RU2270010C2 - Pharmaceutical composition possessing soporofic effect - Google Patents

Abstract

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the medicinal preparation zolpidem. Pharmaceutical composition comprises zolpidem hemitartrate as active substance taken in the effective dose and ludipress, aerosil and stearate as special additives. Pharmaceutical composition is made preferably as a tablet covered by envelope. Invention solves the problem for the development of the nonprolonged soporofic medicinal agent based on zolpidem corresponding to all requirements of the State Pharmacopoeia of XI Edition. Proposed nonprolonged formulation of zolpidem is suitable for workers contingent suffering with insomnia, especially, in professions requiring attention and concentration.

EFFECT: improved and valuable medicinal properties of composition.

6 cl, 2 tbl, 3 ex

Description

The invention relates to the field of medicine, specifically to a tool that can be used for various types of insomnia.

The decline in the social well-being of the population in several countries of the world, the increasing rhythm of life, the growth of unemployment, crime and other unfavorable living conditions have sharply increased in recent years the number of people suffering from various types of insomnia (chronic, abnormal, transient). Despite the presence of various sleeping pills in medical practice, the creation of new effective sleeping pills is necessary due to the fact that some of the sleeping pills used have side narcotic effects, fast addiction develops to some of them and their initial effectiveness is lost.

Zolpidem, a hypnotic drug from the imidazopyridine group, is a specific agonist of central nervous system receptors. It also has a sedative, insignificant anxiolytic, anticonvulsant and central muscle relaxant effect. It is used for sleep disorders. Zolpidem was first mentioned in European application EP0050563, 1982, which describes imidazo [1,2-a] pyridin-3-acetamide derivatives, their preparation and use in therapy, in particular zolpidem (in the form of a free base). In European patents EP 251859, 1988 and EP 1038875, 2000, methods for producing imidazopyridines, including zolpidem, are described.

International application WO00 / 58310, 2000 describes various zolpidem salts, including those used in solid dosage forms for oral administration, zolpidem tartrate and hemp tartrate.

US Pat. No. 5,891,891, 1999, describes the use of imidazo [1,2-a] pyridin-3-acetamide derivatives for the therapeutic treatment of neuropsychiatric syndromes. Zolpidem is used to treat Parkinson's disease and parkinsonism syndromes. Sedative and hypnotic effects are observed at much lower doses than those required to obtain other effects of zolpidem (anticonvulsant, anxiolytic and muscle relaxant). The composition in unit dosage form preferably comprises from 5 to 20 mg of the active ingredient zolpidem hemitartrate.

The main dosage forms of zolpidem described in the literature are sustained release dosage forms, controlled-release dosage forms. Thus, in international application WO 95/20947, 1995, tablets are described which contain two or more layers, including one or more drug substances (A) and one or more gelling agents (B), which are contained in separate layers of the tablet. The weight of the gelling agent in the gelling layer is from 20 to 60%, the amount of the gelling layer in the tablet is from 50 to 80%. The gelling agent is modified cellulose, sodium alginate, alginic acid, tragacanth, polyacrylic acid and xanthan gum.

Example 10 of international application WO 95/20947, 1995 describes a bilayer tablet based on zolpidem tartrate:

Part A, wt.%: Zolpidem Tartrate 5,0 Lactose 64.5 Microcrystalline cellulose 25.0 Croscarmellose sodium 5,0 Magnesium stearate 0.5 Part B, wt.%: Hydroxypropyl methylcellulose 40,0 Calcium Phosphate 19,2 Lactose 29.0 Microcrystalline cellulose 5,0 Povidone K 30 6.0 Colloidal silicon dioxide 0.3 Magnesium stearate 0.5

Bilayer tablets containing 5 mg of zolpidem hemitartrate weighing 325 mg and containing 125 mg of part A composition and 200 mg of part B composition are prepared on a tablet press by two-stage compression molding and coated with a film using a coating solution containing hydroxypropyl methylcellulose, polyethylene glycol and suitable colorants.

International application WO 00/33835, 2000, describes dosage forms with controlled release, including zolpidem or its salts. Zolpidem is released after a certain period of time in accordance with the two-phase release profile, in which the first phase is the immediate release phase, and the second phase is the prolonged release phase. The first phase has a maximum duration of ~ 30 minutes, during which 40 to 70% of the total amount of zolpidem is released. The time for which about 90% of the total amount of zolpidem is released is from 2 to 6 hours.

The prolonged form of zolpidem as a sleeping pill is very convenient for the disabled patient population. For workers suffering from insomnia, a prolonged form of the drug can be an obstacle in the performance of their duties, especially in professions that require attention and concentration (for example, drivers of all types of vehicles, rescue services, law enforcement agencies, etc.).

Therefore, the development of a non-prolonged form of zolpidem is very relevant.

The objective of the invention is to prolong the hypnotic drug based on zolpidem, which meets all regulatory requirements of the Gosfarmakopei XI edition (see table 2).

The problem is solved by a pharmaceutical composition having hypnotic action, which contains a therapeutically effective amount of zolpidem hemitartrate and target additives in an amount of 7.2-8.8 parts by weight per 1 part by weight of the active substance (parts by weight per 1 wt. hours).

As target additives, use ludipress, aerosil and a stearic acid salt in the following ratio of components, parts by weight per 1 part by weight active substance:

Ludipress 7,100-8,680 Aerosil 0.018-0.022 Stearic acid salt 0.081-0.099

As a salt of stearic acid, a pharmaceutical composition having hypnotic action contains magnesium and / or calcium salts.

The new pharmaceutical composition is in the form of a solid dosage form, preferably in the form of a coated tablet.

As a shell, the following composition is proposed with a ratio of components, parts by weight per 1 part by weight active substance:

Hydroxypropyl methylcellulose 0.128-0.157 Propylene glycol 0,036-0,045 Talc 0,112-0,138 Titanium dioxide 0.126-0.158 Dye 0.001-0.002

Indigo carmine and / or acid red and / or tropeolin and others can be used as a dye.

The proposed ratio of active substance and target additives is found experimentally and is optimal, providing the drug zolpidem compliance with all the requirements of the Gosfarmakopei XI ed. (see table 2).

The following examples illustrate the invention.

Example 1. (Target additives - 8.0 parts by weight per 1 part by weight of the active substance; see table 1). The powders of zolpidem hemitartrate in an amount of 40.0 g, ludipress in an amount of 315.0 g, aerosil in an amount of 0.8 g and magnesium stearate in an amount of 3.6 g are mixed, mixed thoroughly and tabletted on a tablet machine. Get 3833 tablets with a total weight of 345 g. Zolpidem core tablets are coated with a film-forming composition prepared in a known manner from powders of 5.46 g of hydroxypropyl methylcellulose (OPMC), 1.54 g of propylene glycol, 5.40 g of titanium dioxide, 4.78 g of talc, 0.0498 g of indigo carmine and 143 ml of water. The film is applied in a known manner on zolpidem core tablets until a uniform coating is obtained. The weight gain of the tablets is on average 5%. The obtained zolpidem tablets meet all the requirements of the Gosfarmakopeyi XI ed (see table 2).

Example 2. (Target additives - 7.2 parts by weight per 1 part by weight of the active substance; see table 1). Obtaining tablets of zolpidem is carried out according to example 1 on the basis of 40 g of zolpidem hemitartrate, 284 g of ludipress, 0.72 g of aerosil and 3.24 g of calcium stearate, 3540 tablets are obtained with a total weight of 311.52 g, which are coated with a membrane according to example 1. Obtained zolpidem tablets meet all the requirements of the State Pharmacopoeia XI ed. (see table 2).

Example 3. (Targeted additives - 8.8 parts by weight per 1 part by weight of the active substance (see table 1). Preparation of zolpidem tablets is carried out according to example 1 based on 40 g of zolpidem hemitartrate, 347 g of ludipress, 0.87 g of Aerosil and 3.95 g of magnesium stearate 4087 tablets are obtained with a total weight of 380 g, which are coated with a film, as in Example 1. The resulting tablets meet all regulatory requirements (see table 2).

A comparative toxicological study was conducted of the claimed pharmaceutical composition of zolpidem and a standard sample, which was used as the drug ivadal company LABORATOIRES SYNTHELABO, France.

The study was conducted using modern physiological, biochemical, hematological and histological methods in accordance with the requirements of the Federal Ministry of Health of the Russian Federation.

Subacute toxicity was studied for two weeks on randomly bred male rats with an average weight of 214 ± 4 g. The drugs were administered intragastrically at doses of 2 (therapeutic) and 20 mg / kg once a day for 2 weeks.

Compared drugs did not significantly affect the integral indicators (weight gain, feed intake, water).

The studied hypnotic drugs had a depressing effect on the behavior of animals. The severity of the effect, the nature and duration of its implementation had a dose dependence. At a dose of 2 mg / kg, the state of oppression was observed for 2-3 hours, at a dose of 20 mg / kg, it continued for 6-8 hours.

According to the results of the experiment, no irritating effect on the mucosa of the gastrointestinal tract in experimental animals was detected when exposed to both drugs.

Experimental data indicate the absence of significant differences in peripheral blood, the content of glucose and total lipids in blood serum, the functional state of the cardiovascular and excretory systems. A two-week exposure to drugs at a dose of 20 mg / kg caused similar changes in the state of the nervous system, manifested in a decrease in the motor and emotional components of animal behavior. The drugs in the studied doses did not cause structural disorders in organs and tissues.

Thus, the studies confirm the bioequivalence of the proposed pharmaceutical composition and standard preparation.

Clinical trials of the proposed prolonged hypnotic drug based on zolpidem were conducted in order to study its effectiveness and tolerability in patients with inorganic insomnia. The studies were conducted in accordance with the requirements of the Federal Ministry of Health of the Russian Federation.

In total, the study included 40 patients (14 men and 26 women aged 24 to 64 years (average age of patients 43.4 years). The average duration of the disease is from 1 month to 5 years.

Before treatment, patients complained of difficulty falling asleep, a short, shallow sleep with frequent awakenings, dreams of a different nature. Patients noted that sleep does not bring a sense of relaxation, felt lethargic, overwhelmed, they were worried about reduced working capacity, increased fatigue during normal workload at home and at work.

Zolpidem tablets were prescribed after a washout period of at least 7 days, with the exception of cases in which other sleeping pills were not reliably used. The drug in the form of monotherapy was used in a dose of 10 mg (one tablet 20-30 minutes before bedtime). For patients over 60 years of age, treatment began with half a tablet (5 mg) during the first 7 days. The maximum dose was 10 mg. The duration of zolpidem therapy was 14 days. The condition of the patients was assessed before the start of therapy (background examination), on the third, seventh days of therapy and at the end of treatment (day 14 of therapy). Drugs with psychotropic activity were excluded.

All 40 patients included in the study completed the course of therapy.

As a result of clinical trials, it was found that the claimed drug zolpidem shortens the time of falling asleep, reduces the number of night awakenings, increases the duration of sleep and improves its quality. It lengthens the phase of II sleep, the phase of deep sleep (III and IV), does not affect the duration of the REM sleep phase.

Zolpidem is rapidly absorbed, the peak concentration of the drug in blood plasma is reached after 1.5-2 hours, and the hypnotic threshold in blood plasma is recorded within 20-30 minutes after administration. The elimination half-life from an organism makes 1,5-4 hours. The drug has no active metabolites. These features allow you to determine the claimed sleeping pills drug based on zolpidem as a sleeping pill fast and short action.

Important qualities of this drug are the speed of hypnotic action, the absence of pronounced side effects and the absence of any negative effect on the level of wakefulness and performance both in the morning and throughout the day.

During the study period (14 days), the applied dose of 10 mg at night remained sufficient and did not require correction. Moreover, there was a tendency to sequentially consolidate and increase the overall effect of therapy, which allows us to talk about restoring sleep in most patients. In this study, all patients were able-bodied and had full-time employment. In the process of the study, a decrease in disability was not noted. Almost all patients noted an improvement in their ability to cope with intellectual and physical stress.

Thus, the preclinical and clinical trials of the inventive non-prolonged hypnotic drug based on zolpidem showed:

- its high efficiency in patients with insomnia of an inorganic nature;

- the speed of falling asleep, the high quality of sleep, the absence or slight severity of postcommunic phenomena;

- therapeutic safety, the absence of pronounced and persistent unwanted and side effects;

- the use of this drug does not interfere with daily activity and does not adversely affect intellectual and physical performance;

- the drug does not cause changes in vital functions.

Thus, the claimed drug zolpidem is a highly effective drug for the treatment of patients with insomnia of inorganic nature, has good tolerance and is recommended for use in medical practice for sleep disorders of inorganic nature as a hypnotic agent.

Table 1 Name of ingredient The ratio of components, parts by weight per 1 part by weight active substance Example 1 Example 2 Example 3 Targeted Supplements Ludipress 7,900 7,100 8,680 Aerosil 0,020 0.018 0,022 Stearic acid salt 0,090 0,081 0,099 Shell Hydroxypropyl methylcellulose 0.143 0.128 0.157 Propylene glycol 0,040 0,036 0,044 Talc 0.125 0,112 0.137 Titanium dioxide 0.141 0,126 0.158 Dye 0.0015 0.0010 0.0020

table 2 Name of quality indicator Quality Standards Actual figures Example 1 Example 2 Example 3 Average weight, g 0.0945 ± 7.5%, i.e. from 0.087 to 0.102 0,094 0,092 0,098 The deviation in the mass of individual tablets from the average weight,% ± 10% (allowed for two
tablets ± 20%) -1.1 + 1.4 -1.9 + 1.1 -1.2 + 1.1 Disintegration, min No more than 15 7 6 10 Dissolution% At least 75 in 45 minutes 100.0 97.0 98.0 The content of zolpidem in 1 table., G 0.01 ± 7.5%, i.e. from 0.0092 to 0.0108 0,0100 0.0102 0.0097 The content of talc, aerosil and titanium dioxide No more than 4.0% 1.70 1.85 2,30 Foreign matter The amount of impurities
no more than 0.5%
0,03
0.02
0.05 any not more than 0.2 0.01 0.01 0,03

Claims (6)

1. A pharmaceutical composition having sleeping pills, comprising zolpidem and target additives as an active ingredient, characterized in that it contains a therapeutically effective amount of zolpidem hemitartrate, and as target additives it contains ludipress, aerosil and stearic acid salt in the following ratio of these additives parts by weight per 1 part by weight active substance: Ludipress 7,100-8,680 Aerosil 0.018-0.022 Stearic acid salt 0.081-0.099 2. The pharmaceutical composition according to claim 1, characterized in that as the salt of stearic acid, it contains magnesium and / or calcium salts. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it is made in the form of a solid dosage form. 4. The pharmaceutical composition according to claim 3, characterized in that it is made mainly in the form of a coated tablet. 5. The pharmaceutical composition according to claim 4, characterized in that the shell contains hydroxypropyl methylcellulose, propylene glycol, talc, titanium dioxide and dye in the following ratio of ingredients, parts by weight per 1 part by weight active substance: Hydroxypropyl methylcellulose 0.128-0.157 Propylene glycol 0,036-0,045 Talc 0,112-0,138 Titanium dioxide 0.126-0.158 Dye 0.001-0.002 6. The pharmaceutical composition according to claim 5, characterized in that as the dye it contains mainly indigo carmine, and / or acid red, and / or tropeolin.