RU2424807C2 - Pharmaceutical composition of prolonged action for correction of psychosomatic manifestations - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, namely to pharmaceutical compositions with prolonged action, used for correction of psychosomatic disorders. As active component, composition contains alimemazine tartrate, as well as target auxiliary substances: lactose, hydroxypropylmethylcellulose, pre-gelled starch, magnesium stearate, colloidal silicon dioxide with the specified component ratio. Composition is made in form of tablets, covered with coating, which consists of polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes.

EFFECT: pharmaceutical composition extends arsenal of medications and has storage term 2 years.

5 cl, 6 tbl, 1 dwg

Description

The invention relates to the field of pharmacology and medicine, in particular to pharmaceutical compositions for therapeutic correction of psychosomatic disorders of various etiologies.

The prevalence of psychosomatic disorders is very high and, according to various sources, ranges from 15 to 50% among the general population, and from 30 to 57% among primary medical practice patients (Smulevich AB, Syrkin A.L., Kozyrev V.N. Psychosomatic disorders (clinic, epidemiology, therapy, models of medical care) // J. Neurology and Psychiatry. - 1999. - T.99, No. 4. - P.4-16).

The data presented are consistent with indicators of the need for various means of psychopharmacotherapy for the treatment of psychosomatic disorders. So, the highest demand is for tranquilizers and antidepressants, which are needed by 40-65% and 12-25% of patients, respectively, while the need for typical antipsychotics is lower than 5%.

Pharmacotherapy of psychosomatic disorders involves the use of a wide range of psychotropic drugs - primarily anxiolytics, as well as antidepressants, nootropics and antipsychotics.

However, the use of psychotropic drugs for psychosomatic disorders is associated with certain difficulties. The latter are due to the properties of psychotropic drugs, namely: potential side effects, the features of their interaction with other, primarily somatotropic drugs, the effect on the patient's somatic state. In this case, the methodology of psychopharmacotherapy should be as simple as possible, since the provision of medical care to patients with psychosomatic disorders is carried out in institutions of the somatic network and mainly by internists.

Accordingly, the basic requirements for psychotropic drugs for the treatment of psychosomatic disorders can be formulated as follows: 1) a wide range of psychotropic activity: an effective effect on anxiety, affective (depressive), hypochondria (asthenic, algic, somatovegetative) disorders; 2) a favorable range of side effects with minimal negative impact on somatic functions; 3) good somatotropic effects (therapeutic effect on concomitant somatic pathology); 4) minimal behavioral toxicity (low severity or lack of sedative effects - drowsiness in the daytime, impaired attention, etc.).

Among the modern means of psychopharmacotherapy that meet these requirements, it is worth highlighting the atypical antipsychotic alimemazine, which is characterized by good absorption in various routes of administration, has minimal side effects, has a short half-life in the body, which is a clear advantage for the drug of the psychotherapeutic group.

The pronounced safety of the described drugs makes it possible to prescribe them for the treatment of psychosomatic disorders in a wide therapeutic dosage range, with different multiples of the day, for the elderly and children and allows to obtain a therapeutic effect with minimal side effects.

Alimemazine is known in the form of tablets, drops, solution for injection under the trade name "Teralen" (Medicines. Handbook edited by M.A. Klyuyev, 2001). Closest to the proposed invention is a dosage form in the form of a tablet of prolonged action of alimemazine tartrate (in the USA the current name of this substance is TRIMEPRAZINE TARTRATE) of the company ALLERGAN HERBERT (radar http://www.rlsnet.ru/mnn_index_id_1257.htm). The daily dose is distributed in 3-4 doses. Inside appoint from 5-10 mg (as sleeping pills) to 60-80 mg (as anxiolytic) per day, with psychotic conditions - up to 200-400 mg per day. Intravenous drip - 25 mg (initial dose) with a further gradual increase to 75-100 mg.

These dosage forms contain a tablet with a dosage of 5 mg of active ingredient. Thus, in order to achieve a therapeutic effect, especially in the treatment of acute psychosomatic disorders, the doctor is forced to prescribe from 4 to 25 tablets per reception 3-4 times a day. Which in itself is inconvenient for the patient and in a similar situation, there is no adherence to the prescribed therapy. And the result of therapy is usually negative.

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. Preparations of this type ensure the maintenance of a constant concentration of the active substance in the blood without peak fluctuations. Durant dosage forms can reduce the frequency of prescribing drugs, and therefore, reduce the frequency of development and severity of possible adverse reactions of drugs. Reducing the frequency of taking medications creates certain conveniences for both medical personnel in clinics and for those patients who perform outpatient treatment, significantly increasing their compliance, which is very important, especially when using medications to treat chronic diseases. The prolonged action of drugs can be achieved in various ways. There are various technological principles for achieving the sustained action of solid dosage forms.

Drugs with a prolonged action can not only increase the effectiveness of drug therapy, significantly reducing the frequency of administration against a background of a reduced daily dose, but also increase the safety of the drugs used and significantly increase patient compliance.

The aim of this invention is to expand the arsenal of drugs with a psychosomatic effect, using a pharmaceutical composition of prolonged action, which is based on alimemazine tartrate. Moreover, the resulting composition must comply with the requirements of the current State Pharmacopoeia of the XI edition, be more economical, convenient for use by the patient by reducing the frequency of admission during the day, be stable during storage and release the active substance in accordance with the given characteristics in the gastrointestinal tract, while maintaining its advantages in the form of a short half-life.

This goal is achieved by a pharmaceutical composition with a psychosomatic effect, including alimemazine tartrate and target excipients as an active component.

To select the composition of tablets with modified release, the technological characteristics of prolonging substances were studied, the use of which allows to obtain a prolonged pharmaceutical composition in the usual production scheme without special technological equipment. It was determined that hydroxypropylmethyl cellulose (HPMC) of the Benecel MP824 brand (F. Hercules Holland) and Metocel (F. Colorcon, USA) have the flowability and compressibility necessary for direct pressing.

As additional targeted additives, lactose (preferably Ludipress LCE, BASF, Germany) is used to give acceptable organoleptic properties and improve the taste of the drug, pregelatinized starch (starch 1500) to give the best technological properties, namely flowability and compressibility, as lubricating and moving substances used silicon dioxide colloidal (aerosil) and magnesium stearate in the following ratio of components, wt.%:

Alimemazine tartrate 8.0-15.0 Lactose 48.0-65.0 Pregelatinized starch 6.0-9.0 Magnesium stearate 0.8-1.2 Silicon Colloidal Dioxide 0.8-1.2 Hydroxypropyl methylcellulose 12.0-35.0

Thus, taking into account the technological characteristics, excipients have been selected to optimize the pharmaceutical compositions of the claimed invention and to obtain tablet dosage forms with rapid release and modified release of active substances by direct compression, and the resulting tablets have properties that satisfy the requirements of a pharmaceutical agent, t .e. they have a marketable appearance without chips and cracks, have sufficient strength, are stored for at least 2 years, while providing a high clinical effect and convenient dosage.

The new pharmaceutical composition is in the form of a solid coated dosage form, preferably in the form of a tablet. The presence of the shell of the claimed composition gives, firstly, the stability of the composition during storage, and secondly, improves its appearance and organoleptic properties.

As a shell, a composition based on polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes or the Opadry II brand ready mix is proposed.

The manufacturing process of tablets is carried out by direct compression (Technology of dosage forms. / Edited by Ivanova L.A. - M .: Medicine, 1991, v.2, p.142).

The claimed technical solution can be obtained and used in industry, therefore, meets the criterion of "industrial applicability".

The possibility of carrying out the invention is illustrated by the following example.

Example

Preparation of raw materials and auxiliary materials.

Alimemazine tartrate, hypromellose, ludipress® LCE, starch 1500, aerosil, magnesium stearate are sieved through a nylon sieve 32.

Preparation of tablet mass.

Ludipress® LCE sifted, alimemazine tartrate sifted, starch 1500 sifted and Metocel® (type K100LV CR) sifted are loaded into the mixer (super-mixer granulator). The mixture of dry components is mixed for 7-12 minutes (the rotation speed of the main mixer is 130-150 rpm). Then, sifted aerosil, sieved magnesium stearate are added to the mixture of dry components, and stirring is continued for 2-3 minutes (the rotation speed of the main mixer is 130-150 rpm). After mixing, the tablet mass is unloaded from the mixer and transferred to the tabletting stage

Tableting.

The resulting tablet mass is tabletted on a RTM-41 M rotary press using biconvex punches with a diameter of 8 mm (deep sphere).

Sheathing.

The film coating on the tablet core is carried out on a BGB-10 apparatus. For film coating, an aqueous suspension of OPADRY II powder is prepared with a mass concentration of 19% ± 1%. Distilled water is poured into the reactor with a variable speed of the stirrer, the stirrer speed is set so that a funnel forms in the liquid, and OPADRY II is loaded in portions. At the end of the powder loading, the number of revolutions of the mixer is reduced almost to the disappearance of the funnel in the liquid. The mixing time is 50-60 minutes, after which the suspension is filtered on a sieve with a 0.250 mm mesh. The suspension in the coating process is in the reactor with constant stirring. The shelf life of the prepared suspension is not more than 24 hours.

Then, tablet cores are loaded into the installation drum, the drum is turned on with a minimum number of revolutions of 6 rpm, the distance from the nozzle to the tablet layer is set to 200 mm ± 10 mm, the exhaust and supply fans of the installation are turned on, and a small discharge is created in the boat body. To heat the air supplied to the coater, include electric heating elements. The task on the temperature of heating the air is set in the range of 55 + 65 ° C. In this mode, within 3 + 5 minutes, dedusting and heating of the tablet cores takes place. When the temperature in the tablet layer reaches 38 + 42 ° C, increase the number of drum revolutions to 14-15 rpm, open the compressed air supply for spraying and forming a torch, and turn on the suspension feed pump to the nozzle. In the process of applying a film coating control:

- the temperature in the layer of tablets 38-42 ° C;

- flow rate of the suspension 25-30 g / min;

- the number of revolutions of the drum, preventing the formation of stagnant zones in the moving mass of tablets;

- the pressure of the compressed air to spray and the formation of a torch, set when setting the nozzle;

- discharge in the coater;

- the appearance of the tablets - the absence on the surface of the tablets of ulcers, pores, cracks, sagging, etc.

The process of applying a film coating lasts 70 + 90 minutes. After the entire suspension has been used up, turn off the pump, stop the supply of compressed air to the nozzle, set the drum speed to 6-8 rpm and dry the tablet at a temperature of 35-38 ° C for 10 minutes. Then turn off the heating of the air and mix the tablet for another 10 minutes, after which it is unloaded in a plastic container and kept for 6-8 hours at room temperature.

In order to confirm the retarded form of the drug, a study of alimemazine tartrate in a dosage of 60 mg was carried out in comparison with tablets of alimemazine tartrate in a dosage of 5 mg. In this case, the dosage of conventional tablets of teraligen in 5 mg, a administered dose of 30 mg was normalized to a dose of 60 mg. The study was conducted at the State Research Institute of Pharmacology named after V.V.Zakusova RAMS head. Laboratory of Pharmacokinetics Dr. med. Sciences, Professor V.P. Zherdev.

The following results were obtained:

1. A simple, reliable and accurate HPLC method was developed for the quantitative determination of alimemazine in the blood plasma of rabbits with a detection limit of 25 ng / ml.

2. The pharmacokinetics of alimemazine in the blood plasma of rabbits was studied after a single injection of two tablet forms of alimemazine (retard and conventional).

3. The time to reach maximum concentrations of alimemazine from retard tablets was 4.38 ± 0.74 hours and for ordinary tablets, 2.69 ± 1.10 hours.

These results are confirmed by the tables below. A comparative analysis of the main pharmacokinetic parameters (Tables 1a and 1b) of alimemazine showed that the studied compound is absorbed from the gastrointestinal tract at almost the same rate when administered in the form of conventional tablets and the retard form of the drug (C _max / AUC _{0 → t} for ordinary tablets amounted to 0.0871 ± 0.0212 h ^-1 ; for retard tablets, 0.0850 ± 0.0202 h ^-1 ). At the same time, the time to reach the maximum concentration (t _max ) for conventional alimemazine tablets came in 2.69 ± 1.10 hours, and for the retard form of the drug in 4.38 ± 0.74 hours. Reliable reliable values were established between the t _max values of the studied dosage forms differences (P = 0.95; Table 2).

The average maximum concentration of alimemazine, determined in the blood plasma of rabbits (C _max ), was 547.04 ± 136.97 ng / ml for conventional tablets, and 947.68 ± 311.6 ng / ml for retard tablets. After recalculating the concentrations of alimemazine per dosage - 60 mg, we obtain C _max for conventional tablets equal to 1094.08 μg / ml, which is 15% higher than the same parameter for retard tablets.

The average value of AUG _{0 → t} for retard tablets was 11918.0 ± 5074.08 and for ordinary tablets - 6648.99 ± 23 80.96 ng / ml × h.

The relative bioavailability of (f) alimemazine, determined by the ratio of individual values of AUC _{0 → t} taking into account the administered doses for teraligen retard tablets relative to conventional teraligen tablets, averaged 89.64 ± 26.99%. If retard tablets are used as the standard dosage form, the relative bioavailability of conventional tablets is 117.28 ± 23.97%.

Studies of the retardated form of Alimemazine tartartrate in a dosage of 20 mg were carried out at the All-Russian Scientific Center for the Safety of Biologically Active Substances (JSC "VSC BAS").

A comparative study involved: 1) drug A: alimemazine tartrate, coated tablets, retard for oral administration, containing 20 mg / ml alimemazine tartrate (table 3a); 2) preparation “B”: “Teralen”, manufactured by “IPSEN PHARMA” (Spain), oral solution containing 40 mg / ml alimemazine tartrate (Table 3b).

The bioavailability of Alimemazine retard tablets compared to Teralen was 115% (Table 4).

The invention is illustrated in the drawing, which reflects the dynamics of changes in the content of alimemazine in the blood serum of rabbits for retard tablets (A) and Teralen (B).

As can be seen in the drawing, the maximum concentration of alimemazine in the blood is reached 3.67 hours after a single administration of retard tablets (A), and the half-life (T _{1 / 2β} ) is 3.29 hours.

Thus, the invention allows:

1) to expand the arsenal of drugs with a psychosomatic effect, with the help of a pharmaceutical composition of prolonged action, which is based on alimemazine tartrate;

2) release the active substance in accordance with the specified characteristics in the gastrointestinal tract, while retaining its advantages in the form of a short half-life.

Table No. 1a Pharmacokinetic parameters of alimemazine in the blood plasma of rabbits after a single administration of teraligen retard tablets at a dose of 60 mg No. / No. Pharmacokinetic parameters AUC _{0 → t} , ng / ml × h t _max hour C _max , ng / ml C _max / AUC _{0 → t} , h ^-1 T _{1/2 el} hour f%

11918,00 4.38 947.68 0.0850 10.76 89.64 SD 5074.08 0.74 311.60 0,0202 2.78 26,99

1792.96 0.26 110.11 0.0071 0.98 9.54 C.V.% 42.57 17.01 32.88 23.72 25.81 30.11

Table No. 1b Pharmacokinetic parameters of alimemazine in the blood plasma of rabbits after a single injection of conventional tablets of teraligen at a dose of 30 mg No. / No. Pharmacokinetic parameters AUC _{0 → t} , ng / ml × h t _max hour C _max , ng / ml C _max / AUC _{0 → t} , h ^-1 T _{1/2 el} hour f%

6648,99 2.69 547.04 0.0871 10.29 117.78 SD 2380.96 1.10 136.97 0.0212 1.46 23.97

841.33 0.39 48.40 0.0075 0.52 8.47

table 2 Significance of differences in tmax values for retard tablets and conventional teraligen tablets Retard Pills Conventional tablets Average 4,375 2.6875 Dispersion 0.553571429 1,209821429 Observations 8 8 Pooled variance 0.881696429 - Hypothetical mean difference 0 - df fourteen - t-statistic 3,594299284 - P (T <= t) one-way 0,001465728 - t critical one-way 1.761310115 - P (T <= t) two-way 0.002931455 - t critical two-way 2,144786681 -

Table 3a Retard Tablet (A) one 2 3 four 5 6 M m T1 / 2 3.48 2,38 3.63 3.31 2.28 4.63 3.29 0.36 Cmax 3.25 2.81 3.22 3.33 2.98 2.84 3.07 0.09 Tmax 4.0 3,5 3,5 4.0 3,5 3,5 3.67 0.11 MRT 6.83 5,4 7.05 7.09 5.55 8.16 6.68 0.43 Auc 21.1 12.1 22.3 18,4 15.00 18.6 17.92 1.55

Table 3b Theralen (B) one 2 3 four 5 6 M m T1 / 2 1,64 1.95 2.73 1.76 2.42 1.86 2.06 0.17 Cmax 5.08 4.17 3.04 4.97 3.28 2.17 3.79 0.47 Tmax 2.5 2.5 2.0 2.5 2.5 2.5 2.42 0.08 MRT 6.67 3.83 4.49 6.94 3.45 4.42 4.97 0.60 Auc 20,2 16,2 14.8 15.8 14.2 12.28 15,58 1,08

Table 4 The results of a standard comparison of the averaged data on the pharmacokinetics of alimemazine after taking the tablets Retard (A) and Teralen (B) T1 / 2 Cmax Tmax MRT Auc A / B 159 82 151 134 115 T 3.09 1.48 3.3 2,32 1.23 R P <0.05 p> 0.05 P <0.05 P <0.05 p> 0.05 where t are the values of the student criterion; p - probability values, p> 0.05 indicates a statistically unreliable difference between the average values of the compared samples

Claims (5)

1. A sustained-release pharmaceutical composition for oral administration comprising, as active substance, alimemazine tartrate or its pharmaceutically acceptable salts and target excipients, characterized in that it contains an effective amount of alimemazine tartrate and, as excipients, lactose, hydroxypropyl methylcellulose, pregelatinized starch, magnesium stearate, colloidal silicon dioxide in the following ratio of ingredients, wt.%:
Alimemazine tartrate 8.0-15.0 Lactose 48.0-65.0 Pregelatinized starch 6.0-9.0 Magnesium stearate 0.8-1.2 Silicon Colloidal Dioxide 0.8-1.2 Hydroxypropyl methylcellulose 12.0-35.0 2. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a solid dosage form. 3. The pharmaceutical composition according to claim 2, characterized in that it is made in the form of coated tablets. 4. The pharmaceutical composition according to claim 3, characterized in that the shell contains polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable colorants or the finished mixture of the brand "Opadry II". 5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that it is used to treat psychosomatic disorders.

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