KR101428149B1 - Granules containing imatinib mesylate, immediate-release tablet composition for oral use comprising said granules and method for preparing thereof - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing imatinib mesylate salt, an oral rapid purification tablet composition containing the same, and a method for preparing the same. More particularly, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, imatinib mesylate or a pharmaceutically acceptable salt thereof, Insoluble polymer, a granule containing the water-insoluble polymer, an oral accelerated tablet composition for treating chronic myelogenous leukemia comprising the granule, and a method for producing the same.

Description

TECHNICAL FIELD [0001] The present invention relates to an imatinib mesylate-containing granules, an oral rapid-purification tablet composition containing the same, and a preparation method thereof. BACKGROUND ART < RTI ID = 0.0 >

The present invention relates to a pharmaceutical composition containing imatinib mesylate salt, an oral rapid purification tablet composition containing the same, and a method for preparing the same. More particularly, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, imatinib mesylate or a pharmaceutically acceptable salt thereof, Insoluble polymer, a granule containing the water-insoluble polymer, an oral accelerated tablet composition for treating chronic myelogenous leukemia comprising the granule, and a method for producing the same.

Methyl] -3 - [[4- (3-pyridinyl) -2-pyrimidinyl] amino] phenyl] - benzamide (4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3- A compound known as imatinib has been well known as a therapeutic agent for chronic phase myeloid leukemia (CML) which has failed to treat accelerated phase, blast crisis or alpha-interferon have. The preparation of this compound and its pharmaceutically acceptable salt is described in Korean Patent Registration No. 10-0261366.

Imatinib mesylate compounds prescribed for the treatment of leukemia are marketed under the trade names Gleevec or Glivec and take 400 to 800 mg depending on the progression of the disease. Korean Patent Registration No. 10-0728846 can provide tablets with high drug content containing about 30 to 80% of imatinib or a pharmaceutically acceptable salt thereof in terms of the weight of the active portion based on the total weight of the tablet . However, in the case of tablets containing 400 mg of imatinib, the total weight of the tablets is more than 700 mg, so it is hard to say that the compliance of the patients with the tablets containing imatinib 100 mg is better than that of tablets containing 100 mg of imatinib. Therefore, oral dosage formulations are needed which provide a single dose that is easy to take while increasing patient adherence.

Korean Patent Laid-Open No. 10-2010-44286 discloses a method for preparing sustained-release pharmaceutical compositions by adding water-soluble, water-swellable and / or water-insoluble polymers as imatinib and a release retarder. However, because of its long half-life due to the drug nature of imatinib, it is necessary to develop a rapid-acting preparation that can exert sufficient pharmacological effects even after one dose of the sustained-release preparation, because it shows therapeutic effect only once per day.

Korean Patent Registration No. 10-0881372 discloses a composition of a granule containing a nonionic surfactant, an enteric polymer, and ethylcellulose and a process for producing the same, in order to inhibit gelation of a poorly soluble drug in a water-soluble medium. Since the above method uses a surfactant that improves the solubility to prevent the gelation of the poorly soluble drug, it is difficult to apply it immediately to formulate a drug exhibiting gelling phenomenon with good solubility in a water-soluble medium such as imatinib .

The imatinib mesylate inherently has a tendency to form a gel phase upon contact with a water-soluble medium due to the nature of the drug, so that absorption is inhibited and physical storage stability is lowered even though it has high solubility. In particular, if the weight of the imatinib mesylate is at least about 70% based on the total weight of the tablet, the gelation phenomenon appears more conspicuously, and disintegration and dissolution are delayed, so that desired rapid drug efficacy can not be expected. In the case of tablets containing 400 mg of imatinib, which is a single dose, this is insufficient disintegration due to the difficulty of penetration of the gastric juice into the tablet nucleus portion as the gelation of the surface of the tablets progresses, because the size of the tablet is limited, There is a problem that elution is reduced.

In order to solve the above problems, the inventors of the present invention have found that a pharmaceutical composition containing, as a main active ingredient, at least 70% by weight of imatinib mesylic acid or a pharmaceutically acceptable salt thereof based on the total weight of tablets, To thereby improve the disintegration delay effect caused by the dissolution of the mesylate-containing granules.

It is another object of the present invention to provide a process for producing the above-mentioned iMedinib mesylate-containing granules which is simple to manufacture and has a low production cost.

It is another object of the present invention to provide an oral rapid-purification tablet composition for treating chronic myelogenous leukemia, wherein the drug content of the small-sized tablets containing the above-mentioned iMedinib mesylate-containing granules is increased to improve compliance.

It is another object of the present invention to provide a method for producing the above-described tablet composition.

The present invention provides an imatinib mesylate containing granules comprising imatinib mesylate or a pharmaceutically acceptable salt thereof as a major active ingredient, a water-insoluble polymer as a binder, and a glidant.

The present invention also provides a process for preparing the above-mentioned imatinib mesylate-containing granules.

The present invention also provides a method for the preparation of an oral delayed tablet composition for the treatment of chronic myelogenous leukemia comprising the above-mentioned imatinib mesylate-containing granules.

The present invention also provides a tablet composition prepared by the above method.

The tablet containing the imatinib mesylate salt-containing granules according to the present invention can effectively prevent the gelation in the aqueous medium by containing the water-insoluble polymer, thereby improving the dissolution delay effect of the preparation. In particular, according to the present invention, it is possible to prepare physically small tablets containing a relatively small amount of excipient and a high content of imatinib mesylate, thereby providing a formulation with substantially high compliance. In addition, the pharmaceutical granular composition containing the imatinib mesylate or pharmaceutically acceptable salt thereof according to the present invention can be produced by a series of processes such as mixing, coalescence, and granulation, It can be easily produced without performing troublesome production processes, and can be manufactured with a simple and low manufacturing cost.

Fig. 1 shows the dissolution test results of the tablet composition containing the imatinib mesylate-containing granules and the control agent according to the present invention.
Formulation Example 1: Tablets which contain 100 mg of imatinib but do not contain water-insoluble polymer
Formulation Example 2: Tablets containing 400 mg of imatinib and containing no water-insoluble polymer
Formulation Example 4: Tablets containing ethylcellulose (water-insoluble polymer) containing 100 mg of imatinib
Formulation Example 7: Tablets containing ethylcellulose (water-insoluble polymer) containing 400 mg of imatinib
Formulation Example 8: Tablets containing Eudragit RLPO (water-insoluble polymer) containing 400 mg of imatinib
Control formulation: Gleevec film coated tablet 100 mg

The present invention provides an imatinib mesylate-containing granule characterized in that it comprises imatinib mesylate or a pharmaceutically acceptable salt thereof as a main active ingredient, a water-insoluble polymer as a binder and a glidant.

The imatinib mesylate used in the present invention may be a crystalline, a crystalline or amorphous mixture, or an amorphous. In the case of crystalline form, both α and β may be used.

The term "pharmaceutically acceptable salts" means salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.

The above-mentioned imatinib mesylate can be used in a therapeutically effective amount. In general, the therapeutically effective amount of imatinib mesylate is divided into 400 mg and 600 mg per day in a daily dose depending on the progress of the disease. The therapeutically effective amount of the imatinib mesylate can be readily selected by those skilled in the art from the total weight of the tablets obtained according to the present invention without any difficulty and is preferably from about 70 to about 90 weight percent based on the total weight of the tablet, About 80% by weight.

The term " water-insoluble polymer "in the present invention means a pH-independent polymer which is insoluble in an acidic or basic solution regardless of pH.

The water-insoluble polymer is selected from the group consisting of water-insoluble cellulose and its derivatives, polymethacrylate or a mixture of polyalkyl acrylate and polymethacrylate, preferably cellulose acetate, ethylcellulose, and aminomethacrylic acid air ≪ / RTI > alone or a mixture thereof.

When ethylcellulose is selected as the water-insoluble polymer, various viscosities can be used. However, when ethylcellulose having a viscosity of 45 cps or more is used, the dissolution is delayed due to a large release effect rather than an effect of preventing gelation, Ethylcellulose having a viscosity of 20 cps can be used.

The mixture of polymethacrylate or polyalkyl acrylate and polymethacrylate may be selected from the group consisting of Eudragit RSPO, RLPO, RS100, RL100, RS30D, RL30D, and NE30D. have.

The imatinib mesylate containing granules of the present invention comprise 1-20% by weight, preferably about 3-10% by weight, of the water-insoluble polymer based on the total weight of the tablet.

The imatinib mesylate, which is a major active ingredient, has a property of rapidly gelling while contacting with an aqueous medium. However, the imatinib mesylate-containing granules containing the water-insoluble polymer according to the present invention are insoluble in the active ingredient of imatinib mesylate And contact with the aqueous medium is minimized, gelation is effectively prevented, and disintegration and dissolution are improved, so that immediate release is possible. That is, in the present invention, the water-insoluble polymer is used as a binder to prevent gelation.

The imatinib mesylate containing granules of the present invention also comprise 0.5-10 wt%, preferably about 1 wt%, of at least one lubricant based on the total weight of the tablet.

The lubricant that may be used in the granules of the present invention is colloidal silicon dioxide, such as Aerosil (Aerosil 200M); Preferably hydrophobic colloidal silicon dioxide, such as hydrophobic aerosil (Aerosil R972); And talc.

The lubricant is used to prevent the physicochemical properties of the imatinib mesylate, which has a strong electrostatic force during granulation and gelation progresses rapidly in the aqueous medium.

The present invention also provides a process for preparing the above-mentioned imatinib mesylate-containing granules.

More particularly, the present invention relates to

(a) 70-90% by weight of imatinib mesylate, 1-20% by weight of a water-insoluble polymer, and 0.5-10% by weight of a lubricant are added to a C ₁ -C ₅ organic solvent or an organic solvent aqueous solution, An associating step; And

(b) granulating the association product obtained in step (a)

Containing mesylate containing granules.

Union of step (a) are the C ₁ -C dissolving the water-insoluble polymer in an organic solvent or an organic solvent aqueous solution of ₅ is mixed with the mixture of double sheet tinip mesylate and lubricant to the resultant solution, or the C ₁ -C _{5 in} an organic solvent or an aqueous solution of an organic solvent to the mixture of imatinib mesylate, a lubricant and a water-insoluble polymer. The association may be carried out by uniformly kneading according to conventional pharmaceutical methods, or may be carried out using a cooperating machine such as a high shear granulator.

As the C ₁ -C ₅ organic solvent or organic solvent aqueous solution, ethanol or ethanol aqueous solution may preferably be used, and the organic solvent aqueous solution (ethanol aqueous solution) may be an organic solvent aqueous solution having 5 to 200% have. The amount of the organic solvent or the organic solvent solution used is not limited as long as it is used in an amount necessary for carrying out a combined process of a mixture of imatinib mesylate, water-insoluble polymer and glidant. If the amount used is too small, it may be difficult to obtain a homogeneous mixture, and if too much, the Union may not want it.

The organic solvent or aqueous organic solvent solution may be used in an amount of 30 to 80% by weight, preferably about 40 to 50% by weight, based on 100 parts by weight of the imatinib mesylate salt-containing mixture.

The granulation of step (b) may be carried out using conventional methods for the association obtained in step (a). For example, granules can be prepared by performing a series of wet granulation, drying and sizing processes.

The wet granulation can be carried out using the coagulant used in step (a) above, and the drying can be carried out in a drying oven or fluidized bed dryer, and the granulation is preferably carried out in a size of 10 to 25 mesh , And more preferably a mesh having 14 to 20 meshes.

The present invention also provides a method for the preparation of an oral rapid release tablet composition for the treatment of chronic myelogenous leukemia comprising the granules containing the imatinib mesylate prepared by the above process.

The process for preparing the tablet composition of the present invention comprises a granule formation step, a granule and a post mixture mixing step, a compression step of the obtained mixture and a coating step of purification.

In the mixing step of the granules and the post-mixture, at least one pharmaceutically acceptable addition of at least one disintegrant, at least one lubricant and at least one basic coating material to the imatinib mesylate-containing granules prepared by the preparation method .

That is,

(a) adding 70 to 90% by weight of the imatinib mesylate-containing granules prepared by the manufacturing method of claim 1, 5 to 20% by weight of a disintegrant and 0.1 to 3% by weight of a lubricant;

(b) compressing the mixture obtained in step (a); And

(c) coating the compressed mixture

The present invention provides a method for preparing an oral pharmaceutical tablet composition for the treatment of chronic leukemia.

Suitable disintegrants according to the present invention include corn starch; CMC-Ca; CMC-Na; Crosslinked PVP, such as those known and marketed under the trade names Crospovidone (R), Polyplasdone (R), or Kollidon CL (R)); Sodium alginate, croscarmellose sodium, such as Vivasol (R), Ac-di-sol (R), preferably crosslinked polyvinylpyrrolidinone, crospovidone Is used.

The amount of the disintegrant may be in the range of 5 to 20% by weight, preferably 8 to 15% by weight, based on the total weight of the tablet.

Suitable lubricants according to the present invention include magnesium stearate, calcium stearate, sodium stearyl fumarate, such as the trade name Pruv (R), preferably magnesium stearate.

The amount of the lubricant may be in the range of 0.1 to 3% by weight, preferably 0.5 to 2% by weight based on the total weight of the tablet.

It is another object of the present invention to provide an oral rapid-purification tablet composition for treating chronic myelogenous leukemia, wherein the drug content of the small-sized tablets containing the above-mentioned iMedinib mesylate-containing granules is increased to improve compliance.

In a preferred embodiment of the present invention, tablets prepared according to the present invention have a total weight of 600 mg (Formulation Examples 7 and 8) even when containing 400 mg of imatinib mesylate, which makes them much easier to take for a single dose Therefore, patients' compliance with medication compliance can be improved compared with taking 4 tablets containing 100 mg of imatinib or taking 1 tablets of glive-back coated tablets containing 400 mg imatinib.

Hereinafter, embodiments of the present invention will be described in detail. However, the following examples are intended to illustrate the invention and are not intended to limit the scope of the invention.

<Examples>

Example  1-8: Imatinib mesylate  Preparation of granules containing

According to the contents of Table 1 below, imatinib mesylate-containing granules were prepared using imatinib mesylate, ethylcellulose or copovidone as the binder, talc as the lubricant or hydrophobic colloidal silicon dioxide (Aerosil R972) .

In Examples 1 to 5, copovidone or ethylcellulose used as a binder was dissolved in ethanol and used as a binding solution. In Example 6, half of the amount of ethylcellulose was dissolved in ethanol and used as a binding solution, and a half amount of ethyl Cellulose was mixed with imatinib mesylate and hydrophobic colloidal silicon dioxide.

In Example 7, ethyl cellulose, imatinib mesylate, and hydrophobic colloidal silicon dioxide were mixed and ethanol was added alone to effect association.

In Example 8, Eudragit RLPO was dissolved in ethanol and used as a binding solution, and the imatinib mesylate and hydrophobic colloidal silicon dioxide were added to the mixture to effect association.

The granules obtained by coalescence and granulation through a high shear granulator were dried in a drying oven to remove ethanol, and the granules were formed into a size of 14 to 20 mesh to prepare granules.

EXAMPLES (mg / tablet) One 2 3 4 5 6 7 8 ethanol 40.00 40.00 40.00 40.00 40.00 40.00 40.00 38.00 Ethyl cellulose 6.00 7.50 9.00 3.75 Copovidone (water-soluble polymer) 3.00 3.00 Eudragit (RLPO) 7.50 Imatinib mesylate ※ 119.50 119.50 119.50 119.50 119.50 119.50 119.50 119.50 Talc 5.25 Hydrophobic colloidal silicon dioxide 5.25 0.75 0.75 0.75 0.75 0.75 0.75 Ethyl cellulose 3.75 7.50

* Imatinib mesylate 119.5 mg is identical to imatinib 100 mg

Examples 1 and 2: granules containing no water-insoluble polymer

Examples 3 to 7: Granules containing ethyl cellulose (water-insoluble polymer)

* Example 8: Granules containing Eudragit RLPO (water-insoluble polymer)

One of Examples 1 and 2, which is a granule example that does not contain a water-insoluble polymer, was selected as a comparative preparation. Examples 6 and 7 contain water-insoluble polymers in the same proportions as in Example 4 but differ only in the production method.

Formulation example  1 to 8: Preparation of film-coated tablets

The granules prepared in Examples 1, 3, 4, 5 and 8 were mixed according to a conventional method according to the following Table 2, and tablets were prepared by tableting. The tablets were then coated on the tablets in the usual manner according to the film coating formulation.

Formulation Example (mg / tablet) One 2 3 4 5 6 7 8 Example 1 Granules 127.75 511.00 Example 3 Granules 126.25 Example 4 Granules 127.75 255.50 511.00 Example 5 Granules 129.25 Example 8 Granules 511.00 Crospovidone 14.75 59.00 16.25 14.75 13.25 29.50 59.00 59.00 Hydrophobic colloidal silicon dioxide 0.75 3.00 0.75 0.75 0.75 1.50 3.00 3.00 Magnesium stearate 0.75 3.00 0.75 0.75 0.75 1.50 3.00 3.00 Opa dry brown (coating) 5.00 20.00 5.00 5.00 5.00 10.00 20.00 20.00 Gross weight 149.00 596.00 149.00 149.00 149.00 298.00 596.00 596.00

Formulation Example 1: Tablets which contain 100 mg of imatinib but do not contain water-insoluble polymer

Formulation Example 2: Tablets containing 400 mg of imatinib and containing no water-insoluble polymer

Formulation Examples 3 to 5: Tablets containing ethylcellulose (water-insoluble polymer) containing 100 mg of imatinib

Formulation Example 6: Tablets containing ethylcellulose (water-insoluble polymer) containing 200 mg of imatinib

Formulation Example 7: Tablets containing ethylcellulose (water-insoluble polymer) containing 400 mg of imatinib

Formulation Example 8: Tablets containing Eudragit RLPO (water-insoluble polymer) containing 400 mg of imatinib

Test Example  One: Comparative disintegration test

The film-coated tablets obtained in the above Preparation Examples 1, 2, 4, 7 and 8 and 100 mg of Gleevec film-coated tablets commercially available as the comparative preparations were subjected to the comparative disintegration test according to the ' Disintegration test was carried out.

Disintegration Tester: Labfine DIT 400s

Temperature of eluent: 37 ± 0.5 ° C

Test Example  2: Comparative dissolution test

The film-coated tablets obtained in Preparation Examples 1, 2, 4, 7 and 8 and the commercially available Gleevec film-coated tablets (100 mg) were used in the dissolution method 2 (paddle method) of the &quot; The elution test was carried out under the condition of pH 1.2 eluate. The dissolution rate was calculated by analyzing the absorbance of imatinib by UV. The conditions of the UV analysis are as follows:

Elution test apparatus: Erweka DT 80

Eluent: pH 1.2

Temperature of eluent: 37 ± 0.5 ° C

Rotation speed: 50 ± 5 rpm

Assay method: UV absorbance method

Detector: UV 264 nm

Formulation example One 2 4 7 8 Control formulation Disintegration time (minutes) 10.3 23.2 10.5 11.5 11.0 8.5 15 minutes dissolution rate 93.18% 58.96% 99.31% 100.96% 97.11% 101.21% 30 minutes dissolution rate 99.52% 95.49% 101.17% 101.03% 100.82% 101.63%

As shown in Fig. 1, in the case of tablets (preparations 7 and 8) containing the ejtaminib mesylate-containing granules containing a high content of imatinib mesylate according to the present invention and containing water-insoluble polymer as binder The dissolution rate of the tablets (preparation example 4) containing the imatinib mesylate containing granules containing the same amount of imatinib mesylate as the control preparation but containing the water-insoluble polymer as the binder was similar to the control formulation. Compared with the control preparation containing 100 mg of imatinib, it was found that 400 mg of imatinib (preparation examples 7 and 8) having an increased drug content according to the present invention exhibited the effect of improving the dissolution without delay in dissolution due to gelation have.

On the other hand, tablets of formulation 2 containing 400 mg of imatinib and having high drug content but not containing water-insoluble polymer showed a maximum gelation effect and a prolonged dissolution delay.

Therefore, it was confirmed that the tablets containing the water-insoluble polymer had a high drug content and an improved early dissolution rate as compared with tablets not containing the water-insoluble polymer, because the content of the imatinib mesylate according to the present invention was high.

Claims (11)

Comprising 70-90% by weight of granules containing imatinib mesylate or a pharmaceutically acceptable salt thereof as a main active ingredient in total tablets, 1-20% by weight of a water-insoluble polymer as a binder and 0.5-10% by weight of a lubricant, Wherein the water-insoluble polymer is selected from the group consisting of water-insoluble cellulose and derivatives thereof, and a mixture of polymethacrylate or polyalkyl acrylate and polymethacrylate alone or a mixture thereof. &Lt; / RTI &gt; delete The method according to claim 1,
Wherein the water-insoluble polymer is ethylcellulose. The method of claim 3,
Wherein the ethylcellulose has a viscosity of 4-20 cps. The method according to claim 1,
Wherein the water-insoluble polymer is selected from the group consisting of Eudragit RSPO, RS100, RS 30D, RL 30D, and NE 30D. delete delete delete delete delete delete

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