RU2550958C2 - Dosage form containing desloratadine and method for producing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a tabletted oral dosage form containing desloratadine in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient. The processing additives consist of sodium croscarmellose, magnesium stearate and povidone. The excipient represents a mixture of lactose disaccharide and microcrystalline cellulose polysaccharide in ratio from 2:1 to 8:1. Lactose and microcrystalline cellulose have an average particle size from 30 to 200 mcm. Producing the table involves granulating desloratadine, lactose and microcrystalline cellulose.

EFFECT: invention provides reducing granulate compression force, increasing process capability and maintaining the high quality of the tablets.

9 cl, 4 tbl, 4 ex

Description

The invention relates to medicine, in particular to the pharmaceutical industry, and describes an oral pharmaceutical composition in the form of a tablet comprising desloratadine and a method for its manufacture.

In recent years, a significant increase in allergic diseases has been observed throughout the world. Every tenth inhabitant of the Earth suffers from allergic diseases, and in some regions - every sixth. According to official statistics, from 10 to 15% of the population suffers from allergic diseases in Russia. According to the WHO, allergic diseases take 3rd place in prevalence. Over the past decade, there has been a doubling of the incidence of allergic rhinitis, bronchial asthma, and atopic dermatitis.

In this regard, today, it seems extremely urgent to create effective, high-quality and affordable anti-allergic medicinal compositions and ensure high manufacturability and productivity of their production.

One of the most effective active ingredients for eliminating allergic symptoms of various etiologies is desloratadine. The chemical name of desloratadine is 8-chloro-6,11-dihydro-11- (4-piperidinylidene) -5H-benzo [5,6] cyclohepta [1,2-b] pyridine.

Desloratadine belongs to the group of long-acting HI-inhibitors of new receptors and is a third-generation antihistamine. Desloratadine inhibits the release of histamine and C4 leukotriene from mast cells, prevents the development and facilitates the course of allergic reactions, has an anti-allergic, antipruritic and anti-exudative effect, reduces capillary permeability, prevents the development of tissue edema, and relieves smooth muscle spasm.

One of the main features of desloratadine is its highest selectivity and minimal risk of developing adverse reactions. This active metabolite of loratadine is characterized by the highest affinity for H1 receptors - 200 times greater than fexofenadine, 50 times larger than loratadine and cetirizine and 3 times greater than levocetirizine. Therefore, desloratadine is a stronger inverse agonist of H1 receptors, which has been proven both in clinical trials and in medical practice (Anthes J., Richard C., West R. et al. Functional characteristics of desloratadine and other anhistamines in human Y1 receptors. Allergy, 2000, 55 (suppl. 63), S279 (Abstract 994); Henz B. The pharmacological profile of desloratadie: a review. Allergy, 2001, 56 (suppl. 65), 7-13.).

In particular, in randomized, double-blind, placebo-controlled studies of desloratadine in case of allergic rhinitis with the participation of about 1 thousand patients, it was reliably proved that desloratadine is superior to placebo and reduces all the main symptoms of rhinitis. nasal congestion. It was found that desloratadine is almost the only blocker of H1-histamine receptors, which demonstrates a constant decongestant effect in controlled studies. Desloratadine can be used to treat both seasonal and non-seasonal allergies in reactions to house dust, fluff, plant pollen, animal dander and dander, and various food allergens. In addition, blind placebo-controlled multicenter studies confirmed the effectiveness of desloratadine in chronic idiopathic urticaria (Lorber R., Salmun L., Danzig M. Desloratadine is effective at relieving nasal congestion, as demonstrated in three placebo-controlled trials in patients with seasonal allergic rhinitis. New Trends in Allergy - V meeting, Davos, 2000; Nathan R. and the Desloradine Study Group. Desloratadine relieved nasal congestion in patients with seasonal allergic rhinitis. Annual meeting of American College of Allergy, Asthma and Immunology, Seattle, 2000.).

Desloratadine has not only an antihistamine effect, but also anti-inflammatory and anti-allergic. It also blocks a number of other mediators involved in the development of systemic allergic inflammation. Also, the drug reduces capillary permeability, prevents the development of tissue edema.

In addition, desloratadine does not have a sedative effect, when taken in therapeutic doses, it does not affect the rate of psychomotor reactions and does not enhance the inhibitory effect of ethanol on psychomotor function. Desloradatin is determined in blood plasma 30 minutes after administration, the half-elimination period reaches 21-24 hours. Eating does not have a significant effect on the absorption of the drug. Therefore, the drug can be taken 1 time / day, regardless of food intake.

Thus, desloratadine significantly improves the quality of life of patients with allergic diseases, and, as shown by population studies, even in cases where previous therapy with other antihistamines was ineffective.

For the first time, the formula of desloratadine and its salts, the method for its preparation, and the pharmaceutical composition with desloratadine as an active substance were described in US Pat. No. 4,657,916 with priority dated 02.15.1984. The method and composition of preparing the dosage form was claimed. The active substance is mixed with a carrier having the necessary binding properties in suitable proportions and pressed into the desired shape and size. Powders and tablets in this case preferably contain from 5 to 20 percent of the active ingredient. Preferred fillers used are: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter, etc.

Antihistamines comprising 5 to 50 mg of desloratadine or a pharmaceutically acceptable salt thereof are also widely known and applicable in the prior art.

In particular, the compositions of the preparations Lordestin (Registration Certificate No. LSR-006570/10, registration date 09.07.2010), Desloratadin Canon (Registration Certificate No. LP-001853, registration date 09/27/2012), Desloratadin-Teva (Registration Certificate) are known. No. LP-001627, registration date 04/06/2012) and others. These drugs are marketed in the form of film-coated tablets, lozenges, and syrups.

The most famous drug containing desloratadine and widely available on the market is Erius® (Registration Certificate No. P N014704 / 02, registration date 06/08/2010), made in the form of film-coated tablets, lozenges and syrups. These film-coated tablets contain the following components, mg:

Components mg Desloratadine 5 Calcium hydrogen phosphate dihydrate 53 Microcrystalline cellulose 28 Corn starch eleven Talc 3 Shell (opadry blue, opadry 6.61 transparent, carnabus wax, wax bee white) Total 106.61

Briefly describing a solid dosage form, such as a tablet preparation, is usually made by compressing a suitable granulate into the desired solid dosage form, the granulate consisting of the desired components in the form of a mixture of solid particles. Typically, such particles are a therapeutically active ingredient, various excipients (fillers), disintegrating agents, lubricants and binders, possibly together with, for example, flavoring, preservative and / or dye. Commercially available Erius® tablets are formulated according to such a general protocol, and such a tablet was first disclosed as set forth in US Pat. No. 4,657,916, the disclosure of which is incorporated herein by reference.

The Erius® tablet currently on the market and thus being produced on an industrial scale consists of the therapeutically active ingredient desloratadine together with calcium hydrophosphate, microcrystalline cellulose as excipients and, accordingly, a suitable amount of a binder and lubricant.

For any compression of a granulate consisting of a mixture of solid particles into tablets, there is a general need to carry out a pressing operation with the highest possible speed while minimizing, at the same time, wear of the mechanism and producing tablets of a quality that meets regulatory requirements.

Currently, there is a need to develop more affordable and easier to manufacture preparations of desloratadine, characterized by high chemical and physical stability during storage, corresponding to modern quality requirements, made preferably in the form of a solid dosage form, the qualitative and quantitative composition of which will provide high performance, manufacturability with a simultaneous low cost of production, and also expand the arsenal of antiallergic drugs from tive production.

It was found that a combination in certain ratios of disaccharide - lactose with polysaccharide - microcrystalline cellulose taken with a certain particle size of these excipients unexpectedly provides a significant increase in speed during the manufacturing process, while the wear of the mechanism and the quality of the tablets remain essentially unchanged compared to the process industrial production used to date. Essentially, the ratio of the components and the size of their particles in question, apparently, affects the flowability of the granulate particles and their relative position in the tablet during and after pressing so as to provide an increased overall productivity and, consequently, the speed of the manufacturing process of the tablet the preparation of desloratadine, and also allows you to get tablets with sufficient mechanical strength using less pressing force, which saves energy.

In modern industrial presses, two-sided compression of the powder in the matrix between two punches is carried out. The researchers believe that the mechanical bond in the tablet is due to the area of the contacting surfaces, as well as the mutual interweaving and engagement of the surface protrusions and unevenness of the particles under pressure. As a result of the applied pressure, the particles move and slide relative to each other and come into closer contact; symmetrical glides easier than rough ones, but the latter create a greater number of gears and therefore give the pressed tablet increased strength. Thanks to the experimental selection of components, particles of which have the listed properties in optimal ratios for the high-performance pressing process, the inventors were able to solve the problem.

More specifically, the present invention relates to a pharmaceutical composition in the form of a solid dosage form containing desloratadine or a pharmaceutically acceptable salt thereof as a therapeutically active ingredient together with a pharmaceutically acceptable excipient, diluent or carrier, or a mixture thereof, where at least one of these excipients, diluent and the carrier in the most preferred embodiment is a disaccharide, more preferably lactose, and the other in the most preferred variant ante is a polysaccharide, more preferably microcrystalline cellulose, and the average particle size of said substances is in the range from 30 to 200 microns. Moreover, the mass ratio of lactose and microcrystalline cellulose is from 8: 1 to 2: 1, and the amount of therapeutically active substance is from 3 to 15%.

The correct use and understanding of the terms excipient, diluent, carrier requires no explanation and is fully within the qualifications of a specialist in the manufacture of pharmaceutical preparations.

The pharmaceutical composition of the present invention may optionally contain at least one additive selected from a disintegrant, a lubricant, a binder, a flavoring agent, a preservative, a coloring agent and a mixture thereof. Where appropriate, other additives may also be included. Typical examples of disintegrants, lubricants (e.g. magnesium stearate), binders (e.g. povidone), flavoring agents, preservatives and colorants, and suitable mixtures thereof, as well as any other conventional additives that may be considered by a person skilled in the art, carrying out the practice of the present invention can be found in the "Handbook of Pharmaceutical Excipients"; Ed. AHKibbe, 3 ^rd Ed., American Pharmaceutical Association, USA, and Pharmaceutical Press UK, 2000, the essence of which is included in this description of the invention. As an example also applicable to the practical implementation of the present invention, it may be mentioned that the usual amounts of lubricants and binders, as well as other traditional processing aids, are of the order of less than 10% by weight of the pharmaceutical composition.

The composition of tablets available on the market that are manufactured by methods used to date, as diluents includes calcium hydrogen phosphate, starch, microcrystalline cellulose. Such a composition, after the manufacture of granulate or mixture from it, does not allow to obtain a pressing speed exceeding 120,000 tablets per hour on a single-rotor rotary press with 45 pressing sets. Compared with this, the method of the present invention allows to obtain a pressing speed of up to approximately 200,000 tablets / h inclusive with the desired tablet quality and to maintain a low level of wear of the tabletting mechanism.

In a preferred embodiment of said pharmaceutical composition, the average particle size is in the range of 30 to 200 microns. In another preferred embodiment, this average particle size is in the range of 90 to 180 microns. In a further preferred embodiment, said average lactose particle size is in the range of 150 to 200 microns, and microcrystalline cellulose is in the range of 70 to 110 microns. In a most preferred embodiment of the present invention, said average particle size is 70-80 microns for lactose and 40-60 microns for microcrystalline cellulose (as measured by a sieve using an air stream).

When measuring particle size using a sieve using an air stream, air is blown through the sieve upward from the rotating slit so that the substance on the sieve becomes fluidized. At the same time, negative pressure is applied to the bottom of the sieve, which removes small particles into the collecting device. Size analyzes and determination of the average particle size are carried out by removing particles from the end of the fine particles in a size distribution using sequentially single sieves. See also “Particle Size Measurement”, 5 ^th Ed., P 178, vol.1; for more details. T. Allen, Chapman & Hall, London, UK, 1997. For a person skilled in the art, such size measurement is thus traditional.

In a preferred embodiment, both said disaccharide and polysaccharide are present in the pharmaceutical composition. In this particular embodiment, the weight ratio of said disaccharide to polysaccharide is usually from 8: 1 to 2: 1, preferably from 7: 1 to 4: 1, and more preferably from 6: 1 to 5: 1.

The total amount of these excipient, diluent and carrier in the aggregate is usually from 75 to 96%, preferably from 80% to 90% by weight of the pharmaceutical composition, with the remainder up to 100% inclusive being the therapeutically active ingredient, possibly together with the above additives, where the latter are preferably are a lubricating, disintegrating and binder.

The ratios of the proportions of the components and the sizes of their particles are determined experimentally and can be justified as follows. Lactose is a crystalline powder, and microcrystalline cellulose has both the properties of fibers and crystalline powder. Lactose particles provide a mixture of fluidity and particle slip during compaction, microcrystalline cellulose particles increase the area of contact surfaces.

With an increase in the ratio of lactose: microcrystalline cellulose more than 8: 1, the pressing process must proceed at high pressure and low speed to achieve sufficient strength, and with a decrease of less than 2: 1, the mixture flows and bulk density to such an extent that problems can arise with the accuracy of dosing the weight of the powder into the matrix during high-speed pressing. Undoubtedly, the presence of an active substance in the mixture also affects the pressing process. The inventors experimentally determined the limits of desloratadine from 3 to 15%. Moreover, the lower limit of 3% is due not to the properties of the powder being subjected to high-performance pressing, but to the fact that for tablets containing an acceptable amount of desloratadine, it is not economically feasible to introduce more than 97% of the diluents.

The pharmaceutical composition in the form of a solid dosage form of the present invention is usually a tablet suitable for oral administration. Such a tablet may be coated.

The composition usually contains desloratadine in an amount of from 3 to 50 mg per unit solid dosage form. As an example: a typical tablet containing 5 mg of desloratadine is a white or almost white, cylindrical biconvex shape with a diameter of 6 mm and a weight of 95 mg.

Accordingly, an additional aspect of the present invention relates to a method for producing a pharmaceutical composition in the form of a solid dosage form containing desloratadine as a therapeutically active ingredient, comprising the steps of:

1) desloratadine and an excipient, diluent or carrier, or mixtures thereof are mixed, possibly in the presence of a moisturizing agent, where at least two of these excipients, diluents and carriers are microcrystalline lactose and cellulose, the average particle size being 70 for lactose -80 microns and for microcrystalline cellulose 40-60 microns

2) granulate is formed from the resulting mixture, possibly in the presence of a moisturizing agent, suitable for compression into said solid dosage form;

3) it is possible to carry out said mixing and / or formation of a granulate in the presence of at least one additive selected from a disintegrant, a lubricating agent, a binding agent, a flavoring agent, a preservative, a coloring agent, and a mixture thereof;

4) it is possible to dry said granulate;

5) compress said granulate into a solid dosage form.

6) it is possible to apply a film coating to said solid dosage form.

The method of the present invention as such can be practiced using conventional pharmaceutical manufacturing equipment once specific components are identified and included. A granulate suitable for compression into tablets typically has an average granule size of at least about 100 microns. Individual granules with a size of more than 2 mm are usually not transferred to the next pressing stage.

By way of non-limiting examples, the following granulation equipment can be mentioned: fluidized bed and direct heating, for example supplied by GEA / Collette NV, BE (UltimaPro ™ series), Huttlin GmbH, DE (HDG series), Diosna Dierks & Soehne GmbH, DE (VAC series) ), Fluid Air Inc., US (Magnaflo® Series) and Vector Corp., US (GMX Series); with a moving solid layer and indirect heat transfer, including paddle systems, rotary systems and shaking systems, which are supplied, for example, by Jay go Inc., US (JRB and Novamix series), Paul O. Abbe Inc., US (Rota-Cone series, Rota-U, Rota Blade, Cylindrical Ribbon / Paddle, Plow and Sigma-blade), Forberg A / S, NO (Forberg II series), Gemco Inc., US (D / 3 Double Cone, V-Shape and Slant- series Cone), LittlefordDay Inc., US (Double Arm, Day Nauta and Daymax series), Patterson-Kelly, Harsco Corp., US (Solids Processor® PK series), Diosna as described above (CCS and VAC series), Romaco Zanchetta SpA, IT (Roto E, Roto D and Roto P Series) and LB Bohle Maschinen und Verfahren GmbH, DE (Granumator GMA and Vagumator VMA series). The above equipment usually also provides drying of the obtained granules.

Accordingly, it is preferable that said substance be a disaccharide, preferably lactose, and more preferably lactose-α-monohydrate. Said polysaccharide is preferably cellulose and more preferably microcrystalline cellulose.

In the method of the present invention, the prepared solid dosage form is usually an orally acceptable tablet. An example of equipment on which the tablet pressing process was carried out is a rotary single-handed press with 45 pressing sets and a feeder with an independent drive.

In a preferred embodiment of the method of the present invention, said mixing and granulating steps are carried out in a fluidized bed of a granulator dryer.

Moreover, as mentioned above, in the pharmaceutical composition, the content of the active active substance, desloratadine, is from 3 to 15%, and the amount of antifriction, disintegrating, binding substances (additives) is contained in an amount of from 1 to 10%. As non-limiting examples of these additives, widely used and known to the person skilled in the pharmaceutical industry, magnesium stearate, povidone and sodium croscarmellose can be mentioned. The preferred amount of active ingredient and additives, therefore, can be from 4 to 25% by weight of the tablet, more preferably but not necessarily from 10 to 20%, but most preferably, but not necessarily their content in an amount of from 12 to 15 %, but the content of the active substance and additives in the amount of 13% is especially preferred.

The method is preferably carried out in such a way as to achieve maximum tablet strength at the optimum pressure for the specified composition and at the same time maximum productivity on the above press. Other qualitative characteristics and indicators, in this case, must comply with those specified in the Global Fund XI, issue 2, pp. 154-160 for the specified dosage form. Moreover, despite the permissible GF, the abrasion resistance is 97%, one of the objectives of the present invention is to achieve an abrasion resistance in the range of 99.2-99.99%, since, as a rule, less than 99.5% of the abrasion is already visible with the naked eye chips and material defects.

To achieve this result, the authors of the present invention have used various combinations of compositions, in particular combinations of fillers. Examples and options describing the present invention are shown in more detail in table 1 and table 2. Table 1 shows the test results of various variants of the compositions. Table 2 shows the compositions for each option from table 1. All options were produced in the same manner described below.

The specialist in the manufacture of pharmaceutical preparations knows the terms, methods and methods for determining the qualitative characteristics of the tablets obtained in Table 1 and are completely within his qualifications.

Table 1. Option No. Filler The ratio of substance 1 to substance 2 (part) The filler content in the mass of tablets (%) Productivity (pcs / h) Abrasion resistance (%) Tablet compressive strength (N) Substance 1 Substance 2 one Lactose MCC 10: 1 87 200,000 98.2 45 2 Lactose MCC 8: 1 87 200,000 99.5 55 3 Lactose MCC 2: 1 87 150,000 99.9 70 four Lactose Corn starch 6: 1 87 98000 96.6 35 5 Calcium hydrogen phosphate MCC 6: 1 87 120,000 98.7 60 6 Calcium hydrogen phosphate MCC 8: 1 87 133,000 98.3 55 7 Lactose MCC 1: 1 87 106000 99.8 80 8 Lactose MCC 6: 1 87 200,000 99.8 55

As indicated above, it is preferable to obtain granules from the resulting mixture obtained with an average granule size of at least 100 μm, preferably in the range from 100 μm to 300 μm.

In a preferred embodiment of the process, both said disaccharide and polysaccharide are present in the mixing step. Then the mass ratio of the indicated disaccharide and polysaccharide is usually from 8: 1 to 2: 1.

The method is preferably carried out in such a way that the total amount of these excipients, diluent and carrier in the aggregate is from 75 to 96, preferably from 80 to 90 percent by weight of the pharmaceutical composition.

In the most preferred embodiment, desloratadine is used and mixed with the indicated excipient, diluent and / or carrier in an amount that ultimately provides a desloratadine content of 3 to 50 mg per unit solid dosage form.

Thus, the most acceptable composition and surprisingly randomly selected combination of substances that are the filler of the dosage form is the 8th option shown in the table. The authors of the present invention, experimentally as a result of multiple combinations of formulations and studies of the qualitative characteristics of the obtained dosage forms, unexpectedly managed to find the optimal ratio of components, method and production technology to obtain the best quality product with maximum productivity at the same time.

Most preferred, but not required, is the following content of components in wt. %:

A specific embodiment of the most preferred formulation of the claimed composition is presented in table 4.

The following are examples of the manufacture of tablets in which the formulations were used in accordance with the invention, namely, the amount of desloratadine from 3 to 15% and filler from 75 to 96%, as well as the use of lactose and MCC with an average particle size of from 30 to 200.

Examples of tablets.

In the above examples 1-4:

- when pressing cores, the productivity of the press was 200-210 thousand pieces of tablets per hour, the deviations in the weight of individual tablets did not exceed ± 5% of the average weight;

- used brands of fillers, characterized by an average particle size:

lactose monohydrate 450M with an average particle size of about 30 microns, brand Pharmatose 450M, manufacturer "Friesland Foods", the Netherlands,

lactose monohydrate SD with an average particle size of about 200 microns, Fast Flo brand, manufacturer "Foremost Dr.", USA,

MCC-105 with an average particle size of about 30 microns, brand VIVAPUR105, manufacturer "JRS Pharma", Germany,

MCC-200 with an average particle size of about 200 microns, Comprecel M200D + brand, manufacturer "MINGTAI", Taiwan.

Example 1

Desloratadine, lactose and MCC are mixed in a cubic laboratory mixer, then sieved through a sieve with a hole size of 0.63 mm and placed in the mixer again, silicon colloidal dioxide and magnesium stearate are added. The mixture is sieved again through a sieve. The sieved mixture is pressed using a press tool with a diameter of 10 mm biconvex round cylindrical shape. Tablet cores with a compressive strength of 110-120N and an abrasion resistance of 99.4% are obtained, which are then coated with a film coating by spraying an aqueous suspension onto cores rotating in a perforated drum.

Example 2

Desloratadine, lactose, MCC and croscarmellose sodium are mixed in a paddle mixer. The mixture is granulated in the fluidized bed of a laboratory granulator dryer by spraying an aqueous solution of povidone 25 on it through the nozzle. After granulation, the product is dried in the same equipment to a residual moisture content of 2-3%, then magnesium stearate is added and fluidization is started for several seconds. The resulting mixture is passed through a 0.63 mm sieve and pressed into a 6 mm round tablet core of circular cylindrical biconvex shape. The abrasion resistance of the cores is 99.8%, and the compressive strength is 95-100N.

Example 3

Desloratadine, lactose, MCC, povidone, croscarmellose sodium, silicon dioxide colloidal and sodium stearyl fumarate are mixed in a paddle mixer for 30 seconds. The mixture is passed through a conical mill with an installed mesh with a hole diameter of about 2 mm. The sifted mixture is pressed into capsule-shaped tablets, which have a compressive strength of 80-100N and an abrasion resistance of 99.5%.

Example 4

Desloratadine, lactose, MCC and half the magnesium stearate are mixed in a paddle mixer and passed through the sealing rolls, the compacted material is then ground in a cone mill and mixed in the mixer with the remaining magnesium stearate. From the resulting mixture pressed tablets with a diameter of 9 mm round cylindrical biconvex. The abrasion resistance of the cores is 99.8%, the compressive strength is 70-85N.

Claims (9)

1. A dosage form containing desloratadine as an active ingredient in an amount of from 3 to 15%, processing aids and a pharmaceutically acceptable excipient, where the excipient is a mixture of lactose disaccharide and microcrystalline cellulose polysaccharide, taken in a ratio of from 2: 1 to 8: 1, for the manufacture of the dosage form, suspended deloratadine, lactose monohydrate, microcrystalline cellulose are mixed in a mixer, the resulting mixture is granulated, calibrated, dusted and tabletted, and zuyut lactose and microcrystalline cellulose with an average particle size of from 30 to 200 microns. 2. The dosage form according to claim 1, where the specified ratio is in the range from 4: 1 to 7: 1. 3. The dosage form according to claim 1, where the specified ratio is in the range from 5: 1 to 6: 1. 4. The dosage form according to claim 1, where the specified ratio is 6: 1. 5. The dosage form according to claim 1, where the total amount of excipient is 75-96% by weight of the tablet. 6. The dosage form according to claim 1, where the composition of these technological additives contains croscarmellose sodium. 7. The dosage form according to claim 1, where the composition of these technological additives contains magnesium stearate. 8. The dosage form according to claim 1, where the composition of these technological additives contains povidone. 9. The dosage form according to any one of paragraphs.6-8, where these technological additives are contained in an amount of from 1 to 10%.