxes. PEG molecular weight 1000-6000 mg/mol and silicones, in a concentration of 0.1 to 2.0%.

Coating tablets with a film coating is carried out for several reasons: to protect the core, to mask the unpleasant taste of the active substance, to ensure easier swallowing and to achieve the targeted release of acetylsalicylic acid in the proximal part of the small intestine.

Gastroresistant, enterosolvent dressings with Eudragit<®-> are used for the gradual release of the active substance in the digestive tract from oral dosage forms. They dissolve depending on the pH value of the environment, providing optimal solutions.

Coatings that dissolve at higher pH values. for the release of the active substance in the duodenum, they contain:

-EUDRAGIT L 100-55 or

water dispersion EUDRAGIT L 30 D-55 pH value above 5.5

To release the active substance from the jejunum to the small intestine, the dressings contain:

- EUDRAGIT L 100 pH values above 6.0

or a mixture of EUDRAGIT L 100 and EUDRAGIT S 100 pH range from 6.0 to 6.5

To release the active substance near the large intestine, the linings contain:

- EUDRAGIT S 100 pH range from 6.5 to 7.5.

Controlled release of the active substance was achieved using Eudragit L 12.5 (0.5-5%). In addition to the above-mentioned acrylate polymers, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate or polyvinyl acetate phthalate can be used for the preparation of enterosolvent coatings in the concentrations mentioned above.

Hydrogenated castor oil is present in the film coating in concentrations of 0.01-1% and increases the ability of the film to stretch during application.

The quality of the film produced by the polymer can be improved by adding a plasticizer that increases the elasticity of the film. This has the effect of increasing his endurance. Polyethylene glycol - Makrogol 6000 is most often used, and tests were also performed with glycerol, propylene glycol, citrate and phthalate esters in concentrations from 0.1 to 1.0%.

Pigments and dyes are most often used to improve the aesthetic appearance of the product and as a filler to increase the total solids content of the coating system. In certain circumstances, they can also improve the physical properties of the applied film. In order to improve their efficiency, micronized pigments are applied. In the solution according to our invention, titanium dioxide was used in a concentration of 0.1 to 1.0%.

Sweeteners, odor and taste corrigents (saccharin, vanillin, allylvanillin) affect the patient's better acceptability of the product and are applied in the amount of 0.01 to 1.0%.

In order to obtain tablets with the desired pharmaceutical-technological characteristics, the manufacturing process must be carried out according to a pre-defined and validated sequence of operations: mixing, granulation. production of mass for tableting. compressing, coating and packaging. Of particular importance is the choice of appropriate equipment, primarily a high-shear mixer, which achieves the uniformity of the content of the active substance in the powder mixture, which, in addition to acetylsalicylic acid, consists of a filling agent (hydrophilic carrier) and a disintegrating agent. The powder mixture is wetted with a granulation solution. which contains a binding agent and a surfactant - hydrogenated castor oil. By applying the wet granulation procedure, a greater firmness and stability of the product is achieved within the expected shelf life. The homogeneously moistened mass is agglomerated to a maximum particle size of 4 mm.

When defining the drying conditions of the granulate, we took into account literature data that indicate a significant influence of elevated temperature on the degradation of acetylsalicylic acid. Therefore, the drying process of wet granulate is carried out in the temperature range of 40°C to 50°C. in the course of 30-40 min. in a fluidization dryer until reaching a maximum moisture content of 2%.

Grinding is a stage in the process that ensures obtaining granules of uniform size, up to 1 mm in diameter. The compression is preceded by the mixing of the granules with a disintegrant, slip and lubricant, and the biconvex shape of the tablet facilitates the filming process.

Application of an enterosolvent coating, which includes: film-forming agent, plasticizer. pigment, surfactant - hydrogenated castor oil and other pharmaceutical acceptable substances. it is carried out in a coating device with a perforated drum, at a speed of 1-15 rpm, an inlet air temperature of 10-40°C. inlet air flow rate of 10-60%, inlet air flow rate of 3000-4000 m<J>/h and nozzle opening of 0.5-3 mm.

Special attention in protecting the product from the influence of moisture from the external environment is devoted to the packaging of the preparation, enterosolvent tablets, on which its stability largely depends. The tablets are packed in a blister made of ALU/PVC and PVC/PVdC strips which. according to the latest literature data confirmed in practice, it provides the desired protection of the preparation.

In terms of in vitro release from tablets, the goal was to obtain a preparation from which after 2 hours in 0.1 mol/l HCl, a maximum of 10% of ASA will be released, and after 2 hours in a phosphate buffer (pH 6.8) - at least 85% of ASA. Such an in vitro release should enable, upon application of the preparation, the appropriate therapeutic effect of the mentioned active substance.

Stability tests were conducted on 3 reproducible, pilot batches over 6 months at 25°C and 60% relative humidity and 30°C and 75% relative humidity. The aim of the stability test is to determine whether there are changes in the active substance or the finished product under the influence of external factors, such as temperature, moisture and light, and to determine the appropriate storage conditions and expiration date of the product based on this. Based on the stability results, a product shelf life of 2 years is suggested. For the sake of illustration, we attach the results shown in Table 1.

The invention will further be illustrated by way of examples. without intending to be limited to them. EXAMPLE 1

Film tablet production

I Preparation of tablet core with acetylsalicylic acid

Cremophor (2.50 g) and Povidone (5.00 g) are easily dissolved in isopropanol (50.00 g) to obtain a clear solution (granulation solution). The following substances are mixed: acetylsalicylic acid (500.00 g), corn starch (10.00 g) and microcrystalline cellulose (30.00 g), and then the homogeneous mixture of powders is wetted with a previously prepared granulation solution. Agglomerated mass, maximum particle size up to 4 mm. is dried for 30 to 40 min in a tluidization dryer, in a stream of warm air, at a temperature of 45°C, until the optimum moisture content of the granulate of no more than 2% is reached. The dried granulate is sieved on an oscillatory granulator through a sieve of the appropriate opening size (1.00 mm). Microcrystalline cellulose (34.85), colloidal silicon dioxide (1.70 g) and stearic acid (2.95 g) are added to the sieved dry granulate, mixed in a mixer for 10 minutes. and the resulting mixture is compressed into

tablets, on a rotary tableting machine.

II The procedure of coating tablet cores with a film coating

Macrogol 6000 (1.245 g) was dissolved in purified water (5.00 g) with heating. Prepare a suspension of the following substances: talc (0.150 g), titanium dioxide (1.155 g) and isopropanol (15,000

g). The prepared solution and suspension are mixed. and then Cremophor (0.270 g) is added. Macrogol solution is poured into the resulting suspension while stirring. Pre-measured

The suspension was added to Eudragit® L 12.5% (50,000 g) and then supplemented with isopropanol (42,000 g) and acetone (26,000 g) with stirring. The tablets are coated with the prepared suspension in the rimming drum, at a speed of 1-15 rpm, an inlet air temperature of 10-40°C, an inlet air flow rate of 10-60%. the amount of incoming air flow 3000-4000 m7h and nozzle opening of 0.5-3 mm. Film-coated tablets have the following characteristics:

EXAMPLE 2

Film tablet production

The procedures for making and covering the tablet core with a film coating are the same as in Example 1. The characteristics of tablets and film-coated tablets are the same as in Example 1.

Tablets are packed in blisters made of ALU/PVC and PVC/PVdC strips.

EXAMPLE3

Film tablet production

I Preparation of a tablet core with acetylsalicylic acid The procedure for making a tablet core is carried out as in example 1.

Wear: 0.0-1%

Loss on drying: 1.5-2.5%

II The procedure of coating tablet cores with a film coating

The procedure of coating the tablet core with a film coating is carried out as in example 1. Film-coated tablets have the following characteristics:

The tablets are packed in blisters made of ALU/PVC and PVC/PVdC strips.

EXAMPLE4

Film tablet production

I Preparation of tablet core with acetylsalicylic acid

The procedure for making the tablet core is carried out as in example 1.

II The start of covering tabical cores with a film coating

The procedure of coating the tablet core with a film coating is carried out as in example 1. Film-coated tablets have the following characteristics:

EXAMPLE 5

Film tablet production

1 Preparation of tablet core with acetylsalicylic acid

The procedure for making the tablet core is carried out as in example 1.

II The procedure of coating tablet cores with a film coating

The procedure of coating the tablet core with a film coating is carried out as in example 1. Film-coated tablets have the following characteristics:

EXAMPLE 6

Production of film tablets-I Preparation of tablet core with acetylsalicylic acid

The procedure for making the tablet core is carried out as in example 1.

II The procedure of coating tablet cores with filmoblog

The procedure of coating the tablet core with a film coating is carried out as in example 1. Film-coated tablets have the following characteristics:

Tablets are packed in a blister of AFU/PVC and PVC/PVdC tape.

EXAMPLE 7

Film tablet production

1 Preparation of the tablet core with acetylsalicylic acid The procedure for making the tablet core is carried out as in example 1.

II The procedure of coating tablet cores with a film coating

The procedure of coating the tablet core with a film coating is carried out as in example 1.

Claims (12)

1. Pharmaceutical formulation of acetylsalicylic acid in the form of an enteric film tablet with controlled release, characterized by the fact that the core of the tablet contains an active substance - acetylsalicylic acid and a surface-active substance - hydrogenated castor oil, which is included in the composition of the film coating of the tablet, in addition to agents for replenishment (hydrophilic carrier), binding, disintegration, sliding, lubricant, film-forming substance, plasticizer and pigment. 2. Pharmaceutical formulation according to claim 1, characterized by the fact that particles of the active substance in the size of 200 to 500 µm are represented by a maximum of 50%, and particles larger than 700 µm by a maximum of 10%. 3. Pharmaceutical formulation according to claims 1 and 2, characterized in that the filler (hydrophilic carrier) is selected from: lactose monohydrate. anhydrous lactose. several types of starch and modified starch, cellulose, cellulose powders. sugars-sucrose and dextrose and sugar alcohols-mannitol or sorbitol 4. Pharmaceutical formulation according to claims 1-3. indicated by that. which binding agent is selected from the following polymers: polyvinylpyrrolidone, cellulose derivatives, gelatin, tragacanth, starch paste, polyethylene glycol and alginate. 5. Pharmaceutical formulation according to claims 1-4, characterized in that the disintegrant is selected from: microcrystalline cellulose, starch, modified starch, cellulose, cellulose derivatives, cross-linked polyvinylpyrrolidone, sodium alginate and colloidal silicon dioxide. 6. Pharmaceutical formulation according to claims 1-5. indicated by that. which is colloidal silicon dioxide as a lubricant. 7. Pharmaceutical formulation according to claims 1-6. characterized in that the sc lubricant is selected from: stearic acid, magnesium stearate, calcium stearate, paraffin, talc, oil, wax, polyethylene glycol or silicone. 8. Pharmaceutical formulation according to claims 1-7, characterized in that the film-forming substance is selected from: acrylate polymers (Fudragit" F 12.5). cellulose acetate phthalate. hydroxypropylmethylcellulose phthalate or polyvinyl acetate phthalate. 9. Pharmaceutical formulation according to claims 1-8, characterized by. which sc plasticizer chooses from: polyethylene glycol. propylene glycol. citrate or phthalate esters. 10. Pharmaceutical formulation according to claims 1-9, characterized by. which is the insoluble pigment titanium dioxide. 11. The method of obtaining a pharmaceutical formulation according to claims 1-10, characterized in that the disintegrant is added in part to the granulate, and in part is incorporated extragranularly. 12. Method of obtaining a pharmaceutical formulation of enterosolvent film tablet with controlled release according to claims 1-11, characterized by the fact that: a powder mixture composed of an active substance, means for replenishment and means for decomposition, granulate with a granulation solution. which contains a binding agent and a surfactant - hydrogenated castor oil, and then the homogeneously wetted mass is agglomerated to a maximum particle size of 4 mm, dry for 30-40 min in a fluid dryer at 40-50°C to a maximum moisture content of 2%, sifted until granules with a maximum particle size of up to 1 mm are obtained, then the disintegrating agent, sliding agent and mass lubricant are added, mixed in a mixer in flow for 10 min and compress into biconvex tablets with a minimum hardness of 4.5 kp. and then an enteric-solvent film coating composed of a film-forming agent is applied to the tablets, plasticizer. pigments, surfactants - hydrogenated castor oil and other pharmaceutical acceptable substances, in a coating device at a drum rotation speed of 1-15 rpm, inlet air temperature of 10-40°C. inlet air flow rate of 10-60%, inlet air flow rate of 3000-4000 m7h and nozzle opening of 0.5-3 mm.