JP7226697B2 - Blonanserin-containing tablet - Google Patents

Description

The present invention relates to tablets containing blonanserin as an active ingredient.

Blonanserin is known as a therapeutic agent for schizophrenia. Blonanserin is disclosed, for example, in US Pat.

Japanese Patent Publication No. 7-47574

While the present inventors are studying tablets containing blonanserin (hereinafter referred to as blonanserin-containing tablets), blonanserin-containing tablets undergo discoloration over time, and related substances increase, which is a problem related to stability. was found to have

An object of the present invention is to provide a blonanserin-containing tablet with improved stability.

As a result of intensive studies, the present inventors have found that one of the reasons for the insufficient stability of blonanserin-containing tablets lies in the glidant used in the tablets. Then, the inventors have come to realize that the stability of blonanserin-containing tablets can be improved by using a specific fluidizing agent when a fluidizing agent is used, or by not using a fluidizing agent.

The present invention has the following aspects.
[1] A tablet containing blonanserin or a pharmaceutically acceptable salt thereof, crystalline cellulose, lactose hydrate, hydroxypropylcellulose, and magnesium stearate and containing no fluidizing agent.
[2] The tablet according to [1], wherein the glidant is one or more selected from light anhydrous silicic acid, magnesium aluminometasilicate, and synthetic aluminum silicate.
[3] The tablet according to [1] or [2], which is an uncoated tablet.

According to the present invention, a blonanserin-containing tablet with improved stability can be provided.

The present invention will be described in detail below.
[Blonanserin-containing tablet]
The blonanserin-containing tablet of the present invention (hereinafter also simply referred to as "tablet") is a tablet containing blonanserin or a pharmaceutically acceptable salt thereof, and containing a specific fluidizing agent, namely hydrous silicon dioxide, hydrogen phosphate It includes an embodiment containing one or more selected from calcium and talc, and an embodiment containing no fluidizing agent.
In this way, when the tablet contains a specific fluidizing agent or does not contain a fluidizing agent, discoloration of the tablet over time and increase of related substances are suppressed, resulting in a blonanserin-containing tablet with improved stability. be able to.

Pharmaceutically acceptable salts of Blonanserin include, for example, hydrochloride, hydrobromide, sulfate, phosphate, maleate, fumarate, tartrate and the like.
The content of blonanserin or a pharmaceutically acceptable salt thereof in 100% by mass of blonanserin-containing tablet is not particularly limited, but as blonanserin, 0.1 to 10% by mass is preferable, and 1 to 7% by mass is more preferable. , 2 to 4% by mass is more preferable.

When the tablet of the present invention contains one or more fluidizing agents selected from hydrated silicon dioxide, calcium hydrogen phosphate and talc, the amount of fluidizing agents is preferably 0.01 to 3 mass%, preferably 0.1 to 2%. % by mass is more preferred, and 0.1 to 1.5% by mass is even more preferred.

As described above, the tablet of the present invention includes an aspect containing a specific fluidizing agent and an aspect not containing a fluidizing agent. In addition to improving the above, the use of hydrous silicon dioxide as a fluidizing agent is preferable from the viewpoint of obtaining tablets with high tablet hardness and suppressed chipping and cracking.
On the other hand, if any one or more of light anhydrous silicic acid, magnesium aluminometasilicate, and synthetic aluminum silicate is included as a glidant, discoloration of the tablet over time and an increase in related substances will be significant, resulting in decreased stability. do. Therefore, it is preferable not to use them.
Preferred specific embodiments of the tablet of the present invention include those containing hydrated silicon dioxide and containing none of light anhydrous silicic acid, magnesium aluminometasilicate, and synthetic aluminum silicate.

The tablet of the present invention may contain one or more additives other than a glidant. Examples of additives include excipients, disintegrants, lubricants, binders, colorants, surfactants, and the like, and any additive that can be used in the pharmaceutical field can be used.

Excipients include, for example, crystalline cellulose, lactose hydrate, anhydrous lactose, D-mannitol, refined sucrose, potato starch, pregelatinized starch, etc. One or more of these can be used.
The excipient content is preferably 60 to 95% by mass, more preferably 70 to 90% by mass, and even more preferably 80 to 85% by mass based on 100% by mass of the tablet.

Examples of disintegrants include cellulose-based disintegrants (croscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropylcellulose, etc.), crospovidone, starch-based disintegrants (corn starch, sodium starch glycolate, partial pregelatinized starch, hydroxypropyl starch, etc.) and the like, and one or more of these can be used.
The content of the disintegrant is preferably 0.1 to 20% by mass, more preferably 5 to 15% by mass, and even more preferably 7 to 12% by mass in 100% by mass of the tablet.

Lubricants include, for example, stearic acid metal salts such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid esters and sucrose fatty acid esters, sodium stearyl fumarate and the like, and at least one of these. can be used.
The content of the lubricant is preferably 0.1 to 5% by mass, more preferably 0.5 to 3.5% by mass, even more preferably 0.5 to 2% by mass, based on 100% by mass of the tablet.

Examples of binders include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearyl alcohol, ammonio methacrylate copolymer, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, dextrin, and starch syrup. One or more of these can be used.
The binder content is preferably 0.1 to 10% by mass, more preferably 1 to 5% by mass, even more preferably 1 to 3% by mass, based on 100% by mass of the tablet.

Examples of the coloring agent include yellow iron sesquioxide, iron sesquioxide, food yellow No. 4, food yellow No. 5, food red No. 2, food red No. 3, food red No. 102, etc. One of these You can use more than

Surfactants include sodium lauryl sulfate, polysorbate 80, and the like, and one or more of these can be used.
Other additives include titanium oxide and carnauba wax.

Examples of the tablet of the present invention include ordinary tablets, intraorally rapidly disintegrating tablets that disintegrate with saliva or a small amount of water, and the like. The plain tablet may consist of only an uncoated tablet, or may be a film-coated tablet (including enteric-coated tablets, sustained-release coated tablets, etc.). A plain tablet is preferable as the tablet of the present invention.
When the tablet is a film-coated tablet consisting of an uncoated tablet and a coating covering the uncoated tablet, the above excipients are contained in both the uncoated tablet and the coating. may

[Tablet manufacturing method]
The method for producing the tablet of the present invention is not particularly limited as long as it can produce a tablet containing blonanserin or a pharmaceutically acceptable salt thereof. A tableting step of tableting the mixture containing the additives. A tableting machine generally used for tableting can be used for the tableting step. The mixture contains blonanserin or a pharmaceutically acceptable salt thereof and one or more selected from hydrated silicon dioxide, calcium hydrogen phosphate, and talc as a fluidizing agent, or does not contain a fluidizing agent, A blonanserin-containing tablet with improved stability can be obtained by suppressing the significant discoloration of the tablet and the increase of related substances.

Before the tableting step, it is preferable to have a granulation step of pre-granulating a mixture containing blonanserin or a pharmaceutically acceptable salt thereof and other additives. In the tableting step, only the granules obtained in the granulation step may be tableted, or components may be post-added to the granules before tableting. Examples of components to be added later include fluidizing agents such as hydrated silicon dioxide, calcium hydrogen phosphate, and talc.
When the tablet of the present invention is a film-coated tablet, it may further have a coating step of coating the uncoated tablet obtained in the tableting step. The granulation step and the coating step can each be performed by a known method.

[Examples 1 to 4, Comparative Examples 1 to 3]
According to the recipe in Table 1 below, 60 mg tablets were produced.
First, each component described in the column of granules in Table 1 is mixed to obtain a powder for granulation. Obtained. To the obtained sieved product, each component described in the last column of Table 1 was added and mixed to obtain a mixture for tableting, and this mixture was subjected to a rotary tableting machine (VELA5, manufactured by Kikusui Seisakusho). to obtain tablets.

<color difference>
The tablets before and after storage under severe thermal conditions (2 weeks in a 60°C environment or 4 weeks in a 60°C environment) were measured with a color difference meter (CR-300, manufactured by Minolta) based on a white calibration plate. values were measured. Tablets before and after storage under thermal stress conditions using the measured Lab values

<Purity>
At the time of manufacture (Initial), after storage under severe light conditions (accumulated illuminance of 600,000 lx·h, accumulated illuminance of 1,200,000 lx·h), severe heat conditions (2 weeks under 60 ° C environment, 4 weeks under 60 ° C environment ), the purity was evaluated by measuring the total amount of related substances in the obtained tablets. Table 4 shows the results.
The total amount of related substances is the sum of the total amount of multiple related substances measured and quantified by an automatic analysis method using high-performance liquid chromatography. The ratio of the sum of the peak areas of each related substance to the

<Hardness>
The tablet hardness (kgf) was measured using a tablet hardness tester (PC-30, manufactured by Okada Seiko Co., Ltd.) for tablets compressed with a rotary tableting machine at a compression pressure of 7.5 KN. The hardness shown in Table 5 is the average value of 10 tablets.

程度の変色しか示さなかった。また、表４に示すとおり、全ての条件での保存後においてＩｎｉｔｉａｌからの総類縁物質の増加量が小さかった。
これに対して、含水二酸化ケイ素、リン酸水素カルシウム、タルク以外の流動化剤（軽質無水ケイ酸、メタケイ酸アルミン酸マグネシウム、合成ケイ酸アルミニウム）を含む比較例１～３の錠剤は、表２に示すとおり、６０℃２週間および６０℃４週間の各条件での

られた。また、表４に示すとおり、実施例１～４の錠剤に比べ全ての条件での保存後においてＩｎｉｔｉａｌからの総類縁物質の増加量も大きかった。
さらに、表５に示すように、実施例のなかでも、流動化剤として含水二酸化ケイ素を含む実施例１の錠剤は、錠剤硬度が十分に高かった。
以上の結果から、流動化剤として含水二酸化ケイ素、リン酸水素カルシウム、タルクから選ばれる一つ以上を含むか、流動化剤を含まない実施例１～４の錠剤は安定性に優れ、なかでも流動化剤として含水二酸化ケイ素を使用することにより、硬度の高い錠剤が得られることが明らかとなった。The tablets of Examples 1 to 4 containing one or more selected from hydrated silicon dioxide, calcium hydrogen phosphate, and talc as a fluidizing agent or containing no fluidizing agent were stored at 60° C. for 2 weeks, as shown in Table 2.

It showed only moderate discoloration. In addition, as shown in Table 4, the increase in total related substances from Initial was small after storage under all conditions.
On the other hand, the tablets of Comparative Examples 1 to 3 containing hydrated silicon dioxide, calcium hydrogen phosphate, and fluidizing agents other than talc (light anhydrous silicic acid, magnesium aluminometasilicate, synthetic aluminum silicate) are shown in Table 2. As shown in , under each condition of 60 ° C. 2 weeks and 60 ° C. 4 weeks

was taken. In addition, as shown in Table 4, the amount of increase in total related substances from the initial value was also large after storage under all conditions compared to the tablets of Examples 1-4.
Furthermore, as shown in Table 5, among the examples, the tablet of Example 1 containing hydrous silicon dioxide as a fluidizing agent had sufficiently high tablet hardness.
From the above results, the tablets of Examples 1 to 4 containing one or more selected from hydrated silicon dioxide, calcium hydrogen phosphate, and talc as a glidant or containing no glidant have excellent stability, especially It has been found that tablets with high hardness can be obtained by using hydrous silicon dioxide as a glidant.

Claims (2)

containing blonanserin or a pharmaceutically acceptable salt thereof, crystalline cellulose, lactose hydrate, hydroxypropylcellulose, and magnesium stearate, and containing no fluidizing agent other than magnesium stearate ,
The content of the crystalline cellulose and lactose hydrate in 100% by mass of the tablet is 70 to 90% by mass,
The tablet, wherein the content of the hydroxypropylcellulose in 100% by mass of the tablet is 0.1 to 10% by mass . The tablet according to claim 1, which is an uncoated tablet.