JP6843498B2 - Tablets, solid dispersion granules and methods for producing them - Google Patents

Description

The present invention relates to tablets, solid dispersions and methods for producing them, magnesium aluminate metasilicate and methods for evaluating them.

Conventionally, tablets containing a solid dispersion containing magnesium aluminate aluminate, a water-soluble polymer substance, and a pharmaceutical active ingredient have been known. For example, Patent Document 1 describes a tablet containing solid dispersion granules containing magnesium aluminometasilicate, a hypromerose phthalate ester, and a 1,4-dihydropyridine derivative.

Japanese Patent No. 5320759

Tablets containing a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient had room for improvement in terms of improving the elution rate of the pharmaceutical active ingredient.

Therefore, the present invention provides a tablet having a fast elution rate of the pharmaceutically active ingredient even though it contains a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and the pharmaceutically active ingredient. With the goal. Another object of the present invention is to provide a solid dispersion as a material for the tablet and a method for producing the same, and magnesium aluminate aluminate as a material for the tablet or the solid dispersion and an evaluation method thereof.

The present invention is as follows.
[1] A tablet containing a solid dispersion containing magnesium aluminate aluminate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutical active ingredient in a particle size distribution.
[2] When an dissolution test was carried out by the paddle method at 37 ° C. and 75 rpm using a phosphate buffer solution having a pH of 6.8 as the test solution, the dissolution rate of the pharmaceutical active ingredient after 90 minutes was 65. % Or more, the tablet according to [1].
[3] The tablet according to [1] or [2], which has a tablet hardness of 260 N or more.
[4] The tablet according to any one of [1] to [3], wherein the water-soluble polymer substance is a hypromerose phthalate ester.
[5] The tablet according to any one of [1] to [4], wherein the pharmaceutically active ingredient is cilnidipine or a pharmaceutically acceptable salt thereof.
[6] The tablet according to any one of [1] to [5], wherein the content of the pharmaceutical active ingredient is 5 mg or more per tablet.
[7] A solid dispersion containing magnesium aluminate aluminate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutical active ingredient in a particle size distribution.
[8] Tableting is performed to produce a tablet having a tablet hardness of 260 N or more, and an dissolution test by a paddle method at 37 ° C. and 75 rpm is performed using a phosphate buffer solution having a pH of 6.8 as a test solution. The solid dispersion according to [7], wherein the elution rate of the pharmaceutical active ingredient after 90 minutes is 65% or more.
[9] The solid dispersion according to [8], wherein the content of the pharmaceutically active ingredient is 5 mg or more per tablet.
[10] The solid dispersion according to any one of [7] to [9], wherein the water-soluble polymer substance is a hypromerose phthalate ester.
[11] The solid dispersion according to any one of [7] to [10], wherein the pharmaceutically active ingredient is cilnidipine or a pharmaceutically acceptable salt thereof.
[12] In the particle size distribution, a powder containing magnesium aluminometasilicate having a D90 / D10 of 4 or more as a main component and a binding liquid containing a water-soluble polymer substance and a pharmaceutical active ingredient are mixed and stirred. A method for producing a solid dispersion, which comprises a step of granulating with a grain machine.
[13] Magnesium aluminometasilicate in which D90 / D10 satisfies the following formula (3) in the particle size distribution.
D90 / D10 = (L-63.5) / K (3)
[In the formula (3), L contains a solid dispersion containing the magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient, and a tablet having a tablet hardness of 260 N or more is produced and tested. The dissolution rate (%) of the active ingredient of the drug after 90 minutes when the dissolution test by the paddle method at 37 ° C. and 75 rpm was performed on the tablet using a phosphate buffer solution having a pH of 6.8 as a solution. Shown, K represents a real number of 0.47 to 4.7. ]
[14] The magnesium aluminate metasilicate according to [13], wherein the D90 / D10 is 4 or more.
[15] The magnesium aluminate metasilicate according to [13] or [14], wherein the water-soluble polymer substance is a hypromerose phthalate ester.
[16] Any of [13] to [15] for producing the tablet according to any one of [1] to [6] or the solid dispersion according to any one of [7] to [11]. Magnesium aluminometasilicate described in.
[17] A step of measuring the particle size distribution of magnesium aluminometasilicate and an dissolution test of a tablet containing a solid dispersion containing the magnesium aluminate metasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient are carried out. A method for evaluating magnesium aluminometasilicate, which comprises a process.
[18] The magnesium aluminometasilicate is agitated by a stirring granulator equipped with a torque meter, and the measurement step of measuring the maximum current value of the spindle after stirring for a predetermined time and the aluminate metasilicate based on the maximum current value of the spindle. A method for evaluating magnesium aluminometasilicate, which comprises a step of evaluating magnesium.

According to the present invention, it is possible to provide a tablet having a fast elution rate of a pharmaceutical active ingredient despite containing a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient. Can be done. Further, it is possible to provide a solid dispersion used as a material for the tablet and a method for producing the same, and magnesium aluminate aluminate as a material for the tablet or the solid dispersion and an evaluation method thereof.

It is a graph which plotted the relationship between the value of D90 / D10 of magnesium aluminometasilicate and the elution rate of a tablet (20 mg tablet). It is a graph which plotted the relationship between the value of D50 / D10 of magnesium aluminometasilicate and the elution rate of a tablet (20 mg tablet). It is a graph which plotted the relationship between the spindle maximum current value and the elution rate of a tablet (20 mg tablet) in the case of granulating magnesium aluminometasilicate.

[tablet]
In one embodiment, the present invention provides a tablet containing a solid dispersion containing magnesium aluminometasilicate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutically active ingredient in a particle size distribution. To do. The tablet of the present embodiment contains the pharmaceutical active ingredient after 90 minutes when an dissolution test is carried out by the paddle method at 37 ° C. and 75 rpm using a phosphate buffer solution having a pH of 6.8 as a test solution. The dissolution rate may be 65% or more. Further, the tablet of the present embodiment may have a tablet hardness of 260 N or more.

According to the tablet of the present embodiment, by setting the tablet hardness to be high, the solid dispersion granules containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient are contained. It is possible to provide tablets having a high dissolution rate of a pharmaceutical active ingredient.

Conventionally, it has been considered that the higher the tablet hardness, the slower the elution rate of the pharmaceutical active ingredient. On the other hand, in the tablet of the present embodiment, the elution rate of the pharmaceutical active ingredient is high despite the high tablet hardness.

Here, the high elution rate means that, more specifically, when an elution test is carried out by the paddle method at 37 ° C. and 75 rpm using a phosphate buffer solution having a pH of 6.8 as a test solution, the elution rate is high. It means that the dissolution rate of the pharmaceutical active ingredient after 90 minutes is 65% or more, for example 70% or more, for example 75% or more, for example 80% or more.

The dissolution test can be carried out according to the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia.

Magnesium aluminate metasilicate may be a compound represented by the following chemical formula (F1). Since the compound represented by the chemical formula (F1) does not have a clear structure, it cannot be represented by the structural formula. It is known to be a substance having an amorphous structure, being porous, having a large specific surface area, and having excellent oil absorption.
_{Al 2 O 3 · MgO · 1.7SiO} 2 · 7H 2 O (F1)

Examples of water-soluble polymer substances include methyl cellulose, hypromellose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate (hypromellose phthalate), hydroxypropyl methyl cellulose acetate succinate, carbosiki methyl ethyl cellulose, sodium carboxyl methyl cellulose, hydroxy ethyl cellulose, and phthal acetate. Cellulose such as acid cellulose and derivatives thereof; polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl acetal diethylaminoacetate, aminoalkylmethacrylate copolymer E, aminoalkylmethacryl copolymer RS, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S , Synthetic polymers such as carboxylvinyl polymers; natural polymers such as gum arabic, sodium alginate, propylene glycol alginate, agar, gelatin, tragant, xanthan gum; and sugars. One type of water-soluble polymer substance may be used alone, or two or more types may be mixed and used.

In the tablet of the present embodiment, the pharmaceutically active ingredient may be cilnidipine or a pharmaceutically acceptable salt thereof. Cilnidipine is at (±) -2-methoxyethyl 3-phenyl-2 (E) -propenyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinecarboxylate. Examples of the pharmaceutically acceptable salt include acid addition salts (for example, hydrochlorides) and the like.

The tablet of the present embodiment may contain a plurality of ingredients as a pharmaceutical active ingredient. That is, the tablet of the present embodiment may be a mixture. Examples of the pharmaceutically active ingredient other than silnidipine or a pharmaceutically acceptable salt thereof include losartan, valsartan, candesartan cilexetil, telmisartan, olmesartan medoxomil, irbesartan, azilsartan, and pharmaceutically acceptable salts thereof. Be done.

The content of the above-mentioned pharmaceutical active ingredient may be 5 mg or more, 10 mg or more, or 20 mg or more per tablet. When the content of the pharmaceutically active ingredient in the tablet is high, the elution rate of the pharmaceutically active ingredient tends to be slow. However, according to the tablet of the present embodiment, a sufficient dissolution rate can be achieved even if the content of the pharmaceutically active ingredient is the above amount.

Here, a sufficient dissolution rate means that the drug is effective after 90 minutes when the dissolution test is performed by the paddle method at 37 ° C. and 75 rpm using a phosphate buffer solution having a pH of 6.8 as a test solution. It means that the elution rate of the component is 65% or more, for example 70% or more, for example 75% or more, for example 80% or more.

In the present specification, the particle size distribution may be measured by any method such as a dynamic light scattering method, a laser diffraction / scattering method, and an image imaging method. For example, it may be measured by a dry laser diffraction / scattering type particle size distribution measuring device.

The tablet of the present embodiment contains a pharmaceutically acceptable excipient, a binder, a disintegrant, a lubricant, etc., in addition to the active pharmaceutical ingredient, magnesium aluminometasilicate, and a water-soluble polymer substance. You may.

Excipients include, for example, sugars such as lactose, mannitol, sucrose and glucose, starches such as potato starch, corn starch and partially pregelatinized starch, inorganic salts such as precipitated calcium carbonate, calcium phosphate and sodium chloride, and crystalline cellulose. And so on.

Examples of the binder include partially saponified polyvinyl alcohol, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, pullulan, methyl cellulose, gum arabic, starches and the like.

Examples of the disintegrant include crospovidone, low-degree-of-substitution hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, partially pregelatinized starch, hydroxypropyl starch and the like.

Examples of the lubricant include magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, hydrogenated vegetable oil, and talc.

The lubricant may be added in advance to the active ingredient, excipient, etc., and the kneaded product of the active ingredient, excipient, etc. and the lubricant may be tableted (such as this). The method for producing tablets is called the internal smoothing method), and the smoothing agent is sprayed on the surface of the punch or mortar without adding it to the active ingredients of medicines, excipients, etc. A knives or mortar having a lubricant layer may be used to tablet a kneaded product such as a pharmaceutical active ingredient or an excipient (a method for producing such a tablet is called an external tablet method). ). Further, as the coating method, various coating methods can be used as long as it is a conventional coating method, and for example, a pan (or drum) coating method, a fluid coating method, or the like can be used. The film thickness of such a coating may be, for example, about 10 to 150 μm.

[Solid dispersion]
In one embodiment, the present invention provides a solid dispersion containing magnesium aluminate aluminate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutically active ingredient in a particle size distribution. The solid dispersion of the present embodiment is tableted to produce a tablet having a tablet hardness of 260 N or more, and a paddle method at 37 ° C. and 75 rpm is used as a test solution using a phosphate buffer solution having a pH of 6.8. When the dissolution test according to the above is performed on the tablet, the dissolution rate of the pharmaceutical active ingredient after 90 minutes may be 65% or more. Further, in the present specification, the solid dispersion may be solid dispersion granules. Further, examples of the water-soluble polymer substance include the same substances as those described above.

The solid dispersion of the present embodiment is a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient when tablets are tableted to produce tablets having high tablet hardness. Despite the inclusion, it is possible to provide a tablet having a high dissolution rate of a pharmaceutical active ingredient. The above-mentioned tablets may have a content of a pharmaceutical active ingredient of 5 mg or more per tablet. In addition, the upper limit of the pharmaceutical active ingredient contained in the above tablets is, for example, 20 mg per tablet.

In the solid dispersion of the present embodiment, the pharmaceutically active ingredient may be cilnidipine or a pharmaceutically acceptable salt thereof. In addition, the tablet of the present embodiment may contain a plurality of ingredients as a pharmaceutical active ingredient. Examples of the pharmaceutically active ingredient contained in the solid dispersion of the present embodiment include the same as those described above.

[Manufacturing method of solid dispersion]
In one embodiment, the present invention comprises a powder containing magnesium aluminometasilicate having a D90 / D10 of 4 or more as a main component in a particle size distribution, and a binding solution containing a water-soluble polymer substance and a pharmaceutical active ingredient. To provide a method for producing a solid dispersion, which comprises a step of mixing and granulating with a stirring granulator. In the present specification, D10 means a particle size corresponding to a volume accumulation of 10% from the side having a smaller particle size in the particle size distribution. Similarly, D90 means a particle size in which the volume accumulation from the smaller particle size side corresponds to 90% in the particle size distribution. Examples of the water-soluble polymer substance include the same substances as those described above.

In another embodiment, the present invention comprises a powder containing magnesium aluminometasilicate having a D50 / D10 of 2 or more as a main component in a particle size distribution, and a binding liquid containing a water-soluble polymer substance and a pharmaceutical active ingredient. To provide a method for producing a solid dispersion, which comprises a step of mixing and granulating with a stirring granulator. In the present specification, D50 means a particle size corresponding to a volume accumulation of 50% from the side having a smaller particle size in the particle size distribution. Examples of the water-soluble polymer substance include the same substances as those described above.

According to the production method of the above embodiment, it is possible to produce a solid dispersion in which the elution rate of the pharmaceutical active ingredient is high when tablets are produced. The above-mentioned tablets may have a content of a pharmaceutical active ingredient of 5 mg or more per tablet.

In the production method of this embodiment, the pharmaceutically active ingredient may be cilnidipine or a pharmaceutically acceptable salt thereof. Examples of the pharmaceutical active ingredient contained in the solid dispersion include the same as those described above.

[Magnesium aluminate metasilicate]
In one embodiment, the present invention provides magnesium aluminometasilicate in which D90 / D10 satisfies the following formula (3) in a particle size distribution. In the formula (3), L contains a solid dispersion containing the magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient, and a tablet having a tablet hardness of 260 N or more is produced, and a test solution is prepared. The dissolution rate (%) of the pharmaceutical active ingredient after 90 minutes when the dissolution test by the paddle method at 37 ° C. and 75 rpm was performed on the tablet using a phosphate buffer solution having a pH of 6.8 is shown. , K represent a real number of 0.47 to 4.7. Examples of the water-soluble polymer substance include the same substances as those described above.
D90 / D10 = (L-63.9) / K (3)

In the magnesium aluminate aluminate of the present embodiment, the elution rate of the pharmaceutical active ingredient in the case of producing tablets satisfies the formula (3). Therefore, by using magnesium aluminate aluminate of the present embodiment as a material, a tablet showing an elution rate of a pharmaceutically active ingredient in a desired range can be produced.

The D90 / D10 of the above magnesium aluminate aluminate may be 4 or more. By using magnesium aluminate metasilicate having a D90 / D10 of 4 or more as a material, a tablet having a high elution rate of a pharmaceutical active ingredient can be produced.

In one embodiment, the present invention provides magnesium aluminometasilicate in which D50 / D10 satisfies the following formula (4) in a particle size distribution. In the formula (4), L contains a solid dispersion containing the magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient, and a tablet having a tablet hardness of 260 N or more is produced to produce a test solution. The dissolution rate (%) of the pharmaceutical active ingredient after 90 minutes when the dissolution test by the paddle method at 37 ° C. and 75 rpm was performed on the tablet using a phosphate buffer solution having a pH of 6.8 is shown. , K'indicates a real number from 1.0 to 4.7. Examples of the water-soluble polymer substance include the same substances as those described above.
D50 / D10 = (L-64.3) / K'(4)

In the magnesium aluminate aluminate of the present embodiment, the elution rate of the pharmaceutical active ingredient in the case of producing tablets satisfies the formula (4). Therefore, by using magnesium aluminate aluminate of the present embodiment as a material, a tablet showing an elution rate of a pharmaceutically active ingredient in a desired range can be produced.

The D50 / D10 of the above magnesium aluminate aluminate may be 2 or more. By using magnesium aluminate metasilicate having a D50 / D10 of 2 or more as a material, a tablet having a high elution rate of a pharmaceutical active ingredient can be produced.

It can also be said that the above-mentioned magnesium aluminate aluminate is for producing the above-mentioned tablets or solid dispersions.

[Evaluation method of magnesium aluminate metasilicate]
In one embodiment, the present invention comprises a step of measuring the particle size distribution of magnesium aluminometasilicate, a solid dispersion containing the magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient. Provided is a method for evaluating magnesium aluminometasilicate, which comprises a step of performing a tablet dissolution test. The evaluation method of the present embodiment includes a step of measuring the particle size distribution of magnesium aluminometasilicate, and when D90 / D10 is 4 or more in the particle size distribution, the magnesium aluminometasilicate is highly water-soluble. Tablets having a tablet hardness of 260 N or more containing a solid dispersion containing a molecular substance and a pharmaceutical active ingredient are prepared at 37 ° C. and 75 rpm at 37 ° C. using a phosphate buffer solution having a pH of 6.8 as a test solution. The method for evaluating magnesium aluminometasilicate may include a step of determining that the dissolution rate of the pharmaceutical active ingredient after 90 minutes becomes 65% or more when the dissolution test is performed by the paddle method. Examples of the water-soluble polymer substance include the same substances as those described above.

In another embodiment, the present invention comprises a step of measuring the particle size distribution of magnesium aluminometasilicate, and when D50 / D10 is 2 or more in the particle size distribution, the magnesium aluminometasilicate is water-soluble. Tablets having a tablet hardness of 260 N or higher, which contains a solid dispersion containing a sex polymer substance and a pharmaceutical active ingredient, are prepared at 37 ° C. at 75 ° C. per minute using a phosphate buffer solution having a pH of 6.8 as a test solution. Provided is a method for evaluating magnesium aluminometasilicate, which comprises a step of determining that the dissolution rate of the pharmaceutical active ingredient after 90 minutes becomes 65% or more when an dissolution test by a rotary paddle method is performed. Examples of the water-soluble polymer substance include the same substances as those described above.

According to the evaluation method of the present embodiment, when a tablet is produced using the target magnesium aluminometasilicate, whether or not the elution rate of the pharmaceutical active ingredient can achieve a predetermined value is determined by actually producing the tablet. You can predict without doing anything.

In one embodiment, the present invention is based on a measurement step of stirring magnesium aluminometasilicate with a stirring granulator equipped with a torque meter and measuring the maximum spindle current value after stirring for a predetermined time, and the maximum spindle current value. The present invention provides a method for evaluating magnesium aluminometasilicate, which comprises the step of evaluating magnesium aluminometasilicate. The evaluation method of the present embodiment is based on a measurement step of stirring magnesium aluminometasilicate with a stirring granulator equipped with a torque meter and measuring the maximum current value of the spindle after stirring for a predetermined time, and based on the maximum current value of the spindle. A tablet having a tablet hardness of 260 N or more containing a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient is a phosphate buffer solution having a pH of 6.8 as a test solution. When the dissolution test by the paddle method at 37 ° C. and 75 rpm is performed using the above, a determination step for determining whether or not the dissolution rate of the active ingredient of the pharmaceutical substance after 90 minutes is 65% or more is determined. Provided is a method for evaluating magnesium aluminometasilicate.

In the evaluation method of the above embodiment, in the measurement step, 17.5 g of magnesium aluminometasilicate is put into a stirring granulator equipped with a torque meter, the magnesium aluminometasilicate is stirred for 2 minutes, and the agitated metasilicate magnesium is then stirred. To magnesium aluminate, 26 g of a buffer solution containing 3.33 parts by mass of Macrogol 400 3.33 parts by mass, 19.04 parts by mass of hypromerose phthalate, 57.8 parts by mass of methanol and 57.8 parts by mass of dichloromethane was added. It is a step of measuring the maximum current value of the spindle after further stirring for 12 minutes, and when the maximum current value of the spindle is 0.048 A or more, the magnesium aluminometasilicate and the hypromerose phthalate are determined. A tablet containing a solid dispersion granule containing the ester and the active ingredient of the drug and having a tablet hardness of 260 N or more is prepared at 37 ° C. and 75 rpm at 37 ° C. using a phosphate buffer solution having a pH of 6.8 as a test solution. When the dissolution test by the paddle method is performed, it may be a step of determining that the dissolution rate of the pharmaceutical active ingredient after 90 minutes is 65% or more.

The maximum spindle current value measured in the measuring step may be 0.03 A or more, 0.045 A or more, or 0.1 A or more. Examples of the stirring granulator with a torque meter include the trade name "PalmXer" manufactured by Imoto Seisakusho Co., Ltd. When PalmXer (trade name, manufactured by Imoto Seisakusho Co., Ltd.) is used as a stirring granulator with a torque meter, the maximum spindle current value measured in the measuring process may be 0.48 A or more, and 0.1 A or more. It may be 0.125A or more.

According to the evaluation method of the present embodiment, when a tablet is produced using the target magnesium aluminometasilicate, whether or not the elution rate of the pharmaceutical active ingredient can achieve a predetermined value is determined by actually producing the tablet. You can predict without doing anything.

Hereinafter, the present invention will be described with reference to Experimental Examples, but the present invention is not limited to the following Experimental Examples.

<Evaluation of magnesium aluminate metasilicate>
[Measurement of D90 / D10]
Lots 1 to 5 of magnesium aluminometasilicate were prepared, and the particle size distribution was measured with a dry laser diffraction / scattering type particle size distribution measuring device (model "LA-950S2", manufactured by HORIBA, Ltd.). Subsequently, the values of D90 / D10 were calculated based on the measurement results of the particle size distribution. The results are shown in Table 1.

[Measurement of D50 / D10]
Similar to the measurement of D90 / D10, the values of D50 / D10 of magnesium aluminometasilicate in lots 1 to 5 were calculated respectively. The results are shown in Table 1.

[Measurement of maximum spindle current value of stirring granulator when granulated]
Subsequently, lots 1 to 5 of magnesium aluminometasilicate were granulated with a stirring granulator with a torque meter (trade name "PalmXer", manufactured by Imoto Seisakusho Co., Ltd.), and the maximum current value of the spindle after stirring for a predetermined time was measured. ..

Specifically, first, 17.5 g of each lot of magnesium aluminate aluminate was put into a stirring granulator with a torque meter and stirred for 2 minutes. Subsequently, the stirred magnesium aluminometasilicate contains 3.33 parts by mass of macrogol 400, 19.04 parts by mass of hypromerose phthalate, 57.8 parts by mass of methanol, and 57.8 parts by mass of dichloromethane. 26 g of the binder was added, and the maximum spindle current value was measured after further stirring for 12 minutes. The measurement results are shown in Table 1.

<Manufacturing of tablets>
[Example 1]
(Manufacturing of A granules)
A solution prepared by dissolving 10.0 mg of silnidipine, 4007 mg of macrogol, and 40.0 mg of hydroxypropyl cellulose in 180 mg of a mixed solvent of methanol-dichloromethane was added to 110.0 mg of magnesium aluminometasilicate of the above lot 1 and an appropriate amount of lactose. In addition to 31.4 mg of crystalline cellulose and 25 mg of croscarmellose sodium, the mixture was mixed and stirred, and the solvent was distilled off to prepare 248 mg of the solid dispersion granules (A granules) of Example 1.

(Manufacturing of B granules)
A solution prepared by dissolving 10.0 mg of silnidipine, 4007 mg of macrogol, and 40.0 mg of hypromerose phthalate in 242 mg of a mixed solvent of methanol-dichloromethane was added to 110.0 mg of magnesium aluminometasilicate in Lot 1 in an appropriate amount. In addition to lactose, crystalline cellulose (31.4 mg) and croscarmellose sodium (25.0 mg), the mixture was mixed and stirred, and the solvent was distilled off to prepare 248 mg of the solid dispersion granules (B granules) of Example 1.

(Manufacturing of tablets)
Example 1 in which the above A granules and B granules are mixed at a mass ratio of 3: 7, and 2 mg of magnesium stearate and 2 mg of talc are added to each tablet for tableting to contain 20 mg of cilnidipine per tablet. Tablets (uncoated tablets) (500 mg per tablet) were produced. The shape of the tablet was an ellipse with a score line for dividing.

[Examples 2 to 4, Comparative Example 1]
Example 2 and Example 1 in the same manner as in Example 1 except that lot 2, lot 3, lot 3, lot 4 and lot 5 magnesium aluminometasilicate were used instead of the magnesium aluminometasilicate of lot 1, respectively. 3. Solid dispersion granules (A granules), solid dispersion granules (B granules) and tablets of Example 4 and Comparative Example 1 were produced.

<Evaluation of tablets>
For the tablets of Examples 1 to 4 and Comparative Example 1, the tablet hardness and the elution rate of cilnidipine were measured.

(Tablet hardness)
Using a tablet hardness tester (manufactured by Okada Seiko Co., Ltd., TS-50N or TS-75N), pressure was applied in the long axis direction of each tablet to measure the tablet hardness. The tablet hardness was measured for 10 tablets, and the average value was taken as the tablet hardness. The results are shown in Table 2.

(Elution rate)
The dissolution rate of cilnidipine was measured according to the dissolution test method (paddle method) described in the 16th revised Japanese Pharmacopoeia. The measurement conditions were as follows. The results are shown in Table 2.
(Measurement conditions for elution rate)
Test solution: 0.1% (W / V) polysorbate 80 / pH 6.8 phosphate buffer 900 mL
Paddle speed: 75 rpm
Test solution temperature: 37 ± 0.5 ° C
Elution rate (%): Measure the elution rate of cilnidipine after 90 minutes

<Relationship between the value of D90 / D10 and the dissolution rate of tablets (20 mg tablets)>
FIG. 1 is a graph plotting the relationship between the D90 / D10 value of magnesium aluminate aluminate and the elution rate of tablets (20 mg tablets). A positive correlation was observed between the value of D90 / D10 and the dissolution rate of the tablet, and it was shown that the following formula (5) holds when the dissolution rate is y and D90 / D10 is x. In the formula (5), the correlation coefficient ^{(R 2)} was 0.748.
y = 0.9726x + 63.541 (5)

Here, the formula (3) is obtained by replacing the slope of the straight line represented by the formula (5) with K and replacing the elution rate with L.
D90 / D10 = (L-63.5) / K (3)

As a result of conducting many similar studies on the relationship between the value of D90 / D10 and the dissolution rate of the tablet (20 mg tablet), when K in the formula (3) is in the range of 0.47 to 4.7, the tablet (20 mg tablet) The dissolution rate of 20 mg tablets) tended to be 65% or more.

<Relationship between the value of D50 / D10 and the dissolution rate of tablets (20 mg tablets)>
FIG. 2 is a graph plotting the relationship between the D50 / D10 value of magnesium aluminate aluminate and the elution rate of tablets (20 mg tablets). A positive correlation was observed between the value of D50 / D10 and the dissolution rate of the tablet, and it was shown that the following formula (6) holds when the dissolution rate is y and D50 / D10 is x. In the formula (6), the correlation coefficient (R2) was 0.7383.
y = 1.7478 x +63.291 (6)

Here, the equation (4) is obtained by substituting the slope of the straight line represented by the equation (6) with K'and the elution rate with L and transforming it.
D50 / D10 = (L-63.3) / K'(4)

As a result of conducting many similar studies on the relationship between the value of D50 / D10 and the dissolution rate of the tablet (20 mg tablet), when K'in the formula (4) is in the range of 1.0 to 4.7, the tablet The dissolution rate of (20 mg tablet) tended to be 65% or more.

<Relationship between maximum spindle current value and elution rate of tablets (20 mg tablets)>
FIG. 3 is a graph plotting the relationship between the maximum current value of the spindle and the dissolution rate of the tablet (20 mg tablet). A positive correlation was observed between the maximum spindle current value and the dissolution rate of the tablet, and it was shown that the following equation (7) holds when the dissolution rate is y and the maximum spindle current value is x. In the formula (7), the correlation coefficient ^{(R 2)} was 0.7306.
y = 64.641x + 61.922 (7)

According to the present invention, it is possible to provide a tablet having a fast elution rate of a pharmaceutical active ingredient despite containing a solid dispersion containing magnesium aluminometasilicate, a water-soluble polymer substance, and a pharmaceutical active ingredient. Can be done. Further, it is possible to provide a solid dispersion used as a material for the tablet and a method for producing the same, and magnesium aluminate aluminate as a material for the tablet or the solid dispersion and an evaluation method thereof.

Claims (11)

It contains solid dispersion granules containing magnesium aluminate aluminate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutical active ingredient in a particle size distribution.
The water-soluble polymer substance is one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, hypromellose phthalate and polyethylene glycol, and the pharmaceutically active ingredient is cilnidipine or its pharmaceutically active ingredient. Acceptable salt,
tablet. When the dissolution test was carried out by the paddle method at 37 ° C. and 75 rpm using a phosphate buffer solution having a pH of 6.8 as the test solution, the dissolution rate of the pharmaceutical active ingredient after 90 minutes was 65% or more. The tablet according to claim 1. The tablet according to claim 1 or 2, wherein the tablet hardness is 260 N or more. The tablet according to any one of claims 1 to 3, wherein the water-soluble polymer substance is one or more selected from the group consisting of hypromerose phthalate, hydroxypropyl cellulose and polyethylene glycol. .. The tablet according to any one of claims 1 to 4, wherein the content of the pharmaceutical active ingredient is 5 mg or more per tablet. In the particle size distribution, it contains magnesium aluminometasilicate having a D90 / D10 of 4 or more, a water-soluble polymer substance, and a pharmaceutical active ingredient.
The water-soluble polymer substance is one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, hypromellose phthalate and polyethylene glycol, and the pharmaceutically active ingredient is cilnidipine or its pharmaceutically active ingredient. Acceptable salt,
Solid dispersion granules . Tablets were tableted to produce tablets having a tablet hardness of 260 N or more, and an dissolution test was carried out on the tablets by the paddle method at 37 ° C. and 75 rpm at 37 ° C. using a phosphate buffer solution having a pH of 6.8 as a test solution. The solid dispersion granule according to claim 6, wherein the elution rate of the pharmaceutical active ingredient after 90 minutes is 65% or more. The solid dispersion granule according to claim 7, wherein the content of the pharmaceutically active ingredient is 5 mg or more per tablet. The solid according to any one of claims 6 to 8, wherein the water-soluble polymer substance is one or more selected from the group consisting of hypromerose phthalate, hydroxypropyl cellulose and polyethylene glycol. Dispersion granules . In the particle size distribution, a powder containing magnesium aluminometasilicate having a D90 / D10 of 4 or more as a main component and a binder liquid containing a water-soluble polymer substance and a pharmaceutical active ingredient are mixed, and a stirring granulator is used. Equipped with a granulation process
The water-soluble polymer substance is one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, hypromellose phthalate and polyethylene glycol, and the pharmaceutically active ingredient is cilnidipine or its pharmaceutically active ingredient. Acceptable salt,
A method for producing solid dispersion granules. The method for producing solid dispersion granules according to claim 10, wherein the water-soluble polymer substance is one or more selected from the group consisting of hypromerose phthalate, hydroxypropyl cellulose and polyethylene glycol.

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