JP2014015438A - Producing method of stable crystal solid preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a producing method of a tablet inhibited transition from α type crystal to β type crystal, the tablet being a solid preparation containing the α type crystal of imatinib mesilate.SOLUTION: A producing method of a solid preparation inhibited transition to β type crystal during formulation and preservation by coating a solid preparation such as a granule and an uncoated tablet containing the α type crystal of imatinib mesilate with a polymer compound with high moistureproofness such as polyvinyl acrylate. The polymer compound with high moistureproofness is particularly preferably a polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer.

Description

  The present invention relates to imatinib mesylate (Japanese generic name) useful as an antineoplastic agent, ie, 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- (4-pyridine- The present invention relates to a method for producing a solid preparation of 3-yl) pyrimidin-2-ylamino] phenyl] -benzamide methanesulfonate, which stably holds α-form crystals.

In Patent Document 1, the imatinib mesylate has amorphous, α-form and β-form crystal polymorphs, and α-form crystals are obtained by producing mesylate by a conventional method using free imatinib and mesylate. And that the α-form crystal transitions to the β-form crystal under certain conditions.
When this α form crystal imatinib mesylate is tableted, if the crystal form transition to β form occurs during storage, the chemical and physical properties will also change, affecting the drug dissolution in the digestive tract. Therefore, it is required to prevent crystal form transition during the production and storage of solid preparations such as granules and tablets.
In Patent Document 2, crospovidone (cross-linked polyvinyl pyrrolidone) having high disintegration is blended in an amount of 10 to 35% based on the total amount of tablets containing imatinib mesylate, and further, microcrystalline cellulose having high water absorption is blended. A method for producing high drug-filled tablets by wet granulation is disclosed. However, when the wet granulation method is applied to the production of imatinib mesylate α-form crystal-containing tablets, the crystal form transitions to β-form due to the influence of moisture.

Japanese Patent No. 3276359 JP 2010-31019 A

  An object of the present invention is to provide a method for producing a tablet, which is a solid preparation containing an α-form crystal of imatinib mesylate, in which the transition from the α-form crystal to the β-form crystal is suppressed.

Granules are produced by dry granulation using α-form crystals of imatinib mesylate, mixed with magnesium stearate, compressed into tablets, and then coated with hypromellose, a commonly used coating base. When a test (60 ° C., relative humidity 75%, glass bottle open) was performed, the transition to β-form crystals began 17 days after the start of storage, and most of them transitioned to the β-form 28 days after the start of storage. This crystal form transition is considered to be caused by water used in the hypromellose coating solution.
On the other hand, when the tableted product was coated with a coating solution containing polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer and water and subjected to the same severe test as in the previous period, it was a coating using water. As a result of studying various high moisture-proof polymer compounds as coating agents, the present invention has been completed.

That is, the present invention provides the following inventions (1) to (7).
(1) A method for producing a stable crystalline solid preparation, which comprises coating a solid preparation containing α-form crystals of imatinib mesylate with a highly moisture-proof polymer compound.
(2) The method for producing a stable crystalline solid preparation according to (1), wherein the solid preparation is a granule or an uncoated tablet.
(3) The method for producing a crystalline stable solid preparation according to the above (1) or (2), wherein the high moisture-proof polymer compound is a polyvinyl alcohol polymer.
(4) The method for producing a crystalline solid stable preparation according to (3), wherein the polyvinyl alcohol polymer is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer.
(5) The method for producing a crystalline solid stable preparation according to (1) to (4), wherein the granulation method is dry granulation or melt granulation.
(6) The method for producing a stable crystalline solid preparation according to the above (1) to (5), wherein the tablet is a tablet containing 80 to 99% by weight of α-form crystals of imatinib mesylate in the solid preparation.

  According to the present invention, by coating a solid preparation of imatinib mesylate α-form crystals, particularly granules and uncoated tablets, with a highly moisture-proof polymer compound, crystal transition is suppressed, and a constant quality over a long period of time. Can be provided. This coated solid preparation is highly effective in preventing crystal transition even when water is used for coating.

FIG. 5 is a powder X-ray diffraction diagram of α-form crystal of imatinib mesylate (refraction angle 2θ plotted on the horizontal axis and relative line intensity plotted on the vertical axis; the same applies to the following drawings). It is a powder X-ray diffraction pattern of the β-form crystal of imatinib mesylate. 2 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablet of Example 1. FIG. FIG. 3 is a powder X-ray diffraction pattern of the tablet of Example 1 measured 28 days after Test Example 1. 3 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablet of Example 2. FIG. FIG. 3 is a powder X-ray diffraction diagram of the tablet of Example 2 measured 28 days after Test Example 1. 2 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablet of Example 3. FIG. FIG. 3 is a powder X-ray diffraction diagram of the tablet of Example 3 measured 28 days after Test Example 1. 4 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablets of Example 4. FIG. FIG. 4 is a powder X-ray diffraction pattern of the tablet of Example 4 measured 28 days after Test Example 1. 6 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablet of Example 5. FIG. FIG. 6 is a powder X-ray diffraction pattern of the tablet of Example 5 measured 28 days after Test Example 1. 3 is a powder X-ray diffraction pattern measured at the start of Test Example 1 for the tablet of Comparative Example 1. FIG. FIG. 3 is a powder X-ray diffraction pattern measured 28 days after Test Example 1 for the tablet of Comparative Example 1.

The solid preparation containing α-form crystals of imatinib mesylate according to the present invention, particularly granules and uncoated tablets can be produced by a usual method. For example, the α-form crystals of imatinib mesylate can be granulated with a lubricant to form granules, and the granules can be tableted by a conventional method.
As the granulation method, either a wet granulation method or a dry granulation method can be used. In the present invention, the dry granulation method is more preferable. In the dry granulation, granules are formed by compression-molding powder with a general dry granulator such as a roller compactor. The pressure at the time of compression molding is preferably 1 to 30 MPa, more preferably 3 to 12 MPa. Moreover, 1-50 rpm is preferable and, as for the rotation speed of the roll at the time of compression molding, More preferably, it is 3-20 rpm. At this time, it is preferable that the formed granules are crushed with a comil or the like. A granulated product can be produced by coating a tablet formed by adding a lubricant to the granulated product and compressing it to produce a film-coated tablet, or coating the granulated product.
Examples of the lubricant used for granulation include sodium stearyl fumarate, talc, stearic acid, magnesium stearate, calcium stearate, hydrogenated oil, glycerin fatty acid ester, sucrose fatty acid ester, and talc. In particular, talc and sodium stearyl fumarate are preferred. The amount of lubricant used is preferably 0.1 to 2.0% by weight of the tablet.
In addition, an excipient such as lactose hydrate, a binder such as hydroxypropylcellulose, hypromellose, and methylcellulose, and a disintegrant such as crospovidone, low-substituted hydroxypropylcellulose, and calcium calcium may be added during dry granulation. .

The highly moisture-proof polymer compound that can be used in the present invention has a water vapor transmission rate of 500 g / m in a film having a film thickness of 150 μm according to the standard permeability test method (ASTM) of a film-like substance at 25 ° C. and 90% RH. A coating base of m ² · 24 hr or less, preferably 50 to 350 g / m ² · 24 hr is preferred. Examples of the compound include polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol / graft copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer RS, etc. Polyvinyl alcohol which is a polyvinyl alcohol polymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer [average polymerization degree 450 to 550, weight average molecular weight about 40,000, water vapor transmission rate by standard permeability test method (ASTM) 190 g / m ² · 24 hr, trade name POVACOAT (registered trademark)] is particularly preferable.

  When coating in the present invention, a lubricant can be used. This lubricant is not limited as long as it can prevent adhesion between tablets and aggregation between granules at the time of coating, such as fats and oils such as talc, carnauba wax and hardened oil, and light anhydrous silicic acid. Examples thereof include silicates such as silicic acid and calcium silicate, higher fatty acids such as stearic acid, higher fatty acid salts such as magnesium stearate and calcium stearate, higher fatty acid esters such as sucrose fatty acid ester, and glycerin fatty acid ester. Of these, talc is preferred. The weight ratio of the lubricant to the high moisture-proof polymer compound in the coating liquid is preferably 1: 0.05 to 1: 3, more preferably 1: 0.1 to 1: 2.

  The film coating method is not particularly limited, but the uncoated tablet can be performed using a general air-permeable coating machine, a sugar-coated bread, or the like, and the granule can be performed using a general fluidized bed granulation coating machine or the like. In the present invention, a coating solution is prepared by dispersing a high moisture-proof polymer compound, a lubricant and the like in water. Other solvents that can be used include ethanol, methanol and isopropyl alcohol, with water being more preferred.

  Although there is no restriction | limiting in particular in the content ratio of the imatinib mesylate in the tablet manufactured by the method of this invention, In the case of this agent, since the daily dose is large, it is 80-99 weight in the meaning which prevents becoming bulky. % Is preferable.

  In addition, the present invention may use a colorant such as iron sesquioxide, yellow iron sesquioxide, titanium oxide for the purpose of identifying tablets, and may be added to granules or dispersed in a coating solution. Good.

239 g of imatinib mesylate α-form crystal (manufactured by Sumitomo Chemical Co., Ltd.) is put into a roller compactor (Freund Sangyo / TF-Labo type), molded at a pressure of 6 MPa and a roll speed of 4 rpm, and crushed with an oscillator of mesh 24 mesh. did. The obtained granulated product was mixed with 2 g of magnesium stearate (manufactured by Taihei Chemical Industry), and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). 1 tablet mass 120.5 mg, diameter A 7.5 mm uncoated tablet was obtained.
An uncoated tablet is put into a coating machine (DRC-200 type / Pauleck), and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT (water vapor permeability 190 g / m ² .24 h) / Daido Chemical) Industrial) 2.0g, talc (Victory Light / Katsumine) 2.0g, ferric sesquioxide 0.04g and yellow ferric oxide 1.0g are added to 46g of purified water. Then, the uniformly dispersed liquid was sprayed, coated to a mass of 123 mg per tablet, and dried until reaching 65 ° C. to obtain a coated tablet (imatinib mesylate content 97% by weight).

239 g of imatinib mesylate α-form crystals (manufactured by Sumitomo Chemical Co., Ltd.) and 3 g of sodium stearyl fumarate (manufactured by Nissei Chemical Co., Ltd.) are mixed and charged into a roller compactor (Freund Sangyo / TF-Labo type), pressure 6 MPa, roll rotation speed It was molded at 4 rpm and crushed with an oscillator having a mesh size of 24 mesh. The obtained sized product is mixed with 3 g of sodium stearyl fumarate and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). One tablet has a mass of 122.5 mg and a diameter of 7.5 mm. I got a tablet.
An uncoated tablet is put into a coating machine (DRC-200 type / Pauleck), and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT (water vapor permeability 190 g / m ² .24 h) / Daido Chemical) Industrial) 2.0g, talc (Victory Light / Katsumine) 2.0g, ferric sesquioxide 0.04g and yellow ferric oxide 1.0g are added to 46g of purified water. Then, the uniformly dispersed liquid was sprayed, coated until the mass of 1 tablet reached 125 mg, and dried until the exhaust temperature reached 65 ° C. to obtain a coated tablet (imatinib mesylate content 97% by weight).

239 g of imatinib mesylate α-form crystals (manufactured by Sumitomo Chemical Co., Ltd.) and 3 g of sodium stearyl fumarate (manufactured by Nissei Chemical Co., Ltd.) are mixed and charged into a roller compactor (Freund Sangyo / TF-Labo type), pressure 6 MPa, roll rotation speed It was molded at 4 rpm and crushed with an oscillator having a mesh size of 24 mesh. The obtained sized product is mixed with 3 g of sodium stearyl fumarate and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). One tablet has a mass of 122.5 mg and a diameter of 7.5 mm. I got a tablet.
An uncoated tablet is put into a coating machine (DRC-200 type / Paulec), and polyvinyl alcohol (partially saponified product) (EG-05 / Nippon Gosei Co., Ltd.) 2.0 g, talc (Victory Light / Katsumine) 2.0 g, 0.03 g of iron sesquioxide (manufactured by Kasei Kasei) and 1.0 g of yellow iron sesquioxide (manufactured by Kasei Kasei) are added to 46 g of purified water, sprayed with a uniformly dispersed solution, and 1 tablet mass 125 mg And dried until the exhaust temperature reached 65 ° C. to obtain coated tablets (imatinib mesylate content 97% by weight).

239 g of imatinib mesylate α-form crystals (manufactured by Sumitomo Chemical Co., Ltd.) and 3 g of sodium stearyl fumarate (manufactured by Nissei Chemical Co., Ltd.) are mixed and charged into a roller compactor (Freund Sangyo / TF-Labo type), pressure 6 MPa, roll rotation speed It was molded at 4 rpm and crushed with an oscillator having a mesh size of 24 mesh. The obtained sized product is mixed with 3 g of sodium stearyl fumarate and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). One tablet has a mass of 122.5 mg and a diameter of 7.5 mm. I got a tablet.
An uncoated tablet is put into a coating machine (DRC-200 type / Pauleck), and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT (water vapor permeability 190 g / m ² .24 h) / Daido Chemical) Industrial water) 2.0 g, light anhydrous silicic acid (Azo Solider 101 / Freund Sangyo) 2.0 g, ferric sesquioxide 0.04 g and yellow ferric sesquioxide 1.0 g In addition to 46 g, the uniformly dispersed liquid was sprayed and coated until the mass of 1 tablet reached 125 mg, and dried until the exhaust temperature reached 65 ° C. to obtain a coated tablet (imatinib mesylate content 97 wt%). .

239 g of imatinib mesylate α-form crystals (manufactured by Sumitomo Chemical Co., Ltd.) and 3 g of sodium stearyl fumarate (manufactured by Nissei Chemical Co., Ltd.) are mixed and charged into a roller compactor (Freund Sangyo / TF-Labo type), pressure 6 MPa, roll rotation speed It was molded at 4 rpm and crushed with an oscillator having a mesh size of 24 mesh. The obtained sized product is mixed with 3 g of sodium stearyl fumarate and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). One tablet has a mass of 122.5 mg and a diameter of 7.5 mm. I got a tablet.
An uncoated tablet is put into a coating machine (DRC-200 type / Pauleck), and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT (water vapor permeability 190 g / m ² .24 h) / Daido Chemical) Industrial) 2.0g, Calcium silicate (Florite RE / Eisai Food Chemical) 2.0g, Iron sesquioxide 0.04g and Yellow iron sesquioxide 1.0M In addition to 46 g of purified water, spray uniformly dispersed liquid, coat until the mass of 1 tablet reaches 125 mg, and dry until the exhaust temperature reaches 65 ° C. to obtain coated tablets (imatinib mesylate content 97% by weight) Obtained.

[Comparative Example 1]
239 g of imatinib mesylate α-form crystal (manufactured by Sumitomo Chemical Co., Ltd.) is put into a roller compactor (Freund Sangyo / TF-Labo type), molded at a pressure of 6 MPa and a roll speed of 4 rpm, and crushed with an oscillator of mesh 24 mesh. did. The obtained granulated product was mixed with 2 g of magnesium stearate (manufactured by Taihei Chemical Industry), and tableted with a rotary tableting machine (Clean Press Collect 19K / manufactured by Kikusui Seisakusho). 1 tablet mass 120.5 mg, diameter A 7.5 mm uncoated tablet was obtained.
An uncoated tablet is put into a coating machine (DRC-200 type / Paulec), and 3.4 g of hypromellose (TC-5 (M) / Shin-Etsu Chemical Co., Ltd.), talc (Victory Light / Katsumine) 0 .2 g, Macrogol 6000 (Sanyo Chemical Industries) 0.4 g, Ferric sesquioxide (0.04 g) and Yellow Ferric oxide (1.0 g) are added to 46 g of purified water and dispersed uniformly. The resulting solution was sprayed, coated to a mass of 123 mg per tablet, and dried until the exhaust temperature reached 65 ° C. to obtain a coated tablet (imatinib mesylate content 97% by weight).

[Test Example 1]
About the tablet obtained in Example 1 and Comparative Example 1, the tablet at the start of the test, the tablet after storage at a temperature of 60 ° C., a relative humidity of 75% and 28 days, and α-form crystals of imatinib mesylate and β The shape crystal was measured by powder X-ray diffraction under the following conditions, and the crystal form of each sample was examined.
(1) Measurement of powder X-ray diffraction Equipment used: D8 DISCOVER with EADDS CS manufactured by Bruker AXS
Measurement conditions: tube Cu tube voltage 45 KV tube current 40 mA
(2) Differential scanning calorimetry (DSC)
Equipment used: DSC204F1 Phoehix made by NETZSCH
Measurement conditions: Temperature rising rate 5 ° C./min Measurement range 50 ° C. to 250 ° C.

(3) Confirmation of Crystal Form When comparing FIG. 1 related to the α-type crystal and FIG. 2 related to the β-type crystal, the peaks peculiar to the α-type crystal are 2θ: 10.5 °, 14.9 °, 21.4 °, 21.7 °, 25.0 ° and 28.6 °, while the peaks characteristic of the β-type crystal are 2θ: 9.7 °, 17.4 ° and 20.6 °. 21.1 ° and 22.1 °.
Among these, the two crystal forms are most easily discriminated. For the α-form crystal, the peak at 2θ: 25.0 ° is selected. For the β-form crystal, the peak at 2θ: 20.6 ° is selected, and imatinib mesylate in the test sample is selected. The crystal form of the salt was confirmed.
In addition, since the content rate of the imatinib mesylate crystal contained in each tablet of Example 1, Example 2, and Comparative Example 1 is as high as 92 to 97% by weight, it is easy to distinguish each crystal form.

(4) Results The α-form crystals of imatinib mesylate in the tablet of Example 1 according to the present invention were not observed to be transformed into β-form crystals even after storage for 28 days at 60 ° C. and 75% relative humidity. On the other hand, in the tablet of Comparative Example 1, the transition to β-form started 17 days later, and after 28 days, it was found by powder X-ray diffraction measurement that almost no α-form crystal peak was observed (Figure and Table 1). ).
In Table 1, the α-form crystal content was calculated using a calibration curve created from the respective heats of fusion obtained by differential scanning calorimetry of the mixed powder of α-form crystals and β-form crystals.

  ADVANTAGE OF THE INVENTION According to this invention, the imatinib mesylate tablet which ensured fixed quality for a long period of time can be manufactured, and a useful antineoplastic agent can be provided to medical treatment.

  In the figure, α when 2θ is around 25.0 ° and β when 2θ is around 20.6 ° show peaks peculiar to α-form crystals and β-form crystals of imatinib mesylate, respectively.

Claims (6)

A method for producing a stable solid preparation of a crystal system, which comprises coating a solid preparation containing α-form crystals of imatinib mesylate with a highly moisture-proof polymer compound. The method for producing a stable crystalline solid preparation according to claim 1, wherein the solid preparation is a granule or an uncoated tablet. The method for producing a crystalline solid stable preparation according to claim 1 or 2, wherein the high moisture-proof polymer compound is a polyvinyl alcohol polymer. The method for producing a crystalline solid stable preparation according to claim 3, wherein the polyvinyl alcohol polymer is a polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer. The granulation method is dry granulation or melt granulation, The method for producing a crystalline solid stable preparation according to any one of claims 1 to 4. The method for producing a stable solid preparation of crystal system according to any one of claims 1 to 5, wherein the tablet is a tablet containing α-form crystals of imatinib mesylate in an amount of 80 to 99% by weight of the solid preparation.