RU2444359C1 - Pharmaceutical composition with 2-ethyl-6-methyl-3-hydroxypyridine succinate for oral administration and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, medicine and veterinary science, and describes a composition with 2-ethyl-6-methyl-3-hydroxypyridine succinate for oral administration in the form of a tablet containing substantially 2-ethyl-6-methyl-3-hydroxypyridine succinate as an active ingredient and excipients: lactose monohydrate, sodium carboxymethyl cellulose and/or kollidon 30, magnesium stearate, opadry white. The invention can be used in medicine or veterinary science as the drug preparation 2-ethyl-6-methyl-3-hydroxypyridine succinate for oral administration for the purpose of treating and preventing various diseases and pathological conditions of an human or animal body.

EFFECT: composition is characterised by high bioavailability, three-year stability, minimum excipient content.

2 cl, 5 ex, 1 tbl

Description

The invention relates to the pharmaceutical industry, medicine, and veterinary medicine and describes a composition with 2-ethyl-6-methyl-3-hydroxypyridine succinate for oral administration in the form of a tablet containing mainly 2-ethyl-6-methyl-3-hydroxypyridine succinate as active ingredient and excipients for tablet formation. The invention can be used in medicine or veterinary medicine as a medicine for oral administration of 2-ethyl-6-methyl-3-hydroxypyridine succinate for the treatment and prevention of various diseases and pathological conditions of the human or animal body. The composition is characterized by high bioavailability, stability, minimal content of excipients, convenient and safe for clinical use.

2-ethyl-6-methyl-3-hydroxypyridine succinate (ethylmethyl-hydroxypyridine succinate, trade name Mexidol® and others) is widely used in medicine and veterinary medicine as an antioxidant and antihypoxic agent, characterized by a wide spectrum of pharmacological action and high efficiency (nootropic and tranquilizing effect - Pat. RU 2065299, anti-ischemic and anti-atherosclerotic action - Pat. RU 2144822, antianginal - Pat. RU 2168993, hepatoprotective - Pat. RU 2189817, antibacterial - Pat. RU 2157686 and others).

Known compositions based on 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of various dosage forms: solution for parenteral administration (Order of the Ministry of Health of the Russian Federation dated 31.12.1996 No. 432 "Mexidol® 5% solution for injection", Pat. RU 2205640 , 2380089, 2398583), tablets (Order of the Ministry of Health of the Russian Federation dated 01.26.1998 No. 21 “Mexidol® coated tablets, 0.125 g”), capsules (Pat. RU 2144822, 2145855), dressings (Pat. RU 2149648), etc. .

In order to ensure maximum bioavailability of the active substance, accurate dosage, as well as intensive care of patients in cases where it is necessary to quickly create high concentrations of the drug in the blood, dosage forms for injection are most preferred. At the same time, a number of drawbacks of this route of administration are well-known - the risk of infection, the need for the presence of qualified personnel, the pain of injections, and, as a consequence, the impossibility of prolonged (more than 3-4 weeks) treatment with parenteral dosage forms.

Given the above circumstances, it is relevant to develop dosage forms for oral administration for the purpose of long-term therapy of patients on an outpatient basis.

The objective of the invention is to develop a composition for oral administration in the form of tablets based on 2-ethyl-6-methyl-3-hydroxypyridine succinate, which has good solubility and high bioavailability, stability, minimal content of auxiliary substances.

Known anti-ischemic and anti-atherosclerotic drug used in the form of capsules and having the following composition (Pat. RU 2144822), wt.%:

2-ethyl-6-methyl-3-hydroxypyridine succinate 50,0 Starch 40.5-50.5 Polyvinylpyrrolidone 2.4-2.8 Magnesium stearate 0.9-1.2 Talc 0.9-1.1

As follows from the claims, the starch content is almost equivalent to the content of 2-ethyl-6-methyl-3-hydroxypyridine succinate. This composition does not provide quality capsule powder. The talc contained in it has an irritating effect on the mucous membrane of the gastrointestinal tract, which suggests possible restrictions on the oral administration of compositions with its content. The disadvantages of gelatin capsules include high sensitivity to moisture, which requires compliance with certain storage conditions. Gelatin capsules are a favorable medium for the reproduction of microorganisms, especially when storage conditions are violated (high humidity).

Also known anxiolytic, anti-alcohol and cerebroprotective agent used in the form of capsules and having the following composition (Pat. RU No. 2145855), wt.%:

2-ethyl-6-methyl-3-hydroxypyridine succinate 30.0-60.0 Potato starch 17.0-35.0 Polyvinylpyrrolidone 2.5-3.5 Magnesium stearate 0.8-1.2 Microcrystalline cellulose 7.7-12.2 Milk sugar 12.0-18.0

This composition also does not provide stable powder quality, the total sugar content of milk and starch from 29% to 53% leads to yellowing of the mass, despite the introduction of microcrystalline cellulose. The disadvantages of gelatin capsules are indicated above.

Known stable pharmaceutical composition (Pat. RU No. 2205640), intended for tabletting and containing the following components, wt.%:

2-ethyl-6-methyl-3-hydroxypyridine succinate 50.0-60.0 succinic acid 0.5-5.0 Trilon B 0,0-0,2 Microcrystalline cellulose 14.0-25.0 Starch 15.0-25.0 Low molecular weight polyvinylpyrrolidone 4.0-6.0 Sodium Starch Glycolate 0,0-5,0 Magnesium stearate 0.8-1.0 Talc 0,0-1,0 Collidon CL 0,0-3,0

The disadvantage of this tool is a multicomponent composition, which determines the multi-stage and duration of the process, which negatively affects the cost of the finished product. The shelf life of the finished product is about two years, while it is known that similar compositions (tablets, capsules) containing 2-ethyl-6-methyl-3-hydroxypyridine succinate can be stored for at least three years in accordance with the requirements of regulatory documents . Talc contained in the composition has an irritating effect on the mucous membrane of the gastrointestinal tract. Trilon B is not indifferent to the body, and its long-term administration, given the pronounced ability to complex with metal cations, does not exclude the possibility of a deficiency of trace elements.

A known composition of 2-ethyl-6-methyl-3-hydroxypyridine or its pharmaceutically acceptable salt (succinate and others) in the form of tablets of the following composition (Pat. RU 2384330), wt.%:

2-ethyl-6-methyl-3-hydroxypyridine or its pharmaceutically acceptable salt 20.0-30.0 Hydroxypropyl cellulose 2.0-5.0 Succinic acid or its pharmaceutically acceptable salt 15.0-25.0 Starch 10.0-15.0 Stearic acid or its pharmaceutically acceptable salt (preferably magnesium stearate) 0.5-1.0 Magnesium carbonate 10.0-20.0 Microcrystalline cellulose 14.0-20.0

The main disadvantage of the proposed composition is the chemical incompatibility of the ingredients and, accordingly, instability. In accordance with the method described in the aforementioned patent, when a mixture of the active substance (ethyl methylhydroxypyridine succinate) with succinic acid and magnesium carbonate is moistened during granulation, a chemical reaction of the latter takes place with the release of gaseous carbon (IV) oxide, since succinic acid (succinate anion solution) is stronger than carbonic acid. A similar reaction will occur during further storage, as a result of which the finished product does not meet the requirements of regulatory documents.

Also known is the composition of tablets of 2-ethyl-6-methyl-3-hydroxypyridine succinate with a modified release (Application RU 2008137778). The described dosage form is a tablet having in its structure the active substance, presented in the form of "spheroids", coated membranes (microcapsules). Depending on the composition of the shells, it is possible to create prolonged forms with different duration of release. However, for this class of tablets, completely different principles of production, dosage and use are characteristic, therefore it is not considered as an analogue.

As the closest analogue of the prototype selected (Pat. RU 2065299), describing a nootropic and tranquilizing agent, which is made in the form of a tablet consisting of a core containing 16.7-41.6 wt.% Mexidol, and from a polymer shell. Although the formula applies to any core and any polymer shell, the only composition (wt.%) Has been confirmed and disclosed, including white clay - 16.7-33.3, potato starch - 16.7-33.7, calcium as auxiliary substances stearic acid - 0.3-0.5, stearic acid - 0.3-0.5, talc - 0.5-1.0 and methyl cellulose 25.0-50 with the addition of tween 80 - 8.3-25.0 and titanium dioxide - 8.3-25.0.

The drug of this composition has passed clinical trials in the Russian Federation and the CIS countries and is registered by the Order of the Ministry of Health of the Russian Federation dated 01.26.1998 No. 21 under the trade name "Mexidol® coated tablets, 0.125 g."

The disadvantages of this tool include a significant amount of excipients (up to 84% of the total weight of the tablet), as well as a multi-component composition, which determines the multi-stage and duration of the process, which negatively affects the cost of the finished product. When using this composition of excipients, problems were noted during tabletting: the fragility of the tablet cores, chips along the edges, which does not provide the proper quality of the finished drug. The resulting tablets, in addition, are characterized by incomplete solubility in an aqueous medium: about 75-80% of the active substance passes into the solution within 45 minutes. In addition, the well-known disadvantages of some of the ingredients used in this technological solution: white clay has adsorbing properties, which does not contribute to the full release of the active substance; the disadvantages of talc are indicated above.

The objective of the invention is to remedy these disadvantages.

The problem is solved by the proposed composition of the pharmaceutical composition and the method of its preparation.

The present invention relates to a pharmaceutical composition in the form of tablets for oral administration based on 2-ethyl-6-methyl-3-hydroxypyridine succinate of the following composition, wt.%:

2-ethyl-6-methyl-3-hydroxypyridine succinate 45.0-55.0 Lactose Monohydrate 35.0-45.0 Binder 5.0-15.0 Magnesium stearate 0.5-1.5 For shell: Opadry II white 1.0-5.0

The technical result achieved using the claimed invention is to obtain a composition having good solubility and high bioavailability, stability, minimal content of auxiliary substances.

The composition contains sodium carboxymethyl cellulose or collidone 30 or a mixture thereof as a sodium binder. In the process of experimental confirmation of the reproducibility of the technology based on the proposed recipe, it was found that the composition of the binder component used (only sodium carboxymethyl cellulose or a mixture of sodium carboxymethyl cellulose and collidone 30 or only collidone 30) can be changed in order to obtain the desired properties depending on the type of equipment used and other technological features process.

Excipient lactose monohydrate is widely used in food, chemical and pharmaceutical industries. In the manufacture of tablets, it is used as a filler. It is included in a number of pharmacopeias (Eur. Pharm., US. Pharm. And others).

The excipient sodium carboxymethyl cellulose (carmellose sodium) is also widely used in various industries. Used in the manufacture of tablets as a binder. It is included in a number of pharmacopeias (Eur. Pharm., US. Pharm. And others).

The excipient magnesium stearate is widely used in the food and pharmaceutical industries. In the manufacture of tablets, it is used as a lubricating and sliding component, ensuring the fluidity of the tablet mass and the absence of adhesion. It is included in a number of pharmacopeias (Eur. Pharm., US. Pharm.-NF, etc.).

Collidone 30 (polyvinylpyrrolidone, povidone) is used in the food and pharmaceutical industries (Collidon®. Polyvinylpyrrolidone for the pharmaceutical industry / BASF Pharma Ingredients // translated from English and edited by K.V. Alekseev - 2001, 6th ed. - Kaliningrad : FGUIPP “Amber Tale.” - 310 p.). In the manufacture of tablets is used as a binder (in this case). It is included in a number of pharmacopeias (Eur. Pharm., US. Pharm. And others).

Opadry II white is a multicomponent excipient intended for coating tablets and other dosage forms with a coating. It consists of hydrophilic polymers (macrogol, polyvinyl alcohol, water-soluble cellulose derivatives) and pigment (titanium dioxide). Allows you to quickly prepare and apply a water-soluble film coating of white color, as it is well distributed over the surface of the tablets. It is widely used in the pharmaceutical industry in the production of solid dosage forms (www.colorcon.com/products/coatings/immediate-release).

A method of obtaining the proposed composition is implemented as follows:

1. Mix 2-ethyl-6-methyl-3-hydroxypyridine succinate, lactose monohydrate and a binder (only sodium carboxymethyl cellulose or a mixture of sodium carboxymethyl cellulose and collidone 30 or only collidone 30);

2. The resulting mixture is moistened. As a humidifier use purified water or an aqueous solution of a binder;

3. Spend granulation of the mixture;

4. Dry the granulate;

5. Powder granulate magnesium stearate;

6. Tablets to obtain core tablets;

7. The resulting cores are coated with a coating by applying a suspension of Opadra II white in water and drying.

The resulting product can be used in medicine or veterinary medicine as a medicine for oral administration of 2-ethyl-6-methyl-3-hydroxypyridine succinate for the treatment and prevention of various diseases and pathological conditions of the human or animal body.

The preparation of the proposed composition is described in the following examples.

Example 1

The sieved components are loaded into a high-speed granulator mixer: 97.7 g (37.9 wt.%) Lactose, 125.0 g (48.5 wt.%) 2-ethyl-6-methyl-3-hydroxypyridine succinate, 25, 0 g (9.7 wt.%) Sodium carboxymethyl cellulose. The stirrer is turned on and the mixture is stirred for 5 minutes at a rotation speed of 100 rpm. After 5 minutes, increase the speed of rotation of the mixer to 300 rpm, turn on the chopper (rotation speed of 1000 rpm) and gradually pour water through the nozzle purified at a temperature of 25 ° C (44 g in 2 minutes). After adding the humidifier, stirring is continued until the humidifier is evenly distributed in the mass (20 seconds at a main mixer 300 rpm, chopper 1000 rpm).

The resulting mass is transferred to wet granulation, which is carried out on a grinding and granulating machine. The nominal diameter of the holes in the glass of the granulating machine is 1.5 mm.

The granulate is collected in a container and transferred for drying in a fluidized bed at a temperature in the material of 35-40 ° C until a residual moisture content of 4-5% is reached.

The dried granulate is transferred to a high-speed granulator mixer and mixed with 2.5 g (0.97 wt.%) Magnesium stearate for 2 minutes at a stirrer speed of 150 rpm. At the end of the dusting process, the resulting mixture is unloaded into a container and sieved on a sieve with a hole diameter of 0.5 mm. In the case of screenings of coarse granulate, they are passed through a grinding and granulating machine with a diameter of aperture of the glass 0.5 mm, and then through a sieve with a diameter of 0.5 mm.

The preparation of 2-ethyl-6-methyl-3-hydroxypyridine succinate core cores is carried out on a rotary tablet press.

The geometric dimensions of the tablet core: the diameter of the tablet core (9.0 ± 0.3) mm; radius of curvature 0.9.

The core tablets are collected in a container, viewed on a sieve, conditional tablets are collected in a container and transferred to the film-coating step.

The coating is carried out on a coating machine using a suspension of Opadra II white in water purified with a concentration of 20% (7.5 g (2.9 wt.%) Opadra II white + 30.0 ml of purified water). The film-forming suspension is sprayed onto the tablet cores until the suspension is fully used and until the average weight of the tablets increases: from 0.2382 g to 0.2768 g, at the end of the coating process, the tablets are dried at 60 ° C for 10-20 minutes.

About 900 coated tablets are obtained, with an average weight of 0.2575 g ± 7.5%, containing 0.125 g of 2-ethyl-6-methyl-3-hydroxypyridine succinate (the Dissolution test — passes into the solution for at least 98 % of active substance).

Example 2

After preliminary sieving, 48.0 kg (48.73 wt.%) Of 2-ethyl-6-methyl-3-hydroxypyridine succinate, 37.4 kg (37.96 wt.%) Of lactose monohydrate are loaded into the granulator-dryer of the fluidized bed, 9.1 kg (9.23 wt.%) Of carboxymethyl cellulose sodium. The loaded components are heated and mixed on the filters with incoming air at a temperature of 60-65 ° C. The frequency of shaking the filters is 1-2 minutes, the duration of shaking is 7 seconds. After reaching a temperature in the product layer from 38 to 40 ° C, a humidifier (25.0 kg, a previously prepared 2% aqueous solution of sodium carboxymethyl cellulose) begins to be supplied at a rate of 660 to 990 ml / min. The total load weight is 119.5 kg (for solids 94.5 kg). After the end of irrigation, they switch to the drying mode, which leads to the content in the granulate of the mass fraction of residual moisture from 1.7 to 3.2%. The granulate is cooled to 25 ° C and discharged through a calibrator, the grid of which has a hole diameter of 1 mm. The yield of granulate is 98.9% of the feedstock.

The tabletting mass is prepared in a mixer, where the granulate is placed, gradually adding 1.0 kg (1.02 wt.%) Of magnesium stearate to it. After sampling for quality control, tablet cores are made from the resulting mass on a tablet press with 9 mm spherical punches. The average weight of the tablet core is 0.250 g.

A film-forming suspension of Opadra II white in purified water with a concentration of 18% (3.0 kg (3.05 wt.%) Opadra II white + 13.6 L of purified water) is prepared in a separate reactor with a stirrer. The tablet cores are loaded into the coating unit drum and nozzles are placed to spray the suspension at a distance of 20-22 cm from the surface of the tablets. The coating process includes 4 stages: heating of the core tablets, irrigation, drying and cooling.

Pa of the first stage, the drum rotation speed is 2-3 rpm; inlet air temperature - 60 ° С. In the second stage, the rotation speed of the drum is increased to 8-14 rpm; inlet air temperature - up to 65-67 ° С; suspension flow for irrigation - 50-110 ml / min. In the third and fourth stages, the rotation speed of the drum is again reduced to 3-4 rpm; in the fourth stage, the air temperature is also lowered to 25-30 ° C, both at the inlet and at the outlet.

About 360 thousand coated tablets are obtained, having a round, biconvex form, white or with a slightly cream tint, with an average weight of 0.2575 g ± 7.5%, containing 0.125 g of 2-ethyl-6-methyl-3-hydroxypyridine succinate (“Dissolution” test - in 45 minutes at least 98% of the active substance passes into the solution).

Example 3

To obtain tablets, the same operations are carried out as in Example 2, with the same components, additionally introducing collidone 30. The sodium content of carboxymethyl cellulose in the total mixture is reduced to 1.0 kg, and collidone 30 is added in an amount of 8.1 kg Humidifier - 2% aqueous solution of sodium carboxymethyl cellulose.

Example 4

To study stability, three experimental series of tablets were prepared in accordance with Example 1 and stored for storage under natural conditions (temperature + 25 °, humidity 55-65%).

During storage, samples were taken and a full analysis was carried out for compliance with regulatory requirements. Data on the stability of the tablets are shown in the table. The shelf life of the tablets is 3 years. No significant changes in the composition of the drug were observed during the entire storage period.

Example 5

A study was conducted of the antioxidant activity of tablets made in accordance with Example 1, in comparison with tablets made according to the recipe given in the patent (Pat. RU 2065299), used as an analogue of the prototype. The samples of the tablets contained an identical amount of active ingredient — 0.125 g. The test was carried out on a TsvetYauza-01-AA antioxidant activity measuring device by measuring the electric current in the cell arising from the oxidation of an antioxidant analyte on the surface of a glassy carbon working electrode at a certain potential. Both drugs (aqueous solution of tablets) showed an equally high antioxidant activity of 3.6 mg / g in terms of standard quercetin. Thus, it was proved that the selected composition of excipients does not interfere with the activity of 2-ethyl-6-methyl-3-hydroxypyridine succinate.

Series No. Exp term storage, year Description Authenticity Average weight Dissolution Foreign matter quantitation ND requirement Round tablets, biconvex, coated, from white to white with a cream tint Qualitative reactions, TLC, UV spectrum 0.245 to 0.271 g Not less than 70% in 45 minutes No more than 0.5% 0.119 to 0.131 g of 2-ethyl-6-methyl-3-hydroxypyridine succinate in 1 tablet 010307 0 Acc. Acc. 0.255 99% Less than 0.5% 0.123 010307 0.5 Acc. Acc. 0.253 99% Less than 0.5% 0.123 010307 one Acc. Acc. 0.253 99% Less than 0.5% 0.122 010307 1,5 Acc. Acc. 0.254 99% Less than 0.5% 0.122 010307 2 Acc. Acc. 0.253 98% Less than 0.5% 0.121 010307 2.5 Acc. Acc. 0.253 99% Less than 0.5% 0.121 010307 3 Acc. Acc. 0.253 98% Less than 0.5% 0.121 020307 0 Acc. Acc. 0.257 98% Less than 0.5% 0,126 020307 0.5 Acc. Acc. 0.256 99% Less than 0.5% 0.125 020307 one Acc. Acc. 0.256 99% Less than 0.5% 0.125 020307 1,5 Acc. Acc. 0.256 99% Less than 0.5% 0.124 020307 2 Acc. Acc. 0.254 98% Less than 0.5% 0.123 020307 2.5 Acc. Acc. 0.255 98% Less than 0.5% 0.123 020307 3 Acc. Acc. 0.255 98% Less than 0.5% 0.123 030307 0 Acc. Acc. 0.261 99% Less than 0.5% 0.124 030307 0.5 Acc. Acc. 0.261 99% Less than 0.5% 0.123 030307 one Acc. Acc. 0.261 99% Less than 0.5% 0.124 030307 1,5 Acc. Acc. 0.260 99% Less than 0.5% 0.123 030307 2 Acc. Acc. 0.260 98% Less than 0.5% 0.123 030307 2.5 Acc. Acc. 0.258 99% Less than 0.5% 0.122 030307 3 Acc. Acc. 0.259 99% Less than 0.5% 0.122

Claims (2)

1. A pharmaceutical composition for oral administration in the form of a tablet consisting of a core containing 2-ethyl-6-methyl-3-hydroxypyridine succinate and excipients, and a polymer shell, characterized in that it contains lactose monohydrate as a binder selected from sodium carboxymethyl cellulose, collidone 30, or a mixture thereof, and magnesium stearate, and as a polymer shell Opadry II is white with the following content of components, wt.%:
2-Ethyl-6-methyl-3-hydroxypyridine succinate 45.0-55.0 Lactose Monohydrate 35.0-45.0 Binder 5.0-15.0 Magnesium stearate 0.5-1.5 for shell: Opadry White 1.0-5.0 2. The method of obtaining the pharmaceutical composition according to claim 1, characterized in that 2-ethyl-6-methyl-3-hydroxypyridine succinate, lactose monohydrate and a binder are mixed, the mixture is moistened with purified water or an aqueous binder solution, the mixture is granulated, and drying is carried out granulate, dust granulate magnesium stearate, tablet the mixture, the resulting cores are coated with Opadra II white coating by applying a suspension and subsequent drying.