JP7304691B2 - Tablets containing Zopiclone, its optical isomers, or salts thereof as active ingredients - Google Patents

Description

TECHNICAL FIELD The present invention relates to a tablet containing Zopiclone, an optical isomer thereof, or a salt thereof as an active ingredient.

the following formula,

Zopiclone represented by (±) 6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4 -methylpiperazine-1-carboxylate; (±)-6-(5-Chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate), and its 5S form, eszopiclone, improve sleep by binding to benzodiazepine receptors and enhancing the inhibitory mechanism of the GABA system by affecting GABA receptors. As a therapeutic agent, it is now widely used in Japan and around the world. (Patent Document 1, Non-Patent Documents 1 and 2)
According to Non-Patent Documents 1 and 2, the active ingredients of these drug substances, zopiclone and eszopiclone, were found to be slightly brown in color in a light stress test, and the content decreased by 4% after 24 hours. , the latter has also been reported to produce an analogue.
In addition, according to Non-Patent Document 1, Amoban (registered trademark) Tablets 7.5 decreased in content by 4% in a severe test of 320 hours under direct sunlight under PTP packaging, and as the main photodegradant, There is a description that substance VI was produced and impurity V was also increased.
On the other hand, according to Non-Patent Document 2, Lunesta (registered trademark) tablets 1 mg, 2 mg, and 3 mg were subjected to a storage stability test at 25°C and 75% RH without packaging. There is a statement to that effect.

Special table 6-504548

Interview form for “Amoban (registered trademark) tablets 7.5, 10” Interview form for "Lunesta (registered trademark) tablets 1, 2 and 3 mg"

Regarding tablets containing zopiclone or eszopiclone, it has been reported that related substances increased in storage stability tests, and there is a demand for the provision of stable formulations.
The present inventors completed the present invention as a result of extensive research on tablets containing eszopiclone and having excellent storage stability.

That is, the present invention
(1) any one of zopiclone, an optical isomer thereof, or a salt thereof;
(2) at least one of anhydrous calcium hydrogen phosphate, D-mannitol or lactose hydrate;
(3) A tablet containing at least one of L-methionine, hydrogenated oil and sucrose fatty acid ester.
The present invention also relates to tablets containing eszopiclone, anhydrous calcium hydrogen phosphate and hydrogenated oil.

In the tablet of the present invention, the increase of related substances is suppressed during the storage period.

FIG. 1 is a diagram showing test results confirming the difference in storage stability depending on the presence or absence of hydrogenated oil under open conditions of 40° C. and 75% RH. In the figure, the solid line represents the formulation without hydrogenated oil (reference formulation A), the dotted line represents the formulation with hydrogenated oil (formulation 1), the vertical axis represents the total affinity (%), and the horizontal axis represents the test period (weeks). represents FIG. 2 is a diagram showing the stability test results under the 40° C. sealed condition. In the figure, the solid line is the preparation containing 30% anhydrous calcium hydrogen phosphate (formulation 3), the dotted line is the preparation containing 45% anhydrous calcium hydrogen phosphate (formulation 4), and the dashed line is the preparation containing 15% anhydrous calcium hydrogen phosphate. (Formulation 2), and the vertical axis represents total affinity (%) and the horizontal axis represents study duration (weeks). FIG. 3 is a diagram showing the stability test results under the 60° C. sealed condition. In the figure, the solid line is the preparation containing 30% anhydrous calcium hydrogen phosphate (formulation 3), the dotted line is the preparation containing 45% anhydrous calcium hydrogen phosphate (formulation 4), and the dashed line is the preparation containing 15% anhydrous calcium hydrogen phosphate. (Formulation 2), and the vertical axis represents total affinity (%) and the horizontal axis represents study duration (weeks). FIG. 4 is a diagram showing the stability test results under the 40° C. sealed condition. In the figure, the solid line represents the internal addition of anhydrous calcium hydrogen phosphate (Formulation 5), the dotted line represents the external addition of anhydrous calcium hydrogen phosphate (Formulation 6), the vertical axis represents the total affinity (%), and the horizontal axis. represents the test period (weeks). FIG. 5 is a diagram showing the stability test results under the 60° C. sealed condition. In the figure, the solid line represents the internal addition of anhydrous calcium hydrogen phosphate (Formulation 5), the dotted line represents the external addition of anhydrous calcium hydrogen phosphate (Formulation 6), the vertical axis represents the total affinity (%), and the horizontal axis. represents the test period (weeks). FIG. 6 is a diagram showing the stability test results under the 40° C. sealed condition. In the figure, the solid line represents Formulation 7, the dashed line represents Formulation 8, and the vertical axis represents total affinity (%) and the horizontal axis represents study duration (weeks). FIG. 7 is a diagram showing the stability test results under the 60° C. sealed condition. In the figure, the solid line represents Formulation 7, the dashed line represents Formulation 8, and the vertical axis represents total affinity (%) and the horizontal axis represents study duration (weeks).

The present invention will be described in more detail below.
(1) The present invention is
(a) any one of zopiclone, an optical isomer thereof or a salt thereof;
(b) at least one of anhydrous calcium hydrogen phosphate, D-mannitol or lactose hydrate;
(c) A tablet containing at least one of L-methionine, hydrogenated oil or sucrose fatty acid ester.
(2) The present invention also relates to tablets containing eszopiclone, anhydrous calcium hydrogen phosphate and hydrogenated oil.
(3) The present invention also relates to the tablet described in (1) or (2) above, which contains 0.5 to 10 mg of eszopiclone per tablet.
(4) The present invention also relates to the tablet according to any one of (1) to (3) above, containing 5 to 45% of anhydrous calcium hydrogen phosphate in the tablet.
(5) The present invention also relates to the tablet according to any one of (1) to (3) above, which contains 10 to 30% of anhydrous calcium hydrogen phosphate in the tablet.
(6) The present invention also relates to the tablet according to any one of (1) to (5) above, wherein the BET surface area of anhydrous calcium hydrogen phosphate is 20 m ² /g or less.
(7) The present invention also relates to the tablet according to any one of (1) to (6) above, which contains 0.5 to 5% of hydrogenated oil in the tablet.
(8) The present invention also relates to the tablet according to any one of (1) to (7) above, which may further contain an excipient.
(9) The present invention also relates to the tablet according to any one of (2) to (8) above, wherein the excipient is selected from wheat starch, corn starch, lactose hydrate and crystalline cellulose.
(10) The present invention also relates to the tablet according to any one of (1) to (9) above, which may further contain a disintegrant.
(11) The present invention also relates to the tablet according to (10) above, wherein the disintegrant is selected from sodium starch glycolate, carmellose calcium, croscarmellose sodium and L-HPC.
(12) The present invention also relates to the tablet according to any one of (1) to (11) above, which may further contain a binder.
(13) The present invention also relates to the tablet according to (12) above, wherein the binder is selected from HPC and pregelatinized starch.
(14) The present invention also relates to the tablet according to any one of (1) to (13) above, which may further contain a lubricant.
(15) The present invention also relates to the tablet according to (14) above, wherein the lubricant is selected from magnesium stearate, calcium stearate and sodium stearyl fumarate.
(16) The present invention also relates to the tablet according to any one of (1) to (15) above, which is produced by a wet granulation method.
(17) The present invention also relates to the tablet according to any one of (1) to (16) above, wherein the anhydrous calcium hydrogen phosphate is present extragranularly.
(18) Furthermore, the present invention relates to the tablet according to any one of (1) to (17) above, which may be further film-coated.

Excipients other than anhydrous calcium hydrogen phosphate that can be used in the present invention include D-mannitol, lactose hydrate, wheat starch, corn starch, potato starch, partially pregelatinized starch, crystalline cellulose, glucose, white sugar, Examples include fructose and calcium phosphate, preferably D-mannitol, lactose hydrate, corn starch and crystalline cellulose, and more preferably crystalline cellulose.
Examples of the disintegrant that can be used in the present invention include carmellose calcium, L-HPC, partially pregelatinized starch, croscarmellose sodium, crospovidone, hydroxypropyl starch, sodium starch glycolate and the like, preferably carmellose. Examples include sucrose calcium, L-HPC, and partially pregelatinized starch.
Binders that can be used in the present invention include HPC, crystalline cellulose, hypromellose, pregelatinized starch, PVP, gelatin, starches and the like, and preferably HPC, crystalline cellulose, hypromellose, pregelatinized starch and PVP. mentioned.
Lubricants that can be used in the present invention include magnesium stearate, calcium stearate, talc, sodium stearyl fumarate, sucrose fatty acid esters, etc. Magnesium stearate, calcium stearate and sodium stearyl fumarate are preferred. and more preferably magnesium stearate.

The uncoated tablet of the present invention may further contain a fluidizing agent, a surfactant and a coloring agent.

Furthermore, the tablet of the present invention may be film-coated. The film coating layer contains light-shielding agents such as titanium oxide, coloring agents such as iron sesquioxide and yellow iron sesquioxide, plasticizers such as PEG, triethyl citrate and triacetin, film bases such as HPC and hypromellose, and carnauba wax. Polishing agents and the like can be used.
Eszopiclone is known to have a bitter taste, and a bitterness masking agent can be added to the film coating layer and the uncoated tablet.

The tablet of the present invention can be used by either a granule compression method or a direct compression method (direct compression method), and in addition to ordinary tablets (uncoated tablets), film-coated tablets and OD tablets may also be used.
For example, in the granule tableting method,
(1) Mix eszopiclone, excipients, disintegrant and hydrogenated oil.
(2) Granulation with a binder solution to obtain granules.
(3) Dry the granulated granules to obtain sized granules.
(4) Mix sized granules, anhydrous calcium hydrogen phosphate and lubricant.
(5) Tablets are obtained by tableting with a tableting machine.

As a stabilizer in the eszopiclone preparation of the present invention, sucrose fatty acid ester and L-methionine can be used instead of hydrogenated oil. (Example 1)
It is clear from FIG. 1 that in the eszopiclone formulation of the present invention, the presence of hydrogenated oil suppresses the production of related substances.
In the eszopiclone formulation of the present invention, the amount of calcium hydrogen phosphate in the uncoated tablet is preferably 10 to 40%, but the amount of calcium hydrogen phosphate in the uncoated tablet is higher than that of the formulation containing 30 or 40%. 2 and 3 show that the production of analogues is suppressed in the other.
In the eszopiclone formulation of the present invention, the addition of calcium hydrogen phosphate is preferably extragranular rather than intragranular. (Figures 4 and 5)
The BET surface area of calcium hydrogen phosphate in the eszopiclone preparation of the present invention is preferably 20 m ² /g or less. (Figures 6 and 7)

EXAMPLES The present invention will be described in more detail below with reference to Examples, but the present invention is not limited to these.

Blending change test Eszopiclone and additives were mixed and a blending change test was carried out at 60°C for 4 weeks under sealed conditions and at 40°C and 75% RH for 4 weeks.
Amounts of related substances were determined by HPLC.

The results are listed in Table 1.

As is clear from Table 1, it was found that hydrogenated oil and sucrose fatty acid ester did not change the composition.
On the other hand, meglumine, anhydrous citric acid, and magnesium oxide were found to change in composition after 4 weeks of exposure to 40°C and 75% RH.

Production method Eszopiclone, crystalline cellulose, carmellose calcium and hardened oil were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.
Next, the granulated granules were sized, and through a drying process and a dry sizing process, sized granules were obtained.
The obtained sized granules, anhydrous calcium hydrogen phosphate, light anhydrous silicic acid, and magnesium stearate were mixed, and tablets (formulation 1) shown in Table 2 having a tablet weight of 100 mg were obtained with a rotary tableting machine.

Stability Test Formulation 1 obtained in Example 1 and Reference Formulation A in Table 3 below were subjected to a storage stability test at 40° C. and 75% RH open conditions for 4 weeks.

Reference formulation A

(Manufacturing method of reference formulation A)
Eszopiclone, crystalline cellulose and carmellose calcium were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.
Next, the granulated granules were sized, and through a drying process and a dry sizing process, sized granules were obtained.
The obtained sized granules, anhydrous calcium hydrogen phosphate, light anhydrous silicic acid and magnesium stearate were mixed and tablets with a tablet weight of 100 mg were obtained by a rotary tableting machine.

Test Results Tests were carried out by the following methods, and the test results are shown in FIG.
As is clear from FIG. 1, it was found that the addition of hydrogenated oil suppressed the generation of related substances.

(Measuring method)
Powder this product, take an amount corresponding to 10 mg of eszopiclone, add 20 mL of pH 4.0 phosphate solution/acetonitrile (62:38), sonicate for 5 minutes, then Filter through a membrane filter. Remove the first 2 mL of the filtrate and use the next filtrate as the sample solution. Accurately measure 1 mL of this solution, add pH 4.0 phosphate solution/acetonitrile (62:38) to make exactly 100 mL, and use it as a standard solution. Accurately take 10 μL each of the sample solution and the standard solution, and perform the test by liquid chromatography (HPLC) under the following conditions.

(HPLC conditions)
Detector: UV absorption photometer (measurement wavelength: 303 nm)
Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm octadecylsilylated silica gel for liquid chromatography.
Column temperature: Constant temperature around 30°C Mobile phase A: pH 4.0 phosphate solution Mobile phase B: Acetonitrile Gradient control.

Differences in storage stability due to differences in the content of anhydrous calcium hydrogen phosphate

Production method Eszopiclone, crystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and hydrogenated oil were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.
Next, the granulated granules were sized, and through a drying process and a dry sizing process, sized granules were obtained.
The obtained sized granules, anhydrous calcium hydrogen phosphate, light anhydrous silicic acid and magnesium stearate were mixed and tableted with a rotary tableting machine so that the tablet weight was 100 mg. Got 4.

Test method The test was conducted in the same manner as the test method of Example 3.

Test results
The test results are shown in Figures 2 and 3.
As is clear from FIGS. 2 and 3, the formulation containing 15% anhydrous calcium hydrogen phosphate inhibited the production of related substances.

Differences in storage stability due to differences in the addition method of anhydrous calcium hydrogen phosphate

Manufacturing method of formulation 5 (up to granulation)
Eszopiclone, crystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and hydrogenated oil were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.

Manufacturing method of formulation 6 (up to granulation)
Eszopiclone, crystalline cellulose, croscarmellose sodium and hydrogenated oil were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.

After granulation (common)
The granulated granules were sieved, dried, and dried to obtain sieved granules.
The obtained sieved granules and the rear portion were mixed, and tablets 5 and 6 of Table 6 having a mass of 100 mg were obtained with a rotary tableting machine.

Test Method The test was performed in the same manner as the test method of Example 3.

Test results The test results are shown in Figures 4 and 5.
As is clear from FIGS. 4 and 5, the preparation with post-addition of anhydrous calcium hydrogen phosphate had better storage stability than the preparation with intragranular content.

Difference in storage stability due to difference in specific surface area of anhydrous calcium hydrogen phosphate

Production method
Eszopiclone, crystalline cellulose, anhydrous calcium hydrogen phosphate, croscarmellose sodium and hydrogenated oil were mixed and granulated with a hydroxypropylcellulose solution dissolved in water to obtain granules.
Next, the granulated granules were sized, and through a drying process and a dry sizing process, sized granules were obtained.
The obtained sieved granules and the powder (magnesium stearate) were mixed, and formulations 7 and 8 of Table 7 having a mass of 100 mg were obtained with a rotary tableting machine.

Formulations 7 and 8 used anhydrous calcium hydrogen phosphate having physical properties shown in Table 8.

Physical properties of anhydrous calcium hydrogen phosphate

Test Method The test was performed in the same manner as the test method of Example 3.

Test results The test results are shown in Figures 6 and 7.
As is clear from FIGS. 6 and 7, the storage stability was superior to that of anhydrous calcium hydrogen phosphate having a small specific surface area and having a large specific surface area.

The tablet of the present invention can be used as a tablet of eszopiclone because the increase of related substances is suppressed during the storage period.

Claims (13)

A plain tablet containing granules,
(a) any one of zopiclone, an optical isomer thereof or a salt thereof;
(b) anhydrous calcium hydrogen phosphate;
(c) at least one of hydrogenated oil, sucrose fatty acid ester or L-methionine ;
and
(b) is contained at 10 to 30% in ordinary tablets,
(b) has a BET surface area of 20 m ² /g or less,
A plain tablet in which (a) and (c) are intragranular and (b) is extragranular. The plain tablet according to claim 1, which contains eszopiclone, anhydrous calcium hydrogen phosphate and hydrogenated oil. The plain tablet according to claim 1 or 2, wherein one tablet contains 0.5 to 10 mg of eszopiclone. The plain tablet according to any one of claims 1 to 3, which contains 0.5 to 5% of hydrogenated oil in the plain tablet. The plain tablet according to any one of claims 1 to 4, further comprising an excipient. The plain tablet according to any one of claims 2 to 5, wherein the excipient is selected from wheat starch, corn starch, lactose hydrate or microcrystalline cellulose. The plain tablet according to any one of claims 1 to 6, further comprising a disintegrant. The plain tablet according to claim 7, wherein the disintegrant is selected from sodium starch glycolate, carmellose calcium, croscarmellose sodium or L-HPC. The plain tablet according to any one of claims 1 to 8, further comprising a binder. Plain tablet according to claim 9, wherein the binder is selected from HPC or pregelatinized starch. The plain tablet according to any one of claims 1 to 10, which may further contain a lubricant. 12. Plain tablet according to claim 11, wherein the lubricant is selected from magnesium stearate, calcium stearate or sodium stearyl fumarate. The tablet according to any one of claims 1 to 12, which is further film-coated.

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