RU2613192C1 - Tablets of clozapine with sustained release - Google Patents

Abstract

FIELD: pharmacy.

SUBSTANCE: group of inventions relates to a pharmaceutical formulation of clozapine with sustained release in the form of tablets, film coated, containing 30.0-50.0 wt % of clozapine, 20.0-30.0 wt % of microcrystalline cellulose, 4.0-6.0 wt % of lactose monohydrate, 15.0-25.0 wt % of hydroxypropyl methylcellulose HPMC K15M, 1.0-3.0 wt % of hydroxypropyl methylcellulose HPMC 2910, 1.0-3.0 wt % of colloidal silicon dioxide, 0.05-1.5 wt % of pharmaceutically acceptable salts of stearic acid and 2.0-4.0 wt % of film coating which comprises polyvinyl alcohol, titanium dioxide, macrogol and acceptable dyes or a mixture Opadry II yellow; as well as to a process for preparing such a pharmaceutical composition.

EFFECT: obtaining a stable pharmaceutical composition of clozapine in the form of tablets with sustained release and stable technological properties, as well as reproducible release kinetics of the active substance.

9 cl, 5 ex, 1 tbl, 2 dwg

Description

The invention relates to the field of 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 by introducing into the practice of psychiatry the so-called atypical antipsychotics.

One of the significant events in the history of antipsychotic drugs was the appearance of an atypical antipsychotic - clozapine. A description of the first experience with clozapine was presented in [Gross H, Langner E. Effect profile of a chemically new broad spectrum neuroleptic of the dibenzo-diazepine group / Wien Med Wochenschr. - 1966. - Vol. 116. - pp. 814-816]. 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 effect 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 their intolerance), 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 Leponex (Leponex®) is used, immediate release tablets in doses of 25 mg and 100 mg, the owner of the registration certificate for which is Novartis Pharmaceuticals UK Ltd. The active pharmaceutical substance is clozapine. Each tablet with a risk contains 25 mg or 100 mg of clozapine as an active agent, and as adjuvants magnesium stearate, colloidal silicon dioxide, corn starch, talc, lactose monohydrate, povidone K30.

Reception of clozapine, as a rule, is recommended to start 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 ( 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 and apply a sustained release clozapine formulation.

The prior art [patent RU No. 2441651 C1, publ. 02/10/2012] known clozapine 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

The method of their preparation is that a previously prepared 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 obtained granules 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. The indicated source solves the problem of increasing the bioavailability of clozapine.

However, these clozapine tablets are not a sustained release formulation.

The prior art also known composition of sustained release clozapine containing clozapine, polyvinylpyrrolidone, polyethylene glycol, ethyl cellulose, talc, acetone, alcohol and water [patent application WO No. 2006059194 A2, publ. 06/08/2006]. By wet granulation, granules with the active substance are obtained, dried, coated, and loaded into capsules.

The disadvantage of this composition is the use of toxic solvents in the technology for its preparation.

The closest analogue of the present invention is [patent RU No. 2414903 C1, publ. 03/27/2011] prolonged-release pharmaceutical composition for oral administration, including clozapine and excipients as hydroxypropylmethyl cellulose, microcrystalline cellulose, stearic acid salt in the following ratio, 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 tablets may be coated with a polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable colorants. The method for producing such a composition is characterized in that sifted hydroxypropyl methylcellulose, clozapine, a complex of microcrystalline cellulose and silicon dioxide are loaded into the mixer, stirred for 7-10 minutes at a rotational speed of the main mixer of 80-100 rpm, added sieved magnesium stearate and continue to mix in for 2-3 minutes, the tablet mass is discharged from the mixer and transferred to the tabletting stage.

The disadvantages include the lack of a sufficient number of experiments on the pharmacokinetics of the specified clozapine composition in the indicated source, which does not allow us to assess the reproducibility of the kinetics of the release of the active substance, as well as the lack of data on the stability of the indicated dosage form.

The technical result of the present invention is to obtain a stable pharmaceutical composition of clozapine in the form of sustained release tablets with stable technological properties, as well as reproducible release kinetics of the active substance.

The technical result is achieved by the new pharmaceutical composition of clozapine with delayed release in the form of a tablet, film-coated, containing the following components, wt.%:

Clozapine 30.0-50.0 Microcrystalline cellulose 20.0-30.0 Lactose Monohydrate 4.0-6.0 Hydroxypropyl methylcellulose GPMC K15M 15.0-25.0 Hydroxypropyl methylcellulose GPMC 2910 1.0-3.0 Colloidal silicon dioxide 1.0-3.0 Pharmaceutically acceptable salt stearic acid 0.05-1.5 Film sheath 2.0-4.0

The film coating includes polyvinyl alcohol (e.g., 1.0-2.0 wt.% By weight of the tablet), titanium dioxide (e.g., 0.5-1.0 wt.% By weight of the tablet), macrogol (e.g., 0.5 -1.0 wt.% By weight of the tablet), acceptable colorants (for example, aluminum quinoline yellow varnish and iron oxide red in an amount of 0.05-1.0 wt.% By weight of the tablet) or Opadry II yellow mixture.

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

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

The active pharmaceutical ingredient, namely clozapine, is capable of adhesion and exhibits poor mobility, as evidenced by the 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.

We have 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 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 unsatisfactory uniformity 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 d 90 <50 microns: d 90-62.62 microns, d 50-25.86 microns, d 10-8.23 microns.

The method for preparing the pharmaceutical composition of sustained-release clozapine in the form of a tablet is characterized in that clozapine, microcrystalline cellulose, lactose monohydrate and a combination of HPMC K15M hydroxypropyl methylcellulose and HPMC 2910 hydroxypropylmethyl cellulose are sieved together, mixed until homogeneous, pharmaceutically acceptable silica , the mixture is compacted by rolling, colloidal silicon dioxide is added and mixed together with the precursor but compacted granules, followed by addition of pharmaceutically acceptable salts of stearic acid, mixing, compressing tablets and applying film coating to the tablet.

Stirring is preferably 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 in size for preliminary granulation and 0.63 mm for fine granulation can be used. The process is preferably carried out at a hydraulic pressure of 90 bar.

The film coating step is preferably carried out on a BGB-10 apparatus in the presence of an aqueous suspension containing the components of the shell in accordance with the proposed composition.

The presence of a film membrane ensures the stability of the proposed dosage form during storage (at least 2-3 years), and also improves its appearance and organoleptic properties.

The proposed method provides good fluidity and compressibility in the finished mixture through the use of a combination of certain auxiliary components according to the proposed composition.

The present invention can be illustrated by the following examples:

Examples 1-3 show pharmaceutical compositions of clozapine according to the present invention.

Example 1

Example 2

Example 3

The method of obtaining pharmaceutical compositions in accordance with examples 1-3 includes:

1. Screening of intragranular components. Clozapine substance, microcrystalline cellulose, lactose monohydrate, a combination of HPMC K15M and HPMC 2910 were sieved together through an ASTM # 30 sieve. Colloidal silicon dioxide was sieved through an ASTM # 20 sieve. Magnesium stearate was sieved through an ASTM # 60 sieve.

2. Mixing (preliminary compaction). 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. Colloidal silica was sieved through an ASTM # 20 sieve. Magnesium stearate was sieved through an ASTM # 60 sieve.

5. Mixing (preliminary lubrication). Sifted colloidal silicon dioxide was placed in a 1 L mixer with pre-compacted granules. The mixing time was 4 minutes at 20 rpm. The sieved 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 0.516 g / ml; density after compaction 0.727 g / ml; Carr index 29.03%; Hausner ratio 1.41. Compression of the compositions according to examples 1-3 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 Cr.

7. Application of a film coating. The film coating was carried out on a BGB-10 apparatus in the presence of an aqueous suspension containing the components of the membrane in accordance with the proposed composition.

Example 4. The study of the stability of clozapine tablets according to the claimed invention

Clozapine tablets, obtained in accordance with examples 1-3 and in accordance with the prototype, were packed in aluminum foil blisters ('Alu-Alu') and placed in a climatic chamber for 6 months under accelerated and long-term conditions (“in real time” ) tests. The impurity content was determined by HPLC using standards. The results are presented in table 1.

The data obtained showed that the clozapine formulations proposed in the claimed invention, which differ in the concentration of the active substance and auxiliary ingredients, have almost equal stability indicators and are more stable compared to the prototype.

Example 5. The study of the kinetics of the release of tablets of clozapine according to the claimed invention

When tested on dogs, the claimed clozapine formulations showed the necessary delayed action, the maximum concentration of clozapine in blood plasma is achieved gradually and not earlier than after 8-10 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.

It was found that the use of a combination of HPMC K15M and HPMC 2910 in clozapine tablets provides higher stability and reproducible kinetics of release of the active substance, the maximum concentration of clozapine in blood plasma is achieved gradually and not earlier than after 8-10 hours and is maintained for more than 23 hours (Fig. . 1), while the use of one of the HPMC K15M or HPMC 2910 demonstrates either a too fast or too slow dissolution and absorption profile of the active substance (Fig. 2). It is worth noting that the pharmaceutical compositions of clozapine according to the prototype ensure that the maximum concentration of clozapine in the blood is achieved after 6 hours, while the compositions of the present invention after 8-10 hours.

Claims (11)

1. The pharmaceutical composition of sustained release clozapine in the form of a film-coated tablet containing the following components, wt.%: Clozapine 30.0-50.0 Microcrystalline cellulose 20.0-30.0 Lactose Monohydrate 4.0-6.0 Hydroxypropyl methylcellulose GPMC K15M 15.0-25.0 Hydroxypropyl methylcellulose GPMC 2910 1.0-3.0 Colloidal silicon dioxide 1.0-3.0 Pharmaceutically acceptable salt stearic acid 0.05-1.5 Film sheath 2.0-4.0, wherein the film coating comprises polyvinyl alcohol, titanium dioxide, macrogol and acceptable colorants or a mixture of Opadry II yellow. 2. The pharmaceutical composition of clozapine under item 1, characterized in that the amount of polyvinyl alcohol is 1.0-2.0 wt.% By weight of the tablet, the amount of titanium dioxide is 0.5-1.0 wt.% By weight of the tablet, the amount of macrogol is 0.5-1.0 wt.% by weight of the tablet, and the amount of acceptable dyes is 0.05-1.0 wt.% by weight of the tablet. 3. The pharmaceutical composition of clozapine in paragraphs. 1 and 2, characterized in that the acceptable dyes are aluminum quinoline yellow varnish and iron oxide red. 4. The pharmaceutical composition of clozapine under item 1, characterized in that the film shell includes Opadry II yellow in an amount of 2.0-4.0 wt.% By weight of the tablet. 5. The pharmaceutical composition of clozapine according to claim 1, characterized in that magnesium stearate, calcium stearate or a mixture thereof are used as a pharmaceutically acceptable salt of stearic acid. 6. A method for producing the sustained release pharmaceutical composition of clozapine in the form of a tablet according to claim 1, characterized in that clozapine, microcrystalline cellulose, lactose monohydrate and a combination of hydroxypropyl methyl cellulose HPMC K15M and hydroxypropyl methyl cellulose HPMC 2910 are sieved together, the pharmaceutically uniformity is mixed, and the uniformity is added; acids and colloidal silicon dioxide are mixed, the mixture is compacted by rolling, colloidal silicon dioxide is added and mixed together with digested pellets, followed by the addition of a pharmaceutically acceptable salt of stearic acid, stirring, compressing the tablets and applying a film coating to the tablets. 7. The method according to p. 6, characterized in that the mixing is carried out at a stirrer speed of 20 rpm 8. The method according to p. 6, characterized in that any of the stages of mixing is carried out for 3-6 minutes. 9. The method according to p. 6, characterized in that at the rolling stage, a mesh of 1.6 mm for preliminary granulation and a mesh of 0.63 mm for fine granulation were used, and the process is carried out at a hydraulic pressure of 90 bar.

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