JP2018108950A - Levocetirizine hydrochloride-containing orally disintegrating tablet - Google Patents
Levocetirizine hydrochloride-containing orally disintegrating tablet Download PDFInfo
- Publication number
- JP2018108950A JP2018108950A JP2016256841A JP2016256841A JP2018108950A JP 2018108950 A JP2018108950 A JP 2018108950A JP 2016256841 A JP2016256841 A JP 2016256841A JP 2016256841 A JP2016256841 A JP 2016256841A JP 2018108950 A JP2018108950 A JP 2018108950A
- Authority
- JP
- Japan
- Prior art keywords
- orally disintegrating
- levocetirizine hydrochloride
- water
- tablet
- disintegrating tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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Landscapes
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- Medicinal Preparation (AREA)
Abstract
Description
本発明は、レボセチリジン塩酸塩を含有する口腔内崩壊錠に関する。 The present invention relates to an orally disintegrating tablet containing levocetirizine hydrochloride.
レボセチリジン塩酸塩は、ヒスタミンＨ１受容体拮抗作用を有し、アレルギー性疾患治療剤として用いられている。レボセチリジン塩酸塩を含有する医薬製剤としては、ザイザル錠（グラクソ・スミスクライン株式会社）が知られている（非特許文献１）。
ここで、近年、高齢化社会の到来や服薬コンプライアンスの向上のため、水無しでも服用できる口腔内崩壊錠の意義が重要視されるようになってきた。口腔内崩壊錠は、適度な溶解性と強度を兼ね備えることが必要であり、また、味などの服用感が良いことが必要である。
Levocetirizine hydrochloride has a histamine H 1 receptor antagonistic action and is used as a therapeutic agent for allergic diseases. As a pharmaceutical preparation containing levocetirizine hydrochloride, Zaisal tablet (Glaxo SmithKline Co., Ltd.) is known (Non-patent Document 1).
Here, in recent years, the significance of orally disintegrating tablets that can be taken without water has come to be regarded as important for the arrival of an aging society and the improvement of medication compliance. The orally disintegrating tablet needs to have appropriate solubility and strength, and needs to have a good feeling such as taste.
レボセチリジン塩酸塩は、苦みと塩酸塩由来の酸刺激を有しているため、口腔内崩壊錠とするためには、味のマスキングが必要である。レボセチリジン塩酸塩の味をマスキングすることは種々提案されている。
例えば、特許文献１は、医薬組成物において、レボセチリジン塩酸塩とグリチルリチン酸塩とを共存させることにより、レボセチリジン塩酸塩の苦みをマスキングできることを開示している。
また、特許文献２は、レボセチリジン塩酸塩を含む第一処方の組成物と、マンニトールを含む第二処方の組成物とを用いて２重層構造の製剤とすることにより、レボセチリジン塩酸塩の苦みをマスキングできることを開示している。
また、特許文献３は、レボセチリジン塩酸塩を含む口腔内崩壊錠にクエン酸塩を配合することにより、レボセチリジン塩酸塩の苦みをマスキングできることを開示している。
Since levocetirizine hydrochloride has bitterness and acid stimulation derived from hydrochloride, masking of taste is necessary to obtain an orally disintegrating tablet. Various proposals have been made to mask the taste of levocetirizine hydrochloride.
For example, Patent Document 1 discloses that the bitterness of levocetirizine hydrochloride can be masked by allowing coexistence of levocetirizine hydrochloride and glycyrrhizinate in a pharmaceutical composition.
Patent Document 2 masks the bitterness of levocetirizine hydrochloride by using a composition of the first formulation containing levocetirizine hydrochloride and a composition of the second formulation containing mannitol as a double-layered preparation. We disclose what we can do.
Patent Document 3 discloses that the bitterness of levocetirizine hydrochloride can be masked by blending citrate with an orally disintegrating tablet containing levocetirizine hydrochloride.
しかし、特許文献１、２は、レボセチリジン塩酸塩の苦みをマスキングする技術を開示しているだけであり、酸刺激をマスキングすることを教えていない。また、これらの文献の製剤は口腔内崩壊錠ではない。
また、特許文献３も、レボセチリジン塩酸塩の苦みをマスキングする技術を開示しているだけであり、酸刺激をマスキングすることを教えていない。また、同文献が教える製剤は口腔内崩壊錠であるが、クエン酸塩の効果は苦みのマスキングだけであり、崩壊性には何ら効果を示さない。
従って、レボセチリジン塩酸塩の酸刺激がマスキングされていると共に、優れた崩壊性を有する口腔内崩壊錠が求められている。
However, Patent Documents 1 and 2 only disclose a technique for masking the bitterness of levocetirizine hydrochloride, and do not teach masking acid stimulation. Moreover, the preparations of these documents are not orally disintegrating tablets.
Further, Patent Document 3 only discloses a technique for masking the bitterness of levocetirizine hydrochloride, and does not teach masking acid stimulation. Moreover, although the formulation which the literature teaches is an orally disintegrating tablet, the effect of citrate is only masking of bitterness, and does not show any effect on disintegration.
Accordingly, there is a need for an orally disintegrating tablet in which the acid stimulation of levocetirizine hydrochloride is masked and has excellent disintegration properties.
成分を工夫することで錠剤の口腔内崩壊性を向上させることが提案されている。例えば、特許文献４は、薬剤を含むマイクロカプセルと発泡性崩壊剤を含む口腔内崩壊錠を開示している。発泡性崩壊剤としては、水溶性及び水不溶性の炭酸塩を例示しているが、効果を実証しているのは、水溶性の炭酸水素ナトリウムだけである。
また、特許文献４は、発泡性崩壊剤は、心地よいしゅーしゅーする感じ又は泡立つ感じを与えることにより、種々の薬物を含有する錠剤の摂取を快適なものとして、摂取し易くすることを開示している。しかし、同文献は、薬物として、レボセチリジン塩酸塩を記載しておらず、従って、レボセチリジン塩酸塩特有の酸刺激をマスキングすることを開示していない。
It has been proposed to improve the disintegration property of the tablet in the oral cavity by devising the ingredients. For example, Patent Document 4 discloses an orally disintegrating tablet containing a microcapsule containing a drug and an effervescent disintegrant. Examples of effervescent disintegrants include water-soluble and water-insoluble carbonates, but it is only water-soluble sodium bicarbonate that has proved effective.
Patent Document 4 discloses that an effervescent disintegrant makes a tablet containing various drugs easy to ingest by giving a pleasant squeezing or foaming feeling. doing. However, the document does not describe levocetirizine hydrochloride as a drug, and therefore does not disclose masking the acid stimulation specific to levocetirizine hydrochloride.
また、製造工程を工夫することで崩壊性を向上させることも提案されている。例えば、特許文献５は、薬剤、水溶性結合剤、及び水溶性賦形剤を含む乾燥状態の錠剤原料を錠剤形態として次の工程に移行させる際に、その形態を維持可能な硬度とするために必要最低限の低圧力で加圧する工程と、得られた錠剤に吸湿させる工程と、得られた加湿錠剤を乾燥させる工程とを備える方法を開示している。しかし、この方法は工程が煩雑である。 It has also been proposed to improve disintegration by devising the manufacturing process. For example, in Patent Document 5, when a tablet raw material in a dry state containing a drug, a water-soluble binder, and a water-soluble excipient is transferred to the next step as a tablet form, the form can be maintained to have a hardness that can be maintained. Discloses a method comprising a step of pressurizing at a minimum necessary low pressure, a step of absorbing the obtained tablet, and a step of drying the obtained humidified tablet. However, this method is complicated.
上記の通り、レボセチリジン塩酸塩は、苦みと酸刺激を有しているため、口腔内崩壊錠とするためには、レボセチリジン塩酸塩の不快味のマスキングが必要である。しかし、レボセチリジン塩酸塩の酸刺激を抑制する方法は知られておらず、レボセチリジン塩酸塩の不快味が抑制された口腔内崩壊錠が望まれていた。また、口腔内崩壊錠は、成分の不快味が抑えられているだけでなく、口腔内で速やかに崩壊することが必要である。さらに、レボセチリジン塩酸塩は、酸化分解し、類縁物質を生じ易いため、類縁物質の生成を抑制する工夫が必要である。従って、実用可能なレボセチリジン塩酸塩含有口腔内崩壊錠を製造するためには、これら３つの課題の全てを解決することが必要である。
即ち、本発明は、レボセチリジン塩酸塩を含有し、口腔内崩壊性、味、及び安定性の全てにおいて優れる口腔内崩壊錠を提供することを課題とする。
As described above, since levocetirizine hydrochloride has bitterness and acid irritation, masking of the unpleasant taste of levocetirizine hydrochloride is necessary to obtain an orally disintegrating tablet. However, a method for suppressing acid stimulation of levocetirizine hydrochloride is not known, and an orally disintegrating tablet in which the unpleasant taste of levocetirizine hydrochloride is suppressed has been desired. Moreover, the orally disintegrating tablet is required not only to suppress the unpleasant taste of the ingredients but also to disintegrate rapidly in the oral cavity. Furthermore, since levocetirizine hydrochloride tends to be oxidatively decomposed to produce an analogous substance, it is necessary to devise a technique for suppressing the production of the analogous substance. Therefore, in order to produce a practicable levocetirizine hydrochloride-containing orally disintegrating tablet, it is necessary to solve all these three problems.
That is, this invention makes it a subject to provide the orally disintegrating tablet which contains levocetirizine hydrochloride and is excellent in all orally disintegrating property, taste, and stability.
本発明者は、上記課題を解決するために研究を重ね、レボセチリジン塩酸塩を含有する錠剤に、炭酸塩の中でも特に水不溶性炭酸塩を配合することにより、レボセチリジン塩酸塩による酸刺激がマスキングされ、錠剤の口腔内崩壊性が向上し、しかもレボセチリジン塩酸塩の安定性が向上することを見出した。即ち、レボセチリジン塩酸塩を含有する錠剤に、水不溶性炭酸塩を配合するだけで、実用的なレボセチリジン塩酸塩含有口腔内崩壊錠を製造する上での上記３つの課題を一度に解決することができる。 The present inventor has conducted research in order to solve the above problems, and by blending a water-insoluble carbonate among carbonates with a tablet containing levocetirizine hydrochloride, acid stimulation by levocetirizine hydrochloride is masked, It was found that the disintegration property of the tablet in the oral cavity was improved and the stability of levocetirizine hydrochloride was improved. That is, the above three problems in producing a practical levocetirizine hydrochloride-containing orally disintegrating tablet can be solved at a time only by adding a water-insoluble carbonate to a tablet containing levocetirizine hydrochloride. .
すなわち、本発明は、以下の（１）〜（２）を提供する。
（１）レボセチリジン塩酸塩、及び水不溶性炭酸塩を含有する口腔内崩壊錠。
（２）水不溶性炭酸塩が、炭酸カルシウム、及び／又は炭酸マグネシウムである（１）に記載の口腔内崩壊錠。
That is, the present invention provides the following (1) to (2).
(1) An orally disintegrating tablet containing levocetirizine hydrochloride and a water-insoluble carbonate.
(2) The orally disintegrating tablet according to (1), wherein the water-insoluble carbonate is calcium carbonate and / or magnesium carbonate.
本発明の錠剤は、レボセチリジン塩酸塩と水不溶性炭酸塩を含むことにより、口腔内崩壊錠として実用できる適度な崩壊性を有する。本発明の口腔内崩壊錠は、水不溶性炭酸塩という汎用の成分を配合するだけの簡単な手法で崩壊性が向上しており、特殊な組成や煩雑な製造工程を要しない点で、非常に有用なものである。
また、レボセチリジン塩酸塩は酸刺激を有しているため、本来、口腔内崩壊錠にすることに適していない。この点、本発明のレボセチリジン塩酸塩含有口腔内崩壊錠は、このような酸刺激がマスキングされており、非常に有用なものである。
また、レボセチリジン塩酸塩は、酸化分解して類縁物質が生じ易いが、本発明の口腔内崩壊錠は、レボセチリジン塩酸塩の分解が抑制されており、非常に安定である。
このように、本発明は、口腔内崩壊錠に、水不溶性炭酸塩を配合するだけで、口腔内崩壊性、味、及び安定性における課題が全て解決されるという点で優れている。
By including levocetirizine hydrochloride and water-insoluble carbonate, the tablet of the present invention has moderate disintegrability that can be used as an orally disintegrating tablet. The orally disintegrating tablet of the present invention has improved disintegration by a simple method of simply blending a general-purpose ingredient called water-insoluble carbonate, and is very difficult in that it does not require a special composition or complicated manufacturing process. It is useful.
Moreover, since levocetirizine hydrochloride has acid stimulation, it is not originally suitable for making an orally disintegrating tablet. In this regard, the levocetirizine hydrochloride-containing orally disintegrating tablet of the present invention is very useful because such acid stimulation is masked.
In addition, levocetirizine hydrochloride is likely to be oxidatively decomposed to produce a related substance, but the orally disintegrating tablet of the present invention is very stable because the decomposition of levocetirizine hydrochloride is suppressed.
As described above, the present invention is excellent in that all the problems in orally disintegrating property, taste, and stability are solved only by adding a water-insoluble carbonate to the orally disintegrating tablet.
以下、本発明を詳細に説明する。
本発明の口腔内崩壊錠は、レボセチリジン塩酸塩と水不溶性炭酸塩を含む錠剤である。
Hereinafter, the present invention will be described in detail.
The orally disintegrating tablet of the present invention is a tablet containing levocetirizine hydrochloride and water-insoluble carbonate.
レボセチリジン塩酸塩
レボセチリジン塩酸塩は、化学名が、２−（２−{４−［（Ｒ）−（４−クロロフェニル）フェニルメチル］ピペラジン−１−イル}エトキシ）酢酸 二塩酸塩である化合物である。レボセチリジン塩酸塩は、例えば、粉体のものを使用することができる。
Levocetirizine hydrochloride Levocetirizine hydrochloride is a compound whose chemical name is 2- (2- {4-[(R)-(4-chlorophenyl) phenylmethyl] piperazin-1-yl} ethoxy) acetic acid dihydrochloride . As levocetirizine hydrochloride, for example, powder can be used.
レボセチリジン塩酸塩の含有量は、１錠中に０．５〜２５０ｍｇ程度とすることができ、特に、１錠中に５ｍｇとすることができる。 The content of levocetirizine hydrochloride can be about 0.5 to 250 mg per tablet, and particularly 5 mg per tablet.
水不溶性炭酸塩
水不溶性炭酸塩としては、炭酸カルシウム、炭酸マグネシウムなどが挙げられる。中でも、炭酸マグネシウムが好ましい。
水不溶性炭酸塩は、１種を単独で、又は２種以上を組み合わせて使用できる。
The water-insoluble carbonates, water-insoluble carbonates, calcium carbonate, magnesium carbonate, and the like. Among these, magnesium carbonate is preferable.
A water-insoluble carbonate can be used individually by 1 type or in combination of 2 or more types.
水不溶性炭酸塩の含有量は、錠剤の全量（本発明の錠剤がコーティングを有する場合は素錠の全量）に対して、０．１重量％以上が好ましく、１重量％以上がより好ましく、３重量％以上がさらにより好ましい。また、水不溶性炭酸塩の含有量は、錠剤の全量（本発明の錠剤がコーティングを有する場合は素錠の全量）に対して、２０重量％以下が好ましく、１５重量％以下がより好ましく、１０重量％以下がさらにより好ましい。 The content of the water-insoluble carbonate is preferably 0.1% by weight or more, more preferably 1% by weight or more, based on the total amount of the tablet (when the tablet of the present invention has a coating, the total amount of the plain tablet). Even more preferred is weight percent or more. In addition, the content of the water-insoluble carbonate is preferably 20% by weight or less, more preferably 15% by weight or less, more preferably 10% by weight or less based on the total amount of the tablet (or the total amount of the plain tablet when the tablet of the present invention has a coating). Even more preferred is weight percent or less.
添加物
本発明の錠剤は、有効成分のレボセチリジン塩酸塩と、水不溶性炭酸塩に加えて、種々の添加物を含むことができる。添加物としては、例えば、賦形剤、結合剤、崩壊剤、甘味剤、矯味剤、流動化剤、滑沢剤、香料、着色料などの内服用錠剤に使用される任意の添加物を使用できる。添加物は、１種を単独で、又は２種以上を組み合わせて使用できる。
Additives The tablet of the present invention may contain various additives in addition to the active ingredient levocetirizine hydrochloride and water-insoluble carbonate. As additives, for example, any additives used for tablets for internal use such as excipients, binders, disintegrants, sweeteners, corrigents, fluidizers, lubricants, fragrances, and coloring agents are used. it can. An additive can be used individually by 1 type or in combination of 2 or more types.
（賦形剤）
賦形剤としては、例えば、乳糖、乳糖水和物、白糖、マルトース、果糖、ブドウ糖（デキストロース）、トレハロースのような糖類；マンニトール、マルチトール、ソルビトール、キシリトール、エリスリトール、ラクチトールのような糖アルコール；デンプン、アルファ化デンプン、部分アルファ化デンプンのようなデンプン類；結晶セルロースのようなセルロース類；デキストリン；プルラン；アラビアゴム；軽質無水ケイ酸、合成ケイ酸アルミニウム、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、無水リン酸水素カルシウム、炭酸カルシウム、硫酸カルシウムのような無機賦形剤などが挙げられる。
(Excipient)
Examples of excipients include lactose, lactose hydrate, sucrose, maltose, fructose, glucose (dextrose), sugars such as trehalose; sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, erythritol, lactitol; Starches such as starch, pregelatinized starch, partially pregelatinized starch; celluloses such as crystalline cellulose; dextrin; pullulan; gum arabic; light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminate metasilicate And inorganic excipients such as anhydrous calcium hydrogen phosphate, calcium carbonate, and calcium sulfate.
（結合剤）
結合剤としては、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース（ヒプロメロース）、メチルセルロース、エチルセルロース、カルボキシメチルセルロース（カルメロース）のようなセルロース類；ポリビニルピロリドン（ポピドン）；デンプン；ゼラチン；トラガントゴム；ポリビニルアルコール；ポリビニルエーテルなどが挙げられる。
(Binder)
Examples of the binder include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose), methylcellulose, ethylcellulose, carboxymethylcellulose (carmellose); polyvinylpyrrolidone (popidone); starch; gelatin; tragacanth gum; Etc.
（崩壊剤）
崩壊剤としては、例えば、クロスポピドン；カルメロース、カルメロースカルシウム、カルメロースナトリウム、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロース、結晶セルロースのようなセルロース類；デンプン、アルファ化デンプン、部分アルファ化デンプン、カルボキシメチルスターチナトリウム、デンプングリコール酸ナトリウム、ヒドロキシプロピルスターチのようなデンプン類；デキストリン；ケイ酸カルシウムなどが挙げられる。
(Disintegrant)
Examples of disintegrants include crospovidone; carmellose, carmellose calcium, carmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, celluloses such as crystalline cellulose; starch, pregelatinized starch, partially pregelatinized starch , Starches such as sodium carboxymethyl starch, sodium starch glycolate, hydroxypropyl starch; dextrin; calcium silicate and the like.
（滑沢剤）
滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、ステアリン酸、タルク、ラウリル硫酸ナトリウム、酒石酸カリウムナトリウム、マイクロクリスタリンワックス、ショ糖脂肪酸エステル、ポリエチレングリコール、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシプロピレン・ポリオキシエチレンブロック共重合体（ポロキサマーなど）などが挙げられる。
(lubricant)
Examples of lubricants include magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talc, sodium lauryl sulfate, potassium sodium tartrate, microcrystalline wax, sucrose fatty acid ester, polyethylene glycol, polyoxyethylene sorbitan fatty acid Examples thereof include esters and polyoxypropylene / polyoxyethylene block copolymers (such as poloxamers).
（甘味剤）
甘味剤としては、例えば、マンニトール、デンプン糖、還元麦芽糖水あめ、ソルビット、砂糖、果糖、乳糖、蜂蜜、キシリトール、エリスリトール、ソルビトール、サッカリン、甘草およびその抽出物、グリチルリチン酸、甘茶、アスパルテーム、ステビア、ソーマチン、アセスルファムカリウム、クエン酸ナトリウム、スクラロースなどが挙げられる。
(Sweetener)
Sweeteners include, for example, mannitol, starch sugar, reduced maltose syrup, sorbitol, sugar, fructose, lactose, honey, xylitol, erythritol, sorbitol, saccharin, licorice and extracts thereof, glycyrrhizic acid, sweet tea, aspartame, stevia, thaumatin Acesulfame potassium, sodium citrate, sucralose and the like.
（矯味剤）
矯味剤としては、例えば、クエン酸、クエン酸ナトリウム、酒石酸、ＤＬ−リンゴ酸、グリシン、ＤＬ−アラニンなどが挙げられる。
(Flavoring agent)
Examples of the corrigent include citric acid, sodium citrate, tartaric acid, DL-malic acid, glycine, and DL-alanine.
（流動化剤）
流動化剤としては、例えば、含水二酸化ケイ素、軽質無水ケイ酸、合成ケイ酸アルミニウム、合成ヒドロタルサイト、乾燥水酸化アルミニウムゲル、カオリン、ケイ酸カルシウム、メタケイ酸アルミン酸マグネシウム、タルクなどが挙げられる。
(Fluidizer)
Examples of the fluidizing agent include hydrous silicon dioxide, light anhydrous silicic acid, synthetic aluminum silicate, synthetic hydrotalcite, dry aluminum hydroxide gel, kaolin, calcium silicate, magnesium metasilicate aluminate, and talc. .
（香料）
香料としては、例えば、ストロベリー、レモン、レモンライム、オレンジ、ｌ−メントール、ハッカ油などが挙げられる。
(Fragrance)
Examples of the fragrances include strawberry, lemon, lemon lime, orange, l-menthol, mint oil and the like.
（着色料）
着色料としては、例えば、黄色三二酸化鉄、酸化チタン、三二酸化鉄、食用タール色素、天然色素などが挙げられる。
(Coloring agent)
Examples of the colorant include yellow iron sesquioxide, titanium oxide, iron sesquioxide, edible tar dye, natural dye, and the like.
口腔内崩壊錠
本発明の錠剤の口腔内での崩壊時間は、４０秒以内が好ましく、３０秒以内がより好ましい。
Orally disintegrating tablet The disintegration time of the tablet of the present invention in the oral cavity is preferably within 40 seconds, and more preferably within 30 seconds.
製造方法
本発明の口腔内崩壊錠の製造方法は特に限定されない。例えば、レボセチリジン塩酸塩を含む医薬組成物を、常法に従い、湿式又は乾式で造粒し、必要に応じて乾燥、整粒した後、得られた造粒物を打錠するか、又は得られた造粒物と添加物とを混合して打錠する方法により製造することができる。湿式造粒法としては、流動層造粒法、撹拌造粒法、転動造粒法、押出造粒法、破砕造粒法、練合造粒法などが挙げられ、乾式造粒法としては、圧片造粒法、ブリケット造粒法、溶融造粒法などが挙げられる。また、造粒せずに全成分を打錠する直接打錠法も採用できる。
レボセチリジン塩酸塩を含む医薬組成物を造粒した後、添加物と混合して打錠する場合、水不溶性炭酸塩は、医薬組成物に配合してもよく、添加物に配合してもよく、両方に配合してもよい。医薬組成物を湿式造粒する場合は、水不溶性炭酸塩を添加物の方に配合することが望ましい。
Manufacturing method The manufacturing method of the orally disintegrating tablet of this invention is not specifically limited. For example, a pharmaceutical composition containing levocetirizine hydrochloride is granulated wet or dry according to a conventional method, dried and sized as necessary, and then the obtained granulated product is tableted or obtained. The granulated product and additives can be mixed and tableted. Examples of the wet granulation method include fluidized bed granulation method, stirring granulation method, rolling granulation method, extrusion granulation method, crushing granulation method, kneading granulation method and the like. , Pressure piece granulation method, briquette granulation method, melt granulation method and the like. A direct tableting method in which all ingredients are tableted without granulation can also be employed.
When granulating a pharmaceutical composition containing levocetirizine hydrochloride and then mixing with an additive and tableting, the water-insoluble carbonate may be blended in the pharmaceutical composition or in the additive, You may mix | blend with both. When wet granulating a pharmaceutical composition, it is desirable to add a water-insoluble carbonate to the additive.
以下、実施例を挙げて、本発明をより詳細に説明するが、本発明はこれらに限定されない。 EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in detail, this invention is not limited to these.
（１）口腔内崩壊錠の製造
レボセチリジン塩酸塩、β-シクロデキストリンを流動層造粒機で混合し、水で造粒した後、乾燥を行った。乾燥物を２２号篩で整粒し、Ｄ−マンニトール（グラニュトールＦ）、クロスポピドン（ＣＬ−Ｆ）、結晶セルロース（ＫＧ−８０２）、各種炭酸塩、スクラロース、及びステアリン酸マグネシウムを加えて混合し、打錠した。
実施例１〜５の錠剤の組成を表１に示し、比較例１〜６の錠剤の組成を表２に示す。表１、２中の成分量は、１錠当たりの含有量（ｍｇ）である。
(1) Production of orally disintegrating tablets Levocetirizine hydrochloride and β-cyclodextrin were mixed with a fluid bed granulator, granulated with water, and then dried. The dried product is sized with No. 22 sieve, D-mannitol (Granitol F), crospovidone (CL-F), crystalline cellulose (KG-802), various carbonates, sucralose, and magnesium stearate are added and mixed. And tableted.
The composition of the tablets of Examples 1 to 5 is shown in Table 1, and the composition of the tablets of Comparative Examples 1 to 6 is shown in Table 2. The amount of ingredients in Tables 1 and 2 is the content (mg) per tablet.
（２）評価
口腔内崩壊性
実施例１〜５、及び比較例１〜６で得た各錠剤を、２名の被験者が服用し、口腔内で崩壊するまでの時間を測定した。崩壊するまでに要した時間の平均値を表１、表２に示す。
水不溶性の炭酸カルシウム又は炭酸マグネシウムを含む実施例１〜５の錠剤は２７〜２９秒の適度な崩壊時間を示し、これらの崩壊時間は、水溶性の炭酸水素ナトリウム又は炭酸ナトリウムを含む比較例２〜６の錠剤に比べて、明らかに短かった。また、実施例１〜５の錠剤は、炭酸塩を含まない比較例１の錠剤に比べても、崩壊までの時間が短かった。
(2) Evaluation
Oral disintegration properties Each tablet obtained in Examples 1 to 5 and Comparative Examples 1 to 6 was taken by two subjects, and the time until disintegration in the oral cavity was measured. Tables 1 and 2 show the average values of the time required to collapse.
The tablets of Examples 1-5 containing water-insoluble calcium carbonate or magnesium carbonate show a reasonable disintegration time of 27-29 seconds, these disintegration times being Comparative Example 2 containing water-soluble sodium bicarbonate or sodium carbonate Obviously shorter than ~ 6 tablets. Moreover, the tablet of Examples 1-5 had a short time to disintegration compared with the tablet of the comparative example 1 which does not contain carbonate.
酸刺激のマスキング
実施例１〜５、及び比較例１〜６で得た各錠剤を、２名の被験者が服用して、口腔内で崩壊させ、酸刺激に対するマスキング効果の有無を評価した。結果を表１、表２に示す。
水不溶性炭酸塩を配合した場合は、何れも酸刺激が感じられなかった。一方、水溶性炭酸塩のうち炭酸ナトリウムを配合した場合は、酸刺激が感じられた。
Acid Stimulation Masking Each of the tablets obtained in Examples 1 to 5 and Comparative Examples 1 to 6 was taken by two subjects and disintegrated in the oral cavity, and the presence or absence of a masking effect on acid stimulation was evaluated. The results are shown in Tables 1 and 2.
When water-insoluble carbonate was blended, no acid irritation was felt. On the other hand, acid stimulation was felt when sodium carbonate was added among the water-soluble carbonates.
類縁物質生成抑制
実施例１〜３、及び比較例１〜５で得た各錠剤を温度４０℃、相対湿度７５％の条件下で４週間静置した。静置前、２週間後、及び４週間後に、高速液体クロマトグラフィーを行い、レボセチリジン塩酸塩の主要な類縁物質である４−クロロベンゾフェノンの生成量（％）を下記ＨＰＬＣ条件で測定した。
（ＨＰＬＣ条件）
検出器：紫外吸光光度計（測定波長：２３０ｎｍ）
カラム：フェニル化シリカゲル
カラム温度：４０℃付近の一定温度
移動相：ｐＨ３．０の１−オクタンスルホン酸ナトリウム緩衝液及びメタノールの混液
流量：０．６５ｍＬ／ｍｉｎ
Inhibition of production of related substances Each tablet obtained in Examples 1 to 3 and Comparative Examples 1 to 5 was allowed to stand for 4 weeks under conditions of a temperature of 40 ° C. and a relative humidity of 75%. Before standing, 2 weeks, and 4 weeks, high performance liquid chromatography was performed, and the production amount (%) of 4-chlorobenzophenone, which is a main related substance of levocetirizine hydrochloride, was measured under the following HPLC conditions.
(HPLC conditions)
Detector: UV absorptiometer (measurement wavelength: 230 nm)
Column: Phenylated silica gel Column temperature: Constant temperature around 40 ° C. Mobile phase: Mixed solution flow rate of sodium 1-octanesulfonate buffer solution of pH 3.0 and methanol: 0.65 mL / min
水不溶性炭酸塩を配合した実施例１〜３の錠剤は、４週間後にも類縁物質がほとんど生成していなかった。一方、水溶性炭酸塩を配合した場合は、炭酸塩を配合しない場合と同程度に類縁物質が生成した。 The tablets of Examples 1 to 3 containing water-insoluble carbonate produced almost no related substance even after 4 weeks. On the other hand, when water-soluble carbonate was blended, similar substances were produced to the same extent as when no carbonate was blended.
本発明の口腔内崩壊錠は、汎用の成分を配合するだけで製造できる点で、非常に有用なものである。また、レボセチリジン塩酸塩特有の酸刺激がマスキングされており、この点でも口腔内崩壊錠として有用なものである。さらに、レボセチリジン塩酸塩は、一般に、製剤化時や保管時に分解して類縁物質が生じ易いが、本発明の口腔内崩壊錠は、非常に安定である。 The orally disintegrating tablet of the present invention is very useful in that it can be produced simply by blending general-purpose components. Moreover, the acid stimulation peculiar to levocetirizine hydrochloride is masked, and this is also useful as an orally disintegrating tablet. Furthermore, levocetirizine hydrochloride generally tends to be decomposed during formulation or storage to produce a related substance, but the orally disintegrating tablet of the present invention is very stable.
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Cited By (3)
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|---|---|---|---|---|
| JP2020015690A (en) * | 2018-07-25 | 2020-01-30 | ニプロ株式会社 | Levocetirizine-containing tablets |
| JP2022008042A (en) * | 2020-04-15 | 2022-01-13 | 大正製薬株式会社 | Pharmaceutical composition |
| CN115252568A (en) * | 2022-08-26 | 2022-11-01 | 苏州中化药品工业有限公司 | Cetirizine hydrochloride tablet and preparation method thereof |
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| JP2002509873A (en) * | 1998-03-31 | 2002-04-02 | アスタ メディカ アクチエンゲゼルシャフト | Fast disintegrating solid cetirizine formulation |
| US20060105038A1 (en) * | 2004-11-12 | 2006-05-18 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions prepared by coacervation |
| WO2010092828A1 (en) * | 2009-02-12 | 2010-08-19 | 富士化学工業株式会社 | Disintegrating particle composition and rapidly disintegrating compression-molded material comprising same |
| JP2012046446A (en) * | 2010-08-26 | 2012-03-08 | Sawai Pharmaceutical Co Ltd | Method for producing intraorally disintegrating tablet containing zolpidem tartrate |
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| JP2002509873A (en) * | 1998-03-31 | 2002-04-02 | アスタ メディカ アクチエンゲゼルシャフト | Fast disintegrating solid cetirizine formulation |
| US20060105038A1 (en) * | 2004-11-12 | 2006-05-18 | Eurand Pharmaceuticals Limited | Taste-masked pharmaceutical compositions prepared by coacervation |
| WO2010092828A1 (en) * | 2009-02-12 | 2010-08-19 | 富士化学工業株式会社 | Disintegrating particle composition and rapidly disintegrating compression-molded material comprising same |
| JP2012046446A (en) * | 2010-08-26 | 2012-03-08 | Sawai Pharmaceutical Co Ltd | Method for producing intraorally disintegrating tablet containing zolpidem tartrate |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2020015690A (en) * | 2018-07-25 | 2020-01-30 | ニプロ株式会社 | Levocetirizine-containing tablets |
| JP2022008042A (en) * | 2020-04-15 | 2022-01-13 | 大正製薬株式会社 | Pharmaceutical composition |
| JP7667528B2 (en) | 2020-04-15 | 2025-04-23 | 大正製薬株式会社 | Pharmaceutical Compositions |
| CN115252568A (en) * | 2022-08-26 | 2022-11-01 | 苏州中化药品工业有限公司 | Cetirizine hydrochloride tablet and preparation method thereof |
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