WO2021118403A1

WO2021118403A1 - System for delivering 2-ethyl-6-methyl-3-hydroxypyridine succinate for peroral administration

Info

Publication number: WO2021118403A1
Application number: PCT/RU2020/000665
Authority: WO
Inventors: Дамир Хизбуллаевич САЛАХЕТДИНОВ; Александр Александрович ЗАБОЗЛАЕВ; Александр Викторович РОЖДЕСТВЕНСКИЙ
Original assignee: Общество С Ограниченной Ответственностью "Научно-Производственная Компания "Фармасофт"
Priority date: 2019-12-10
Filing date: 2020-12-07
Publication date: 2021-06-17
Also published as: RU2734970C1

Abstract

The invention relates to the chemical and pharmaceutical industry, medicine and veterinary science, and describes an agent for delivering 2-ethyl-6-methyl-3-hydroxypyridine succinate for peroral administration, providing an gastroretentive effect, and dosage forms based thereon. The agent contains at least one polyalkylene oxide. The invention makes it possible to improve the bioavailability of the active substance and reduce the dose frequency for the drug.

Description

DELIVERY SYSTEM OF 2-ETHYL-6-METHYL-3-HYDROXYPIRIDINE SUCCINATE FOR Oral USE

Technology area

The invention relates to the chemical-pharmaceutical industry, medicine and veterinary medicine and describes a delivery system for 2-ethyl-6-methyl-3-hydroxypyridine succinate (hereinafter EMHPS) for oral administration in the form of a tablet. The invention can be used in medicine or veterinary medicine as a drug for oral administration of EMHPS for the treatment and prevention of various diseases and pathological conditions of the human or animal organism.

Medicines with EMHPS have found effective use in various areas of clinical medicine: neurology, psychiatry, cardiology, ophthalmology, surgery, dentistry, endocrinology, etc.

Prior art

Preparations with EMHPS (trade name - Mexidol®, etc.) are widely used as an antioxidant and antihypoxic agent, characterized by a wide spectrum of pharmacological action and high efficiency (nootropic and tranquilizing action - patent RU2065299, anti-ischemic and antiatherosclerotic action - patent RU 2144822, antianginal - patent RU 2168993, hepatoprotective - patent RU 2189817, antibacterial - US Pat. RU 2157686 and others).

EMHPS is used in the treatment of the following human diseases / conditions:

- heart failure;

- ischemic heart disease as part of complex therapy;

- acute disorders of cerebral circulation;

- the consequences of acute disorders of cerebral circulation, including after transient ischemic attacks, in the phase of subcompensation as preventive courses;

- minor craniocerebral trauma, consequences of craniocerebral trauma;

- encephalopathy of various origins (discirculatory, dysmetabolic, post-traumatic, mixed);

- syndrome of vegetative dystonia;

- mild cognitive disorders of atherosclerotic genesis;

- anxiety disorders in neurotic and neurosis-like states;

- relief of withdrawal symptoms in alcoholism with a predominance of neurosis-like and vegetative-vascular disorders, post-withdrawal disorders; - conditions after acute intoxication with antipsychotic drugs;

- asthenic conditions, as well as for the prevention of the development of somatic diseases under the influence of extreme factors and loads;

- exposure to extreme (stress) factors; and prevention:

- exacerbations of heart failure;

- exacerbations of coronary heart disease.

Known compositions based on EMHPS in the form of various dosage forms: solution for parenteral administration (Mexidol® 5% solution for injection P N002161 / 01, patents RU2205640, 2380089, 2398583), tablets (Mexidol® coated tablets, 0.125 g LSR-002063 / 07), capsules (patent RU 2144822, 2145855).

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 disadvantages of this route of administration are well known - the risk of infection, the need for the presence of qualified personnel, the painfulness of injections, and how as a consequence, the impossibility of long-term (more than 3-4 weeks) treatment with parenteral dosage forms.

In addition, the injectable form does not provide a long-term nootropic effect, while there is a change in the spectrum of the pharmacological activity of the drug, which is expressed in an increase in aggressiveness, emotional reactivity, and a decrease in anti-stress action [see. description RU 2065299].

The multifaceted use of EMHPS requires the creation of dosage forms with different absorption rates, the penetration of the active substance into the blood and the maintenance of its active concentration in the blood (from the fastest possible in emergency situations to prolonged with long-term treatment), which directly raises the question of the need to obtain a delivery system that provides both high bioavailability of the active substance, and making it possible to maintain its concentration in the blood plasma, sufficient for a long-term therapeutic effect. The finished dosage forms known to date cannot satisfy this demand. Maintaining an active plasma concentration for a relatively long period of time occurs by taking large doses of dosage forms or by administering them several times a day. Such doses can create toxic and undesirably high drug levels in the patient's body. Administration of the drug with at some time intervals leads to the formation of fluctuating levels of the drug, the so-called peak and failure action, which in turn leads to ineffectiveness or failure of treatment, an increase in the risk of side toxic effects. Therefore, it is desirable for patients with long-term therapy of certain diseases / conditions to have a relatively constant concentration of the administered drug in the blood. Considering the above circumstances, the development of dosage forms for oral administration for long-term therapy of patients on an outpatient basis is urgent. Disclosure of invention

The objective of the invention is to develop a system for the delivery of EMHPS for oral administration in the form of a tablet, providing increased bioavailability with simultaneous long-term maintenance of the required concentration of the active substance in the blood plasma.

The authors of the invention described in patent RU 2444359, which can be indicated as the closest analogue, have attempted to solve this problem. They have developed the composition of tablets with modified release EMHPS. The described dosage form is are tablets having in their structure, spheroids with an active substance, coated. Depending on the composition of the shells, forms with different solubility of the active substance were created. For each group of obtained spheroids, the dissolution profile was determined and, based on the data obtained, the required ratio of spheroids in the finished dosage form was calculated to achieve the required dissolution profile. The dissolution profile was obtained using USP Apparatus 2 (USP Apparatus 2): volume of dissolution medium 900 ml; stirrer rotation speed 50 rpm; bath temperature 37 ± 0.5 ° C. Dissolution medium 0.1 N HC1 ⁰ for 2 hours, the rest of the time - phosphate buffer, pH 6.8.

However, in the description of the patent there is no information to make sure that the problem has been solved. The studies presented in the patent indicate only a change in the dissolution profile when the dosage form passes from one dissolution medium (corresponding to the pH of the stomach) to another (corresponding to the pH of the intestine). Achievement and maintenance of the required concentration in blood plasma, as well as the degree of absorption / absorption of the active substance in the presented studies were not studied.

Dosage forms are formed to provide and control the required release and dissolution of the active ingredient. The dissolved the substance, in this regard, the dissolution process (the amount and rate of transition of the drug into the solution) is one of the most significant factors in ensuring the required bioavailability of the pharmacologically active substance from the finished dosage form. However, in addition to solubility, there are other biopharmaceutical factors that can significantly modify the final properties of the tableted microsystem, which ultimately can lead to significant differences in bioavailability (see S.B. Setkina et al. Biopharmaceutical aspects of drug technology and ways of modifying bioavailability, Bulletin VSMU, 2014, volume 13, No4, pp. 62-172). Only when a reliable in vivo in vitro correlation is identified can it be allowed to assess the behavior of a drug in vivo by studying its dissolution kinetics and, thus, to assess its bioavailability (see Ramenskaya G.V. et al. In vivo - in vitro correlation (ivivc ): a modern tool for assessing the behavior of dosage forms in vivo, Medical Almanac, 2011, No 1 (14) March, pp. 222-226). In the patent RU 2444359 there is no information about in vivo in vitro correlation, in this regard, the above solubility studies cannot indicate an increase in the bioavailability of EMHPS.

As a result of our studies, it was unexpectedly found that bioavailability can be increased as a result of creating an EMHPS delivery system capable of retaining the active substance for more than 6 hours in the stomach. Also it has been proven that bioavailability when using dosage forms with prolonged action is comparable to immediate release tablets. Our studies have refuted the opinion of experts that using a prolonged form with EMHPS can increase bioavailability. Sustained-release formulations begin to release EMHPS in different parts of the gastrointestinal tract (from the stomach to the rectum), which does not contribute to an increase in its bioavailability.

The solution to the problem of controlled absorption of the active substance into the blood to achieve the desired concentration and its maintenance and / or change over time is achieved by excipients that modulate / control the release of the active substance, while it was found that an increase in bioavailability is possible if the delivery system releases EMHPS in the stomach for a long time.

The present invention provides a novel drug delivery technology (EMHPS) with a gastro-retentive (gastro-retention) delivery system.

The advantages of this method of drug delivery (EMHPS) in comparison with similar drugs, including EMHPS of different release modes, are that release occurs only in a certain part of the gastrointestinal tract (most of it in the stomach), where the greatest bioavailability (absorption) of EMHPS is observed.

It has now been found that EMHPS, which is highly soluble, can be administered orally in a manner that prolongs its release time in order to distribute its absorption rate more evenly over time. This will significantly reduce the problems of temporary overdose caused by an initial spike in concentration entering the bloodstream immediately after administration and subsequent underdosing, and instead monitors the dosage to safer and more effective levels over an extended period of time.

In addition, EMHPS has been found to be problematic due to its release in the lower gastrointestinal tract due to its poor absorption capacity into the bloodstream in the lower gastrointestinal tract.

It is an object of the present invention to provide a drug delivery system that remains in the stomach for at least 6 hours.

The invention relates to a gastro-retentive delivery system for EMHPS, providing a long residence time in the stomach. Gastro-retentive delivery systems in the form of stomach swellable tablets, as well as methods for their preparation, are described in patents EP 1886665, US6340475 and international application W003035177. Polymers used in gastro-retentive gastric swellable tablets are known from these documents. Retention in the stomach can result from swelling and / or mucoadhesion of the delivery system. However, the suitability, much less the effectiveness of these delivery systems for EMHPS with improved bioavailability has not been previously described.

The selection of polymers for such a delivery system is within the skill of the art and depends on the properties of the polymers, their molecular weight and the desired rate of release of EMHPS and the duration of retention in the stomach. A properly selected combination of polymers can provide a more controlled release and absorption of EMHPS, which leads not only to an increase in bioavailability, but also to a reduction in the number of doses of the drug.

The object of the invention is a system for the oral delivery of 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form of a gastro-retentive tablet.

The agent for preparing an EMHPS delivery system according to the invention contains at least one polymer that combines gastric swelling control, gastric EMHPS release and mucoadhesive properties. According to the invention, the system can contain one polymer with such properties or a combination of polymers, providing the necessary properties. Examples of polymers are shown in Table 1.

As such a polymer, polyapkylene oxides (polyethylene oxide and polypropylene oxide; copolymers of ethylene oxide and propylene oxide) can preferably be used. Most preferred is the use of polyethylene oxide (PEO). This polymer can be combined with other functional excipient polymers listed in Table 1.

The weight ratio of 2-ethyl-6-methyl-3-hydroxypyridine succinate to polyethylene oxide is preferably 2.6: 1 to 1.3: 1.

The invention also relates to a gastric retained tablet in which the matrix is a delivery agent and EMHPS in a therapeutically effective amount. The tablet may contain from 125 mg to 1500 mg of EMHPS.

The tablet according to the invention optionally contains additional pharmaceutically acceptable excipients to aid in the production, compressibility, appearance and taste of the formulation.

Such agents include, for example, diluents or fillers, glidants, binders, granulating agents, release agents, lubricants, flavors, colorants, and preservatives. Other common excipients known in the art may also be included. Table 1.

The filler can be selected from soluble fillers, for example sucrose, lactose, in particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol.

A lubricant can be used to enhance the release of the tablet from the device on which it is formed.

Suitable lubricants include magnesium stearate, calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, and the like. ...

The composition of the tablets can be developed taking into account the technological properties of the pharmaceutical substance, as well as its compatibility with various excipients. The choice of auxiliary components and production technology can be carried out experimentally.

The new dosage form provides the concentration of the active substance in the blood in the range of therapeutic activity, if possible, without short-term peaks Cmax. The dosage form, by keeping the EMHPS in the area of absorption, shows an improvement in bioavailability due to a slow release rate. Controlled release has several distinct advantages over conventional formulations immediate release. In addition, the controlled release dosage form lowers the maximum plasma concentration.

The action of the active substance in the stomach (gastro-retention) occurs due to the swelling of the tablet and its adhesive capacity (mucoadhesion). Unlike the prolonged form, the gastro-retentive tablet can have the following degree of swelling up to 243% in 6 hours, and the prolonged 60% in 6 hours. The prolonged form does not have mucoadhesive ability, while the gastro-retentive form can maintain this ability for 14 hours.

The invention also relates to a method for increasing the bioavailability of EMHPS, which provides for the administration of a tablet once a day to a subject in need thereof.

Increased bioavailability and prolonged action can reduce the frequency of taking EMHPS to 1 time per day.

Brief Description of the Drawings FIG. 1-6. Solubility curve of EMHPS from different compositions (on the abscissa axis - time in hours, on the ordinate axis EMHPS release in%).

FIG. 7. Curve "concentration-time" (abscissa - time in hours, ordinate - concentration of EMHPS in ng / ml) after taking HF EMHPS by dwarf pigs: comparison drug - after three times oral administration - * -; Object N “1, p / o 375 mg and Object 2, p / o 375 mg after a single oral administration, (n = 3, X ± Sx).

FIG. 8. Curve "concentration-time" (abscissa - time in hours, ordinate - Ln concentration of EMHPS) after taking HF EMHPS by miniature pigs: comparison drug - after three times oral administration

Object Nsl, p / o 375 mg

and Object 2, p / o 375 mg ~ ~ after a single oral administration in semilog coordinates (n = 3, X ± Sx).

The methods for preparing gastro-retentive tablets are no different from those for conventional tablets. The delivery system and tablets can be produced by the following methods: direct compression technology, wet granulation technology, dry granulation technology, etc.

The most preferred adjuvants are as follows.

Microcrystalline cellulose

Microcrystalline cellulose 102. This brand of microcrystalline cellulose has an average particle size of 130 microns, which makes it possible to use it to improve flowability and compressibility.

Microcrystalline cellulose is used as a filler and diluent, which improves flowability and adhesion between particles during tableting. Cellulose microcrystalline ensures the preservation of the integrity of the tablet shape under mechanical stress. The content of microcrystalline cellulose will be selected experimentally. The content of microcrystalline cellulose is limited due to the large geometry of the tablets.

Carmellose sodium

Carmellose sodium grade CMC 7H4F in concentration was selected based on Ashland's recommendations for use in sustained release tablets by wet granulation. Carmellose sodium acts as a binding agent in wet granulation. Carmellose sodium has mucoadhesive (mucoadhesive) properties.

Povidone

Povidone is a well-known and readily available high performance binder. Depending on the concentration in the formulation, it can be used: 1) to form complexes with the substance, in order to improve its dissolution; 2) for binding the components in order to agglomerate them (obtaining granules); 3) to impart technological properties to the tablet cores (hardness and abrasion strength of the tablets). Povidone is a universal component and is used in drug production technologies using the direct pressing, dry granulation, wet granulation, compacting. The 90 F grade was selected based on the manufacturer's recommendations, BASF, as a binding agent for wet granulation.

Hypromellose

This component is included in the formulation of the medicinal product as a binding agent in order to impart abrasion and chipping resistance to the tablets so that a film coating can be applied to the tablet cores, as well as to increase the degree of swelling in combination with polyethylene oxide. Hypromellose provides the desired dissolution profile.

Polyethylene oxide

POLYOX ™ Water Soluble Resins (NF Grades) are nonionic poly (ethylene oxide) polymers. They are hydrophilic polymers available in a wide range of molecular weights and are supplied as white free flowing powders. POLYOX provides fast wetting and swelling for use in osmotic pump technologies and forms a gel in a hydrophilic matrix. Polyethylene oxide is used as a hydrophilic matrix in gastro-retentive dosage forms and has mucoadhesive (mucoadhesive) properties. Magnesium stearate

Magnesium stearate was chosen because of the large tablet size, which has a high tablet end, which can cause high ejection forces when tableted at high speed on an industrial scale.

Magnesium stearate is a hydrophobic lubricant in nature and is used to prevent mixtures from sticking to the press tool.

Film casing

In the drug, a casing of the Colorcon company of the Opadry II brand based on polyvinyl alcohol is proposed. The polyvinyl alcohol-based film coat spreads quickly and evenly over the tablet surface, and also reduces the risk of chipping due to greater adhesion and lower viscosity than the hypromellose-based film coat. Also, the shell based on polyvinyl alcohol ensures easy swallowing of tablets, which is important for large tablets of the drug.

To obtain tablets, two production technologies have been proposed: wet granulation and direct compression. The use of wet granulation technology allows:

• prevent stratification of the multicomponent mixture;

• improve the flowability of the mixture;

• provide the required bulk density; • ensure the dosing accuracy.

The pharmaceutical substance EMHPS has unsatisfactory technological properties, which complicates the use of direct compression technology.

In the course of pharmaceutical development, laboratory samples were obtained using direct compression technology. This concept was consistent with the “Quantification” and “Dissolution” quality indicators, but had the following disadvantages:

• insufficient strength of tablet cores;

• high abrasion of core tablets;

• adhesion of the tablet cores to the press tool during the tabletting process.

The use of the direct compression method in production will be complicated by the unsatisfactory physicochemical and technological properties of the substance itself, which can affect the critical indicators of the quality of the drug. It is most preferable to use wet granulation technology.

The best example of carrying out the invention

In particular, one of the variants of gastro-retentive tablets can be obtained by the method described below. Description of the production process Preparation of raw materials Sifting of raw materials EMHPS is sieved manually through a 1.0 mm sieve.

The rest of the raw materials are sieved on a CISA RP 200N vibrating sieve through a 0.5 mm sieve.

Weighing raw materials

Each type of raw material is weighed into separate clean containers.

Preparing the humidifier solution

The entire amount of Povidone K90 is added to a container with purified water with constant stirring. Stirring is carried out until complete dissolution (visual control). The concentration of the humidifier solution is 8.0%. Mixture preparation for tabletting Mixing

Sifted EMHPS, sieved MCC, polyethylene oxide and / or sifted sodium carmellose are loaded into a modular installation with a fluidized bed. The components are mixed until homogeneous (visual control).

Granulation

With constant stirring of the mixture, a humidifier solution is introduced into the fluidized bed. Carry out mixing until fine friable granulate is formed (visual control).

Drying of granules

The granulate is dried in a fluidized bed dryer to a residual moisture content of no more than + 0.5% to the original at a temperature of 50-55 ° C.

Calibration of granulate

The granulate is sieved on a CIS A RP 200N vibrating sieve through a 1.0 mm sieve. The screening of the granulate is rubbed manually through a 1.0 mm sieve.

Dusting

Granulate, Hypromellose 2208 or Polyethylene oxide and Hypromellose 2208 are introduced into the mixer. Mixing is carried out until homogeneous (visual control).

Sifted magnesium stearate is loaded into the mixer and the components are mixed until homogeneous (visual control).

The tabletting mixture is discharged into a labeled container.

Tabletting

The tableting process is carried out on a Fasttab 3000 tablet press. The tableting process is carried out on a press tool with a geometry of 19x8 (18x10) mm.

The tablet press is tuned for production of average weight. After adjusting the average weight of the tablets, the tablet press is adjusted according to the rest of the indicators:

• hardness;

• abrasion;

• height;

• deviations from the average weight of the tablets.

After setting up the tablet press, the tabletting process is carried out until the tabletting mixtures are completely consumed. In the process of tabletting, at least once every 5 minutes, control is carried out:

• average weight of tablets;

• the hardness of the tablets.

During the tabletting process, tablets are collected in labeled containers.

Coating of tablets-cores with a coating Preparation of a film suspension

In the process of applying a film shell, an 18% film suspension is used.

Set the stirring of water, purified so that a funnel is formed on the surface of the water. A dry film shell is gradually introduced, preventing the formation of agglomerates on the surface of the solution, then after that the stirring speed is reduced so that foaming does not occur, and the solution is left to mix for 45 minutes. Sheathing

Before carrying out the coating process, the tablets are heated to 37-39 ° C with periodic stirring in the drum of the coater. When the temperature of the tablets is reached, spraying of the film suspension is started. In the process, the appearance of tablets and the weight gain of the shell are controlled.

The coating process is carried out until the average weight of the tablets is obtained. When the predetermined mass of tablets is reached, the process is stopped and the tablets are cooled to a temperature not higher than 33 ° C. After the end of the process, the containers are closed.

A tablet composition with gastro-retention properties can be the following:

Composition 1

Component name Amount,% EMHPS

Microcrystalline 2.0-40.0 cellulose

Povidone 2.0-10.0

Sodium carboxymethyl cellulose 2.0-20.0 Polyethylene oxide 15.0-50.0

Magnesium stearate 0.2-1.0 Composition 2

Component name Amount,%

EMGPS 30.0-65.0

HPMC 5.0-15.0

Copovidone 2.0-10.0

Polyethylene oxide 15.0-30.0

Magnesium stearate 0.2-1.0

Composition 3

Component name Amount,%

EMGPS 30.0-65.0

HPMC 3.0-30.0

Povidone 2.0-10.0

Sodium carboxymethyl cellulose 2.0-20.0 Polyethylene oxide 15.0-50.0

Magnesium stearate 0.2-1.0

Microcrystalline 2.0-40.0 cellulose Composition 4

Component name Amount,%

EMGPS 30.0-65.0

HPMC 3.0-30.0

Povidone 2.0-10.0

Sodium carboxymethyl cellulose 2.0-20.0 Polyethylene oxide 15.0-50.0 Microcrystalline cellulose 2.0-40.0 Methacrylic acid and 5.0-30.0 ethyl acrylate copolymer [1: 1] Glyceryl monostearate (or talc) 0.5-5.0 Triethyl citrate 0, 5-5.0 Polysorbate 0.5-5.0 Magnesium stearate 0.2-1.0

Composition 5

Component name Amount,%

EMGPS 30.0-65.0

HPMC 3.0-30.0

Carbomer 5.0-30.0

Povidone 2.0-10.0

Sodium carboxymethyl cellulose 2.0-20.0 Polyethylene oxide 15.0-50.0

Magnesium stearate 0.2-1.0

Microcrystalline 2.0-40.0 cellulose

Roster 6

Component name Amount,%

EMGPS 30.0-65.0

HPMC 3.0-30.0

Hydroxyethyl cellulose 5.0-30.0 Povidone 2.0-10.0

Sodium carboxymethyl cellulose 2.0-20.0 Polyethylene oxide 15.0-50.0

Magnesium stearate 0.2-1.0

Microcrystalline 2.0-40.0 cellulose

The composition and ratio of the components (as well as the degree of swelling and mucoadhesion) help to achieve the desired release profile in the stomach (in-vitro test). Experiments were carried out in which the dissolution curves of EMHPS of the following tablet compositions were obtained:

The solubility curve at pH 1, 2 is shown in FIG. one.

The solubility curve at pH 6.8 is shown in FIG. 2.

The solubility curve at pH 6.8 is shown in FIG. 3.

Solubility curves at pH 1.2 and 6.8 are shown in FIG. 4 and 5 respectively.

It has been studied that in a gastric dissolution medium (pH 1.2 in vitro), the release of the active substance is faster. After changing the composition, a release curve was obtained for the following composition.

The solubility curve at pH 1.2 is shown in FIG. 6. This composition allows to obtain the required release profile and the necessary additional parameters (degree of swelling, mucoadhesiveness) for a gastro-retentive tablet, as well as satisfactory technological properties (flowability of the mixture, strength and abrasion of the tablet). Wet granulation technology makes the tabletting process stable and controlled. Study of the comparative pharmacokinetics of three experimental finished dosage forms of EMHPS in dwarf pigs.

Research objects:

Comparison drug: Mexidol, of the following composition: EMHPS 125 mg, excipients: lactose monohydrate - 97.5 mg, povidone - 25.0 mg, magnesium stearate - 2.50 mg. Sheath: opadry II white - 7.5 mg.

Object N ° 1 Prolonged Form

Component name Amount, mg Ethylmethylpyridine succinate 375.00 Microcrystalline cellulose 149.26 Sodium carmellose 27.30 Povidone-K90 17.85

Hypromellose K100M type 2208 202.80 Magnesium stearate 7.80

Film casing based on PVA 30,00 Object N “2. Modified-release gastro-retentive form

Hypromellose K15M type 2208 31.00

Polyethylene oxide 221.40

Magnesium stearate 8.20

Film casing based on 30,00

PVS

Materials and methods.

The study was carried out on sexually mature male dwarf pigs, since it is possible for them to administer the studied objects in the form of tablets without destroying the integrity of the finished dosage form. Dwarf pigs are a standard subject of pharmacokinetic studies (Guidelines for the maintenance and use of laboratory animals. Eighth edition / translated from English. Edited by IV Belozertseva, DV Blinov, MS Krasilytsikova. - M .: IRBIS , 2017 - 362 s). Before the start of the study, laboratory animals were kept in enclosures for adaptation.

The duration of the adaptation period for animals was 5 days. During the adaptation period, the animals were monitored daily for clinical condition by visual inspection. No deviations were found.

The distribution of animals into groups was not carried out, because only 3 animals were involved in the experiment. The introduction of objects JVb 1, 2 was carried out sequentially after the introduction of the object of comparison: the tested object No. 1 was introduced 2 days after the introduction of the object of comparison; tested object

- 4 days after the introduction of the test object N ° l.

The animals were kept under standard conditions in accordance with Directive 2010/63 / EU of the European Parliament and of the Council of the European Union of 22 September 2010 on the protection of animals used for scientific purposes.

The experimental design is shown in Table 2.

For humans, it is recommended to use two GLF preparations with EMHPS, which are forms with a modified release of EMHPS, in the dosage form a film-coated tablet - 1 tablet once a day. That is, according to EMHPS 1 * 375 mg = 375 mg / day.

Thus, the highest therapeutic dose (VTD) of EMHPS for a person weighing 60 kg is 375/60 = 6.25 mg / kg. For miniature pigs, the equivalent dose is 6.25x1.1 (Guidance for industry dose conversion factor. Estimating the maximum safe starting dose for initial clinical trials for therapeutics in adult healthy volunteers. US Department of health and human services. FDA. CDER. . - 2005) = 6.88 mg / kg.

When a dwarf pig weighing 20 kg is administered 1 tablet of the EMHPS preparation, the dose will be 375 mg / 20 kg = 18.75 mg / kg, which corresponds to approximately 2.7 VTD. The tested objects represent a dosage form of prolonged action, which implies its minimal destruction when introduced into the test system during the study and does not allow crushing of the dosage form. Therefore, this study provides for the introduction of the EMHPS preparation without destroying the integrity of the dosage form. Thus, the peculiarities of the dosage form of the EMHPS preparation determine the selected dose, 1 tablet, as the minimum and the closest possible to VTD in terms of dwarf pigs, taking into account the interspecific coefficients.

Table 2.

Scheme of an experiment for studying the pharmacokinetics of drugs with

EMHPS

The selected dose made it possible to assess the main parameters of the EMHPS pharmacokinetics after a single administration of the test objects.

The test objects were administered to miniature pigs unchanged orally, once, before the morning feed distribution at a dose of 1 tablet / animal using a tablet.

The comparison drug was administered 3 times a day, 1 tablet with an interval of 2.5 hours, to each animal, which is equivalent to the dose of administration for the tested objects (EMHPS drug). The first tablet - before the morning feed distribution, 2 and 3 - regardless of food intake.

At the experimental stage, the animals in the enclosure were examined to identify deviations in animal behavior and mortality.

Biomaterial sampling

Each animal was placed a 22G intravenous catheter (KD Medical GmbH Hospital Products, Germany) into the ear vein, through which blood samples were taken in a volume of 2.0 ml per exposure point.

At 0 o'clock, the biomaterial was taken before the administration of the drugs. Then, the study drugs were injected, and then the biomaterial was taken at the appropriate time points. Method for quantitative determination of EMHPS in biological samples 0.2 ml of blood plasma was placed in a plastic centrifuge tube with a capacity of 2 ml (type "Eppendorf"), 0.6 ml of ethyl acetate was added, vigorously shaken for 3 minutes, after phase separation, the organic layer was taken, the solvent was removed, to dissolve the analyte, the dry residue was added 0.2 ml of 0.03% trifluoroacetic acid solution, vortexed for 30 seconds, the sample was transferred to an autosampler vial and dosed into the HPLC system. HPLC analysis conditions

The analysis was performed on a high-pressure liquid chromatograph (Shimadzu, Japan) with a diode array detector and a Luna Cl 8 (2) 4.6x150 mm column (sorbent particle size 5 μm) and a guard column (3 mm) filled with the same sorbent (Phenomenex, USA ) in isocratic mode of elution with a mixture of 0.03% solution of trifluoroacetic acid and acetonitrile in a ratio of 95: 5, the flow rate of the eluent is 1 ml / min, the dosed volume of samples is 20 μL, the detection wavelength is 295 nm. Registration and processing of chromatograms was performed using the LabSolutions LCSolution Version 1.25 software (Shimadzu, Japan). Statistical data processing

Tables 3-5 show the arithmetic mean values (X), their corresponding standard deviations (SD), standard errors of the mean (ST).

Pharmacokinetic parameters (maximum concentration C _max, time to maximum concentration _{is the} T x, area under the curve "concentration-time» AUC, MRT the average retention time, half-life T 1/2 and rate of absorption speed C _max / AUC _t) calculated by vnemodelnym statistical moments (Piotrovsky V.K. Method of statistical moments and integral model-independent parameters of pharmacokinetics // Pharmacology and toxicology. - 1986. - T. 49, N ° 5. - S. 118-127). To statistically evaluate the differences between pharmacokinetic parameters, a two-sample t-test for means was used (assessed at a 95% confidence level).

At the zero point (before drug administration), the study of blood plasma samples did not reveal the presence of an analyte.

The dynamics of changes in the concentrations of EMHPS in the blood plasma of animals is presented in Tables 3-5. Average pharmacokinetic curves in linear and semi-logarithmic coordinates are shown in FIG. 7 and 8. Table 3.

The content of EMHPS in the blood plasma of dwarf pigs after three times oral administration of the reference drug, ng / ml

Table 4.

The content of EMHPS in the blood plasma of dwarf pigs after a single oral administration of the object JV2I, ng / ml

Table 5.

The content of EMHPS in the blood plasma of dwarf pigs after a single oral administration of object No. 2, ng / ml

The kinetics of detecting EMHPS in blood plasma differed in the shape of the curves, but was characterized by the presence of the analyte in the blood for 6-8 hours.

After three times administration of the reference drug, an increase in the level of EMHPS in the blood was observed after 0.5 hours (34.33 ± 6.66 ng / ml); 3 hours (18.67 ± 0.58 ng / ml) and 5.5 hours (23.67 ± 4.16 ng / ml) after the first injection of the drug, which corresponds to the maximum concentration of the analyte in the blood 0.5 hours after each drug administration. After each increase in the concentration of EMHPS in the blood, a gradual decrease in its concentration was observed. By the 10th hour of the experiment after the administration of the drugs, the analyte was not detected in the blood plasma.

The maximum concentration of EMHPS in blood plasma after a single injection of objects No. 1,2 was observed in the interval 0.75-1.0 hours: 36.67 ± 13.87 ng / ml for object N "1 and 99.67 ± 89.37 ng / ml for object N “2. Further, a gradual decrease in the concentration of EMHPS in blood plasma was observed. By the 8th hour of the experiment, after the administration of the drugs, the analyte was not detected in the blood plasma.

Pharmacokinetic profiles of a pharmacological agent in the blood when administered orally should be characterized by such parameters as maximum concentration (C _max ), time to reach maximum concentration (T _max ), area under the concentration-time curve (AUC), mean retention time (MRT ), period elimination half-life (T) and rate of absorption C _max / AUC _t [13]. Pharmacokinetic parameters were calculated by the non-model method - the method of statistical moments (Piotrovsky V.K. Method of statistical moments and integral model-independent parameters of pharmacokinetics // Pharmacology and toxicology. - 1986. - T. 49, Ne5. - P. 118-127), vol. .to. with the chamber approach, various pharmacokinetic parameters can be obtained, which can significantly affect the research results (Zherdev V.P., Kolyvanov G.B., Litvin A.A. et al. Harmonization of conducting bioequivalence studies of drugs: questions and their possible solution // Experimental and Clinical Pharmacology. - 2003. - T.66, Sh2. - S. 60-64). Tables 6 - 8 contain individual and average values of the main pharmacokinetic parameters characterizing the bioavailability of EMHPS.

Table 6.

Pharmacokinetic parameters of EMHPS after three times oral administration of the reference drug

Table 7.

Pharmacokinetic parameters of EMHPS after a single oral administration of the object JVfe 1

Table 8.

Pharmacokinetic parameters of EMHPS after a single oral administration of the object JVb2

Analysis of the basic pharmacokinetic data of EMHPS showed that the values of the maximum concentration (C _max ) in blood plasma, calculated as the average value of the highest measured values in each animal, were: 34.33 ± 6.66 ng / ml for the reference drug; 47.33 ± 6.43 ng / ml for object JV l and 108.67 ± 81.45 ng / ml for object JM ° 2. The coefficients of variation for this parameter were 16, 11 and 61% for the reference drug, objects N ° 1 and 2, respectively.

Values of the main parameter characterizing the degree of bioavailability of the drug, AUCo-48, for the drug comparisons, objects JVbl and 2 were close and amounted to 121.63 ± 4.66 hng / ml; 108.75 ± 32.77 h><ng / ml and 160.08 ± 46.28 hng / ml, respectively. The coefficients of variation for this parameter were 5, 25, and 24% for the reference drug, objects N2I and 2, respectively.

For the parameter T _{max, the} values were 0.5 hours for the reference drug and 0.75 hours for objects N2 1 and 2. The variation coefficients of this parameter did not exceed 28%.

The values of the average EMHPS retention time (MRT) for the reference drug, objects JV2I and 2 were 4.88 ± 0.93; 3.59 ± 1.43 and 2.68 ± 1.43 hours, respectively.

The variation coefficients of this parameter did not exceed 44%.

The values of the half-life parameter (Tt) for the reference drug, objects JV2I and 2 were 1.83 ± 0.72; 2.25 ± 0.97 and 1.74 ± 0.93, respectively. The variation coefficients of this parameter were 32-43%.

The values of C _max / AUCo-24, characterizing the rate of absorption, were: 0.28 ± 0.05; 0.48 ± 0.20 and

0.65 ± 0.34, respectively, for the reference drug, objects N2I and 2.

Studies have shown a higher bioavailability of EMHPS with oral administration of gastro-retentive tablets as compared to prolonged-release tablets. An increase in the solubility of EMHPS was found at a pH corresponding to the environment of the stomach. Studies suggest the presence of in vivo - in vitro correlations of EMHPS solubility for gastro-retentive tablets.

Industrial applicability The invention can be used in medicine or veterinary medicine as a drug 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. Medicinal preparations with 2-ethyl-6- methyl 3-hydroxypyridine succinate are effectively used in various fields of clinical medicine: neurology, psychiatry, cardiology, ophthalmology, surgery, dentistry, endocrinology, etc.

Claims

CLAIM

1. The use of at least one gastric release controlling polymer with mucoadhesive properties, wherein at least one said polymer is selected from polyalkylene oxide, to obtain an oral delivery system for 2-ethyl-6-methyl-3-hydroxypyridine succinate in the form gastro-retentive pill.

2. Use according to claim 1, wherein at least one said polyalkylene oxide is selected from polyethylene oxide, polypropylene oxide, or a copolymer of ethylene oxide and propylene oxide.

3. Use according to claim 2 wherein the weight ratio of 2-ethyl-6-methyl-3-hydroxypyridine succinate to polyethylene oxide is 2.6: 1 to 1.3: 1.

4. Use according to claim 1 or claim 2, wherein said gastro-retentive tablet further comprises a polymer selected from the group consisting of sodium carmellose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, or mixtures thereof.

5. A gastro-retentive tablet comprising an oral delivery system according to any one of claims 1 to 4 and 2-ethyl-6-methyl-3-hydroxypyridine succinate in a therapeutically effective amount.

6. A tablet according to claim 5, characterized in that it is film-coated.

7. A tablet according to claim 5, further comprising a lubricant.

8. A tablet according to claim 7, characterized in that it contains magnesium stearate as a lubricant.

9. A tablet according to claim 5, characterized in that it contains 2-ethyl-6-methyl-3-hydroxypyridine succinate in an amount from 125 mg to 1500 mg.

10. A tablet according to claim 5, characterized in that it contains components in the following ratio, wt%:

2-ethyl-6-methyl-3 - hydroxypyridine succinate 30.0-65.0 microcrystalline cellulose 2.0-40.0 povidone 2.0-10.0 sodium carboxymethylcellulose 2.0-20.0 polyethylene oxide 15.0- 50.0 magnesium stearate 0.2-1.0 11. A tablet according to claim 5, characterized in that it contains components in the following ratio, wt%: 2-ethyl-6-methyl-3-hydroxypyridine 30.0-65 , 0 succinate hydroxypropyl methylcellulose 5.0-15.0 copovidone 2.0-10.0 sodium carboxymethylcellulose 2.0-20.0 polyethylene oxide 15.0-30.0 magnesium stearate 0.2-1.0

12. A tablet according to claim 5, characterized in that it contains components in the following ratio, wt%:

2-ethyl-6-methyl-3-hydroxypyridine 30.0-65.0 succinate hydroxypropyl methylcellulose 3, 0-30.0 povidone 2.0-10.0 sodium carboxymethylcellulose 2.0-20.0 polyethylene oxide 15.0-50 , 0 microcrystalline cellulose 2.0-40.0 magnesium stearate 0.2-1.0 or

2-ethyl-6-methyl-3-hydroxypyridine 30.0-65.0 succinate hydroxypropyl methylcellulose 3.0-30.0 povidone 2.0-10.0 methacrylic acid and ethyl acrylate 5.0-30.0 copolymer [1: 1] glyceryl monostearate (or talc) 0.5-5.0 triethyl citrate 0.5-5.0 polysorbate 80 0.5-5.0 sodium carboxymethylcellulose 2.0-20.0 polyethylene oxide 15.0-50.0 microcrystalline cellulose 2.0-40.0 magnesium stearate 0, 2-1, 0 or

2-ethyl-6-methyl-3-hydroxypyridine 30.0-65.0 succinate hydroxypropyl methylcellulose 3.0-30.0 povidone 2.0-10.0 carbomer 5.0-30.0 sodium carboxymethylcellulose 2.0-20 .0 polyethylene oxide 15.0-50.0 microcrystalline cellulose 2.0-40.0 magnesium stearate 0.2-1.0 or

2-ethyl-6-methyl-3-hydroxypyridine 30.0-65.0 succinate hydroxypropyl methylcellulose 3.0-30.0 povidone 2.0-10.0 hydroxyethyl cellulose 5.0-30.0 sodium carboxymethylcellulose 2.0-20 .0 polyethylene oxide 15.0-50.0 microcrystalline cellulose 2.0-40.0 magnesium stearate 0.2-1.0

13. Tablet according to any one of paragraphs. 5-12, characterized in that it is intended for antioxidant and / or antihypoxant and / or membrane-protective action.

14. A method of increasing the bioavailability of 2-ethyl-6-methyl-3-hydroxypyridine succinate, characterized in that it is administered orally in the form of a gastro-retentive tablet according to any one of paragraphs. 5-12 subject in need of this once a day.