RU2659200C1 - Pharmaceutical composition containing alimamazine tartrate - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine. Pharmaceutical composition contains alimamazine tartrate and auxiliary components. As auxiliary components, microcrystalline cellulose, hypromellose, silica colloidal dioxide and magnesium stearate in the amounts indicated in the claims are selected. Pharmaceutical composition of alimamazine tartrate is in the form of a tablet coated with a film coating.

EFFECT: tablet according to invention provides a sustained release of alimamazine tartrate, while retaining advantages in the form of a short half-life; characterized by satisfactory stability, strength of more than 70 N, and an abrasion resistance of at least 98,5%.

5 cl, 4 tbl, 5 ex

Description

The invention relates to the field of the pharmaceutical industry and medicine and relates to methods for producing new formulations of antipsychotics.

In recent decades, there has been a tendency to increase the prevalence of psychogenic diseases, such as neurosis and other diseases with mild mental disorders, the occurrence, course, compensation and decompensation of which are mainly determined 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 a market leader in its segment, both in Europe and in America.

Alimemazine tartrate is an antipsychotic drug that is one of phenothiazine derivatives - 10- (3-dimethylamino-2-methylpropyl) -phenothiazine hydrotartrate, and is close in chemical structure to diprazine and levomepromazine. The drug has an antihistamine, antispasmodic, serotonin blocking, moderate alpha-adrenergic blocking, antiemetic, hypnotic, sedative and antitussive effects [Ibragimov DF "Alimemazine in medical practice" // Journal. Neurology and Psychiatry. S.S. Korsakova, 2008; T. 108, No. 9, S. 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).

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

Currently, the issue of creating prolonged dosage forms that can ensure the long-term effect of the drug while reducing its daily dose is becoming increasingly relevant.

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

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 present invention is to develop a new pharmaceutical composition of prolonged action, with a psychosomatic effect, containing alimemazine tartrate.

The technical results of the present invention are:

- improving the pharmacokinetic parameters of the claimed composition;

- improving 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. As auxiliary components, microcrystalline cellulose, hypromellose, silicon dioxide colloidal and magnesium stearate were selected. 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 of the invention:

- said composition does not contain lactose;

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

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

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

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

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

The film coating may include, but is not limited to, polyvinyl alcohol, partially hydrolyzed polyvinyl acetate, cellulose derivatives such as ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC) as film-forming substances, polyethylene glycol, propylene glycol, 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, dyes may be titanium dioxide, aluminum varnishes, 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 the most preferred embodiment, round biconvex coated tablets may be prepared.

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

Dosage forms of retard (from Lat. Retardo - to slow down, tardus - quiet, slow; synonyms - retarders, dosage forms retardized) are prolonged dosage forms that provide the body with a supply of a medicinal substance and its subsequent slow release. These dosage forms are mainly used orally, but are sometimes used for rectal administration.

To select the composition of the tablets with modified release were tested substances-prolongers and excipients, the use of which allows you to get a prolonged pharmaceutical with improved pharmacokinetic properties. At the same time, the composition of the filler and the prolonging component was selected, which allows one to obtain a solid dosage form in the usual production scheme without special technological equipment. It was determined that the combination of hypromellose and microcrystalline cellulose possesses the necessary characteristics.

The inventors unexpectedly found that the composition of the alimemazine tartrate according to the present invention has improved pharmacokinetic parameters and increased stability compared to 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 impaired adaptation; dissociative (conversion) disorders; somatoform disorders; unspecified disorder of the autonomic (autonomous) nervous system, other disorders of the autonomic (autonomous) nervous system; anorexia nervosa; emotionally unstable personality disorder (impulsive and borderline types); hysterical personality disorder, anxious (evading, avoiding) personality disorder; persistent personality change after experiencing a disaster; hyperkinetic behavior disorder; family disorder; unsocialized behavior 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 for childhood, as an antiallergic agent, itching, regardless of place and etiology; asthma, hay fever, whooping cough (as an antiallergic drug to relieve cough, shortness of breath and asthma attacks); unspecified allergy.

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

Example 1. Obtaining tablets of prolonged action, film-coated.

Sifted microcrystalline cellulose and alimemazine tartrate are loaded into a 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 “mass loss on drying” indicator reaches 3.0 ± 0.5.

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

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

The tablet mass is pressed on a rotary press using round punch (deep sphere) with a diameter of 8.0 ± 0.2 mm (for all dosages).

The finished film coating is applied to the tablet cores.

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

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

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

Film coating composition (1).

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

Film coating composition (2).

A mixture of HPMC, macrogol 400, polysorbate 80 and titanium dioxide (for example, Opadry ^® "White coating premix", company Colorcon).

Film coating composition (3).

A mixture of HPMC, macrogol 400 and maltodextrin (e.g., Opadry ^® "Clear coating premix", Colorcon).

Example 2. The study of the pharmacokinetics of a prolonged-release film-coated tablet.

In order to confirm the prolonged action proposed tablets depot, covered with a film 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 the composition according to 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 pharmacokinetics alimemazine in rabbit blood plasma after single administration of three tablet forms alimemazin (Tablet depot, covered with a film coating as described in Example 1, Table 1, retard mold of the prior art and tablets Teralidzhen ^®, 5 mg, "CG-Pharm ").

Materials and methods.

The study was conducted on 10 male rabbits weighing 2.4 ± 0.52 kg contained under standard vivarium conditions. Animals once through the probe was administered 1 tablet of a prolonged action, film-coated, according to the invention or 1 retard tablet of a prolonged action, film-coated, according to the prototype, or 12 tablets Teraligen ^® "HG-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).

Quantification of alimemazine in rabbit plasma was performed by HPLC with a detection limit of 25 ng / ml.

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

The main pharmacokinetic parameters were calculated.

Results.

A comparative analysis of the main pharmacokinetic parameters of alimemazine showed that the time to reach maximum concentrations of alimemazine (t _max ) for the claimed sustained-release tablets coated with a film coating was 6.8 ± 0.28 hours, according to the prototype - 4.18 ± 0.72 hours, and from Teraligen ^® HG-Pharm tablets - 2.70 ± 0.38 h (see Table 2). Between the values of t _max for the claimed tablets of prolonged action, film-coated, and tablets retard according to the prototype established significant differences (p <0.05).

The half-life for a prolonged dosage form was 10.84 ± 2.80 hours, according to the prototype - 10.76 ± 2.78 hours, for comparative tablets Teraligen ^® "HG-Pharm" - 10.29 ± 1.46 hours

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

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

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

The purpose 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 in small laboratory animals, identification of the most sensitive organs and systems of the body and study of the degree of reversibility of damage caused

The study of acute toxicity.

Materials and methods.

A study of the acute toxicity of the claimed sustained-release tablet film-coated tablet with a single intragastric administration was carried out on 20 white non-linear male mice weighing 18-20 g contained in standard vivarium conditions with free access to water and food. The doses of 180, 250, 320 and 390 mg (for alimemazine) / kg body weight were tested. For 14 days, the general condition of the animals was evaluated. 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.

Acute toxicity parameters yielded the following results:

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

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

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

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

Statistical comparison of the experimental and control groups was carried out by t-student test.

Results.

In groups of animals that received intragastric suspensions of the studied drug at a dose of 60 mg / kg, there was a tendency to a decrease in the rate of increase in body weight, an insignificant but significant increase in the activity of blood transaminases, and a decrease in 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 daily diuresis for groups of animals treated with the experimental drug, relative 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, but 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 taking into account interspecific conversion doses.

The claimed drug does not exhibit mutagenic properties in experiments on Drosophila, does not have allergenicity, and does not have reproductive toxicity.

Example 4. Determination of the stability of tablets of prolonged action, film-coated, accelerated aging.

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

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

The study was conducted in the IC PJSC "Valenta Pharm".

The tablets obtained in accordance with Example 1 of the present invention and in accordance with the prototype are packaged in aluminum foil blisters ('Alu-Alu') and placed in a climate chamber under accelerated testing conditions. The content of the active substance alimemazine tartrate is determined by HPLC using standards.

The method of "accelerated aging" is to withstand the test drug at temperatures and humidity exceeding the temperature and humidity of its storage during handling. At elevated temperatures, as a rule, physicochemical processes occurring in medicines are accelerated, leading to undesirable quality changes over time. Thus, at elevated temperatures, the period of time during which controlled quality indicators of the drug 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 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 that provides any specified shelf life.

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

C = K⋅C _Oe ,

.where K - compliance coefficient is calculated as

.

The temperature coefficient of the chemical reaction rate (A) is taken equal to 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 an increase in temperature by 10 ° С.

In accordance with pharmacopoeial article OFS.1.1.0009.15, the value of the compliance coefficient (K), depending on the selected temperature interval (t _e -t _xp ), 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 the results of the study 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 is 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 accelerated aging method, the extended-release tablets of the present invention possess statistically significantly increased stability and remain chemically pure. The tablets obtained in accordance with the prototype remain chemically clean 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.

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

The determination and normalization of the mechanical strength of tablets is necessary both in the conditions of industrial production (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 article OFS.1.4.2.0011.15.

The equipment consists of two clamps located opposite each other, 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 compression surfaces of the clamps should be flat and larger than the area of contact with the tablet. The device should ensure the termination of compression in case of any violation of the integrity of the tablets. The instrument is calibrated using a system that provides 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 the edge, is compressed until it breaks. Measurements are carried out for ten tablets. Before each measurement, all fragments of the previous tablet are carefully removed.

Abrasion is expressed as loss in mass, calculated as a percentage of the initial weight of the test tablets.

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 not electrified. On the inner perimeter of the wall of the drum there are 12 blades (35 × 35 mm) at an angle of 20 ° to the tangent of the drum, which rotate the tablet and move it. The drum is attached to the horizontal axis of the device, providing rotation of the drum at a speed of 20 rpm The device should automatically turn off after the set test time.

Ten tablets, dust-free and weighed to the nearest 0.001 g, are placed in a drum, screw on the lid and turn on the device for 5 minutes, which corresponds to 100 revolutions 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 mass loss should not exceed 3%.

If cracked, cracked or broken tablets are found after the test, 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 3 tests should not exceed the normalized value.

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

Claims (7)

1. The pharmaceutical composition containing alimemazine tartrate and auxiliary components, made in the form of a tablet, film-coated, characterized in that microcrystalline cellulose, hypromellose, silicon dioxide colloidal and magnesium stearate are selected as auxiliary components with the following components in wt.%: alimemazine tartrate 10.00-30.00 microcrystalline cellulose 35.00-42.00 hypromellose 33.50-46.00 silicon dioxide colloidal 1.00-2.00 magnesium stearate 0.50-2.00 2. The pharmaceutical composition according to claim 1, characterized in that said composition does not contain lactose. 3. The pharmaceutical composition according to claim 1, characterized in that said composition is in the form of a capsule or tablet. 4. The pharmaceutical composition according to claim 2, characterized in that the pharmaceutical composition is in the form of a tablet, which is a coated core. 5. The pharmaceutical composition according to claim 4, characterized in that the film coating is 2.50-6.00% by weight of the core.