JP7049610B2 - Levocetirizine solid product - Google Patents

Description

The present invention relates to a solid preparation containing levocetirizine or a pharmaceutically acceptable salt thereof as an active ingredient.

Levocetirizine hydrochloride is known as a therapeutic agent for allergic rhinitis, urticaria and the like. Currently, tablets and syrups are sold as preparations containing levocetirizine hydrochloride, but it is also desired to develop orally rapidly disintegrating tablets and dry syrups that are easy to take even for children and the elderly.
In general, oral fast-disintegrating tablets and dry syrups are easy to feel the taste of the drug substance when taken. Is often blended. As such an ingredient, D-mannitol having a refreshing sensation and an appropriate sweetness is widely used (see Patent Document 1).

Japanese Unexamined Patent Publication No. 2017-12001

However, when D-mannitol is added to the levocetirizine hydrochloride preparation, the stability during storage is reduced.

The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a levocetirizine solid preparation having excellent stability during storage.

As a result of diligent studies, the present inventor has used powdered reduced malt sugar water candy in a levocetirizine solid preparation containing levocetirizine or a pharmaceutically acceptable salt thereof (hereinafter, may be simply referred to as a solid preparation), and further, an alkali. By blending a metal hydroxide, a sweetness is imparted to form a solid preparation with a good taste, and these components serve as an inhibitor that suppresses the formation of unknown related substances (impurities whose structure is unknown) during storage of the preparation. We have found that a solid preparation that works and has excellent stability can be obtained, and has completed the present invention.

The present invention has the following aspects.
[1] A levosetilidine solid preparation containing levosetilidine or a pharmaceutically acceptable salt thereof, powdered reduced maltose water candy, and an alkali metal hydroxide.
[2] Revocetilidine or a pharmaceutically acceptable salt thereof is contained in an amount of 0.05 to 5% by mass as levosetilidine, powder-reduced maltose-hydrated candy is contained in an amount of 45 to 97% by mass, and an alkali metal hydroxide is contained in an amount of 0.05 to 2% by mass. %, The levocetilidine solid preparation according to [1].
[3] The levocetirizine solid preparation according to [1] or [2], which further contains cyclodextrin.
[4] The levocetirizine solid preparation according to any one of [1] to [3], which is a granule preparation.
[5] The levocetirizine solid preparation according to [4], which is a dry syrup agent.

According to the present invention, it is possible to provide a levocetirizine solid preparation having excellent stability during storage.

Hereinafter, the present invention will be described in detail.
The levosetilidine solid preparation of the present invention contains levosetilidine or a pharmaceutically acceptable salt thereof, powdered reduced maltose water candy, and an alkali metal hydroxide.

Examples of the pharmaceutically acceptable salt of levocetirizine include hydrochloride and the like, and among them, levocetirizine dihydrochloride is preferable.
The content of levocetirizine or a pharmaceutically acceptable salt thereof in 100% by mass of the solid preparation is not particularly limited and can be appropriately set according to the dosage form of the solid preparation, etc., but as levocetirizine, 0.05 to 5% by mass. % Is preferable. When the solid preparation is, for example, a granule preparation, 0.05 to 2% by mass is preferable, 0.1 to 1% by mass is more preferable, and 0.2 to 0.7% by mass is further preferable.

As the powder-reduced maltose water candy, a commercially available product for pharmaceutical use can be used. The content of the powdered reduced maltose water candy is preferably 45 to 97% by mass in 100% by mass of the solid preparation, and can be appropriately set according to the usage ratio and dosage form of other additives described later. In the case of a granule preparation, 70 to 97% by mass is preferable.
Examples of the alkali metal hydroxide include sodium hydroxide and potassium hydroxide, and sodium hydroxide is particularly preferable. The content of sodium hydroxide in 100% by mass of the solid preparation is not particularly limited, but is preferably 0.05 to 2% by mass, more preferably 0.05 to 0.5% by mass, and 0.05 to 0. 2% by mass is more preferable.
When the content of powdered reduced maltose water candy and alkali metal hydroxide is within the above range, the increase of related substances over time can be suppressed, and a solid preparation having better stability during storage can be obtained. In addition, sufficient sweetness is imparted, and the taste of the solid preparation is improved.

The solid pharmaceutical product of the present invention may contain one or more additives other than the powder-reduced maltose water candy and the alkali metal hydroxide. The additive can be appropriately selected depending on the dosage form of the solid preparation and the like.

Additives include sugars or sugar alcohols such as sucrose, trehalose, fructose, xylose, maltose, lactose hydrate, anhydrous lactose, starch, erythritol, xylitol, sorbitol, mannitol, lactitol; β-cyclodextrin, ascorbic acid, aspartame. , Erythritol, xylitol, citrate hydrate, monoammonium glycyrrhizinate, sucralose, l-menthol and other flavoring agents; excipients such as crystalline cellulose, potato starch, pregelatinized starch, calcium hydrogen phosphate and the like; cellulose-based disintegrants (Crosscarmellose sodium, carmellose calcium, carmellose, low-substituted hydroxypropyl cellulose, etc.), crospovidone, starch-based disintegrant (corn starch, sodium starch glycolate, partially pregelatinized starch, hydroxypropyl starch, etc.), etc. Disintegrant; Stabilizers such as citrate, malate, phosphate; Metallic salts of stearate such as magnesium stearate and calcium stearate, fatty acid esters such as glycerin fatty acid ester and sucrose fatty acid ester, fumaric acid Excipients such as stearyl sodium; binders such as polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, stearyl alcohol, ammoniomethacrylate copolymer, aminoalkylmethacrylate copolymer E, polyvinylacetal diethylaminoacetate; yellow iron sesquioxide , Iron sesquioxide, edible yellow No. 4, edible yellow No. 5, edible red No. 2, edible red No. 3, edible red No. 102, colorants such as caramel, surfactants such as sodium lauryl sulfate, polysorbitol 80; etc. Can be mentioned. Further, additives such as titanium oxide and carnauba wax, fragrances and the like can also be mentioned.

Among the additives, the content of the flavoring agent is preferably 1 to 20% by mass, more preferably 10 to 18% by mass, based on 100% by mass of the solid preparation. It is preferable to use β-cyclodextrin as the flavoring agent because the stability of the solid preparation tends to be further improved.
On the other hand, among the above additives, mannitol is preferably not used from the viewpoint of stability of the solid preparation during storage.

Examples of the levocetirizine solid preparation of the present invention include ordinary tablets, orally rapidly disintegrating tablets, granule preparations, powders, chewable tablets and the like. In any of these dosage forms, a solid preparation having excellent stability can be obtained by blending powdered reduced maltose water candy and an alkali metal hydroxide. In the case of a granule preparation, it may be taken as it is, but it is also preferable to suspend it in water and take it, that is, to make a dry syrup. The granule preparation of the present invention exhibits a good taste whether taken as it is or suspended in water.

The method for producing a solid preparation of the present invention is not particularly limited as long as it can produce a solid preparation containing levosetilidine or a pharmaceutically acceptable salt thereof, powder-reduced malt sugar water candy and an alkali metal hydroxide. It can be manufactured by a known manufacturing method according to the dosage form.
For example, in the case of a granule preparation, a production method using a known granulation step such as a dry granulation method or a wet granulation method can be mentioned, and an appropriate selection can be made according to the type of additive to be used and the like.
In the case of tablets such as ordinary tablets and orally rapidly disintegrating tablets, the granulated product obtained through the granulation step as described above is compressed by the compression step, and the obtained tablet is coated. It can be manufactured by a method of performing a coating process as needed. Further, the tablet may be produced by a direct tableting method that does not undergo a granulation step.

[Test Examples 1 and 2]
The levocetirizine solid preparation (granule preparation (dry syrup)) according to the formulation shown in Table 1 was produced as follows, and a preparation using powdered reduced maltose water candy (Test Example 1) and a preparation using D-mannitol (Test Example). Regarding 2), the stability during storage was compared.
First, levocetirizine dihydrochloride, powdered reduced maltose water candy, and β-cyclodextrin were weighed and mixed. Water was added to the obtained mixture, and granulation, drying, and sizing were performed to obtain a granule preparation (dry syrup) of Test Example 1.
Granule preparation (dry syrup) of Test Example 2 was obtained by the same method as above except that D-mannitol was used instead of powdered reduced maltose water candy.

The granule preparations obtained in Test Example 1 and Test Example 2 were stored at 60 ° C. under open conditions for 1 week, and the amount of related substances before and after storage was measured. As a result, as shown in Table 1, in the pharmaceutical product of Test Example 2 using D-mannitol, the amount of unknown related substances increased remarkably after storage, but the pharmaceutical product of Test Example 1 using powdered reduced maltose water candy was used. In, the amount of unknown related substances increased, but the amount of increase decreased.

The amount of related substances was measured by an automatic analysis method using high performance liquid chromatography. The numerical value of the amount of unknown related substances indicates the ratio of the peak area due to the unknown related substances to the peak area derived from levocetirizine dihydrochloride as a percentage.

[Example 1, Example 2]
From the results of Test Example 1 and Test Example 2, it was clarified that when powdered reduced maltose water candy was used in the levocetirizine solid preparation, the increase in the amount of unknown related substances over time could be reduced.
Therefore, further studies were carried out using powdered reduced maltose water candy to produce a levocetirizine solid preparation (granule preparation (dry syrup)) according to the formulation shown in Table 2.
In Example 1, levosetilidine dihydrochloride, sodium citrate hydrate, and sodium hydroxide are added to purified water to a mixture of powdered reduced malt sugar water candy and β-cyclodextrin weighed and mixed. The mixed solution was added and mixed for granulation, drying and sizing, and then Acesulfam potassium and fragrance were added and mixed to obtain a granule preparation.
In Example 2, a granule preparation was obtained in the same manner as in Example 1 except that sodium hydroxide was not added and the proportion of powdered reduced maltose water candy was increased accordingly.

The granule preparations obtained in Example 1 and Example 2 were stored at 40 ° C. and 75% RH for 2 weeks, and the amount of related substances before and after storage was measured. As a result, as shown in Table 2, when the granule preparation of Example 2 containing no sodium hydroxide was stored at 40 ° C. and 75% RH for 2 weeks, an unknown related substance was produced by the storage, but hydroxide was generated. In the granule preparation of Example 1 containing sodium, no unknown related substance was detected even when stored under the same conditions.
As described above, in the levocetirizine solid preparation using powdered reduced maltose water candy, by blending sodium hydroxide, it is possible to suppress the formation of unknown related substances due to storage and to produce a preparation having excellent stability during storage. It became clear.

Claims (5)

A levosetilidine solid preparation containing levosetilidine or a pharmaceutically acceptable salt thereof, powdered reduced maltose water candy, and an alkali metal hydroxide. It contains 0.05 to 5% by mass of levosetilidine or a pharmaceutically acceptable salt thereof as levosetilidine, 45 to 97% by mass of powdered reduced maltose water candy, and 0.05 to 2% by mass of alkali metal hydroxide. The levosetilidine solid preparation according to claim 1. The levocetirizine solid preparation according to claim 1 or 2, further containing cyclodextrin. The levocetirizine solid preparation according to any one of claims 1 to 3, which is a granule preparation. The levocetirizine solid preparation according to claim 4, which is a dry syrup agent.