JP2020015689A - Levocetirizine-containing tablet - Google Patents

Abstract

To provide a levocetirizine-containing pharmaceutical preparation having excellent storage stability.SOLUTION: The present invention provides a film coating tablet containing levocetirizine or a pharmaceutically acceptable salt thereof. A film coating layer contains at least triacetin or triethyl citrate as a plasticizer.SELECTED DRAWING: None

Description

  The present invention relates to tablets containing levocetirizine. More particularly, it relates to a film-coated tablet comprising levocetirizine having good stability.

で表され、二塩酸塩の形態で白色粉末として用いられ、ヒスタミンＨ₁受容体に選択的に結合することにより、ヒスタミンの作用を阻害する。ヒスタミンＨ₁受容体に対する親和性は、ラセミ体であるセチリジンよりも約２倍高く、ヒスタミンＨ₂、ヒスタミンＨ₃、アドレナリン、ドパミン、アセチルコリン、セロトニンの核受容体に対する親和性は低いことが知られている。また、インビトロにおいては、エオタキシン刺激による好酸球の血管内皮細胞間隙遊走を抑制し、花粉抗原刺激による皮膚血管内皮細胞からの血管内皮細胞接着分子（ＶＣＡＭ−１）産生を抑制することが知られており、アレルギー性鼻炎、じんましん、湿疹・皮膚炎、痒疹、皮膚そう痒症などに対する治療剤として、「ザイザル（登録商標）錠５ｍｇ」、「ザイザル（登録商標）シロップ０．０５％」の名称で販売されている（非特許文献１および非特許文献２）。 Persistence selected histamine H ₁ receptor, which is one of the antagonistic-allergy drug levocetirizine (chemical name: 2- (2- {4 - [ (R) - (4- chlorophenyl) phenylmethyl] piperazine-1 Il｝ ethoxy) acetic acid) has the formula (I):

In expressed, used as a white powder in the form of a dihydrochloride, by selectively coupling the histamine H ₁ receptor, it inhibits the action of histamine. Affinity for the histamine H ₁ receptors, approximately 2 times higher than cetirizine racemic, histamine H _2, histamine H _3, adrenaline, dopamine, acetylcholine, affinity for the nuclear receptors of serotonin is known to be low ing. In vitro, it is known that eotaxin stimulates eosinophils to inhibit vascular endothelial cell gap migration, and that pollen antigen stimulation inhibits vascular endothelial cell adhesion molecule (VCAM-1) production from skin vascular endothelial cells. As therapeutic agents for allergic rhinitis, urticaria, eczema / dermatitis, prurigo, cutaneous pruritus, etc., the names of "Zyzal (registered trademark) tablet 5 mg" and "Zyzal (registered trademark) syrup 0.05%" (Non-Patent Document 1 and Non-Patent Document 2).

  Patent Document 1 discloses, as a preparation containing levocetirizine, an orally disintegrating tablet containing a polyol and a pH adjuster and having a pH of 4 to 7 in a 5% by weight aqueous suspension or a 5% by weight aqueous solution. And that it can provide a stable and less bitter formulation.

  Patent Document 2 discloses that a pharmaceutical composition containing racemic cetirizine is added with a predetermined polyol in order to achieve a good taste, and particularly, a highly reactive polyol and cetirizine are separately formulated to provide taste and stability. It is described that the property is improved.

  Patent Document 3 describes that, for a granular preparation and a dry syrup preparation of racemic cetirizine, citric acid is added to a layering solution or a coating solution to improve stability and mask bitterness.

JP-A-2006-94364 JP 2005-518405 A JP 2014-159393 A

Package insert of "Zyzal (registered trademark) tablet 5mg" "Zaisal (registered trademark) syrup 0.05%" package insert

  However, the orally disintegrating tablet of Patent Document 1 cannot be expected to be easy to handle like a tablet, and there is room for improvement in stability. In addition, the conventional preparation of Non-Patent Document 1 has room for improvement in long-term storage stability.

  Further, in Patent Literature 2, by dividing the prescription into two, the manufacturing process becomes complicated. Therefore, a method for improving stability by a simpler manufacturing method is required.

  Furthermore, Patent Document 3 does not disclose a method for improving the stability by specifying the type of the plasticizer.

  Therefore, an object of the present invention is to provide a pharmaceutical preparation containing levocetirizine having good storage stability.

  The present inventors have found that a more stable oral preparation can be obtained by including at least triacetin or triethyl citrate as a film coating agent in a film-coated tablet containing levocetirizine or a pharmaceutically acceptable salt thereof. Heading, the present invention has been completed.

That is, the present invention
[1] A film-coated tablet containing levocetirizine or a pharmaceutically acceptable salt thereof,
Film coated tablet containing at least triacetin or triethyl citrate as a plasticizer in the film coating layer,
[2] The content of triacetin and / or triethyl citrate in the film coating layer is 0.1 to 20% by mass, preferably 0.1 to 10% by mass, more preferably 0.2 to 10% by mass, and still more preferably Is 3 to 10% by mass, most preferably 5 to 10% by mass, and the film-coated tablet according to the above [1], and [3] the above-mentioned [1] or [2], further comprising hypmelose and titanium oxide in the film-coating layer. ] The film-coated tablet of the above.

  According to the present invention, the storage stability of a film-coated tablet containing levocetirizine can be improved by using at least triacetin or triethyl citrate as a plasticizer in the film coating agent layer.

It is a graph which shows the storage stability of a film-coated tablet.

  The present invention is characterized in that a film-coated tablet containing levocetirizine or a pharmaceutically acceptable salt thereof as an active ingredient contains at least triacetin or triethyl citrate as a plasticizer in a film coating layer. Thus, when polyethylene glycol containing a large number of hydroxyl groups is used as a plasticizer in the film coating layer, analogous substances of levocetirizine increase, but not polyethylene glycol containing a large number of hydroxyl groups, but triacetin or triethyl citrate in which the hydroxyl groups are esterified. By using this, a film-coated tablet having good storage stability can be obtained. This film-coated tablet is composed of a plain tablet containing levocetirizine or a pharmaceutically acceptable salt thereof, and a film-coating layer containing triacetin and / or triethyl citrate as a plasticizer.

(Uncoated)
As described above, levocetirizine used in the present invention is 2- (2- {4-[(R)-(4-chlorophenyl) phenylmethyl] piperazin-1-yl} ethoxy) acetic acid, which is racemic by a known method. It may be obtained by optical resolution from cetirizine which is a form, or by asymmetric synthesis.

  Pharmaceutically acceptable salts of levocetirizine include pharmaceutically acceptable non-toxic organic acids such as acetic acid, citric acid, maleic acid, succinic acid, ascorbic acid, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Examples include inorganic acid addition salts, metal salts such as sodium salts and potassium salts, ammonium salts, amine salts and amino acid salts. Of these, levocetirizine dihydrochloride is particularly preferred.

  The amount of levocetirizine in an uncoated tablet is usually 5 to 10 mg orally per day for an adult, but in consideration of the ease of taking it, 5 mg per tablet (1 day per day) as levocetirizine dihydrochloride. ~ 2 tablets). In the case of children, since 5 mg is administered twice a day, a tablet containing 2.5 mg of levocetirizine dihydrochloride in one tablet may be produced. For example, a tablet containing 2.5 mg of levocetirizine dihydrochloride is required to have a higher storage stability than a tablet containing a larger amount of levocetirizine because the content of levocetirizine is smaller. Therefore, a method that can further improve the storage stability is required. For that purpose, it is more effective to use the film-coated tablet of the present invention.

  In uncoated tablets, in addition to the active ingredient levocetirizine or a pharmaceutically acceptable salt thereof, for example, excipients, disintegrants, flow agents, lubricants, surfactants, binders, stabilizers, Additives commonly used in this field, such as colorants, can be included.

  Examples of the excipient include, but are not particularly limited to, celluloses (crystalline cellulose, ethyl cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose) and the like) and derivatives thereof, starch (corn starch, potato starch). , Wheat starch, rice starch, partially pregelatinized starch, hydroxypropyl starch, etc.) and its derivatives, sugars (such as glucose, lactose, sucrose, purified sucrose, powdered sugar, trehalose, dextran, dextrin and hydrates thereof), sugars Alcohol (D-mannitol, xylitol, sorbitol, erythritol, etc.), glycerin fatty acid ester, inorganic powder (magnesium aluminate metasilicate, synthetic hydrotalcite), phosphoric anhydride Siumu, precipitated calcium carbonate, calcium silicate, calcium hydrogen hydrate phosphoric acid, inorganic salts such as sodium hydrogen carbonate. Among them, celluloses such as crystalline cellulose and sugars such as lactose and lactose hydrate are preferred. The excipients may be used alone or as a mixture of two or more.

  When an excipient is used, the amount used in the uncoated tablet depends on the content of levocetirizine dihydrochloride in the uncoated tablet and the weight of the uncoated tablet to be designed, and is not particularly limited. It is preferably from 40 to 95% by mass, more preferably from 50 to 90% by mass, based on the total mass of the tablet.

  Examples of the disintegrant include, but are not particularly limited to, crospovidone, sodium carboxystarch, sodium carboxymethyl starch, starch, partially pregelatinized starch, corn starch, lactose, calcium citrate, light anhydrous silicic acid, and synthetic silicic acid. Examples include aluminum crystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose, croscarmellose sodium, calcium carboxymethylcellulose, carmellose, and hydroxypropyl starch. Among them, carmellose and the like are preferable in that the dissolution characteristics are good and the tableting pressure can be endured. The disintegrants may be used alone or as a mixture of two or more.

  When the disintegrant is used, the amount used in the uncoated tablet varies depending on the disintegration rate of the uncoated disintegrant to be used, and the type of the disintegrating agent to be used, and is not particularly limited. Is preferably 3 to 10% by mass, more preferably 5 to 9% by mass.

  Examples of the lubricant include, but are not particularly limited to, stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, light anhydrous silicic acid, hydrogenated oil, glycerin fatty acid ester , Talc and the like. Of these, magnesium stearate is preferred because of its high lubricity. These may be used alone or in combination of two or more.

  When the lubricant is used, the amount used in the uncoated tablet is such that the above-mentioned various additives can be prevented from adhering to the device (punch or die) for manufacturing the uncoated tablet, and this is the amount used. Although it is not particularly limited because it differs depending on the type of the powder, it is usually preferably 0.5 to 2.0% by mass, and 0.7 to 1.5% by mass based on the total mass of the uncoated tablet. Is more preferred.

  The fluidizing agent is not particularly limited, for example, silicates such as calcium silicate, silicic acid such as light anhydrous silicic acid, hydrous silicon dioxide, talc, titanium oxide, stearic acid, magnesium stearate, Examples include calcium stearate and magnesium aluminate metasilicate. These may be used alone or in combination of two or more.

  The amount used in the uncoated tablet when a fluidizing agent is used may be such that the additive, which is a powder, can be smoothly added in the production of the uncoated tablet. Although it depends on the type, it is not particularly limited, but is usually preferably 0.2 to 1.0% by mass or more, more preferably 0.3 to 0.8% by mass based on the total mass of the uncoated tablet. preferable.

(Method of manufacturing uncoated tablets)
As a method for producing an uncoated tablet, a method generally used in this technical field can be used, and is not particularly limited. For example, levocetirizine or a pharmaceutically acceptable salt thereof is mixed with a suitable excipient, disintegrant, lubricant, glidant, or the like as described above to obtain a mixture. The resulting mixture, for example, using a die for tableting, an upper punch and a lower punch for tableting, a hydraulic hand press machine, a single-shot tableting machine, tableting with a rotary tableting machine, etc. Can be obtained. Tableting may be performed at a tableting pressure such that the obtained tablet has an appropriate hardness, and the tableting pressure is determined according to the tableting method, the equipment used for tableting, the size of the tablet, the type of the pharmaceutical ingredient, and the like. Is adjusted appropriately.

  The resulting uncoated tablet preferably has an appropriate hardness.Specifically, cracks or chips may occur during the manufacture of tablets, during transportation or storage of products, prescriptions at hospitals and pharmacies, and during handling by patients. It has a hardness of preferably from 40 to 200 N, more preferably from 50 to 100 N, from the viewpoint of preventing cracking. In particular, in the case of film-coated tablets, ensuring the "strength (hardness)" of the tablet is one of many effects of the film coating so that the tablet does not wear or break (defect) during the film coating. One. The hardness is a value measured by a general method using a tablet hardness tester.

  The shape of the obtained uncoated tablet is not particularly limited, and may be, for example, a disk shape, a donut shape, a polygonal plate shape, a spherical shape, an elliptical shape, a caplet shape, or the like. The size is preferably small. For example, in the case of an elliptical shape, the major axis is preferably about 8 to 9 mm, the minor axis is preferably 4 to 5 mm, and a score line can be inserted. Although the mass depends on the content of the active ingredient, it is preferably about 90 to 110 mg in the case of levocetirizine dihydrochloride 5 mg.

  The uncoated tablet thus obtained is subjected to film coating using a coating agent containing triacetin and / or triethyl citrate by a method generally used in the art.

(Film coating layer)
Film-coated tablets are preparations in which a tablet is coated on the surface of a tablet using a synthetic polymer base such as hydroxypropylcellulose or hydroxypropylmethylcellulose (Hypmelose). By applying the film coating, effects such as masking of bitterness and bad smell, improvement of the stability of the active ingredient from external conditions such as moisture, light or oxygen, improvement of appearance and increase of commercial value can be expected. The film coating agent is generally composed of a polymer base (polymer), a plasticizer, a colorant, a solvent (solvent), and the like.

  Examples of the film coating base include, but are not particularly limited to, hydroxypropyl cellulose, hypromellose, carmellose sodium, ethyl acrylate / methyl methacrylate copolymer dispersion, polyvinylpyrrolidone, polyvinyl alcohol, and polyoxyethylene polyoxypropylene glycol. And the like. Further, by selecting a base having a sustained release or enteric function, a sustained release or enteric function can be added to the tablet.

  By adding an appropriate amount of the plasticizer to the polymer base, elasticity, impact resistance and abrasion resistance can be added to the coating film. Examples of the plasticizer include, but are not particularly limited to, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. In the present invention, at least triacetin and / or triethyl citrate are used as a plasticizer in the film coating layer.

  In addition, if necessary, a coloring agent such as titanium oxide, iron sesquioxide, and aluminum lake, and a brightening agent such as carnauba wax can be appropriately added to the coating agent.

  The content of the plasticizer, triacetin and triethyl citrate, in the film coating layer is preferably 0.1 to 20% by mass from the viewpoint of ensuring the plasticity of the film coating base, and more preferably 0.1 to 10% by mass. Preferably, 0.2 to 10% by mass is more preferable, 3 to 10% by mass is particularly preferable, and 5 to 10% by mass is most preferable.

(Film coating method)
As a method for coating the uncoated tablet with a film, a general method for producing a film-coated tablet used in the technical field can be used. For example, an uncoated tablet containing levocetirizine or a pharmaceutically acceptable salt thereof is charged into a film coating machine, and the film coating agent or additive is added to an organic solvent such as water or ethanol, or a mixed solution thereof (for example, water / ethanol). The mixture can be coated by spraying a coating solution dissolved or dispersed in a suitable solvent such as a liquid mixture) onto an uncoated tablet, followed by drying.

  In the obtained film-coated tablet, the mass of the film-coating layer is not particularly limited as long as it is an amount that can cover the entire uncoated tablet. Therefore, when the mass of the whole uncoated tablet is 100%, the mass is preferably 0.1 to 5%, more preferably 1 to 3%.

  The film-coated tablet of the present invention is useful for treating allergic rhinitis, urticaria, eczema / dermatitis, prurigo, pruritus cutis and the like.

  Hereinafter, the present invention will be specifically described based on Examples, but the present invention is not intended to be limited to these Examples.

The details of the reagents used in the examples are described below.
Levocetirizine dihydrochloride lactose monohydrate: Japanese Pharmacopoeia XVI
Microcrystalline cellulose: Japan Pharmaceutical XVI
Carmellose: JP XVI
Light Silicic Anhydride: Japan Pharmaceutical XVI
Magnesium stearate: JP XVI
Hypromellose: JP XVI
Triacetin: Medicinal Regulation Macrogol 400: Japan Pharmaceutical XVI
Titanium oxide: Japan Pharmaceutical XVI

  In the above, the Japanese Pharmacopoeia XVI refers to the 16th Revised Japanese Pharmacopoeia, and the pharmaceutical rule refers to the Pharmaceutical Excipient Standard 2003 and its supplement.

Example 1
According to the formulation of Table 1, levocetirizine dihydrochloride, lactose monohydrate, crystalline cellulose, carmellose, light anhydrous silicic acid and magnesium stearate are weighed, and a mixer (V-type mixer (V-20), Co., Ltd.) (Manufactured by Tokuju Kosakusho). The obtained mixture is charged into a rotary tableting machine (VIRG0512SS1AY, manufactured by Kikusui Seisakusho), tableted at a tableting pressure of 7 kN, and a plain tablet having a mass of 100 mg (major axis: 8.0 mm, minor axis: 4.6 mm). ) 4000 g were obtained. The hardness of the obtained uncoated tablet was 79 N, and the hardness of the film-coated tablet was 82 N.

  4000 g of the obtained uncoated tablet was put into a film coating machine (DRC-500, manufactured by Powrex Corporation). On the other hand, hypromellose, triacetin and titanium oxide were dissolved in a mixed solvent of 720 g of purified water and 10020 g of ethanol to prepare a coating solution (solid content concentration: 5.6% w / w). Thereafter, the uncoated tablets were coated by spraying the coating liquid in a film coating machine, and then dried to obtain tablets having a total amount of 4080 g (102 mg per tablet).

Example 2
As shown in Table 1, a total amount of 4080 g (102 mg per tablet) was obtained in the same manner as in Example 1 except that the amount of triacetin used in the film coating layer was changed from 5% by mass to 10% by mass in the coating layer. Tablets were obtained.

Example 3
As shown in Table 1, a tablet having a total amount of 4120 g (51.5 mg per tablet) was prepared in the same manner as in Example 1 except that the amount of the active ingredient per tablet was halved and the other ingredients were the formulation shown in Table 1. I got

Comparative Example 1
As shown in Table 1, the same as Example 1 except that macrogol 400 (3% by mass) was used instead of triacetin (5% by mass) as a film coating agent, and the amount of hypromellose used was as shown in Table 1. Thus, a tablet having a total amount of 4080 g (102 mg per tablet) was obtained.

Comparative Example 2
As shown in Table 1, tablets having a total amount of 4080 g (102 mg per tablet) were prepared in the same manner as in Example 1 except that macrogol (5% by mass) was used instead of triacetin (5% by mass) as a film coating agent. I got

Comparative Example 3
As shown in Table 1, tablets having a total amount of 4080 g (102 mg per tablet) were prepared in the same manner as in Example 2 except that macrogol (10% by mass) was used instead of triacetin (5% by mass) as a film coating agent. I got

Test Example 1: Stability test Tablets immediately after production in Examples 1 to 3 and Comparative Examples 1 to 3 were respectively put into aluminum pillows (Gaspet specification for outer pillow film for PTP, gusset specifications, manufactured by Shohoku Laminate Industry Co., Ltd.). The package was sealed for 14 days under an environment of a temperature of 60 ° C. and a humidity of 75%.

  Decomposition of levocetirizine dihydrochloride for each tablet (n = 1 each) at the start of storage, 3 days from the start of storage (Example 3 and Comparative Example 3 were not measured), 7 days and 14 days The amount of the product levocetirizine analog was measured by HPLC. The results are shown in Table 2 and FIG. 1 as the content (%) of the total analogs with respect to the amount of levocetirizine dihydrochloride. The HPLC analysis conditions were as follows.

(HPLC analysis conditions)
Detector: UV absorption photometer (measuring wavelength: 232 nm)
Column: A stainless steel tube having an inner diameter of 3.9 mm and a length of 15 cm was filled with 5 μm octylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 30 ° C. Mobile phase: 20 mM KH ₂ PO ₄ / CH ₃ CN (1/1)
Flow rate: 1.0 mL / min Area measurement range: Injection volume for 7 minutes after sample injection: 50 μL
Diluent: 0.05M hydrochloric acid: acetonitrile mixture (1: 1)

  From Table 2 and FIG. 1, it can be seen that in Examples 1 and 2 using a specific coating agent, storage stability was improved as compared with Comparative Examples 1 to 3. In addition, it can be seen that also in Example 3, tablets having good storage stability could be obtained.

Test Example 2: Dissolution test A film-coated tablet (n = 3) produced in Examples 1 and 3 was subjected to a dissolution test. The dissolution test was carried out in accordance with the dissolution test method of the Japanese Pharmacopoeia, using a dissolution tester (trade name: NTR-6000 series, manufactured by Toyama Sangyo Co., Ltd.) as a dissolution test liquid of the Japanese Pharmacopoeia dissolution test second solution (pH 6.8). ) Using the paddle method. The test conditions were as follows: the dissolution solvent volume was 900 ml, the temperature was 37 ± 0.5 ° C., and the paddle speed was 50 rpm. The results are shown in Table 3 as average values.

  Table 3 shows that the film-coated tablets of Examples 1 and 3 provide good dissolution behavior.

Claims (3)

A film-coated tablet containing levocetirizine or a pharmaceutically acceptable salt thereof,
A film-coated tablet containing at least triacetin or triethyl citrate as a plasticizer in the film-coating layer. The film-coated tablet according to claim 1, wherein the content of triacetin and / or triethyl citrate in the film coating layer is 0.1 to 20% by mass. 3. The film-coated tablet according to claim 1, wherein the film-coating layer further contains hypmelose and titanium oxide.

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