EA035980B1 - Clozapine tablet with sustained release and method for manufacturing same - Google Patents

Abstract

The invention relates to the chemical pharmaceutical industry and concerns neuroleptic class drugs. A pharmaceutical formulation in tablet form with sustained release contains clozapine as the active ingredient and, as excipients, a mixture of hydroxypropyl methylcellulose Metocel K 100 LV and hydroxypropyl methylcellulose Metocel K4M, microcrystalline cellulose, copovidone, colloidal silicon dioxide and a stearic acid pharmaceutically acceptable salt. A method for producing the tablet form is based on a roller compaction method. The invention provides for the manufacture of a stable pharmaceutical clozapine formulation in tablet form with sustained release, with stable handling characteristics and reproducible release kinetics for the active ingredient.

Description

The invention relates to the pharmaceutical industry and relates to the means of the group of neuroleptics.

Mental health is currently one of the most serious problems facing all countries, since at one time or another in life, such problems arise in at least one in four people. They account for 19.5% of all life years lost as a result of disability. According to WHO, in the European Region alone, over 4 million people suffer from schizophrenia; roughly 4 million with bipolar disorder and slightly more with panic disorder.

Treatment of mental patients, in particular patients with schizophrenia, is associated 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 antipsychotics was the emergence of the atypical antipsychotic drug clozapine. Description of the first experience of using clozapine was presented in the source [Gross H., Langner B. // Wien Med Wochenschr. 1966. Vol. 116, pp. 814-816]. Clozapine was historically the first member of the class of so-called atypical antipsychotics, i.e. antipsychotics, which differ from the traditional ones in the low probability of extrapyramidal side effects, better tolerance and less influence on the secretion of prolactin. The mechanism of action of clozapine is somewhat different from that of many antipsychotics. These differences determine significant features of the profile of its psychotropic effects. The antipsychotic effect of clozapine is usually attributed to its ability to block the dopamine 1) 2- and serotonin 5-HT2 receptors in the brain.

Currently, clozapine is used for the following diseases: schizophrenia (including with resistance to therapy with other neuroleptics 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® is used, immediate-release tablets in doses of 25 and 100 mg, the holder of the marketing authorization for which is Novartis Pharmaceuticals UK Ltd. Clozapine is the active pharmaceutical ingredient. Each scored tablet contains 25 or 100 mg of clozapine, and as excipients - magnesium stearate, colloidal silicon dioxide, corn starch, talc, lactose monohydrate, povidone K30.

It is generally recommended to start taking clozapine with a dose of 12.5 mg once or twice a day with a gradual increase in the dose from 25 to 50 mg per day, and if the drug is well tolerated, the planned dose of 300 to 450 mg per day is achieved (taken separately doses) by the end of the second week. The maximum daily dose is 900 mg. The mean terminal half-life of clozapine is 12 hours, so multiple doses are required to maintain steady state. Thus, it is desirable to prepare and use a sustained release formulation of clozapine.

From the prior art [patent RU 2441651 C1, publ. 02/10/2012] known 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 and drying are carried out at a temperature of 45-50 ° C. The resulting granules are subjected to dry granulation to obtain granules with an average diameter of 1.0-1.5 mm, dusting with aerosil and stearic acid and / or its salt. The resulting mixture is tableted to obtain tablets with the following ratio of components, wt%:

Clozapine 23-42 Lactose 47-52 Potato starch 10-20 Kollidon 25 4-5 Aerosil 1-2 Stearic acid 12.

This source solves the problem of increasing the bioavailability of clozapine. However, these clozapine tablets are not a sustained release formulation.

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 the dose from 25 to 50 mg per day, and if the drug is well tolerated, the planned dose of 300 to 450 mg per day is achieved (taken in divided doses ) by the end of the second week. The maximum daily dose is 900 mg. The mean terminal half-life of clozapine is

- 1,035,980 hours, therefore, to maintain a steady state, multiple administration of the drug is required.

Thus, it is desirable to obtain a sustained release formulation.

From the prior art [international application WO 2006059194 A2, publ. 06/08/2006] known composition with a delayed release containing clozapine, polyvinylpyrrolidone, polyethylene glycol, ethylcellulose, talc, acetone, alcohol and water. The active substance granules are obtained by wet granulation, dried, coated and loaded into capsules. The disadvantage of this composition is the use of toxic solvents in the technology of its production.

Patent RU 2414903 [publ. 03/27/2011], disclosing a pharmaceutical composition of prolonged action for oral administration, including clozapine as an active ingredient and hydroxypropyl methylcellulose, microcrystalline cellulose, stearic acid salt as an active ingredient, with the following ratio of ingredients, wt%:

Clozapine 24.33-45.15

Silicon dioxide modified microcrystalline cellulose 12.12-37.71

Hydroxypropyl methylcellulose 33.95-38.83

Stearic acid salt 1.00.

The tablets can be coated with a coating comprising polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, and suitable colorants. The method of obtaining the mold consists in the fact that sifted hydroxypropyl methylcellulose, clozapine, a complex of microcrystalline cellulose (MCC) and silicon dioxide are loaded into the mixer, stirred for 7-10 minutes at a rotation speed of the main stirrer of 80-100 rpm, sifted magnesium stearate is added and continue mixing for 2-3 minutes, mix and transfer to the tableting stage.

As disadvantages, we can note the absence in the specified source of a sufficient number of experiments to study the pharmacokinetics of the specified composition of clozapine, which does not allow assessing the reproducibility of the kinetics of the release of the active substance, as well as the lack of data on studying the stability of the specified dosage form.

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

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 kinetics of the release of the active substance.

The problem is solved, and the technical result is achieved by a new composition of the tablet form with a sustained release of the active principle, containing the following components, wt%:

Clozapine 30-40

Methocel (METHOCEL) K 100 LV20-35

Methocel (METHOCEL) K4M10-15

Microcrystalline cellulose 12-30

Copovidone2-3

Colloidal silicon dioxide 0.5-1

Pharmaceutically acceptable stearic acid salt 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, or their mixture 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, as evidenced by the coefficient compressibility. Low mobility of the material can give tablets with increased variability in weight and content due to uneven distribution of the active substance in the mixture, uneven bulk density before compaction and, as a result, uneven filling of the die cavity of the tablet press. In this regard, the selected manufacturing formula and process must 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 effects of moisture and the potential for thermal degradation of the drug.

- 2,035980th substance during drying. For dry roller granulation, powdered drug particles and excipients are combined under high pressure to form a ribbon, and are crushed to form granules by grinding prior to compression (tableting). We also found that the risk of unsatisfactory tablet composition uniformity and the deviation of clozapine tablet weight can be reduced by controlling the fractional composition and flow properties. Another object of the invention is a method of producing slow-release clozapine tablets by the rolling method, preferably using a clozapine substance micronized with a particle size distribution of d90 <50 μm. In particular, the particle size distribution of particles with d90 <50 μm: d90 - 62.62 μm, d50 - 25.86 μm, d10 - 8.23 μm.

The method is characterized in that clozapine, a combination of Metocel K4M and Metocel K 100 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 stearic acid salt, mixing and compression of the tablets.

The tablets are compressed into capsule form.

Preferably, stirring is carried out at a stirrer speed of 20 rpm. Any of the mixing steps is carried out until uniform, preferably within 3-6 minutes. In the rolling step, a mesh of 1.6 mm for pre-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 proposed method provides especially 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 examples presented below. Example 1.

P/ P G *? Chi > Ingredients • ΑΪ '·· ... Postav CHIK Mg / tab l % content outside Number of tablets equivalent about 100 mg Overall volume (d) ,. 23333 700Λ ‘. Intragranular components 1 Clozapine (lot 050914) (d90 <50 microns). Nobilus / Nobilus 100.00 33.33 233.33 1' 2 Metocel K4M Premium CR Colorcon / Colorcon 30.00 10.00 70.00 r 3 Metocel K100 LV Colorcon / Premium CR Colorkon 70.00 23.33 163.33g 4 Microcrystalline KPM cellulose (Avicel Biopolymer pH 102) / 87.40 29.13 203.93g five Copovidone (KollidonUA 64) BASF 7.50 2.50 17.50 6 Colloidal Silicon Dioxide (Aerosil 200 Pharma) USP / NF * Evonik 'Evonik 1.20 0.40 2.80g " 7 Magnesium stearate NF / NF / Macron / Macron 1.50 0.50 3.50 g Extragranular components 8 Colloidal Silicon Dioxide (Aerosil 200 Pharma) USP / NF * Evonik / Evonik 0.90 0.30 2.10 r nine Mai stearate NF ZNF / Macron / Macron 1.50 0.50 3.50 r Tablet weight / plasticized mixture 300.00 100.0 700.0 r

- 3 035980

Example 2.

-. - ·> ... 1 * v2 and iV * '‘’ Ingredients The supplier Mg / gab l. U ' % content nre ' AND Number of tablets equivalent about 100 mg General • · batch size (g) 23333 700.0 .: Intragranular components - 1 Clozapine (lot 050914) (d90 <90 microns). Nobilus / Nobilus 100.00 33.33 233.33 2 Metocel K4M Premium CR Coiorcon / Colorcon 45.00 15.00 105.00 r 3 Metocel K100 LV Premium CR Coiorcon / Colorcon 105.00 35.00 245.00g 4 Microcrystalline cellulose (Avicel pH 102) KPM Biopolymer / 37.40 12.47 87.27g five KollidonUA 64 BASF 7.50 2.50 17.50g 6 7 Colloidal silicon dioxide (Aerosil 200 Pharma) LSP / NF * Magnesium stearate NF / NF / Evonik / Evonik Macron / Macron 1.20 1.50 1 0.40 0.50 2.80g 3.50 Extragranular components 8 Colloidal Silicon Dioxide (Aerosil 200 Pharma) USP / NF * Evonik / Evonik 0.90 0.30 2.10 nine Mai nia stearate NF / NF / Macron 'Macron 1.50 0.50 3.50 Weight of tablet / last-fired 'U ·. · _____ mixture __________ joo 100.0 700.0 ' r

Example 3. Method of obtaining.

1. Screening of intragranular components.

Clozapine substance, a combination of Metocel K4M and Metocel K 100 LV, Avicel pH 102 and Kollidon VA64 were sieved 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 stirring time was 6 minutes at 20 rpm.

The sifted magnesium stearate was added to the previous phase and mixed again. The stirring time was 3 minutes at 20 rpm.

3. Compaction (compacting) by rolling.

The above mixture was placed in a roller press (Alexanderwerk WP120 equipped with 25 mm rollers. The press was started up according to the parameters below, using a mesh of 1.6 mm for pre-granulation and 0.63 mm for fine granulation.

4. Sifting extragranular auxiliary substances.

Aerosil was sieved through an ASTM # 20 sieve.

Magnesium stearate was sieved through an ASTM # 60 sieve.

5. Mixing (pre-lubrication).

A sieved Aerosil was placed in a mixer with a capacity of 1 L together with pre-compacted granules. The stirring time was 4 minutes at 20 rpm. The sifted magnesium stearate was placed in the aforementioned mixer. The mixer was run for 2 minutes at 20 rpm.

6. Pressing.

The plasticized mixture is placed in a tablet press with D-type punches (2

- 4 035980 stations), pressed according to the following parameters:

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

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

Average strength value is 20.63 Cr.

Example 4. Study of the kinetics and stability of tablets.

Previously obtained 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 methocel K4M or K 100 LV, demonstrates either too fast or too slow dissolution and absorption profile of the active substance (see. Fig. 1-3). We have found that the combination of polymers K4M and K100 LV gives higher results of stability and reproducible kinetics of the release of the active substance, especially in combination with copovidone.

The purpose of a series of experiments is to produce a series of slow-release clozapine (S) tablets by the rolling method using a polymer combination of Metocel K4M and K 100 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 (A1i-A1i) and placed in a climatic chamber for 6 months under the conditions of accelerated and long-term (real-time) tests.

The impurity content was determined by HPLC using standards. The results are presented in the table.

condition Initial / after 6 months of accelerated aging Peak name OVU OVU according to Heb. F prototype Example 2 Example 1 Impurity C * 0.92 0.90 0.03 / ^0.24? '0.03 / 0.1 0.03 / 0.12 Impurity D ** 1.11 1.10 0.03 / 0.2 - / 0.06 0.01 / 0.04 Impurity A ** ¹ 1.56 1.60 - / 0.14 -0.08 - / 0.1 Impurity B *** 1.63 1.70 • / 0.18 ’- / 0.03 - / 0.02 Unknown substance 1 1.15 - 0.01 / 0.03, 0.01 / 0.03 0.01 / 0.03 ' Unknown substance 2 1.64 - 0.01 / 0.1 0.01 / 0.08 0.01 / 0.06 Unknown substance 3 '2.12 - 0.01 / 0.05 0.01 / 0.03 0.01 / 0.03 Water content (by KF) 4.02% 3.64% 3.48% |

* Impurity A 8-chloro-11- (piperazin-1-yl) -5H-dibenzo [b, e] [1,4] diazepine.

* * Impurity B 4-chloro-1- (2 - ((4-methylpiperazin-1-yl) carbonyl) phenyl) benzene-1,2-diamine.

* ** Impurity C 8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11-one.

* *** Impurity D PD (piperazine DD-diyl ^ is ^ -chloro (H-dibenzo ^ e ^^ diazepine).

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

In a study on 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 was more than 50% of the immediate release composition with an equivalent daily dose against the background of a double dose per day.

Claims (8)

CLAIM 1. A pharmaceutical composition in the form of a sustained-release tablet form containing clozapine as an active component and excipients, characterized in that as excipients it contains a mixture of Metocel K 100 LV hydroxypropyl methylcellulose and Metocel K4M hydroxypropyl methylcellulose, microcrystalline cellulose, copovidone, colloidal silicon dioxide and a pharmaceutically acceptable salt of stearic acid at the following content, wt%: - 5 035980 clozapine - 30-40, hydroxypropyl methylcellulose Metocel K 100 LV - 20-35, hydroxypropyl methylcellulose Metocel K4M - 10-15, microcrystalline cellulose - 12-30, copovidone - 2-3, colloidal silicon dioxide - 0.5-1, pharmaceutically acceptable salt of stearic acid - 0.5-1. 2. Composition according to claim 1, characterized in that it contains micronized clozapine with a particle size distribution d90 <50 μm. 3. Composition according to claim 1 or 2, where the mass ratio of Metocel K4M hydroxypropyl methylcellulose and Metocel K100 LV hydroxypropyl methylcellulose 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 hydroxypropyl methylcellulose and Metocel K 100 LV hydroxypropyl methylcellulose, microcrystalline cellulose and copovidone are sieved together, mixed until homogeneous, magnesium stearate is added, colloidal silicon dioxide, mix, the mixture is compacted by rolling, add colloidal silicon dioxide and mix together with the pre-compacted granules, followed by the addition of magnesium stearate, mixing and pressing the tablets. 5. A method according to claim 4, characterized in that stirring is carried out at a stirrer speed of 20 rpm. 6. The method according to claim 5, characterized in that any of the mixing steps is carried out within 3-6 minutes. 7. The method according to claim 4, characterized in that at the stage of rolling, a mesh of 1.6 mm for preliminary granulation and 0.63 mm for fine granulation was used, and the process is carried out at a hydraulic pressure of 9 × 10 ⁶ Pa. 8. The method of claim 4, wherein the finished dosage form is a tablet.