RU2762552C2 - Pharmaceutical composition of oxy-ethylammonium methylphenoxyacetate - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to the field of medicine and pharmaceutics, namely to a solid pharmaceutical composition in the form of a tablet obtained by direct pressing, having an adaptogenic effect, containing oxy-ethylammonium methylphenoxyacetate and excipients with the following component ratio, wt.%: oxy-ethylammonium methylphenoxyacetate 40; microcrystalline cellulose 18.5; lactose monohydrate 40; sodium stearyl fumarate 1; silicon dioxide colloidal (aerosil) 0.5.

EFFECT: increase in the productivity, while improving the quality of obtained tablets due to changing the production technology, namely the use of “direct pressing” instead of “wet granulation”, and obtaining a faster release profile, which leads to increased bioavailability.

1 cl, 4 dwg, 1 tbl, 76 ex

Description

The technical field to which the invention relates

The invention relates to medicine, namely to the pharmaceutical industry and can be used for the production of a drug in a solid dosage form with an adaptogenic effect.

State of the art

- был синтезирован в начале 1970-х годов в Иркутском институте химии им. А.Е. Фаворского СО РАН (ранее - Иркутском институте органической химии АН СССР) отечественным ученым М.Г. Воронковым (авторское свидетельство SU515742, дата подачи: 06.08.1973 г.). Immunostimulant of a wide spectrum of biological activity - INN oxyethylammonium methylphenoxyacetate (tris (2-hydroxyethyl) ammonium 2-methylphenoxyacetate; tris (2-hydroxyethyl) ammonium orthoresoxyacetate) of the formula:

- was synthesized in the early 1970s at the Irkutsk Institute of Chemistry. A.E. Favorsky SB RAS (formerly Irkutsk Institute of Organic Chemistry of the USSR Academy of Sciences) by the Russian scientist M.G. Voronkov (copyright certificate SU515742, date of submission: 08/06/1973).

Oxyethylammonium methylphenoxyacetate has been studied for a long time and only in August 1994 was approved by the Ministry of Health of Russia for medical use under the name Trekrezan® as a broad-spectrum adaptogen, and was also protected by patent RU2063749 "DRUG WITH ADAPTOGENIC PRIORITY" (24.02. ).

Currently, Trekrezan® (INN oxyethylammonium methylphenoxyacetate, LSR-008909/09, Grotex LLC) belongs to the group of adaptogenic drugs. The drug stimulates the production of α- and γ-interferons, which determines the spectrum of its biological activity (immunostimulating, adaptogenic), affects the immune status of the body by activating the cellular and humoral links of immunity, and stimulates the phagocytic activity of macrophages. The drug strengthens the body's immune system, increases endurance during physical and mental stress, reduces the effect of various toxins, increases the body's resistance to hypoxia, low and high temperatures and other unfavorable environmental factors. Oxyethylammonium methylphenoxyacetate is not a hormonal substance by its nature; in chemical structure, it is rather close to aspirin, but does not cause an increase in gastric acidity and, accordingly, does not lead to the formation of stomach ulcers.

The drug Trekrezan® is now presented on the Russian market, which has a composition for 1 tablet:

oxyethylammonium methylphenoxyacetate 0.2 g; Excipients: potato starch 0.0925 g; lactose monohydrate (milk sugar) 0.2 g; sodium stearyl fumarate 0.005 g; colloidal silicon dioxide (aerosil) 0.0025 g.

The active composition of the drug Trekrezan® is the closest analogue of the proposed technical solution.

Also known are preparations based on oxyethylammonium methylphenoxyacetate LP-005865, LP-005402, having a composition for 1 tablet:

oxyethylammonium methylphenoxyacetate 0.2 g; Excipients: potato starch 0.095 g; lactose monohydrate (milk sugar) 0.2 g; calcium stearate 0.005

The production of known formulations of oxyethylammonium methylphenoxyacetate made it possible to obtain drugs that meet the requirements of regulatory documents, however, the disadvantages of these formulations are:

1. long-term and labor-intensive production technology - the only possible technological process for obtaining medicinal products of the available compositions is the wet granulation technology, which leads to a significant increase in the duration of production, due to the need to obtain moist granules with their subsequent drying and rejection of low-quality intermediate products in order to obtain a mass for tableting; in addition, the tablet mass adheres to the pressing tool, which in turn requires additional cleaning of the equipment involved in the production;

2. low quality of the obtained tabletted pharmaceutical compositions - during the production process, chips appear on the tablets due to their low strength.

Thus, the technical problem, the solution of which is provided in the implementation or use of the claimed invention, and which could not be solved in the implementation or use of analogs of the invention, is the need to develop an adaptogenic pharmaceutical composition based on oxyethylammonium methylphenoxyacetate, which allows you to obtain a solid dosage form with high bioavailability and to optimize the technological process of obtaining a medicinal product.

The indicated problem is solved by the optimal selection of auxiliary components and their content in the pharmaceutical composition.

Disclosure of the essence of the invention

A solid pharmaceutical composition having an adaptogenic effect, containing oxyethylammonium methylphenoxyacetate and excipients in the following ratio of components, wt. %:

oxyethylammonium methylphenoxyacetate 20-60 microcrystalline cellulose 10.2-28 lactose monohydrate or mannitol or calcium hydrogen phosphate 29-47 sodium fumarate or magnesium stearate or stearic acid 0.5-3 colloidal silicon dioxide (aerosil) 0.3-2.

A particular embodiment of a pharmaceutical composition is a composition of the following composition, wt. %:

oxyethylammonium methylphenoxyacetate 40 microcrystalline cellulose 18.5 lactose monohydrate 40 sodium stearyl fumarate one colloidal silicon dioxide (aerosil) 0.5

The claimed ratio of ingredients is optimal and found experimentally.

In practice, it was confirmed that the claimed technical result is achieved if magnesium stearate or stearic acid is used instead of sodium stearyl fumarate, and the same effect is also achieved when mannitol or calcium hydrogen phosphate is used instead of lactose monohydrate (milk sugar).

The proposed composition differs from the prior art in that one of the fillers (potato starch) is completely excluded from the composition and replaced by another - microcrystalline cellulose, which made it possible to change the technology of obtaining a solid dosage form to "direct" compression, in the case of obtaining tablets, excluding the stages obtaining wet granules with their subsequent drying to obtain a tablet mass, or obtaining capsules filled with powder from crushed and metered components, which was generally not obtained earlier due to the hygroscopicity of the active component - oxyethylammonium methylphenoxyacetate.

The technical result of the proposed technical solution is to increase the productivity of the technological process for obtaining a solid pharmaceutical composition per unit of time, while improving the quality of the produced solid dosage forms.

The specified technical result is achieved by optimizing the production technology, by reducing the production time by 2 times, by improving the composition of auxiliary substances, which makes it possible to exclude the stages of obtaining moist granules with subsequent drying; increasing the quality of produced solid dosage forms, by eliminating defects in production with an increase in productivity; increasing the bioavailability of a solid drug, due to obtaining a faster release profile of oxyethylammonium methylphenoxyacetate in comparison with the prototype.

Table 1. Comparison of the duration of technological processes

Receiving the prototype composition, hour Receiving the claimed composition, hour 5 2-2.5

Another unexpected technical result was that the claimed pharmaceutical composition for obtaining a medicinal product in a solid dosage form of oxyethylammonium methylphenoxyacetate (including in the form of tablets), successfully combining an active component with an adaptogenic effect with excipients, provides high bioavailability due to faster the entry of the active component into the blood and, accordingly, provides a more rapid onset of the therapeutic effect, as a result of which it is more promising for obtaining an immunostimulating drug.

Excipients play an important role in ensuring the bioavailability, efficacy, stability and safety of the drug and affect the rate, completeness of release and absorption of active ingredients, and, therefore, regulate the time of onset and strength of the pharmacological effect. Due to the optimization of the claimed composition, the dosage form is capable of releasing more than 96% of the active substance into the dissolution medium in 20 minutes (for a tableted composition) and 10 minutes (for a preparation in capsules). It is the combination of optimally selected excipients that allows an increase in bioavailability to be achieved.

The claimed composition in the production process showed the minimum amount of scrap: only 1.3% of tablets with chips for the claimed composition in comparison with 6.9% of scrap on tablets of the prototype composition.

Also, the claimed composition has high stability - after 2 years of storage, the content of impurities does not exceed 1.0% (by weight of the active substance) and other quality indicators also comply with the requirements of regulatory documents.

Brief Description of Drawings

FIG. 1 shows the average dissolution profiles of the Trekrezan® drug, 200 mg tablets of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the prototype composition - Trekrezan®, 200 mg tablets (registered composition LSR-008909/09) (medium - purified water).

Figure 2 shows the average dissolution profiles of the Trekrezan® drug, 200 mg tablets "of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the prototype composition - Trekrezan®, 200 mg tablets (registered composition LSR-008909 / 09) (Wednesday - 0.1 M hydrochloric acid solution).

FIG. 3 shows the average dissolution profiles of the Trekrezan® drug, 200 mg tablets "of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the prototype composition - Trekrezan®, 200 mg tablets (registered composition LSR-008909/09 ) (medium - acetate buffer solution pH 4.5).

FIG. 4 shows the average dissolution profiles of the Trekrezan® drug, 200 mg tablets "of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the prototype Trekrezan®, 200 mg tablets (registered composition LSR-008909/09) ( phosphate buffer solution pH 6.8).

Implementation of the invention

The proposed solid pharmaceutical composition is prepared as follows.

Example 1

The required amount of methylphenoxyacetate oxyethylammonium substance is ground in a mill with a mesh size of 0.8-1.5 mm.

The ground substance is collected in production tanks and sent to the screening operation.

Sift the required amount of ingredients through a sieve with a size of: 0.5-1.0 mm - crushed oxyethylammonium methylphenoxyacetate, microcrystalline cellulose; lactose monohydrate or mannitol or calcium stearate; sodium stearyl fumarate or magnesium stearate or stearic acid; 0.8-1.0 mm - colloidal silicon dioxide (aerosil).

After sieving, the powders are collected in production containers and sent to the stage of obtaining a mass for the dosage form.

Example 2

Carried out analogously to example 1, but the dosage form is a tablet. To obtain a tabletted composition, after sieving, the powders are collected in production containers and sent to the stage of obtaining a mass for tabletting.

The mixer is loaded with lactose monohydrate or mannitol or calcium hydrogen phosphate; oxyethylammonium methylphenoxyacetate, microcrystalline cellulose, stirred for 10-20 minutes.

A weighed amount of sieved colloidal silicon dioxide is added to the mixer and the dry granulate is powdered for 5-15 minutes.

Next, a weighed amount of sodium stearyl fumarate or magnesium stearate or stearic acid is added to the mixer and powdered for 3-5 minutes.

The mass is unloaded for tabletting into a container.

Tabletting the mass is carried out on a tablet press. Adjust the tablet press to obtain 200 mg flat-cylindrical tablets weighing from 475 to 525 mg, 11 mm in diameter, 4.1-4.7 mm in height.

Simultaneously with tabletting, the tablets are dedusted and rejected in appearance, average weight and strength.

Example 3

Conducted analogously to example 1, but the dosage form is a capsule. To obtain a medicinal product in the form of capsules, after sifting, the powders of the components are collected in production containers and sent for filling into an automatic capsule filling machine.

Example 4

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Lactose monohydrate 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 5

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Sodium stearyl fumarate 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 6

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 7

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 8

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 9

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Sodium stearyl fumarate 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 10

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 11

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 12

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 13

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Sodium stearyl fumarate 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 14

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 15

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 125 25 Calcium hydrogen phosphate 225 45 Microcrystalline cellulose 130 26 Sodium stearyl fumarate 12.5 2.5 Colloidal silicon dioxide (aerosil) 7.5 1.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 16

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 190 38 Lactose monohydrate 209 41.8 Microcrystalline cellulose 95.5 19.1 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 17

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Magnesium stearate 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 18

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 19

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 20

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Magnesium stearate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 21

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Magnesium stearate 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 22

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 23

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 24

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Magnesium stearate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 25

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Magnesium stearate 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 26

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 27

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Calcium hydrogen phosphate 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 28

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 210 42 Lactose monohydrate 190 38 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 29

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Stearic acid 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 30

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 31

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Stearic acid 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 32

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 33

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Stearic acid 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 34

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 35

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Stearic acid 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 36

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 37

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Stearic acid 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 38

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 39

Carried out analogously to example 2, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Calcium hydrogen phosphate 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 40

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Lactose monohydrate 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 41

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Sodium stearyl fumarate 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 42

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 43

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 44

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 45

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Sodium stearyl fumarate 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 46

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 47

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 48

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Sodium stearyl fumarate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 49

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Sodium stearyl fumarate 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 50

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Sodium stearyl fumarate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 51

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Calcium hydrogen phosphate 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a tablet weighing 500 mg.

Example 52

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 190 38 Lactose monohydrate 209 41.8 Microcrystalline cellulose 95.5 19.1 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 53

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg The amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Magnesium stearate 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 54

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg The amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 55

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 56

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Magnesium stearate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 57

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Magnesium stearate 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 58

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 59

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 60

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Magnesium stearate 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 61

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Magnesium stearate 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 62

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Magnesium stearate 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 63

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Calcium hydrogen phosphate 171 34.2 Microcrystalline cellulose 72.5 14.5 Magnesium stearate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 64

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 210 42 Lactose monohydrate 190 38 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 65

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Lactose monohydrate 235 47 Microcrystalline cellulose 140 28 Stearic acid 15 3 Colloidal silicon dioxide (aerosil) one hundred 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 66

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Lactose monohydrate 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 67

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Lactose monohydrate 171 34.2 Microcrystalline cellulose 72.5 14.5 Stearic acid 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 68

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Mannitol 200 40 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 69

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Mannitol 200 47 Microcrystalline cellulose 92.5 28 Stearic acid 5 3 Colloidal silicon dioxide (aerosil) 2.5 2

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 70

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Mannitol 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 71

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Mannitol 171 34.2 Microcrystalline cellulose 72.5 14.5 Stearic acid 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is made in the form of a capsule weighing 500 mg.

Example 72

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 200 40 Calcium hydrogen phosphate 200 40 Microcrystalline cellulose 92.5 18.5 Stearic acid 5 one Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 73

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate one hundred twenty Calcium hydrogen phosphate 235 47 Microcrystalline cellulose 140 28 Stearic acid 15 3 Colloidal silicon dioxide (aerosil) 10 2

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 74

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 300 60 Calcium hydrogen phosphate 51 10.2 Microcrystalline cellulose 145 29 Stearic acid 2.5 0.5 Colloidal silicon dioxide (aerosil) 1.5 0.3

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 75

Carried out analogously to example 3, with the following amounts of components:

Component Quantity in mg Amount in wt. % Oxyethylammonium methylphenoxyacetate 250 50 Calcium hydrogen phosphate 171 34.2 Microcrystalline cellulose 72.5 14.5 Sodium stearyl fumarate 4 0.8 Colloidal silicon dioxide (aerosil) 2.5 0.5

The pharmaceutical composition is in the form of a capsule weighing 500 mg.

Example 76

The study of the kinetics of dissolution was carried out according to General Pharmacopoeia Monograph.1.4.2.0014.15 "Dissolution for solid dosage forms" on a rotating basket apparatus (Erweka DT 126 Light, Germany) at a rotation speed of 100 rpm.

The kinetics of dissolution of the Trekrezan® drug, 200 mg tablets of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the Trekrezan® prototype composition, 200 mg tablets (registered composition LSR-008909/09) was found to be nonequivalent with taking into account the convergence factor f2 in dissolution media: purified water (quality control medium), acetate buffer solution pH 4.5, phosphate buffer solution pH 6.8, due to the faster release of the active substance in the studied series of Trekrezan®, tablets 200 mg the claimed composition according to this invention relative to the reference series of the prototype drug Trekrezan®, tablets 200 mg (registered composition LSR-008909/09).

In a medium of 0.1 M hydrochloric acid solution pH 1.2, the convergence factor f2 cannot be used to assess the equivalence of the studied drugs due to the low release of the active substance and the high relative standard deviation of the release values in this dissolution medium.

Dissolution profiles of Trekrezan® drugs, 200 mg tablets of the claimed composition (series: 260720/1, 260720/2, 260720/3) and the Trekrezan® prototype composition, 200 mg tablets are shown in Figs 1-4.

Thus, a new adaptogenic pharmaceutical composition for obtaining a solid medicinal product of oxyethylammonium methylphenoxyacetate, of a well-selected composition, provides a decrease in the duration of the technology for producing drugs, while increasing their quality, provides a faster flow of medicinal substances into the blood and, accordingly, provides a faster onset of the therapeutic effect , as a result of which it is promising for obtaining an immunostimulating drug.

Claims (2)

A solid pharmaceutical composition in the form of a tablet obtained by direct compression, having an adaptogenic effect, containing oxyethylammonium methylphenoxyacetate and excipients in the following ratio of components, wt%: oxyethylammonium methylphenoxyacetate 40 microcrystalline cellulose 18.5 lactose monohydrate 40 sodium stearyl fumarate one colloidal silicon dioxide (aerosil) 0.5

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