RU2517216C2 - Pharmaceutical composition of imatinib or its pharmaceutically acceptable salt, method for preparing it and method(s) of treating - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmaceutics, namely to a pharmaceutical composition (a solid oral dosage form (a tablet or a capsule)) of tyrosine kinase Bcr-Abl inhibitor - imatinib(4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl)-pyrimidin-2-ylamino)phenyl]benzamide). The pharmaceutical composition contains 25-45 wt % of imatinib, preferentially imatinib mesylate, more preferentially an α-crystalline form of imatinib mesylate, a binding agent representing povidone, and at least two desintegrant representing low-substituted hydroxypropyl cellulose and sodium carboxymethyl starch.

EFFECT: invention provides the min 80% imatinib release from the tablet for 15 minutes after oral administration and enables extending the range of drugs used for leukaemia.

14 cl, 4 dwg, 3 tbl, 2 ex

Description

The invention relates to a new pharmaceutical composition (solid oral dosage unit form, preferably a tablet or capsule) of compound (I)

or a pharmaceutically acceptable acid addition salt thereof (such as mesylate (methanesulfonate)), as well as a method for preparing such a pharmaceutical composition and methods of treatment.

Compound (I) (international nonproprietary name: imatinib, chemical name: (4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridin-3-yl) -pyrimidine-2- ilamino) phenyl] benzamide), STI571), disclosed as a base in the patent [1] (as well as in the corresponding Russian patent [2]) and in the publication [3], is an inhibitor of the receptor protein tyrosine kinase that effectively inhibits Bcr- tyrosine kinases Abl, c-Abl at the cellular level both in vitro and in vivo.

The action of imatinib is based on the blocking of the tyrosine kinase sites responsible for binding to ATP, which leads to impaired signal transmission and stops the proliferation or induction of apoptosis in cells expressing Bcr-Abl tyrosine kinase.

Imatinib selectively inhibits proliferation and induces apoptosis of Bcr-Abl positive cell lines, as well as young leukemia cells in patients with chronic myelogenous leukemia with Philadelphia positive chromosome and with acute lymphoblastic leukemia. In ex vivo colony transformation assays on peripheral blood and bone marrow samples, imatinib selectively inhibited Bcr-Abl-positive colonies in patients with chronic myelogenous leukemia.

The activity of imatinib and its pharmaceutically acceptable salts is shown in relation to chronic myeloid leukemia [4]; Philadelphia chromosome positive leukemia (Ph + leukemia) [5]; systemic mastocytosis (in patients with c-Kit D816V mutation) [6], [7]; CD117-positive inoperable and / or metastatic malignant stromal tumors of the gastrointestinal tract (GIST) [8], [9].

Imatinib is also an inhibitor of the tyrosine kinase receptor for platelet growth factor (PDGF) and stem cell factor (SCF), c-Kit (c-kit) and inhibits cellular responses mediated by these factors.

In the prior art, imatinib is known not only in the form of a base [1], [2], but also in the form of pharmaceutically acceptable salts - in particular, D (-) and L (+) - tartrate, succinate, malonate [10].

The PCT international publication [11] and the corresponding patent of the Russian Federation [12] disclose imatinib mesylate ((mono) methanesulfonate), as well as a number of crystalline forms of imatinib mesylate (in particular, the β-crystalline form);

wherein the β-form is characterized by physical and chemical properties that provide a particular advantage in the preparation of solid oral dosage forms of imatinib; in particular, the β-form of imatinib (or its pharmaceutically acceptable salt) is less hygroscopic, has more preferred flow characteristics and is thermodynamically stable at temperatures less than 140 ° C. The solubility of imatinib mesylate in water at a pH of less than 5.5 is> 1300 mg / ml.

Since Novartis AG has exclusive rights until 2018 to the β-crystalline form of imatinib mesylate, as well as to pharmaceutical compositions containing the β-crystalline form of imatinib mesylate [12] (based on this crystalline form of imatinib mesylate, in particular, the preparation Glivec ^®), a need exists for the development of generic oral dosage forms of imatinib (or a pharmaceutically acceptable acid addition salts thereof) on the basis of other crystalline and polymorphic forms of a given substance; a number of such crystalline and amorphous forms of imatinib and its pharmaceutically acceptable salts are disclosed in patent documents [13] - [22].

[23] a pharmaceutical composition for the sustained release of imatinib or a pharmaceutically acceptable salt (in particular mesylate) for oral use, including melamine-derived imatinib granules or any salt thereof and a release retardant in which said release retardant is known, is known [23] a polymer with a glass transition temperature below the melting temperature of imatinib mesylate and / or a non-polymer release retardant that melts at lower temperatures e compared with the melting point of imatinib or the salt of imatinib used;

as a release retardant, said pharmaceutical composition contains hydrogenated castor oil (non-polymer release retardant) or a polymer selected from water-insoluble, but water-swellable polymers based on cellulose (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose), acrylic (methacrylate polymers) , galactomannans, xanthan gum or mixtures thereof) and polyols.

The imatinib composition in accordance with the patent [23] provides the release of not more than 80% of the active substance within 1 hour and not less than 80% within 10 hours after administration (in another embodiment, not more than 80% of the active substance within 2 hours and not less than 80% within 8 hours after administration),

and also provides an average level of imatinib in the plasma of healthy people no more than 3.5 mcg / ml (2 hours after fasting or after a light breakfast).

In some cases, however, there is a need for immediate release pharmaceutical compositions capable of releasing high doses of imatinib within a short period of time after administration (15-20 minutes).

The prior art pharmaceutical composition (tablet) [24], proposed as the closest analogue of the present invention and containing a pharmacologically effective amount of imatinib or its pharmaceutically acceptable salt, in an amount of from about 30 to 80 wt.% (Preferably from 50 to 600 mg of imatinib or its salt, more preferably 100 to 400 mg, most preferably 100 or 400 mg of imatinib or its salt); said tablet contains at least one binder comprising microcrystalline cellulose, or hydroxypropyl methyl cellulose, or mixtures thereof.

Patent [24] also describes a method for producing an imatinib tablet or a pharmaceutically acceptable salt thereof, in which imatinib or a pharmaceutically acceptable salt thereof is mixed with pharmaceutically acceptable excipients, wet granulation is carried out, the granulate is mixed with pharmaceutically acceptable excipients to form a mixture, and the resulting a mixture to obtain a tablet; additionally, a tablet may be coated.

Despite the popularity of the pharmaceutical composition of imatinib in the prior art [24], there remains the challenge of expanding the range of preparations (solid dosage forms, especially tablets) of imatinib or its pharmaceutically acceptable salts (such as imatinib mesylate) containing high doses of active substances and capable of releasing imatinib within a short period of time after taking a solid dosage form (at least 80% of the active substance within 15 minutes after administration), not Tupa in its characteristics to the original drug (Gleevec ^®).

These solid dosage forms must be patent-free (not violate the exclusive rights of the imatinib pharmaceutical company or its pharmaceutically acceptable salts that belong to the developer of imatinib) and have a low production cost.

This problem was solved by the applicant in the framework of the present invention by developing the original composition of the pharmaceutical composition (tablets or capsules) of imatinib or its pharmaceutically acceptable salt containing a binder other than microcrystalline cellulose or hydroxypropyl methylcellulose, or mixtures thereof, and a combination of two disintegrants, where disintegrants include hyprolose (low substituted hydroxypropyl cellulose) and sodium carboxymethyl starch.

It should be emphasized that hydroxypropyl cellulose is indicated in the patent [23] among the possible inhibitors of the release of the active substance from the oral pharmaceutical composition of imatinib (see [23], p. 3 (last paragraph), p. 6, p. 12 (lines 20-25) )).

Brief Description of the Drawings

Figure 1. Dissolution profile of the original imatinib mesylate preparation (β-crystalline form) (Glivec ^® , coated tablets, NOVARTIS AG), dosage 100 mg.

Figure 2. Dissolution profile of the original preparation of imatinib mesylate (β-crystalline form) (Glivec ^® , coated tablets, NOVARTIS AG), dosage of 400 mg.

Figure 3. The dissolution profile of the drug imatinib mesylate (α-crystalline form) in accordance with the invention (coated tablets, ZAO Biocad), dosage 100 mg.

Figure 4. The dissolution profile of the drug imatinib mesylate (α-crystalline form) in accordance with the invention (coated tablets, ZAO Biocad), dosage 400 mg.

SUMMARY OF THE INVENTION

In the framework of the present invention, it was unexpectedly discovered that the use in the composition of a solid dosage form (tablet or capsule) of imatinib of hyprolysis (low substituted hydroxypropyl cellulose) and sodium carboxymethyl starch, on the one hand, and a binder other than microcrystalline cellulose, hydroxypropyl methyl cellulose or mixtures thereof, with another, allows you to create dosage forms that provide quick release of the active principle from the tablet (≥80% of the active substance within 15 minutes after administration Reparata).

The most preferred pharmaceutically acceptable salt of imatinib in accordance with the present invention is imatinib mesylate (monomethanesulfonate); the most preferred crystalline form of imatinib mesylate, in accordance with the invention, is the α-crystalline form of imatinib mesylate.

Thus, one of the objects claimed in accordance with the present invention is a coated tablet containing imatinib as an active substance.

or its pharmaceutically acceptable acid addition salt in an amount of from 25 to 45 wt.% (calculated on the basis of imatinib, in terms of the total weight of the solid dosage form),

and excipients

where the auxiliary substances include at least one binder other than hydroxypropyl methylcellulose, microcrystalline cellulose or mixtures thereof, and at least two disintegrants (disintegrants) other than cross-linked polyvinylpyrrolidone.

It has been experimentally found that the most preferred (although not limiting the scope of claims in accordance with the present invention) composition of a solid dosage form (tablets or capsules) of imatinib (or a pharmaceutically acceptable salt of imatinib, such as imatinib mesylate, in α-crystalline form) includes in itself:

25-45 weight% (wt%) of imatinib or a pharmaceutically acceptable salt thereof, such as imatinib mesylate (calculated on the basis of compound (I), based on the total weight of the pharmaceutical composition);

- 35-50 wt.% (In terms of the total weight of the pharmaceutical composition) of low substituted hydroxypropyl cellulose (hyprolose) (baking powder 1);

- 10-20 wt.% (In terms of the total weight of the pharmaceutical composition) Na-carboxymethyl starch (baking powder 2);

- 0.1-1.0 wt.% (In terms of the total weight of the pharmaceutical composition) of povidone (binder);

- 0.5-5.0 wt.% (In terms of the total weight of the pharmaceutical composition) of colloidal silicon dioxide (glidant, disintegrant);

- 0.5-1.0 wt.% (In terms of the total weight of the pharmaceutical composition) of magnesium stearate (lubricant).

The tablet according to the invention can be (optionally) coated (film coating) based on hypromellose, e.g., such as Opadry ^®.

The most preferred embodiments of the present invention are:

- a tablet containing imatinib mesylate (α-crystalline form), comprising a core and a coating covering it, containing:

Core:

- imatinib mesylate - 45-65 mg (in the most preferred embodiment, 59.75 mg of imatinib mesylate, which corresponds to 50 mg of imatinib base);

- low substituted hyprolose - 60-70 mg;

- povidone - 0.15-0.4 mg;

- sodium carboxymethyl starch - 17-25 mg;

- colloidal silicon dioxide - 1.0-3.0 mg;

- magnesium stearate - 0.5-2.0 mg;

 Shell:

commercially available coating mixture based on hypromellose (for example, Opadry ^® ) - 5-9 mg;

- a tablet containing imatinib mesylate (α-crystalline form), comprising a core and a coating covering it, containing:

Core:

imatinib mesylate - 105-125 mg (in the most preferred embodiment, 119.5 mg of imatinib mesylate, which corresponds to 100 mg of imatinib base);

- low substituted hyprolose - 120-140 mg;

- povidone - 0.4-0.8 mg;

- sodium carboxymethyl starch - 40-45 mg;

- colloidal silicon dioxide - 3.0-5.0 mg;

- magnesium stearate - 1.5-2.5 mg.

Shell:

commercially available hypromellose-based coating mixture (e.g., Opadry ^® ) - 11-17 mg;

- a tablet containing imatinib mesylate (α-crystalline form), comprising a core and a coating covering it, containing:

Core:

- imatinib mesylate - 450-500 mg (in the most preferred embodiment, 478 mg, which corresponds to 400 mg of imatinib base);

- low substituted hyprolose - 480-560 mg;

- povidone - 1.0-4.0 mg;

- sodium carboxymethyl starch - 150-185 mg;

- colloidal silicon dioxide - 12-20 mg;

- magnesium stearate - 6-10 mg.

Shell:

commercially available coating mixture based on hypromellose (e.g. Opadry ^® ) - 25-45 mg.

Another (alternative) preferred embodiment of the present invention are gelatin capsules containing:

- imatinib mesylate - 45-65 mg (in the most preferred embodiment, 59.75 mg of imatinib mesylate, which corresponds to 50 mg of imatinib base);

- low substituted hyprolose - 60-70 mg;

- povidone - 0.15-0.4 mg;

- sodium carboxymethyl starch - 17-25 mg;

- colloidal silicon dioxide - 1.0-3.0 mg;

- magnesium stearate - 0.5-2.0 mg;

or

- imatinib mesylate - 105-125 mg (in the most preferred embodiment, 119.5 mg of imatinib mesylate, which corresponds to 100 mg of imatinib base);

- low substituted hyprolose - 120-140 mg;

- povidone - 0.4-0.8 mg;

- sodium carboxymethyl starch - 40-45 mg;

- colloidal silicon dioxide - 3.0-5.0 mg;

- magnesium stearate - 1.5-2.5 mg;

or

- imatinib mesylate - 450-500 mg (in the most preferred embodiment, 478 mg, which corresponds to 400 mg of imatinib base);

- low substituted hyprolose - 480-560 mg;

- povidone - 1.0-4.0 mg;

- sodium carboxymethyl starch - 150-185 mg;

- colloidal silicon dioxide - 12-20 mg;

- magnesium stearate - 6-10 mg.

Within the framework of the present invention, protection is also claimed for a method for producing a tablet of imatinib or a pharmaceutically acceptable salt thereof, in accordance with which:

(i) a weighed portion of imatinib or a pharmaceutically acceptable salt thereof (preferably imatinib mesylate, in α-crystalline form) is ground;

(ii) sieving a portion of the low substituted and colloidal silica hydroxypropyl cellulose through a sieve;

(iii) preparing an aqueous solution of a binder (povidone);

(iv) mixing the sieved weight of imatinib (or a pharmaceutically acceptable salt of imatinib), low-substituted hydroxypropyl cellulose and colloidal silicon dioxide (disintegrant) in a fluid bed granulator;

(v) wetting the resulting mixture with an aqueous binder (povidone) solution obtained in step (iii);

(vi) dried wet granules in a fluidized bed;

(vii) the granules dried in step (vi) are mixed with hypromellose and sodium carboxymethyl starch;

(viii) dusting the resulting mixture with colloidal silicon dioxide and magnesium stearate;

(ix) compressing the granulate on a tablet machine to obtain tablet cores;

(x) coating the core tablets.

Also claimed within the framework of the present invention is a method for producing a capsule of imatinib or a pharmaceutically acceptable salt thereof, in accordance with which:

(i) a weighed portion of imatinib or a pharmaceutically acceptable salt thereof (preferably imatinib mesylate, in α-crystalline form) is ground;

(ii) sieving a portion of the low substituted and colloidal silica hydroxypropyl cellulose through a sieve;

(iii) preparing an aqueous solution of a binder (povidone);

(iv) mixing the sieved weight of imatinib (or a pharmaceutically acceptable salt of imatinib), low-substituted hydroxypropyl cellulose and colloidal silicon dioxide (disintegrant) in a fluid bed granulator;

(v) wetting the resulting mixture with an aqueous binder (povidone) solution obtained in step (iii);

(vi) dried wet granules in a fluidized bed;

(vii) the granules dried in step (vi) are mixed with hypromellose and sodium carboxymethyl starch;

(viii) dusting the resulting mixture with colloidal silicon dioxide and magnesium stearate;

(ix) fill the resulting gelatin capsule mixture.

Another object of the present invention is a method of treating a patient suffering from a disease selected from a newly detected Philadelphia chromosome positive (Ph +) chronic myeloid leukemia (in children and adults),

Ph + of chronic myeloid leukemia in the chronic phase (in case of failure of previous therapy with interferon α), or in the acceleration phase, or in the blast crisis phase (in children and adults),

first diagnosed with Philadelphia chromosome positive (Ph +) acute lymphoblastic leukemia (ALL) in adult patients,

recurrent or refractory (Ph +) acute lymphoblastic leukemia in adult patients,

myelodysplastic / myeloproliferative diseases,

associated with gene rearrangements of the platelet growth factor receptor (in adult patients),

hypereosinophilic syndrome and / or chronic eosinophilic leukemia in adults with positive or negative abnormal FIP1L1-PDGRF α-tyrosine kinase,

inoperable, recurrent and / or metastatic swelling dermatofibrosarcoma (in adult patients),

wherein said treatment method comprises administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition in accordance with the invention.

The inventive step of the “treatment method” object, in our opinion, is determined, first of all, by the possibility of creating high concentrations of the active substance in the biological media of the patient’s body for a short period of time after taking the pharmaceutical composition in accordance with the invention;

indications for the use of the pharmaceutical composition according to the invention correspond to indications for the use of the drug Glivec ^® manufactured by Novartis AG (CH)) [25].

Below are examples of the preparation of imatinib tablets in accordance with the invention, as well as the results of studying their dissolution profile in a medium simulating human gastric juice (0.1 N HCl).

These examples are provided only to illustrate the present invention, and not to limit the scope of claims.

Example 1. Obtaining tablets of imatinib mesylate in accordance with the invention.

The tablet formulations of the present invention (for doses of imatinib 50 mg, 100 mg and 400 mg) are presented in Table 1. In all formulations, imatinib mesylate (α-crystalline form) was used as the active principle.

Table 1. The formulation of imatinib mesylate tablets in accordance with the invention

Samples of pre-ground and sieved a-crystalline form of imatinib mesylate (59.75 g, 119.5 g or 478.00 g, which corresponds to 50.00 g, 100.00 g or, respectively, 400.00 g of imatinib base), preliminarily

Component Dose I (50 mg) Dose II (100 mg) Dose III (400 mg) Core: The active substance is imatinib mesylate (in terms of base), mg 59.75 mg (50 mg) 119.5 mg (100 mg) 478, 00 mg (400 mg) Low-substituted hyprolose (hydroxypropyl cellulose), mg (Eur. Pharm. ¹ , USP ² ) 65.19 mg 130.38 mg 521.52 mg Povidone (Eur. Pharm., USP) 0.285 mg 0.57 mg 2.28 mg Carboxymethyl starch sodium (Eur. Pharm., USP) 21.055 mg 42.11 mg 168.44 mg Colloidal silicon dioxide (Eur. Pharm., USP) 1.99 mg 3.98 mg 15.92 mg Magnesium stearate (Eur. Pharm., 1.035 mg2.07 mg8 , 28 mgUSP) Shell: Mixture for coating tablets based on hypromellose 7.2 mg14.4 mg34, 64 mg ¹ European Pharmacopoeia ² United States Pharmacopeia, United States Pharmacopeia

sieved low substituted hydroxypropyl cellulose (52.45 g, 104.91 g or 419.64 g, respectively) and colloidal silicon dioxide (Aerosil ^® , 0.99 g, 2.0 g or 8.0 g, respectively) are mixed in a granulator fluidized bed;

a portion of Plasdone ^® K90 povidone (0.285 g, 0.57 g or 2.28 g, respectively) is dissolved in water to give a 0.5% aqueous binder solution;

the mixture in the fluidized bed granulator is moistened with a binder solution;

then the obtained wet granules are dried in a fluidized bed installation until the residual moisture in the granulate is not more than 3%;

another part of the low substituted hydroxypropyl cellulose (12.74 g, 25.47 g or 101.88 g, respectively), together with sodium carboxymethyl starch (1.035 g, 2.07 g or 8.28 g, respectively), is sieved through a sieve, mixed for 10 minutes, with the obtained dry granulate, dusted with magnesium stearate and part II of silicon dioxide of colloidal dioxide (respectively, in an amount of 0.99 g, 1.98 g or 7.92 g) for 3 minutes;

From the resulting mixture using the appropriate press tool on a tablet press, core tablets are obtained.

From each sample of the mixture for tabletting get 1000 pcs. core tablets weighing 149.305 mg, 298.61 mg or 1194.44 mg, containing respectively 59.75 mg, 119.5 mg or 478.00 mg of imatinib mesylate (α-crystalline form), which corresponds to 50 mg, 100 mg and 400 mg of imatinib base.

The resulting tablets are film-coated in a drum-type coating apparatus — a coator; in a particular embodiment of the invention, the shell can be made of commercially available coating mixtures based on hypromellose (Opadry ^® et al.).

Example 2. The dissolution profile of imatinib mesylate tablets in accordance with the invention.

Using the method described in Example 1, tablet formulations were prepared according to the invention containing 119.5 mg and 478 mg of imatinib mesylate (α-crystalline form).

The dissolution profile of these tablets was investigated in accordance with the General Pharmacopoeial Article (OFS) 42-0003-04 “Dissolution”, using the “Paddle Mixer” apparatus, at a dissolution medium temperature of + 37.0 ± 0.5 ° С and at the speed of rotation of the blades mixers 50 rpm

As a dissolution medium used 1000 ml of 0.1 N. hydrochloric acid (a medium simulating human gastric juice); as a comparison drug used the drug Glivec ^® company "NOVARTIS AG", coated tablets (dosages of 100 and 400 mg, respectively).

For each dose of imatinib mesylate (100 mg and 400 mg, calculated on the basis of imatinib), 3 tablets (No. 1-No. 3) from different series of the drug were examined.

At the beginning of the experiment (0 minutes), as well as 5, 10, 15, 20, 30 and 45 minutes after the start of the dissolution of the tablets, a sample of the solution was taken, filtered through a membrane filter, the first portions of the filtrate were discarded and determined (by high performance liquid chromatography) the percentage of imatinib base released on Wednesday.

The results of the study are presented in Tables 2-3 and in Figures 1-4 (in coordinates:% imatinib released - time (min))

table 2 Release (%) of imatinib from Glivec ^® (coated tablets, NOVARTIS AG (CH)) The time from the start of dissolution of the tablet, min Glivec, 100 mg, No. 1 Glivec, 100 mg, No. 2 Glivec, 100 mg, No. 3 Glivec, 400 mg, No. 1 Glivec, 400 mg, No. 2 Glivec, 400 mg, No. 3 0 0 0 0 0 0 0 5 57.42 40.47 55.82 70.15 71.22 77.40 10 90.79 89.94 90.03 90.11 94.51 94.52 fifteen 89.53 88.45 87.86 91.86 96.57 93.84 twenty 90.62 91.26 92.34 93.98 95.07 96,42 thirty 91.44 92.77 93.44 96.47 94.69 98.58 45 92.91 93.20 92.50 95.70 93.68 98.00

Table 3 Release (%) of imatinib from a solid dosage form in accordance with the invention (coated imatinib mesylate tablets, Biocad CJSC) The time from the start of dissolution of the tablet, min Imatinib (Biocad) 100 mg, No. 1 Imatinib (Biocad) 100 mg, No. 2 Imatinib (Biocad) 100 mg, No. 3 Imatinib (Biocad) 400 mg, No. 1 Imatinib (Biocad) 400 mg, No. 2 Imatinib (Biocad) 400 mg, No. 3 0 0 0 0 0 0 0 5 62,20 66.80 71.80 56.91 57.78 61.91 10 76.40 78.90 82.21 74.67 79.33 82.12 fifteen 84.10 85.30 85.70 81.77 85.21 82.06 twenty 88.70 87.50 86.80 89.87 91.50 87.01 thirty 90.80 89.21 93.69 95.39 92.58 90.25 45 91.60 93.90 90.28 97.45 96.81 95.43

The experimental data presented convincingly show that, within the framework of the present invention, it was possible to create a solid dosage form of imatinib or a pharmaceutically acceptable salt thereof (preferably imatinib mesylate, more preferably an α-crystalline form of imatinib mesylate) having a dissolution profile similar to the original imatinib preparation (Glivec ^® ), and capable of quickly (within 15 minutes) entering the body, releasing at least 80% of the active substance, ensuring the creation of high concentrations of it atinib in biological environments of the patient.

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15. PCT International Publication WO 2005/077933 Al “NOVEL POLYMORPHIC FORM OF I MATIN I IN MESYLATE AND A PROCESS FOR ITS PREPARATION)), Applicant NATCO PHARMA LTD [IN], inventors AMALA KOMPELLA [IN]; SRINIVASA RAO THUNGATHURTHI [IN]; ADIBHATLA KALI SATYA BHUJANGA [IN]; RACHAKONDA SREENIVAS [IN]; VENKAIAH CHOWDARY NANNAPANENI [IN]; PODILI KHADGAPATHI [IN], published on 08.25.2005.

16. Published patent application US US 2005/0234069 Al “Novel polymorphs of imatinib mesylate)), Applicant HETERO DRUGS LIMITED [IN], inventors PARTHASARADHI REDDY B [IN]; RATHNAKAR REDDY K [IN]; RAJI REDDY R [IN]; MURALIDHARA REDDY D [IN]; SUB ASH CHANDER REDDY K [IN], published October 20, 2005.

17. PCT International Publication WO 2006/048890 A1 “IMTINIB MESYLATE CRYSTAL FORM AND PROCESS FOR PREPARATION THEREOF *, Applicant SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN], inventors PATEL HETALKUMAR VIRENDRABHAI [IN]; JANI RAJA JYOTIR [IN]; THENNATI RAJAMANNAR [IN], published 05/11/2006.

18. US Patent Application Publication US 2006/0223816 A1 “Imatinib mesylate alpha form and production process therefore)), Applicant CHEMAGIS LTD [IL], inventors ADIN ITAI [EL]; IUSTAIN CARMEN [IL]; DAVIDI GUY [IL]; WEISMAN ALEX [IL]; BENTOLILA MOSHE [IL]; MEYER ELAZAR [IL]; KASPI JOSEPH [IL], published 05.10.2006.

19. PCT International Publication WO 2006/054314 A1 ((POLYMORPHIC FORMS OF I MATIN I IN MESYLATE)), Applicant NATCO PHARMA LIMITED [IN], inventors KOMPELLA AMALA KISHAN [IN]; ADIBHATLA KALI SATYA BHUJANGA [IN]; PODILI KHADGAPATHI [IN]; VENKAIAH CHOWDARY NANNAPANENI [IN], published on 05.26.2006.

20. PCT International Publication WO 2007/023182 A1 ((DELTA AND EPSILON CRYSTAL FORMS OF I MAT IN I IN MESYLATE)), Applicants NOVARTIS AG [CH]; NOVARTIS PHARMA GMBH [AT], invented by MUTZ MICHAEL [DE], published 01.03.2007.

21. PCT International Publication WO 2007/059963 A1 ((F, G, H, I AND K CRYSTAL FORMS OF I MATIN I IN MESYLATE)), Applicants NOVARTIS AG [CH]; NOVARTIS PHARMA GMBH [AT], inventor of MUTZ MICHAEL [DE], published May 31, 2007.

22. Published patent application US US 2007/0197545 A1 ((Crystalline Polymorphs Of Methanesulfonic Acid Addition Salts Of Imatinib, Applicant INSTYTUT FARMACEUTYCZNY [PL], inventors SZCZEPEK WOJCIECH [PL]; SAMSON-LAZINSKA DOROTAOGDZ [PL] PL]; GLICE MAGDALENA [PL]; MARUSZAK WIOLETA [PL]; KORCZAK KATARYZNA [PL]; MODZELEWSKI RYSZARD [PL]; LAWECKA MARTA [PL]; KACZMAREK LUKASZ [PL]; SZELEJEWSKI WIESLAZLA PLA [PL] ; CMOCH PIOTR [PL], published 08/23/2007.

23. RF patent RU 2404775 C2 “PHARMACEUTICAL COMPOSITIONS CONTAINING IMATINIB AND RELEASE Slowdown”, patent holder NOVARTIS AG (SN), inventors WASANTAVADA Madhav (US), LAKSHMAN Jay Partzhdane (US), TANJANDBEIN (US), TENJANDBANDBEIN (TENJANDBEIN) (TENJANDBANDJAN TANJANDBEIN (TENJANDBEIN) (TENJANDBEIN (US), TENJANDBEIN (USA), TENJANDBANDBEIN (TENJANDBEIN) (TENJANDBANDJAN TARTIN (USA), TENJANDBANDJAN TARTIN (USA), M. (US), published on 11.27.2010.

24. RF patent RU 2363450 C2 “TABLET WITH HIGH CONTENT OF MEDICINAL PRODUCT”, patent holder NOVARTIS AG (CH), inventors LUFTENSTEINER Christian-Peter (DE), BANSHI Jean-Claude (FR), OGARK YERG DE), published on 08/10/2009.

25. Instructions for medical use of GLIVEC ^® (GLIVEC ^® ) (imatinib: coated tablets; capsules), NOVARTIS (AG): (available on the Internet as of 08/21/2012).

Claims (14)

1. A pharmaceutical composition containing imatinib mesylate as an active substance in an amount of 25-45 wt.% (Calculated on the basis) and auxiliary substances containing povidone in an amount of 0.1-1.0 wt.%, And as disintegrants, 35-50 wt.% of low substituted hydroxypropyl cellulose (hyprolose) and 10-20 wt.% of Na-carboxymethyl starch. 2. The pharmaceutical composition according to claim 1, characterized in that imatinib mesylate is in α-crystalline form. 3. The pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises a slip agent (glidant), which is colloidal silicon dioxide in an amount of 0.5-5.0 wt.%. 4. The pharmaceutical composition according to claim 1 or 2, characterized in that it further comprises a lubricant (lubricant) selected from the group comprising stearic acid, magnesium stearate or calcium stearate, in an amount of 0.5-1.0 wt.%. 5. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of tablets. 6. The pharmaceutical composition according to claim 5, characterized in that it is further coated. 7. The pharmaceutical composition according to claim 6, characterized in that the shell is a film shell based on hypromellose. 8. The pharmaceutical composition according to claim 1, characterized in that it is made in the form of a capsule. 9. The pharmaceutical composition according to claim 1, characterized in that it releases at least 80% of the active substance within 15 minutes according to the results of the analysis according to the procedure (OFS) 42-0003-04 “Dissolution” using the apparatus “Paddle mixer” (at the rotational speed of the paddle mixer 50 rpm in 1000 ml of 0.1 N. hydrochloric acid and at a temperature of dissolution medium + 37.0 ± 0.5 ° C). 10. A pharmaceutical composition comprising imatinib mesylate, characterized in that it is in the form of a tablet comprising a core and a coating membrane, wherein said tablet contains:
25-45 wt.% Imatinib mesylate (calculated on the basis),
35-50 wt.% Low-substituted hydroxypropyl cellulose (hyproly)
10-20 wt.% Na-carboxymethyl starch,
0.5-5.0 wt.% Colloidal silicon dioxide,
0.5-1.0 wt.% Magnesium stearate, calcium stearate or stearic acid. 11. The pharmaceutical composition of claim 10, wherein the imatinib mesylate is in α-crystalline form. 12. The pharmaceutical composition according to claim 10 or 11, characterized in that it is obtained by the method in accordance with which:
(i) crushing a portion of imatinib mesylate,
(ii) sieving samples of low substituted and colloidal silicon dioxide hydroxypropyl cellulose through a sieve,
(iii) preparing an aqueous solution of povidone,
(iv) mixing the sieved weighed portions of imatinib mesylate, low substituted hydroxypropyl cellulose and colloidal silicon dioxide in a fluid bed granulator,
(v) wetting the resulting mixture with an aqueous solution of povidone obtained in step (iii),
(vi) dried wet granules in a fluidized bed,
(vii) the granules dried in step (vi) are mixed with hypromellose and sodium carboxymethyl starch,
(viii) dusting the resulting mixture with colloidal silicon dioxide and magnesium stearate,
(ix) compressing the granulate on a tablet machine to obtain tablet cores,
(x) coating the core tablets. 13. A pharmaceutical composition comprising imatinib mesylate, characterized in that it is in the form of a capsule, wherein said capsule contains:
25-45 wt.% Imatinib mesylate (calculated on the basis),
35-50 wt.% Of the low substituted hydroxypropyl cellulose (hyprolose),
10-20 wt.% Na-carboxymethyl starch,
0.5-5.0 wt.% Colloidal silicon dioxide,
0.5-1.0 wt.% Magnesium stearate, calcium stearate or stearic acid. 14. The pharmaceutical composition according to p. 13, characterized in that it is obtained by the method in accordance with which:
(i) crushing a portion of imatinib mesylate,
(ii) sieving samples of low substituted and colloidal silicon dioxide hydroxypropyl cellulose through a sieve,
(iii) preparing an aqueous solution of povidone,
(iv) mixing the sieved weighed portions of imatinib mesylate, low substituted hydroxypropyl cellulose and colloidal silicon dioxide in a fluid bed granulator,
(v) wetting the resulting mixture with an aqueous solution of povidone obtained in step (iii),
(vi) dried wet granules in a fluidized bed,
(vii) the granules dried in step (vi) are mixed with hypromellose and sodium carboxymethyl starch,
(viii) dusting the resulting mixture with colloidal silicon dioxide and magnesium stearate,
(ix) fill the resulting gelatin capsule mixture.

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