JP7090847B2 - Atomoxetine Tablets and Atomoxetine Tablets Manufacturing Method - Google Patents

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 oral solutions have been put on the market (see Non-Patent Documents 1 and 2).

Strattera® Capsules 5 mg, 10 mg, 25 mg, 40 mg drug interview form (revised November 2013 (9th edition)) Strattera® Internal Solution 0.4% Pharmaceutical Interview Form (Revised July 2014 (3rd Edition))

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

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an atomoxetine tablet, particularly an atomoxetine tablet having excellent dissolution property, and a method for producing the same.

The present invention has the following configurations.
[1] Atomoxetine tablets containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol (excluding sustained release tablets whose release of a drug is controlled by osmotic pressure).
[2] The atomoxetine tablet according to [1], which comprises a granulated product containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol.
[3] The atomoxetine tablet according to [2], wherein the mass ratio [D-mannitol / crystalline cellulose] of D-mannitol in the granulated product to the crystalline cellulose in the granulated product is 0.5 to 12.

According to the present invention, it is possible to provide an atomoxetine tablet having particularly excellent dissolution property 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") contains atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol.

Salts of atomoxetine include hydrochloride, nitrate, phosphate, sulfate, hydrobromide, iodate bromide, pyrosulfate, sulfite, metaphosphate, acetate, propionate, capric acid. Examples thereof include salts, formates, phthalates, citrates and lactates, and 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, still more preferably 5 to 15% by mass as atomoxetine. ..

The tablets of the present invention contain both crystalline cellulose and D-mannitol. By containing both crystalline cellulose and D-mannitol, an atomoxetine tablet having excellent elution property can be obtained. Such atomoxetine tablets are suitable because they can provide a capsule in which atomoxetine or a salt thereof is easily dissolved, or an elution equivalent to that of an already dissolved internal solution.
The content of crystalline cellulose is preferably 1 to 34% by mass, more preferably 5 to 29% by mass, and preferably 12 to 22% by mass in 100% by mass of the atomoxetine tablet. Within this range, atomoxetine tablets having excellent dissolution property can be easily obtained.
The content of D-mannitol is preferably 40 to 85% by mass, more preferably 55 to 70% by mass. Within this range, atomoxetine tablets having excellent dissolution property can be easily obtained.

The tablets of the present invention preferably contain granules containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol. By including all of these in the granulated product, it is possible to obtain an atomoxetine tablet having not only excellent dissolution property but also sufficient tablet hardness.
In this case, the mass ratio [D-mannitol / crystalline cellulose] of D-mannitol in the granulated product to the crystalline cellulose in the granulated product is preferably 0.5 to 12, more preferably 5.0 to 8.0. 5.8 to 7.0 are more preferable.
Further, 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 portion" described later) includes atomoxetine or a salt thereof. Crystalline cellulose and one or more of D-mannitol may or may not be contained. Among them, it is preferable that atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol contain only crystalline cellulose in a portion other than the granulated product. In this embodiment, an atomoxetine tablet having better elution and tablet hardness can be obtained.
In this case, the content of crystalline cellulose contained in the portion 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. ..

The tablets of the present invention may contain one or more additives other than crystalline cellulose and D-mannitol. Examples of the additive include a disintegrant, an excipient, a binder, a lubricant, a colorant, a fluidizing agent, and the like, and any additive that can be used in the pharmaceutical field can be used.

Examples of the disintegrant include a cellulosic disintegrant (crosscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, etc.), crospovidone, and a starch-based disintegrant (corn starch, sodium starch glycolate, partially). Alfarated starch, hydroxypropyl starch, etc.), etc., and one or more of these can be used, but starch-based disintegrants are preferable from the viewpoint of disintegration, elution and stability, and starch glycol is particularly preferable. Sodium acid acid is preferred.

Examples of the excipient include lactose hydrate, anhydrous lactose, purified sucrose, potato starch, pregelatinized starch, calcium hydrogenphosphate and the like, in addition to the above-mentioned crystalline cellulose and D-mannitol, and one of them. You can use more than seeds.

Examples of the binder include polyvinylpyrrolidone (povidone), hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), polyvinyl alcohol, stearyl alcohol, ammoniomethacrylate copolymer, aminoalkylmethacrylate copolymer E, polyvinylacetaldiethylaminoacetate, dextrin, and water candy. Etc., and one or more of these can be used.

As the lubricant, one or more known ones can be used, but stearic acid metal salt (magnesium stearate, calcium stearate, etc.), stearic acid, glycerin fatty acid ester, etc. can be preferably used, and among them, stearic acid metal salt and the like. It is preferable to use it in combination with glycerin fatty acid ester. When these are used in combination, the mixture for compression is suppressed from adhering to the mortar or the like during tablet molding (compression step).
The content of the lubricant is preferably 0.1 to 5% by mass, more preferably 0.5 to 2.5% by mass in 100% by mass of the tablet. When the stearic acid metal salt and the glycerin fatty acid ester are used in combination, the mass ratio of the glycerin fatty acid ester to the stearic acid metal salt [glycerin fatty acid ester / stearic acid metal salt] is preferably 0.5 to 10, preferably 0.5. ~ 7 is more preferable, and 1 to 4 is even more preferable.
Examples of the glycerin fatty acid ester include the “Poem” series sold by Riken Vitamin Co., Ltd. Specifically, the polyglycerin fatty acid ester having 22 carbon atoms in the main constituent fatty acid (“Poem HB (“Poem HB)) Product name) ”: Triglycerin fatty acid ester (manufactured by RIKEN Vitamin Co., Ltd.), etc.) can be preferably used. One or more kinds of glycerin fatty acid esters can be used.

Examples of the colorant include yellow sesquioxide, iron sesquioxide, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, and the like, and one of them. 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, and the like, and one or more of these can be used.
Examples of other additives include titanium oxide, talc, carnauba wax and the like.

When the tablet is a film-coated tablet (FC tablet) composed of an uncoated tablet and a coating portion that coats the uncoated tablet, the above additive is contained in the coating portion even if it is contained in the uncoated tablet. May be included in both.

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

[Tablet manufacturing method]
The method for producing a tablet of the present invention comprises a granulation step of granulating a granulation powder containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol, and a granulated product obtained by the granulation step. It has a compression step of compressing the containing mixture. When the tablet of the present invention is an FC tablet, it may further have a coating step of applying a coating to the uncoated tablet obtained in the compression step.

When the tablet to be produced contains crystalline cellulose in a portion other than the granulated product, the mixture to which crystalline cellulose is added in addition to the granulated product may be compressed.
The granulation powder and the compression mixture may contain the above-mentioned additives as appropriate.
The granulation step, the compression step and the coating step can be carried out by known methods.

[Examples 1 to 7, Comparative Example 1]
Tablets (uncoated tablets) were produced according to the formulations shown in Tables 1 and 2 below.
First, each component described in the column of granulated product in each table is mixed to obtain a powder for granulation, water is added to the powder for granulation and mixed, and granulation, drying and sizing are performed to granulate. I got something. 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, and this mixture was tableted and molded with a single-shot tableting machine to obtain an uncoated tablet. And said. In this way, the content of atomoxetine hydrochloride in one tablet was 45.71 mg, and an uncoated tablet consisting of a granulated product and a post-addition portion was obtained. The elution rate and tablet hardness of the obtained uncoated tablets (tablets) were measured as follows. The results are shown in Tables 1 and 2.

<Elution rate>
Using one tablet obtained and 900 mL of the test solution (water), the dissolution test was performed at 50 rpm by the paddle method. After a predetermined time from the start of the test (in this example, the result after 5 minutes is shown as shown below), 10 mL or more of the eluate was collected and filtered through a membrane filter having a pore size of 0.45 μm or less. In each filtrate, 1 mL of the next filtrate was accurately weighed and 7 mL of test solution (water) was added accurately, except for 5 mL of the initially collected filtrate. 1 mL of this solution was accurately weighed, and 1 mL of the mobile phase was accurately added to prepare a sample solution.
On the other hand, separately, about 32 mg of atomoxetine hydrochloride for quantification (water content was measured separately) was precisely weighed and dissolved by adding a mobile phase to make exactly 100 mL. 2 mL of this solution was accurately weighed, and the mobile phase was added to make exactly 100 mL. Further, 1 mL of this solution was accurately weighed, and 1 mL of the test solution (water) was accurately added to prepare a standard solution.
The sample solution and the standard solution were tested by the HPLC method, and the ultraviolet absorption at a wavelength of 215 nm was measured to obtain a chromatogram. The elution rate (%) 5 minutes after the start of the elution test of each sample solution was determined based on the peak area of the standard solution.
The mobile phase described above was prepared as follows. 2.9 g of phosphoric acid was added to water to make 1000 mL, and 5.9 g of sodium 1-octanesulfonate was dissolved in 1000 mL of a solution adjusted to pH 2.5 by adding a 5 mol / L potassium hydroxide solution. A mixture of 600 mL of this solution and 400 mL of acetonitrile was used as the mobile phase.

<Tablet hardness>
The hardness of the tablets obtained in each example was measured using a tablet hardness tester PC-30 (manufactured by Okada Seiko Co., Ltd.). The results are shown in Tables 1 and 2. The tablet hardness shown in the table is an average value of tablets (number of samples N = 3).

As shown in Tables 1 and 2, the tablets of Examples containing crystalline cellulose and D-mannitol had a high elution rate and excellent elution property. Further, each of the tablets of Examples 1 and 3 to 7, in which the granulated product contains crystalline cellulose and D-mannitol, had sufficient hardness.

[Examples 8 to 11]
FC tablets were manufactured according to the prescriptions in Table 3 below.
First, each component described in the column of granulated product in each table is mixed to obtain a powder for granulation, water is added to the powder for granulation and mixed, and granulation, drying and sizing are performed to granulate. I got something. 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, and this mixture was used as a rotary tableting machine (manufactured by Kikusui Seisakusho Co., Ltd., VELA5). ) Was compacted into a bare tablet consisting of a granulated product and a post-addition part.
Then, the obtained uncoated tablet was coated with a coating liquid (a liquid containing ethanol, water, hypromellose, titanium oxide, talc, and optionally a colorant (yellow iron sesquioxide or iron sesquioxide)) (. After spraying and drying with a high coater manufactured by Freund Sangyo Co., Ltd., polishing was performed with carnauba wax to obtain FC tablets having a coating portion of the formulation shown in Table 3.
In this way, FC tablets in which the content of atomoxetine hydrochloride in one tablet is 5.71 mg in Example 8, 11.43 mg in Example 9, 28.57 mg in Example 10, and 45.71 mg in Example 11 are obtained. Obtained. The elution rate and tablet hardness of the obtained FC tablets were measured by the methods described above.
The results are shown in Table 3.
However, as described above, in the preparation of the sample solution of Example 1 and the like, 7 mL of test solution (water) is added to 1 mL of the next filtrate after removing 5 mL of the filtrate collected at the beginning to dilute it. However, in Example 8, it was not diluted, and in Example 9, 1 mL of the test solution (water) was added to dilute it, and in Example 10, 4 mL of the test solution (water) was added to dilute it. In Example 11, 7 mL of the test solution (water) was added and diluted in the same manner as in Example 1.
The tablet hardness shown in the table is an average value of tablets (number of samples N = 10).

As described above, the atomoxetine tablet containing crystalline cellulose and D-mannitol was excellent in elution. Further, it was found that, in particular, by adding atomoxetine, crystalline cellulose, and D-mannitol to the granulated product, an atomoxetine tablet having excellent tablet hardness as well as elution property can be obtained.

Claims (3)

Atomoxetine or its salt,
With crystalline cellulose,
With D-mannitol ,
Containing one or more disintegrants selected from the group consisting of cellulosic disintegrants, crospovidone and starch-based disintegrants .
The content of atomoxetine or a salt thereof in 100% by mass of atomoxetine tablets is 5 to 15% by mass as atomoxetine.
The content of crystalline cellulose is 5 to 29% by mass,
The content of D-mannitol is 55 to 70% by mass,
Atomoxetine tablets used for the treatment of attention deficit hyperactivity disorder (excluding sustained release tablets that control drug release by osmotic pressure). The atomoxetine tablet according to claim 1, which comprises a granulated product containing atomoxetine or a salt thereof, crystalline cellulose, and D-mannitol. The atomoxetine tablet according to claim 2, wherein the mass ratio [D-mannitol / crystalline cellulose] of D-mannitol in the granulated product to the crystalline cellulose in the granulated product is 0.5 to 12.