JP2018020999A - Atomoxetine tablet and method for producing atomoxetine tablet - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an atomoxetine tablet that is a therapeutic agent for attention deficit hyperactivity disorder (ADHD), and a method for producing the same.SOLUTION: An atomoxetine tablet contains atomoxetine or a salt thereof, glycerol fatty acid ester, and metal stearate. A method includes using both of glycerol fatty acid ester and metal stearate as lubricants for tableting, to produce an atomoxetine tablet with reduced tableting failures (sticking and binding) and sufficient tablet hardness.SELECTED DRAWING: None

Description

  The present invention relates to an atomoxetine tablet containing atomoxetine or a salt thereof as an active ingredient and a method for producing the same.

  Atomoxetine and its salts are known as therapeutic agents for attention deficit hyperactivity disorder (ADHD), and capsules and internal preparations are sold (see Non-Patent Documents 1 and 2).

Stratera (registered trademark) capsule 5mg, 10mg, 25mg, 40mg pharmaceutical interview form (revised November 2013 (9th edition)) STRATELA (registered trademark) internal medicine 0.4% pharmaceutical interview form (revised July 2014 (3rd edition))

  However, tablets containing atomoxetine and its salts (hereinafter referred to as “atomoxetine tablets”) are not sold. Tablets tend to be easier to drink than capsules and easier to carry than internal solutions. As described above, since tablets have both swallowability and portability, development of atomoxetine tablets is desired.

  The present invention has been made in view of the above circumstances, and provides an atomoxetine tablet, in particular, an atomoxetine tablet in which tableting troubles (sticking and binding) are suppressed and sufficient tablet hardness, and a method for producing the same. For the purpose of provision.

As a result of intensive studies by the present inventors, it has been found that a mixture containing atomoxetine or a salt thereof tends to cause tableting troubles such as sticking (a phenomenon in which a tableting mixture adheres to the punch). And as a lubricant, by using both glycerin fatty acid ester and stearic acid metal salt for tableting, in addition to sticking, binding (a phenomenon that can damage the side of the tablet) can be suppressed and obtained. It was found that the hardness of the tablet was sufficient, and the present invention was completed.
The present invention has the following configuration.
[1] An atomoxetine tablet comprising atomoxetine or a salt thereof, a glycerin fatty acid ester, and a metal stearate.
[2] The atomoxetine tablet according to [1], wherein the metal stearate is at least one of magnesium stearate and calcium stearate.
[3] The atomoxetine tablet according to [1] or [2], wherein the total amount of the glycerin fatty acid ester and the stearic acid metal salt is 0.1 to 5% by mass in 100% by mass of the atomoxetine tablet.
[4] The atomoxetine tablet according to any one of [1] to [3], further comprising light anhydrous silicic acid.
[5] A method for producing atomoxetine tablets, comprising a compression step of compressing a mixture containing atomoxetine or a salt thereof, a glycerin fatty acid ester, and a metal stearate.

  According to the present invention, it is possible to provide an atomoxetine tablet, particularly an atomoxetine tablet in which tableting troubles (sticking and binding) are suppressed and sufficient tablet hardness, and a method for producing the same.

Hereinafter, the present invention will be described in detail.
[Atomoxetine tablets]
The atomoxetine tablet of the present invention (hereinafter also simply referred to as “tablet”) includes atomoxetine or a salt thereof, a glycerin fatty acid ester, and a metal stearate.

Atomoxetine salts include hydrochloride, nitrate, phosphate, sulfate, hydrobromide, bromoiodide, pyrosulfate, sulfite, metaphosphate, acetate, propionate, and caprylic acid. Examples thereof include salts, formate salts, phthalate salts, citrate salts and lactate salts. Among them, atomoxetine hydrochloride is preferable.
The content of atomoxetine or a salt thereof in 100% by mass of the atomoxetine tablet is not particularly limited, but is preferably 1 to 30% by mass, more preferably 3 to 25% by mass, and further preferably 5 to 15% by mass as atomoxetine. .

The tablet of the present invention contains both a glycerin fatty acid ester and a metal stearate as a lubricant. By containing both the glycerin fatty acid ester and the stearic acid metal salt, sticking and binding can be suppressed during tableting (compression process), and an atomoxetine tablet having sufficient tablet hardness can be obtained.
Examples of the glycerin fatty acid ester include “Poem” series sold by Riken Vitamin Co., Ltd., and specifically, a polyglycerin fatty acid ester (“Poem HB ( (Trade name) ”: triglycerin fatty acid ester (manufactured by Riken Vitamin Co., Ltd.) etc. One or more glycerin fatty acid esters can be used.
Examples of the metal stearate include calcium stearate and magnesium stearate that can be used as a lubricant, and one or more of these can be used.

0.1-5 mass% is preferable in 100 mass% of atomoxetine tablets, and, as for the total amount of glycerol fatty acid ester and a stearic acid metal salt, 1.5-2.5 mass% is more preferable. Within this range, it is possible to obtain an atomoxetine tablet having sufficient tablet hardness while suppressing sticking and binding during tableting.
The mass ratio of glycerin fatty acid ester to stearic acid metal salt [glycerin fatty acid ester / stearic acid metal salt] is preferably 0.5 to 10, more preferably 0.5 to 7, still more preferably 1 to 4, and 2.5. -3.5 is most preferred.

  The tablet of the present invention may contain one or more additives other than glycerin fatty acid ester and stearic acid metal salt. Examples of the additive include a disintegrant, an excipient, a binder, a colorant, a lubricant, a fluidizing agent, and the like. Any additive that can be used in the pharmaceutical field can be used.

Examples of the excipient include crystalline cellulose, D-mannitol, lactose hydrate, anhydrous lactose, purified white sugar, potato starch, pregelatinized starch, calcium hydrogen phosphate, and the like, and one or more of these can be used. However, crystalline cellulose and D-mannitol are preferable, and when these are used in combination, elution equivalent to that of a capsule in which atomoxetine or a salt thereof is easily dissolved or an internal solution already dissolved is easily obtained.
The content of the excipient is preferably 40% by mass or more, more preferably 60 to 90% by mass, and further preferably 70 to 85% by mass in 100% by mass of the atomoxetine tablet.
When crystalline cellulose and D-mannitol are used in combination, the crystalline cellulose content is preferably 1 to 34% by mass, more preferably 5 to 29% by mass, and more preferably 12 to 22% by mass in 100% by mass of the atomoxetine tablet. . Within this range, it is easy to obtain atomoxetine tablets with excellent dissolution properties.
The content of D-mannitol is preferably 40 to 85% by mass, and more preferably 55 to 70% by mass. Within this range, it is easy to obtain atomoxetine tablets with excellent dissolution properties.

The tablet of the present invention contains a granulated product, and the granulated product preferably contains atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol. When all of atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol are contained in the granulated product, an atomoxetine tablet having sufficient tablet hardness is easily obtained.
In this case, the mass ratio [D-mannitol / crystalline cellulose] of D-mannitol in the granulated product to crystalline cellulose in the granulated product is preferably 0.5 to 12, and more preferably 5.0 to 8.0. 5.8 to 7.0 are more preferable.
In this case, the content of crystalline cellulose in the granulated product is preferably 1 to 20% by mass, more preferably 5 to 15% by mass, and preferably 8 to 12% by mass in 100% by mass of the atomoxetine tablet.

When atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol are contained in the granulated product, the portion other than the granulated product (corresponding to the “post-addition part” described later) includes atomoxetine or a salt thereof, One or more of crystalline cellulose and D-mannitol may be included, or one may not be included. Especially, the aspect in which only crystalline cellulose is contained in parts other than a granulated material among atomoxetine or its salt, crystalline cellulose, and D-mannitol is preferable. If it is this aspect, it can be set as an atomoxetine tablet which is more excellent in dissolution property and tablet hardness.
In this case, the content of crystalline cellulose contained in a part other than the granulated product is preferably 1 to 15% by mass, more preferably 5 to 11% by mass, and preferably 6 to 10% by mass in 100% by mass of the atomoxetine tablet. .

  Examples of disintegrants include cellulosic disintegrants (croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, etc.), crospovidone, starch disintegrants (corn starch, sodium starch glycolate, partial Alpha-modified starch, hydroxypropyl starch, etc.) can be used, and one or more of these can be used, but from the viewpoint of disintegration, dissolution and stability, starch-based disintegrants are preferable, and starch glycol is particularly preferable. Sodium acid is preferred.

  Examples of the binder include polyvinylpyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinyl alcohol, stearyl alcohol, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, dextrin, water candy Etc., and one or more of these can be used.

  As a lubricant, it may further contain other than glycerin fatty acid ester and stearic acid metal salt, but from the viewpoint of the above-mentioned sticking, binding, tablet hardness, etc., other than glycerin fatty acid ester and stearic acid metal salt It is preferable not to contain a lubricant. For example, it is preferable not to contain a lubricant such as stearic acid, sodium stearyl fumarate, and sucrose fatty acid ester.

Examples of the colorant include yellow ferric oxide, ferric oxide, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, etc., one of these The above can be used.
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, heavy anhydrous silicic acid, synthetic aluminum silicate, etc., and one or more of these can be used. When used, sticking can be further suppressed, which is preferable. The content of light anhydrous silicic acid is preferably 0.1 to 2% by mass in 100% by mass of atomoxetine tablets.
Examples of other additives include titanium oxide, talc, and carnauba wax.

  When the tablet is a film-coated tablet (FC tablet) composed of an uncoated tablet and a coating portion that covers the uncoated tablet, the additive is not contained in the coated portion even if it is included in the uncoated tablet. May be included in both.

Examples of the tablet of the present invention include ordinary tablets and intraoral quick disintegrating tablets that disintegrate with saliva or a small amount of water. The ordinary tablet may be composed of only a plain tablet or may be an FC tablet, but it is preferably an FC tablet from the viewpoint of suppressing eye irritation and bitterness of atomoxetine or a salt thereof.
In the case of an FC tablet, the coating part preferably contains hypromellose, titanium oxide, talc and carnauba wax exemplified above as additives. The coating part may contain a colorant.

[Method for producing tablets]
The manufacturing method of the tablet of this invention has a compression process which compresses the mixture containing atomoxetine or its salt, glycerol fatty acid ester, and a stearic acid metal salt. In the compression step, a tableting machine generally used for tableting can be used. When the mixture contains both the glycerin fatty acid ester and the stearic acid metal salt, sticking and binding are suppressed during tableting, and an atomoxetine tablet having sufficient tablet hardness is obtained.
When the tablet of the present invention is an embodiment having a granulated product containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol, the method for producing the tablet includes atomoxetine or a salt thereof, A granulation step of granulating a granulating powder containing crystalline cellulose and D-mannitol, and a mixture containing the granulated product obtained in the granulation step, glycerin fatty acid ester and stearic acid metal salt are compressed. A method having a compression step is preferred. When the tablet of the present invention is an FC tablet, it may further have a coating step for coating the uncoated tablet obtained in the compression step.

When the tablet to be produced is an embodiment containing crystalline cellulose in a portion other than the granulated product, a mixture in which crystalline cellulose is added to the granulated product may be compressed.
In addition, the additive mentioned above may be suitably contained in the powder for granulation and the mixture for compression.
The granulation step and the coating step can be performed by known methods. As described above, the compression step can be performed using a tableting machine generally used for tablet formation.

[Examples 1 to 3, Comparative Examples 1 and 2]
Tablets (uncoated tablets) were produced according to the formulation shown in Table 1 below.
First, each component described in the column of the granulated product in each table is mixed to obtain a granulating powder, water is added to the granulating powder and mixed, granulated, dried and granulated. I got a thing. To the obtained granulated product, each component described in the column of the post-addition part of each table was added and mixed to obtain a mixture for compression. This mixture was used as a rotary tableting machine (VELA5 manufactured by Kikusui Seisakusho Co., Ltd. ), And 6 punches were formed into tablets. Thus, the content of atomoxetine hydrochloride in one tablet was 45.71 mg, and an uncoated tablet consisting of a granulated product and a post-added part was obtained. About the obtained uncoated tablet (tablet), tablet hardness was measured as follows. Also evaluated sticking and binding. The results are shown in Table 1.

<Tablet hardness>
The hardness of the tablet obtained in each example was measured using a tablet hardness meter PC-30 (Okada Seiko Co., Ltd.). The tablet hardness shown in Table 1 is an average value of 5 tablets (number of samples N = 5).

<Sticking>
Sticking was evaluated according to the following criteria.
○: 150 tablets (25 tablets / claw) were tableted continuously, and even if the claw was visually confirmed, no adhesion of the mixture for compression was observed. Even if it continued, adhesion of the mixture for compression to a ridge was not recognized.
X: 150 tablets (25 tablets / claw) were tableted continuously, and when the wrinkles were visually confirmed, adhesion of the mixture for compression to the wrinkles was observed.

<Binding>
Binding was evaluated according to the following criteria.
○: Even if tableting was continued up to 1200 tablets (200 tablets / 杵) continuously, no tablets with scratches on the side were observed.
×: Scratches were observed on the side of the tablet obtained immediately after the start of tableting.

As shown in Table 1, in Comparative Example 1 using only glycerin fatty acid ester among glycerin fatty acid ester and stearic acid metal salt, although a tablet with high tablet hardness was obtained, sticking was recognized. In Comparative Example 2 using only the stearic acid metal salt among the glycerin fatty acid ester and the stearic acid metal salt, a tablet with low tablet hardness was obtained, and binding was also observed.
In contrast, in the examples in which glycerin fatty acid ester and stearic acid metal salt are used in combination, a tablet having a tablet hardness as high as that of a tablet using only glycerin fatty acid ester is obtained, and sticking and binding are performed. I was not able to admit.

[Examples 4 to 7]
FC tablets were produced according to the formulation in Table 2 below.
First, each component described in the column of the granulated product in each table is mixed to obtain a granulating powder, water is added to the granulating powder and mixed, granulated, dried and granulated. I got a thing. For the obtained granulated product, each component described in the column of the post-addition part of each table is added and mixed to obtain a mixture for compression, and the mixture for compression is a rotary tableting machine (manufactured by Kikusui Seisakusho, VELA 5) was used for tableting by standing 6 wrinkles to form an uncoated tablet consisting of a granulated product and a post-added part.
Next, a coating liquid (a liquid containing ethanol, water, hypromellose, titanium oxide, talc, and a colorant (yellow iron sesquioxide or iron sesquioxide) as desired) is coated on the obtained uncoated tablet (coating machine). After spraying and drying with Freund Sangyo Co., Ltd. (High Coater), polishing was carried out with Carnauba wax to obtain FC tablets having a coating portion with the formulation shown in Table 2.
In this way, FC tablets in which the content of atomoxetine hydrochloride in one tablet was 5.71 mg in Example 4, 11.43 mg in Example 5, 28.57 mg in Example 6, and 45.71 mg in Example 7 were obtained. Obtained. About the uncoated tablet, the tablet hardness was measured by the method described above, and the sticking and binding were evaluated as follows. The tablet hardness was also measured for the obtained FC tablets. The results are shown in Table 2. The tablet hardness shown in Table 2 is an average value of 10 tablets (number of samples N = 10).

<Sticking>
Sticking was evaluated according to the following criteria.
○: About 30000 tablets (approx. 5000 tablets / claw) were tableted continuously, and adhesion of the mixture for compression was not recognized even when the claw was visually confirmed.

<Binding>
Binding was evaluated according to the following criteria.
A: Even if tableting was continued up to about 30000 tablets (about 5000 tablets / 杵), no tablet with scratches on the side was observed.

  As described above, it was found that atomoxetine tablets containing a glycerin fatty acid ester and a metal stearate have sufficient tablet hardness with reduced tableting troubles (sticking and binding).

Claims (5)

  An atomoxetine tablet comprising atomoxetine or a salt thereof, a glycerin fatty acid ester, and a metal stearate.   The atomoxetine tablet according to claim 1, wherein the metal stearate is at least one of magnesium stearate and calcium stearate.   The atomoxetine tablet according to claim 1 or 2, wherein the total amount of the glycerin fatty acid ester and the metal stearate is 0.1 to 5% by mass in 100% by mass of the atomoxetine tablet.   Furthermore, the atomoxetine tablet as described in any one of Claims 1-3 containing a light silicic acid anhydride.   The manufacturing method of an atomoxetine tablet which has a compression process which compresses the mixture containing atomoxetine or its salt, glycerol fatty acid ester, and a stearic acid metal salt.