WO2019022639A1

WO2019022639A1 - Pharmaceutical composition containing alimemazine tartrate

Info

Publication number: WO2019022639A1
Application number: PCT/RU2018/000466
Authority: WO
Inventors: Кирилл Константинович Сыров; Владимир Викторович НЕСТЕРУК
Original assignee: Общество С Ограниченной Ответственностью "Валента-Интеллект"
Priority date: 2017-07-24
Filing date: 2018-07-16
Publication date: 2019-01-31
Also published as: RU2659200C1; EA039058B1; EA202090315A1

Abstract

The invention relates to the field of the chemical and pharmaceutical industry and medicine, and concerns methods for producing new formulations of neuroleptics. The present pharmaceutical composition containing alimemazine tartrate and excipients is characterised in that the following are selected as excipients: microcrystalline cellulose, hypromellose, colloidal silicon dioxide and magnesium stearate.

Description

Pharmaceutical composition containing alimemazine tartrate

The invention relates to the field of pharmaceutical industry and medicine and relates to methods of obtaining new preparative forms of neuroleptics.

In recent decades, there has been a tendency to an increase in the prevalence of psychogenic diseases, such as neurosis and other diseases with mild mental disorders, the occurrence, course, compensation and decompensation of which are determined primarily by psychogenic factors.

Among the drugs used to treat such diseases, alimemazine tartrate has shown its effectiveness. For the first time the drug was synthesized in 1958 in the laboratory of the French firm TgegarIh. This drug quickly became the market leader in its segment, both in Europe and in America.

Alimemazine tartrate is an antipsychotic drug that is among the derivatives of phenothiazine - 10- (3-dimethylamino-2-methylpropyl) -phenothiazine hydrotartrate, and is chemically similar to diprazine and levomepromazine. The drug has an antihistamine, antispasmodic, serotonin-blocking, moderate alpha-blocking, antiemetic, hypnotic, sedative and antitussive action [Ibragimov DF "Alimemazin in medical practice" / / Zhurn. Neurology and Psychiatry. S.S. Korsakova, 2008; T.108, Ν ° 9, P.76-78].

Alimemazine tartrate is produced and prescribed mainly in tablets, for example, under the trade name Teraligen ^® (Teraligen ^® ) (http: // www. Vidal. Ru / poisk_preparatov / teraligen.htm).

Known patent RU2384336 on the pharmaceutical composition, which contains alimemazin tartrate as an active component, as well as target excipients: lactose, potato starch, microcrystalline cellulose, koldidon, magnesium stearate with an appropriate ratio of components. The composition is made in the form of coated tablets consisting of polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes. The composition requires taking several times a day. Currently, the issue of creating prolonged dosage forms that can ensure the long-term effect of a drug with a simultaneous decrease in its daily dose is becoming more topical.

Known patent RU2424807, published 07/27/2011, revealing pharmaceutical compositions with prolonged action, used to correct psychosomatic disorders. The compositions contain alimemazine tartrate as an active component, as well as target excipients: lactose, hydroxypropyl methylcellulose, pregelatinized starch, magnesium stearate, colloidal silicon dioxide with an appropriate ratio of components. The composition is made in the form of coated tablets, consisting of polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes. The process of making tablets is carried out by direct compression.

This solution can be specified as the closest analogue of the prototype. The disadvantage of this technical solution is the high content of lactose in the preparation, which can cause undesirable effects in patients with severe forms of lactose intolerance

(http://digestive.niddk.nih.gov/ddiseases/pubs/ lactoseintolerance / # products).

The present invention is the development of a new pharmaceutical composition of prolonged action, with psychosomatic action, containing alimemazin tartrate.

The technical results of the present invention are:

- improvement of the pharmacokinetic parameters of the claimed composition;

- increase the stability of the composition.

The task is carried out, and technical results are achieved by the development of a pharmaceutical composition of prolonged action, containing alimemazine tartrate and auxiliary components. Microcrystalline cellulose, hypromellose, colloidal silicon dioxide and magnesium stearate are chosen as auxiliary components. The content of the components of the following (in wt.% Of the total mass of the dry mixture):

alimemazina tartrate - 10.00-30.00;

microcrystalline cellulose - 35.00-42.00;

hypromellose - 33.50-46.00; colloidal silicon dioxide - 1.00-2.00;

magnesium stearate - 0.50-2.00.

In preferred embodiments of the invention:

- the above composition does not contain lactose;

- the pharmaceutical composition is made in the form of a capsule or tablet,

- the pharmaceutical composition is made in the form of a tablet, which is a core, coated;

- preferably, the pharmaceutical composition is made in the form of a tablet, which is a core, film-coated;

- film shell is 2.50-6.00% by weight of the core.

The presence of the film shell gives the composition stability during storage and improves its appearance.

The film coating can include, without limitation, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose (GGSch), hydroxypropylmethyl cellulose (HPMC) as film-forming substances, polyethylene glycol, propylene glycol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin, glycerin. as surfactants, stearic acid, talc as glidants, maltodextrin, pharmaceutically acceptable dyes. Dyes can be selected from any dyes or pigments approved for medical use. For example, colorants may be titanium dioxide, aluminum varnishes, iron oxides, or natural pigments (see US Pat. No. 6,448,323).

Film coating can be applied in the amount of 2.50-6.00% by weight of the tablet core.

In the most preferred embodiment, can be obtained round biconvex tablets, film-coated.

The proposed composition does not contain lactose, and therefore will not cause undesirable side effects in patients with lactose intolerance.

Retard dosage forms (from Lat. Retardo - slow down, tardus - quiet, slow; synonyms - retardates, retardated dosage forms) are prolonged dosage forms that provide the body with a supply of drug substance and its subsequent slow release. Data Dosage forms are preferably administered orally, but sometimes are also used for rectal administration.

For the selection of formulations of modified-release tablets, prolonging and excipient substances were tested, the use of which allows obtaining a prolonged pharmaceutical preparation with improved pharmacokinetic properties. In this case, the composition of the filler and the prolonging component was selected, which allows to obtain a solid dosage form on a conventional production scheme without special process equipment. It was determined that the necessary characteristics have a combination of hypromellose and microcrystalline cellulose.

The inventors unexpectedly found that the composition of alimemazine tartrate according to the present invention has improved pharmacokinetic parameters and increased stability compared with the prototype.

Indications for use of the composition according to the present invention: as a sedative (sedative), anxiolytic (anti-anxiety) and hypnotic, dementia (including dementia due to epilepsy), occurring with manifestations of psychomotor agitation, affect, anxiety; organic anxiety disorder; schizophrenia; mood disorders (affective disorders); generalized anxiety disorder; obsessive-compulsive disorder; reaction to severe stress and adaptation disorders; dissociative (conversion) disorders; somatoform disorders; unspecified disorder of the autonomic (autonomic) nervous system, other disorders of the autonomic (autonomic) nervous system; anorexia nervosa; emotionally unstable personality disorder (impulsive and borderline types); hysterical personality disorder, anxious (evading, avoidant) personality disorder; persistent personality change after experiencing a disaster; hyperkinetic behavior disorder; behavior disorder limited by the family; non-socialized conduct disorder; anxiety, agitation and other symptoms and signs related to the emotional state; other neurotic disorders (neurasthenia, unspecified neurotic disorder); insomnia inorganic etiology; emotional disorders, the onset of which is specific to childhood, as antiallergic agents, itching, regardless of location and etiology; asthma, pollinosis, whooping cough (as an antiallergic agent for stopping coughing, shortness of breath and asthma attacks); unspecified allergy.

The possibility of carrying out the invention can be demonstrated by the examples presented below, which illustrate but do not limit the invention.

Example 1. Obtaining a tablet of prolonged action, film-coated.

Sifted microcrystalline cellulose and alimemazine tartrate are loaded into the granulation and drying unit using fluidization technology and start the granulation process, using water as a humidifier. The drying process is continued until the indicator "weight loss on drying" reaches a value of 3.0 ± 0.5.

At the end of the granulation process, the obtained dry granulate is sieved using a screening method and calibrated through a metal sieve with a hole diameter of 0.8 mm (a fraction with a grain size larger than 0.8 mm is forced through the sieve).

Sifted microcrystalline cellulose, calibrated granules and sifted hypromellose are loaded into a drum-type mixer. Stir for 2-4 minutes. Then, sieved silicon dioxide colloidal is loaded, mixed for 2-3 minutes, then sieved magnesium stearate is loaded, mixed for 1-2 minutes.

Tablet mass is pressed on a rotary press using round-shaped punches (deep sphere) with a diameter of 8.0 ± 0.2 mm (for all dosages).

On the tablet cores put the finished film coating.

After analyzing the quality control, the finished tablets are packaged in a blister strip packaging of PVC film and aluminum foil, followed by an investment in a carton box.

Table 1. Tablets of prolonged action (20 mg, 40 mg and 60 mg), film coated.

Components Functional Quantity

medicinal purpose

agents substances Composition 1 Composition 2 Composition 3 Mass, Mass. Mass, Mass. Mass, Mass.

mg% mg% mg%

Main substance

Alimemazine active 20 10 40 20 60 30 tartrate substance

Excipients

MCC filler 84 42 73 36,5 70 35

Hypromellose filler 92 46 79 39.5 67 33.5

(prolonging component)

Silicon sliding 2 1 2 1 2 1 dioxide

colloidal

Magnesium stearate lubricated 2 1 4 2 1 0.5

Mass of the core 200 200 200

pills

Film 5 10 12

shell

Table 2. Tablets of the prolonged action, film coated, 20 mg, 40 mg and 60 mg.

Components Functional Quantity

medicinal prescription

substances substances Composition 4 Composition 5 Composition 6

Mass, Mass. Mass, Mass. Mass, Mass. mg% mg% mg%

Main substance

Alimemazine active 20 10 40 18.2 60 25 tartrate substance

Excipients

MCC filler 84 42 84 38,2 84 35

Hypromellose filler 91 45.5 91 41.4 91 37.9

(prolonged

component)

Silicon sliding 3 1.5 3 1.3 3 1.3 dioxide

colloidal

Magnesium stearate lubricated 2 1 2 0.9 2 0,8

The mass of the core 200 220 240 tablets

Film 10 10 10 shell Tablets of prolonged action was obtained as described above, in accordance with the compositions shown in Tables 1 and 2.

The cores of the tablets were coated with film coating compositions (1), (2) or (3) in an amount of 5, 10 and 12 mg per tablet.

The composition of the film coating (1).

Ready mix of powders for film coating: polyvinyl alcohol partially hydrolyzed, macrogol, talc, titanium dioxide E171, iron dye red oxide E172, iron dye yellow oxide E172.

The composition of the film coating (2).

A mixture of HPMC, macrogol 400, polysorbate 80 and titanium dioxide (for example,

Opadry ^® "White coating premix", Colorcon).

The film coating composition (3).

A mixture of HPMC, macrogol 400 and maltodextrin (for example, Opadry ^® "Clear coating premix", by Colorcon). Example 2. The study of the pharmacokinetics of the tablet of prolonged action, film-coated.

In order to confirm the prolonged action proposed tablets depot, covered with a foil cover, as well as improved pharmacokinetics study the pharmacokinetics of the composition alimemazine tartrate was conducted at a dosage of 60 mg of Example 1, Table 1, compared with the drug Teralidzhen ^® (tablets 5 mg, manufactured by "Hauzang "(" HG-Farm "), Vietnam), as well as a composition according to the patent RU 2424807 in a dosage of 60 mg (prototype). Teralidzhen ^® Tablets 5 mg was administered in a total dose of 60 mg.

Objective: determining alimemazine pharmacokinetics in blood plasma of rabbits after single administration of three tablet forms alimemazin (depot tablet, coated membrane liner of Example 1, Table 1-retard form according to the prior art and Teralidzhen Tablets ^®, 5 mg, "Xr Pharm ").

Materials and methods.

The study was conducted on 10 male rabbits weighing 2.4 ± 0.52 kg contained in standard vivarium conditions. The animals were injected once through a probe with 1 tablet of prolonged action, film-coated according to the invention, or 1 retard-tablet of prolonged action, coated film coated, according to the prototype, or 12 tablets of Traligen "CG-Farm". Blood samples were taken from the marginal ear vein at discrete time intervals (0; 1.0; 2.0; .3.0; 4.0; 6.0; 8.0; 12.0; 24.0 and 36.0 hours)

Quantitative determination of alimemazine in the plasma of rabbits was performed by HPLC with a detection limit of 25 ng / ml.

The obtained experimental data were previously subjected to statistical processing using Statistica 6.0.

Basic pharmacokinetic parameters were calculated.

Results.

A comparative analysis of the main pharmacokinetic parameters of alimemazine showed that the time to reach the maximum concentrations of alimemazine (t _max ) for the stated tablets of prolonged action, film-coated, was 6.8 ± 0.28 h, according to the prototype - 4.18 ± 0.72 h, and from the tablets of Traligen ^® "HG-Farm" - 2.70 ± 0.38 h (see Table 2). Significant differences were established between the t _ma values for the claimed long-acting film-coated tablets and retard tablets according to the prototype (p <0.05).

The elimination half-life for the prolonged dosage form was 10.84 ± 2.80 h, according to the prototype - 10.76 ± 2.78 h, for the comparative tablets Teralidzhen ^® "HG-Farm" - 10.29 ± 1.46 h.

Alimemazin relative bioavailability of sustained-release tablets, coated membrane shell according to the invention with respect to conventional tablets Terapidzhena ^® on average 87.6%.

Thus, studies show improved pharmacokinetic parameters of a new, prolonged-action film-coated tablet (time for maximum concentration) compared with the prototype. The preparation according to the invention releases the active ingredient in accordance with the desired characteristics in the gastrointestinal tract, while retaining the benefits in the form of a short half-life.

Table 3. Pharmacokinetic parameters of alimemazine in the plasma of rabbits after a single injection at a dose of 60 mg.

tmax> SD Ti / 2 hour, SD average average hour

Tablet

6.8 0.28 10.84 2.80 prolonged action covered

film coating

alimemazine tartrate

according to the present

to the invention

Retard tablet

4.18 0.72 10.76 2.78 according to the prototype

Teraligen ^® "CG-

2.70 0.38 10.29 1.46 Farm "

Example 3. The study of General toxic action of the composition in the form of a tablet of prolonged action, film coated.

Objective: to determine tolerable, toxic and lethal doses and causes of death of animals, assess the extent of the damaging effect of the drug during its long-term administration in small laboratory animals, identify the most sensitive organs and body systems and study the degree of reversibility of damage caused

Study of acute toxicity.

Materials and methods.

The study of the acute toxicity of the claimed tablet of prolonged action, film-coated, with a single intragastric administration, was carried out on 20 white non-linear male mice weighing 18-20 g, kept in standard vivarium conditions with free access to water and food. Tested doses of the drug 180, 250, 320 and 390 mg (alimemazinu) / kg of body weight. For 14 days, the general condition of the animals was evaluated. About the toxicity of drugs was judged by the death of animals and the overall picture of intoxication. Statistical analysis was performed using Statistics 6.0 software.

The acute toxicity parameters gave the following results:

DLso = 313 (301 - 326) mg / kg, DLi ₆ = 243 mg / kg, DL ₈₄ = 403 mg / kg.

Thus, the investigated drug according to the parameters of acute toxicity according to the classification of Hodge and Sterner (1943) can be attributed to moderately toxic compounds.

Subchronic toxicity of the drug was investigated in 25 white non-linear rats-males weighing 172-216 g contained in standard vivarium conditions with free access to water and feed. Experimental groups were injected intragastrically in doses of 6 and 60 mg (alimemazine tartrate) / kg body weight as a suspension in 2% starch gel for 30 days to animals of the experimental groups for 30 days, which, respectively, was equal to 10 times the therapeutic dose for humans, taking into account interspecific recalculation. After the end of the experiment, all animals were killed for further pathological examination of internal organs and tissues.

Local irritation was assessed by macroscopic and microscopic examination of the sites of administration of drugs - the gastrointestinal tract.

Statistical comparison of experimental and control groups was carried out according to Student's t-test.

Results.

In groups of animals that received intragastrically suspensions of the studied drug at a dose of 60 mg / kg, there was a tendency to a decrease in the rate of weight gain, a slight but significant increase in the activity of blood transaminases and a decrease in the spontaneous motor activity of animals. The studied drug in doses of 6 and 60 mg / kg did not cause deviations of biochemical and hematological parameters. There was no change in diurnal diuresis for groups of animals treated with the experimental preparation, in relation to the group of control animals receiving intragastrically 2% starch gel in the same volume.

Pathological and microscopic examination of the internal organs indicate that there are no pronounced signs of the toxic effect of the drug on the internal organs in the tested doses, however they indicate a possible manifestation of its local irritating action on the gastric mucosa after 30 days of intraglobe intramuscular administration, 10 times higher than the therapeutic recalculation of doses.

The claimed drug does not show mutagenic properties in experiments on fruit flies, does not possess allergenicity, does not possess reproductive toxicity. Example 4. Determination of the stability of the tablets of the prolonged action, film coated, by the method of accelerated aging.

The stability study is carried out in comparison with the composition according to the prototype (patent RU2424807).

Objective: to determine the stability of the prolonged dosage form of Example 1.

The study was conducted at the IC PJSC "Valenta Farm".

Tablets obtained in accordance with Example 1 of the present invention and in accordance with the prototype, Packed in blisters made of aluminum foil ('Alu-Alu') and placed in a climatic chamber in conditions of accelerated testing. The content of the active substance alimemazine tartrate is determined by HPLC using standards.

The method of "accelerated aging" is to maintain the tested drug at temperatures and humidity exceeding the temperature and humidity of its storage during circulation. At elevated temperatures, physicochemical processes occurring in drugs, as a rule, accelerate, leading to undesirable changes in quality over time. Thus, at elevated temperatures, the period of time during which the controlled indicators of the quality of the medicinal product are kept within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at storage temperature. This can significantly reduce the time required to establish the shelf life.

According to the results obtained in the process of accelerated aging of the medicinal product, the inverse problem can also be solved, i.e. set the storage temperature to ensure any desired shelf life.

Shelf life C) at storage temperature (t _xp ). associated with the experimental shelf life (Ce) at elevated temperature experimental storage (t ₃ ) by the following relationship:

c = k c _e where K - the coefficient of compliance is calculated as The temperature coefficient of the chemical reaction rate (A) is assumed to be 2.5. The given dependence is based on the Vant-Hoff rule about a 2-4-fold increase in the rates of chemical reactions with a temperature increase of 10 ° C.

In accordance with the pharmacopoeial article OFAS.1.1.0009.15, the value of the coefficient of conformity (K), depending on the chosen temperature interval (t ₃ -tx _P ), equal to 30 ° С, is 15.6. The experimental storage period with a selected shelf life of 3 years is 71 days.

Statistical processing of parameters and processing of research results is carried out in accordance with the Rules of Good Clinical Practice of the Eurasian Economic Union using the statistical package SPSS Statistics 19.0.

It is shown that the prolonged dosage form according to the invention has a statistically significantly increased storage stability compared with the prototype.

After 71 days of storage under the conditions of the accelerated aging method, the sustained release tablets of the present invention have been found to have statistically significantly increased stability and remain chemically pure. The tablets obtained in accordance with the prototype, remain chemically pure for less than 10 days, then the content of the active substance alimemazine tartrate is reduced by more than 3%. That is, the tablets of the present invention are significantly more stable compared to the prototype.

Table 4. Assessment of stability during storage by the method of accelerated aging in comparison with the prototype

The amount of active ingredient alimemazine tartrate found in HPLC

Storage time at (t ₃ - * xp) ⁼ % of theoretical content

30 ° С, day

Example Example Example

Prototype

20 mg 40 mg 60 mg

0 100 100 100 100

10,100,100 99.9

20 99.9 99.9 99.9 99.5

30 99.9 99.9 99.9 99.1

40 99.9 99.9 99.9 98.4 50 99.9 99.9 99.9 98.0

60 99.9 99.9 99.9 97.2

71 99.9 99.9 99.9 96.8

Example 5. Determination of mechanical strength and abrasion of tablets with prolonged action, film-coated.

Determination and rationing of the mechanical strength of tablets is necessary both in industrial production conditions (for example, the process of coating tablets and packaging), and to ensure consumer properties of the drug (preserving the integrity of the tablet when removed from the package) in accordance with the CFC.1.4.2.0011.15.

The equipment consists of two opposing clamps, one of which can move towards the other. The surface planes of the clips are perpendicular to the direction of movement. It is allowed to use the device in which both clips can move with constant speed towards each other. The pressure surfaces of the clips must be flat and exceed the area of contact with the tablet. The device should provide a cessation of compression in any violation of the integrity of the tablets. The instrument is calibrated using a system that provides 1 N accuracy (Newton).

The tablet is placed between the clamps with an edge relative to the moving part of the device. A pill placed on the edge is compressed to destruction. Measurements are carried out for ten tablets. Before each measurement, carefully remove all fragments of the previous tablet.

Abrasion express loss in weight, calculated as a percentage of the initial mass of the tested tablets.

The device consists of a drum with a removable cover, with a diameter of about 200 mm and a depth of about 38 mm, made of transparent synthetic polymer; the inner surfaces of the drum must be polished and should not be electrified. Along the inner perimeter of the drum wall are 12 blades (35x35 mm) at an angle of 20 ° to the tangent drum, which, when it rotates, causes the tablets to move. The drum is attached to the horizontal axis of the device, ensuring the rotation of the drum at a speed of 20 rpm. The device should automatically turn off after the specified test time. Ten tablets, dust-free and weighed to the nearest 0.001 g, are placed in the drum, screwed on and turned on the device for 5 minutes, which corresponds to 100 turns of the drum. After the set time has elapsed, the tablets are removed from the drum, dedusted, and weighed again to the nearest 0.001 g. The loss in weight should not exceed 3%.

If, after the test, cracked, chipped or broken tablets are detected, the result of the abrasion test is considered unsatisfactory.

The mass loss in each of the additional tests or the average mass loss calculated from the results of the three tests should not exceed the normalized value.

According to the results of the experiment, the sustained-release tablets obtained according to the claimed invention, film-coated, have a high strength of more than 70 N and an abrasion resistance of not less than 98.5%.

Claims

CLAIM

1. Pharmaceutical composition containing alimemazine tartrate and auxiliary components, characterized in that microcrystalline cellulose, hypromellose, colloidal silicon dioxide and magnesium stearate are selected as auxiliary components with the following content of components in wt.%:

alimemazina tartrate - 10.00-30.00;

microcrystalline cellulose - 35.00-42.00;

hypromellose, 33.50-46.00;

colloidal silicon dioxide - 1, 00-2.00;

magnesium stearate - 0.50-2.00.

2. A pharmaceutical composition according to claim. 1, characterized in that said composition does not contain lactose.

3. The pharmaceutical composition according to p. 1, characterized in that the said composition is made in the form of a capsule or tablet.

4. The pharmaceutical composition according to p. 2, characterized in that the pharmaceutical composition is made in the form of a tablet, which is a coated core.

5. The pharmaceutical composition according to p. 3, characterized in that the pharmaceutical composition is made in the form of a tablet, which represents the core, film-coated.

6. The pharmaceutical composition according to p. 5, characterized in that the film shell is 2.50-6.00% by weight of the core.