EA039058B1 - Pharmaceutical composition containing alimemazine tartrate - Google Patents

Abstract

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

Description

The invention relates to the field of chemical-pharmaceutical industry and medicine and relates to methods for producing new preparative forms of antipsychotics.

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

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

Alimemazine tartrate is an antipsychotic drug that belongs to the phenothiazine derivatives - 10- (3-dimethylamino-2-methylpropyl) phenothiazine hydrotartrate, and is chemically similar to diprazine and levomepromazine. The drug has antihistamine, antispasmodic, serotonin-blocking, moderate alpha-adrenergic blocking, antiemetic, hypnotic, sedative and antitussive action (Ibragimov D.F. Alimemazin in medical practice // Journal of Neurology and Psychiatry named after S.S. , No. 9, p. 76-78).

Alimemazine tartrate is produced and administered mainly in tablets, for example, under the trade name Teraligen® (http://www.vidal.m/poisk_preparatov/teraligen.htm).

Known patent RU 2384336 for a pharmaceutical composition, which contains alimemazine tartrate as an active component, as well as target auxiliary substances: lactose, potato starch, microcrystalline cellulose, collidone, magnesium stearate with an appropriate ratio of components. The composition is made in the form of tablets coated with a shell consisting of polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, and acceptable colorants. The composition requires taking several times a day.

Currently, the issue of creating prolonged dosage forms capable of providing a long-term effect of a drug with a simultaneous decrease in its daily dose is acquiring great urgency.

Known patent RU 2424807, published on July 27, 2011, disclosing pharmaceutical compositions with prolonged action used for the correction of psychosomatic disorders. The compositions contain alimemazine tartrate as an active component, as well as target auxiliary substances: lactose, hydroxypropyl methylcellulose, pregelatinized starch, magnesium stearate, colloidal silicon dioxide with an appropriate ratio of components. The composition is made in the form of tablets, coated with a shell consisting of polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable colorants. The process of making tablets is carried out by the direct compression method.

This solution can be indicated 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 objective of the present invention is to develop a new pharmaceutical composition with prolonged action, having a psychosomatic effect, containing alimemazine tartrate.

The technical results of the present invention are the improvement of the pharmacokinetic parameters of the claimed composition;

increasing the stability of the composition.

The task is being implemented, and the technical results are achieved by the development of a prolonged-release pharmaceutical composition containing alimemazine tartrate and auxiliary components. Microcrystalline cellulose, hypromellose, colloidal silicon dioxide and magnesium stearate were selected as auxiliary components. In this case, the content of the components is as follows (in wt.% Of the total mass of the dry mixture):

alimemazine 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, said composition is lactose free;

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 coated core;

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

the film shell is 2.50-6.00% of the mass of the core.

The presence of a film shell gives stability to the composition during storage and improves it

- 1 039058 exterior.

The film coat may include, but is not limited to, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC) as film-forming agents, polyethylene glycol, propylene glycol 80, glycerol as a surface -active substances, stearic acid, talc as glidants, maltodextrin, pharmaceutically acceptable dyes. The colorants can be selected from any colorant or pigment approved for medical use. For example, the colorants can be titanium dioxide, aluminum lacquers, iron oxides, or natural pigments (see US Pat. No. 6,448,323).

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

In a most preferred embodiment, round, biconvex film-coated tablets can be prepared.

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

Dosage forms of retard (from Latin retardo - to slow down, tardus - quiet, slow; synonyms of retardets, retard dosage forms) are prolonged dosage forms that provide a supply of a drug in the body and its subsequent slow release. These dosage forms are used mainly orally, but sometimes they are also used for rectal administration.

In order to select the formulations of modified release tablets, we tested prolonging agents and fillers, the use of which makes it possible to obtain a prolonged pharmaceutical formulation with improved pharmacokinetic properties. At the same time, the composition of the filler and the prolonging component was selected, which makes it possible to obtain a solid dosage form in a conventional production scheme without special technological equipment. It was determined that a combination of hypromellose and microcrystalline cellulose possesses the necessary characteristics.

The inventors have surprisingly found that the composition of alimemazine tartrate according to the present invention has improved pharmacokinetic parameters and increased stability compared to the prior art.

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), proceeding 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 adjustment 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 (avoidant, avoidant) personality disorder; persistent personality change after experiencing a disaster; hyperkinetic conduct disorder; family-confined conduct disorder; unsocialized conduct disorder; anxiety, agitation and other symptoms and signs related to the emotional state; other neurotic disorders (neurasthenia, unspecified neurotic disorder); insomnia of inorganic etiology; emotional disorders, the onset of which is specific to childhood, as an antiallergic agent, itching regardless of place and etiology; asthma, hay fever, whooping cough (as an antiallergic agent to stop 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 the granulation process is started using water as a humidifier. The drying process is continued until the weight loss on drying reaches 3.0 ± 0.5.

At the end of the granulation process, the obtained dry granulate is calibrated by the sieving method through a metal sieve with a hole diameter of 0.8 mm (the fraction with a granule size larger than 0.8 mm is forcibly rubbed through a sieve).

In a drum mixer load sieved microcrystalline cellulose, calibrated granulate and sieved hypromellose. Stir for 2-4 minutes. Then load the sifted colloidal silicon dioxide, stir for 2-3 minutes, then load the sifted magnesium stearate, mix for 1-2 minutes.

The tablet mass is compressed on a rotary press using round punches (deep

- 2 039058 sphere) with a diameter of 8.0 ± 0.2 mm (for all dosages).

A ready-made film coating is applied to the core tablets.

The finished tablets, after quality control analysis, are packaged in a blister strip made of polyvinyl chloride film and aluminum foil, followed by insertion into a cardboard box.

Table 1. Sustained-release tablets (20, 40 and 60 mg), film-coated

Components of the medicinal product Functional purpose of substances Quantity Composition 1 Composition 2 Composition 3

Weight, mg Mass. % Weight, mg Mass. % Weight, mg Mass. % Main substance Alimemazine tartrate active substance twenty 10 40 twenty 60 thirty Excipients mcz filler 84 42 73 36.5 70 35 Ipromellose filler (prolonging component) 92 46 79 39.5 67 33.5 Colloidal silicon dioxide sliding 2 one 2 one 2 one Magnesium stearate lubricating 2 one 4 2 one 0.5 Tablet core weight 200 200 200 Film casing 5 10 12

Table 2. Sustained-release film-coated tablets, 20, 40 and 60 mg

Components of the medicinal product Functional purpose of substances Quantity Composition 4 Composition 5 Roster 6 Weight, mg Mass. % Weight, mg Mass. % Weight, mg Mass. % Main substance Alimemazine tartrate active substance twenty 10 40 18.2 60 25 Excipients MCC filler 84 42 84 38.2 84 35 Ipromellose filler (prolonging component) 91 45.5 91 41.4 91 37.9 Colloidal silicon dioxide sliding 3 1.5 3 1.3 3 1.3 Magnesium stearate lubricating 2 one 2 0.9 2 0.8 Tablet core weight 200 220 240 Film casing 10 10 10

Sustained-release tablets were prepared as described above, in accordance with the formulations shown in table. 1 and 2.

Tablet cores were coated with film-coating compositions (1), (2) or (3) at 5, 10 and 12 mg per tablet.

Film coating composition (1).

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

Film coating composition (2).

A mixture of HGHMC, macrogol 400, polysorbate 80 and titanium dioxide (e.g. Opadry® White coating premix, Colorcon).

Film coating composition (3).

Blend of HGHMC, Macrogol 400 and maltodextrin (e.g. Opadry® Clear coating premix, Colorcon).

Example 2. Study of the pharmacokinetics of a film-coated sustained-release tablet.

In order to confirm the prolonged action of the proposed prolonged-action film-coated tablet, as well as improved pharmacokinetics, a study of the pharmacokinetics of the composition of alimemazine tartrate at a dosage of 60 mg according to example 1, table was carried out. 1, in comparison with the Teraligen® preparation (5 mg tablets, manufactured by Hauzang (HG-Pharm), Vietnam), as well as the composition according to RU 2424807 at a dosage of 60 mg (prototype). Teraligen® 5 mg tablets were administered in a total dose of 60 mg.

Purpose of the study: determination of the pharmacokinetics of alimemazine in the blood plasma of rabbits after a single administration of three tablet forms of alimemazine (a prolonged-release film-coated tablet, according to example 1, table 1, a retard form according to the prototype and Teraligen® tablets, 5 mg, HG-Pharm ).

Materials and methods.

The study was carried out on 10 male rabbits weighing 2.4 ± 0.52 kg, kept under standard vivarium conditions. Animals were injected once through a gavage with 1 tablet of prolonged action, film-coated, according to the invention, or 1 retard tablet of prolonged action, film-coated, according to the prototype, or 12 tablets of Teraligen® HG-Pharm. 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 h).

The quantitative determination of alimemazine in the blood plasma of rabbits was carried out by HPLC with a detection limit of 25 ng / ml.

The obtained experimental data were preliminarily subjected to statistical processing using the Statistica 6.0 program. The main pharmacokinetic parameters were calculated.

Results.

Comparative analysis of the main pharmacokinetic parameters of alimemazine showed that the time to reach the maximum concentrations of alimemazine (tmax) for the claimed prolonged-release film-coated tablets was 6.8 ± 0.28 h, according to the prototype - 4.18 ± 0.72 h, and from Teraligen® HG-Pharm tablets - 2.70 ± 0.38 hours (see table. 2). Significant differences (p <0.05) were found between the t _max values for the claimed prolonged-release film-coated tablets and retard tablets according to the prototype.

The half-life for the prolonged dosage form was 10.84 ± 2.80 h, for the prototype - 10.76 ± 2.78 h, for the comparative Teraligen® HG-Pharm tablets - 10.29 ± 1.46 h.

The relative bioavailability of alimemazine from prolonged-release film-coated tablets according to the invention in relation to conventional Teraligen tablets averages 87.6%.

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

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

tmax, NUM average SD Т1 / 2, hour average SD Tablet prolonged 6.8 0.28 10.84 2.80

- 4 039058

action film-coated alimemazine tartrate according to the present invention T tablet-retard according to the prototype 4.18 0.72 10.76 2.78 Teraligen® "HGFarm" 2.70 0.38 10.29 1.46

Example 3. Study of the general toxic effect of the composition in the form of a tablet with a prolonged action, film-coated.

Objective of the study: determination of tolerable, toxic and lethal doses and causes of death of animals, assessment of the degree of the damaging effect of the drug during its long-term administration to small laboratory animals, identification of the most sensitive organs and systems of the body, and study of the degree of reversibility of the damage caused.

Acute toxicity study.

Materials and methods.

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

The acute toxicity parameters gave the following results:

DL ₅₀ = 313 (301-326) mg / kg, DL ₁₆ = 243 mg / kg, DL ₈₄ = 403 mg / kg.

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

Subchronic toxicity of the drug was studied on 25 white non-linear male rats weighing 172-216 g, kept under standard vivarium conditions with free access to water and food. The study drug was administered intragastrically to the animals of the experimental groups for 30 days once a day at doses of 6 and 60 mg (according to alimemazine tartrate) / kg of body weight as a suspension in 2% starch gel, which, respectively, is equal to and 10 times higher than the therapeutic dose. for a person, taking into account the interspecific conversion. After the end of the experiment, all animals were sacrificed for further pathomorphological examination of internal organs and tissues.

The local irritant effect was assessed by macroscopic and microscopic examination of the injection sites of the drugs - the gastrointestinal tract.

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

Results.

In the groups of animals that received intragastrically suspensions of the study 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 at doses of 6 and 60 mg / kg did not cause deviations in biochemical and hematological parameters. There was no change in daily urine output for the groups of animals that received the experimental drug in relation to the group of control animals that received intragastrically 2% starch gel in the same volume.

Pathomorphological and microscopic examination of internal organs indicate the absence in the tested doses of pronounced signs of the toxic effect of the drug on the internal organs, however, they indicate a possible manifestation of its local irritating effect on the gastric mucosa after 30 days of intragastric administration at a dose 10 times higher than the therapeutic dose, taking into account the interspecies conversion doses.

The claimed preparation 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 tablets of prolonged action, film-coated, by the method of accelerated aging.

The study of stability is carried out in comparison with the composition according to the prototype (patent RU 2424807).

Objective of the study: to determine the stability of the prolonged dosage form according to example 1.

The research was carried out at IC PJSC Valenta Pharm.

Tablets obtained in accordance with example 1 according to the present invention and in accordance with

- 5 039058 prototype, packed in aluminum foil blisters ('Alu-Alu') and placed in a climatic chamber under accelerated testing conditions. The active ingredient content of alimemazine tartrate is determined by HPLC using standards.

The accelerated aging method consists in keeping the tested medicinal product at temperatures and humidity higher than the temperature and humidity of its storage during circulation. At elevated temperatures, as a rule, physical and chemical processes occurring in medicines are accelerated, leading over time to undesirable changes in quality. Thus, at an elevated temperature, the period of time during which the controlled quality parameters of the medicinal product remain within acceptable limits (experimental shelf life) is artificially reduced in comparison with the shelf life at the storage temperature. This can significantly reduce the time required to establish an expiration date.

According to the results obtained in the process of accelerated aging of the drug, it is also possible to solve the inverse problem, i.e. set the storage temperature to a specified shelf life.

Shelf life (C) at storage temperature (t _xp ). is associated with the experimental shelf life (C _E ) at an elevated experimental storage temperature (t _e ) by the following relationship:

where K - the coefficient of compliance is calculated as ~ 0р,

The temperature coefficient of the rate of the chemical reaction (A) is taken equal to 2.5. The given dependence is based on the Van't Hoff rule about a 2-4-fold increase in the rates of chemical reactions with an increase in temperature by 10 ° C.

In accordance with the pharmacopoeial monograph of OFS.1.1.0009.15, the value of the conformity coefficient (K), depending on the selected temperature range (t g-txp), equal to 30 ° C, is 15.6. The experimental storage period for a selected shelf life of 3 years is 71 days.

Statistical processing of parameters and presentation of research results are 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 has been shown that the prolonged dosage form according to the invention has a statistically significantly increased storage stability compared to the prototype.

It was found that after 71 days of storage under the conditions of the accelerated aging method, the sustained-release tablets of the present invention have a 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 decreases by more than 3%. That is, the tablets of the present invention are significantly more stable than the prototype.

Table 4. Evaluation of storage stability by accelerated aging in comparison with the prototype

Storage time at (6-6ph) = 30 ° С, day The amount of active ingredient alimemazine tartrate detected by HPLC data in% of theoretical content Example 20 mg Example 40 mg Example 60 mg Prototype 0 one hundred one hundred one hundred one hundred 10 one hundred one hundred one hundred 99.9 twenty 99.9 99.9 99.9 99.5 thirty 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 friability of film-coated tablets with prolonged action.

Determination and standardization of the mechanical strength of tablets is necessary both in industrial production (for example, the process of coating tablets and packaging), and to ensure the consumer properties of the drug (preserving the integrity of the tablet when removed from the package) in co

- 6 039058 in accordance with article OFS.1.4.2.ООП.15.

The equipment consists of two opposed clamps, one of which can move towards the other. The surface planes of the clamps are perpendicular to the direction of movement. It is allowed to use a device in which both clamps can move at a constant speed towards each other. The clamping surfaces of the clamps should be flat and larger than the area of contact with the tablet. The device should ensure the termination of squeezing in case of any violation of the integrity of the tablets. The instrument is calibrated using a system providing an accuracy of 1 N (Newton).

The tablet is placed between the clamps with an edge in relation to the moving part of the device. The tablet, placed on its edge, is compressed until it breaks. Measurements are made for ten tablets. Before each measurement, carefully remove all fragments of the previous tablet.

Abrasion is expressed by weight loss calculated as a percentage of the original weight of the tablets tested.

The device consists of a drum with a removable lid, with a diameter of about 200 mm and a depth of about 38 mm, made of a transparent synthetic polymer; the inner surfaces of the drum must be polished and must not be electrified. On the inner perimeter of the drum wall there are 12 blades (35x35 mm) at an angle of 20 ° to the tangent of the drum, which, when it rotates, set the tablets in motion. The drum is attached to the horizontal axis of the device, which rotates the drum at a speed of 20 rpm. The instrument shall switch off automatically after the specified test time.

Ten tablets, dedusted and weighed to the nearest 0.001 g, are placed in a drum, the lid is screwed on and the device is turned on for 5 minutes, which corresponds to 100 revolutions of the drum. After the specified time has elapsed, the tablets are removed from the drum, dedusted and weighed again with an accuracy of 0.001 g. The loss in mass should not exceed 3%.

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

The loss in mass in each of the additional tests or the average loss in mass calculated from the results of 3 tests shall not exceed the specified value.

According to the results of the experiment, the tablets of prolonged action, 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 (2)

1. A pharmaceutical composition made in the form of a tablet, which is a core covered with a film coating, containing tartrate and auxiliary components in the alimemazine core, characterized in that microcrystalline cellulose, hypromellose, colloidal silicon dioxide and magnesium stearate are selected as auxiliary components in the following content of components in wt%: alimemazine 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 the film coat comprises 2.506.00% of the core weight.