RU2624229C2 - Clozapine tablets with delayed release and method of obtaining thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of chemical-pharmaceutical industry, namely to pharmaceutical composition in form of tableted form with delayed release, which contains 30-40 wt % of clozapine as active component and additional substances: 20-35 wt % of Methocel K100 LV, 10-15 wt % of Methocel K4M, 12-30 wt % of microcrystalline cellulose, 2-3 wt % of copovidone, 0.5-1 wt % of colloidal silicon dioxide and 0.5-1 wt % of pharmaceutically acceptable salt of stearic acid, as well as to method of obtaining said pharmaceutical composition.

EFFECT: group of the inventions provides obtaining clozapine tablets, possessing stability and reproducible kinetics of delayed release of active substance.

8 cl, 4 ex, 4 tbl, 3 dwg

Description

The invention relates to the pharmaceutical industry and relates to a group of antipsychotics.

Currently, mental health is one of the most serious problems facing all countries, since at least one in four people have such problems at one time or another. They account for 19.5% of all years of life lost as a result of disability. According to WHO, in the European Region alone, over 4 million people suffer from schizophrenia; approximately 4 million - with bipolar affective disorders and a little more - with panic disorders.

The treatment of mental patients, in particular patients with schizophrenia, is fraught with a number of difficulties, among which it should be noted the absence of a pronounced therapeutic effect of classical antipsychotics on negative symptoms, a rather high frequency of cases of resistance during their use and the presence of pronounced side effects. In recent years, many problems have been resolved through the introduction of so-called atypical antipsychotics into the practice of psychiatry.

One of the significant events in the history of antipsychotic drugs was the appearance of the atypical antipsychotic clozapine. A description of the first experience with clozapine was presented in 1966 by the Austrian psychiatrist H. Gross et al. Clozapine was historically the first representative of the class of so-called “atypical antipsychotics,” that is, antipsychotics that differ from the traditional ones by a low likelihood of extrapyramidal side effects, better tolerance and less impact on prolactin secretion. The mechanism of action of clozapine is somewhat different from the mechanism of action of many antipsychotics. These differences determine significant profile features of its psychotropic effects. The antipsychotic effect of clozapine is usually explained by its ability to block dopamine D2 and serotonin 5-HT2 receptors in the brain.

Currently, clozapine is used for the following diseases: Schizophrenia (including resistance to therapy with other antipsychotics or intolerance to them), manic states, manic-depressive psychosis, psychomotor agitation in psychopathies, emotional and behavioral disorders (including in children), severe sleep disorders (http://www.vidal.ru/drugs/molecule/259).

In clinical practice, the manufactured drug Lenopex (Leponex®), immediate release tablets in doses of 25 mg and 100 mg are used. The owner of the registration certificate for Lenopex (Leponex) is the company Novartis Pharmaceuticals UK Ltd. The active pharmaceutical substance is clozapine. Each risky tablet contains 25 mg or 100 mg of clozapine. Other ingredients are magnesium stearate, colloidal silicon dioxide, corn starch, talc, lactose monohydrate, povidone K30.

Found patent RU 2441651, which discloses clozapine tablets and a method for their preparation. The method consists in the fact that the previously obtained dry mixture of lactose, potato starch and clozapine is moistened with a 10% aqueous solution of Kollidon 25, wet granulation is carried out, drying at a temperature of 45-50 ° C. The granules obtained are subjected to dry granulation to obtain granules with an average diameter of 1.0-1.5 mm, dusted with aerosil and stearic acid and / or its salt. The resulting mixture is tabletted, while tablets with the following ratio of components, wt. %:

Clozapine 23-42 Lactose 47-52 Potato starch 10-20 Collidon 25 4-5 Aerosil 1-2 Stearic acid 1-2

As a rule, it is recommended to start taking clozapine with a dose of 12.5 mg once or twice a day with a gradual increase in dose from 25 mg to 50 mg per day, and with good tolerance to the drug, the planned dose from 300 mg to 450 mg per day is achieved (reception in divided doses) by the end of the second week. The maximum daily dose is 900 mg. The average terminal half-life of clozapine is 12 hours, so multiple doses of the drug are necessary to maintain a steady state. Thus, it is desirable to obtain a sustained release formulation.

Known international application WO 2006059194 (A2) - 2006-06-08 disclosing a sustained release formulation comprising clozapine, polyvinylpyrrolidone, polyethylene glycol, ethyl cellulose, talc, acetone, alcohol and water. By wet granulation, granules with the active substance are obtained, dried, coated, and loaded into capsules. The technology uses toxic solvents.

As the closest analogue, patent RU 2414903 (C1) - 2011-03-27, disclosing a sustained-release pharmaceutical composition for oral administration, including clozapine and as excipients hydroxypropylmethyl cellulose, microcrystalline cellulose, stearic acid salt, when the following ratio of ingredients, wt. %:

Clozapine 24.33-45.15 Silica modified microcrystalline cellulose 12.12-37.71 Hydroxypropyl methylcellulose 33.95-38.83 Stearic acid salt 1.00

The method of obtaining the mold consists in the fact that sieved hydroxypropyl methylcellulose, clozapine, a complex of microcrystalline cellulose (MCC) and silicon dioxide are loaded into the mixer for 7 ÷ 10 minutes at a rotational speed of the main mixer of 80 ÷ 100 rpm, sieved magnesium stearate is added and continued mixing for 2 ÷ 3 minutes, mix the tablet and transfer to the stage of tabletting. The tablet may be coated.

Object of the invention: the development of a method for the preparation and pharmaceutical composition of clozapine - sustained release tablets in the presence of stable technological properties and stability, as well as reproducible kinetics of release of the active substance.

The problem is solved by a new composition of the tablet form with a slow release of the active principle, containing the following components in mass. %:

Clozapine 30-40 Metocel (METHOCEL) K100 LV 20-35 Metocel (METHOCEL) K4M 10-15 Microcrystalline cellulose 12-30 Copovidone 2-3 Colloidal silicon dioxide 0.5-1 Pharmaceutically acceptable salt stearic acid 0.5-1

The target sustained release profile is at least 21 ± 2 hours.

As a pharmaceutically acceptable salt of stearic acid, magnesium stearate, calcium stearate, and a mixture thereof can be used.

Preferably, the weight ratio of Metocel K4M to Metocel K100 LV is 30:70.

The active pharmaceutical ingredient, namely clozapine (8-Chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo- [b, e] [1,4] diazepine), is capable of adhesion and exhibits poor mobility, which confirmed by compressibility factor. Low material mobility can produce tablets with increased variability in weight and content due to uneven distribution of the active substance in the mixture, uneven bulk density prior to compaction, and, as a result, uneven filling of the cavity of the tablet press matrix. In this regard, the selected production formula and process should provide good fluidity and compressibility in the finished mixture.

It has been found that wet granulation tends to have a potential effect on stability due to the influence of moisture and the likelihood of thermal decomposition of the drug substance during drying. For dry granulation by rolling, the powdered particles of the drug substance and excipients are combined under high pressure to form a tape, and before compression (tabletting) they are broken to form granules by grinding. It was also found that the risk of poor homogeneity of the composition of the tablet and the deviation of the mass of the tablets with clozapine can be reduced by monitoring the fractional composition and flow properties. Another object of the invention is a method for producing sustained-release clozapine tablets by rolling, preferably using a clozapine substance micronized with a particle size distribution of d90 <50 microns. In particular, the particle size distribution of particles with d90 <50 microns: d90-62.62 microns, d50-25.86 microns, d10-8.23 microns.

The method is characterized in that Clozapine, a combination of Metocel K4M and Metocel K100 LV, microcrystalline cellulose and copovidone are sieved together, mixed until homogeneous, magnesium stearate, colloidal silicon dioxide are added, mixed, the mixture is compacted by rolling, colloidal dioxide is added and mixed together with pre-compacted granules followed by the addition of a pharmaceutically acceptable salt of stearic acid, mixing and compressing the tablets.

The tablets are compressed in capsule form.

Preferably, mixing is carried out at a stirrer speed of 20 rpm. Any of the mixing steps is carried out until smooth, preferably within 3-6 minutes. At the rolling stage, a mesh of 1.6 mm for preliminary granulation and 0.63 mm for fine granulation can be used, and the process is preferably carried out at a hydraulic pressure of 90 bar.

The proposed method provides particularly good fluidity and compressibility in the finished mixture when using certain auxiliary components according to the proposed composition.

The possibility of carrying out the invention is demonstrated by the following examples.

Example 1

Example 2

Example 3

Production method

1. Screening of intragranular components

Clozapine substance, a combination of Metocel K4M and Metocel K100 LV, Avicel pH 102 and Collidon VA64 were sieved together through an ASTM # 30 sieve.

Colloidal silica was sieved through an ASTM # 20 sieve. Magnesium stearate was sieved through an ASTM # 60 sieve.

2. Mixing (preliminary compacting):

The sieved excipients were mixed in a mixer. The mixing time was 6 minutes at 20 rpm.

Sifted Magnesium Stearate was added to the previous phase and mixed again. The mixing time was 3 minutes at 20 rpm.

3. Compaction (compaction) by rolling

The above mixture was placed in a roller press (Alexanderwerk WP120) equipped with 25 mm rollers. The press was put into operation according to the parameters below, a mesh of 1.6 mm was used for preliminary granulation and 0.63 mm for fine granulation.

4. Screening of extragranular excipients:

Aerosil was sieved through an ASTM # 20 sieve

Magnesium stearate was sieved through an ASTM # 60 sieve

5. Mixing (pre-lubrication)

Sieved Aerosil was placed in a 1 L mixer with pre-compacted granules. The mixing time was 4 minutes at 20 rpm.

Sifted magnesium stearate was placed in the above mixer.

The mixer was put into operation for 2 minutes at 20 rpm.

6. Pressing

The plasticized mixture is placed in a tablet press with punches of type D (2 stations are used), pressed according to the following parameters:

Bulk density (g / ml) 0.516 Density after compaction (g / ml) 0.727 Carra Index (%) 29.03 Hausner Ratio 1.41

Compression of the compositions, as in the case of example 1, and in the case of example 2 was uniform, with a minimum deviation from the set parameters (less than 0.31% in contrast to the prototype with 0.96%).

The average strength is 20.63 Kp.

Example 4

The study of the kinetics and stability of tablets

Previous results showed that the use of hydroxypropyl methylcellulose of the same brand, with one viscosity, for example as in the prototype or, for example, one of the K4M or K100 LV metocels, shows either a too fast or too slow dissolution and absorption profile of the active substance (see Fig. 1- 3). It was found that the combination of both K4M and K100 LV polymers gives better stability and reproducible release kinetics of the active substance, especially in combination with copovidone. The purpose of the series of experiments was to produce a series of sustained-release (CI) clozapine tablets by rolling using a polymer combination of Metocel K4M and K100 LV in a ratio of 30:70. The series differed in the concentration of active substance and polymer in each tablet. The tablets were packed in aluminum foil blisters ('Alu-Alu') and placed in a climatic chamber for 6 months under conditions of accelerated and long-term (“real time”) tests. The impurity content was determined by HPLC using standards.

Thus, the proposed composition has advantages in terms of stability.

When tested in dogs, the drug showed the necessary delayed action, the maximum concentration of clozapine in blood plasma is achieved gradually and not earlier than after 4 hours and is maintained for more than 23 hours. The relative bioavailability amounted to more than 50% of the composition of the immediate release with an equivalent daily dose against a background of two doses per day.

The drug can be widely used in clinical practice as an antipsychotic drug, in particular, for schizophrenia, delusional delusions (delusions, visions that acquire the character of reality), manic syndrome (inadequately elevated mood, accelerated pace of thinking, psychomotor agitation), deterioration of mood and other psychopathic diseases.

Claims (9)

1. A pharmaceutical composition in the form of a sustained release tablet form containing clozapine as an active ingredient and excipients, characterized in that as excipients it contains a mixture of Metocel K100 LV and Metocel K4M, microcrystalline cellulose, copovidone, colloidal silicon dioxide and a pharmaceutically acceptable salt of stearic acid in the following content, wt.%: Clozapine 30-40 Metocel K100 LV 20-35 Metocel K4M 10-15 Microcrystalline cellulose 12-30 Copovidone 2-3 Colloidal silicon dioxide 0.5-1 pharmaceutically acceptable salt stearic acid 0.5-1 2. The composition according to p. 1, characterized in that it contains clozapine micronized with a particle size distribution of d90 <50 microns. 3. The composition according to p. 1 or 2, where the mass ratio of Metocel K4M and Metocel K100 LV is 30:70. 4. A method of obtaining a pharmaceutical composition in the form of a sustained release tablet form according to claim 1, characterized in that clozapine, a combination of Metocel K4M and Metocel K100 LV, microcrystalline cellulose and copovidone are sieved together, mixed until homogeneous, magnesium stearate, colloidal silicon dioxide are added mix, mix the mixture by rolling, add colloidal dioxide and mix together with pre-compacted granules, followed by the addition of magnesium stearate, stirring and pressing iem tablets. 5. The method according to p. 4, characterized in that the mixing is carried out at a stirrer speed of 20 rpm 6. The method according to p. 5, characterized in that any of the stages of mixing is carried out for 3-6 minutes. 7. The method according to claim 4, characterized in that at the rolling stage, a mesh of 1.6 mm was used for preliminary granulation and 0.63 mm for fine granulation, and the process is carried out at a hydraulic pressure of 90 bar. 8. The method according to p. 4, characterized in that the tablets are pressed in capsule form.

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