JP5158318B2 - Orally disintegrating tablets - Google Patents
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本発明は、舌触り、錠剤強度及び崩壊性が良好な口腔内崩壊錠に関する。 The present invention relates to an orally disintegrating tablet having good touch, tablet strength and disintegration.
近年、固形製剤を口中で崩壊させ、水を用いずに服用するタイプの内服固形製剤（以下口腔内崩壊錠と呼ぶ）が提案されている。口腔内崩壊錠は、通常、粉体原料を圧縮成形して得られ、口中に入れた後、唾液を固形製剤表面から浸透させ、粉体間の結合（凝集）を絶って崩壊させる。初期に、粗く噛み砕き、唾液の浸透を促進させる場合もある。 In recent years, an internal solid preparation (hereinafter referred to as an orally disintegrating tablet) of a type in which a solid preparation is disintegrated in the mouth and taken without using water has been proposed. An orally disintegrating tablet is usually obtained by compression molding a powder raw material, and after it is put in the mouth, saliva is permeated from the surface of the solid preparation to disintegrate the bond (aggregation) between the powders. Initially, it may be roughly chewed to promote saliva penetration.
このような口中崩壊錠は、錠剤が崩壊した後、薬物粉末や賦形剤等の微粉末による舌触りが悪く、これを解決することが必要である。錠剤の舌触り改善の検討としては、マンニトール及び／又は乳塘に低嵩比重のソルビトールを配合した固形製剤組成物（特許文献１：特開平５−３１０５５８号公報参照）、打錠成形品の舌触り改善剤としてショ糖ベヘン酸エステルが提案されている（特許文献２：特開２００３−９５９８２号公報参照）。しかしながら、これらの錠剤は、錠剤硬度は確保しているが、口中での崩壊時間が遅いトローチである。 Such an orally disintegrating tablet is poor in the touch of fine powder such as drug powder or excipient after the tablet disintegrates, and it is necessary to solve this problem. As a study for improving the touch of the tablet, a solid preparation composition in which mannitol and / or milk powder is mixed with sorbitol having a low bulk specific gravity (see Patent Document 1: JP-A-5-310558), improvement of the touch of a tableted product. As an agent, sucrose behenate has been proposed (see Patent Document 2: Japanese Patent Application Laid-Open No. 2003-95982). However, these tablets are troches which have a tablet hardness but a slow disintegration time in the mouth.
また、口腔内崩壊錠に求められる錠剤物性として重要なものとして、強度、硬度、崩壊性が挙げられる。しかしながら、これらの物性全てを満足させることは困難である。即ち、安定性から強度を高くすると硬くなり崩壊性を損ない、逆に崩壊性を向上させるため硬度を調整すると、脆く割れやすい錠剤となってしまう。 Moreover, strength, hardness, and disintegration property are mentioned as important tablet properties required for orally disintegrating tablets. However, it is difficult to satisfy all these physical properties. That is, if the strength is increased from the stability, it becomes hard and the disintegration property is lost. Conversely, when the hardness is adjusted to improve the disintegration property, the tablet becomes brittle and easily broken.
上記課題を解決するため、湿らせた糖と薬物と水とを混合して打錠し、その後乾燥させて口腔内崩壊錠を得る方法が提案されている（特許文献３：特開平５−２７１０５４号公報参照。しかしながら、上記方法は、乾燥工程を経なければならず、特別な設備が必要であり、さらに薬物や香料によっては安定性に影響する等の製造性に課題があった。また、薬物、エリスリトール、結晶セルロース、崩壊剤を含有する、強度と崩壊性に優れた口腔内溶解型固形製剤（特許文献４：特開平１０−１８２４３６号公報参照）、薬物、主賦形剤としてのマンニトール、結合性崩壊剤を含有する湿式造粒顆粒と崩壊剤とを混合して圧縮成形する口腔内溶解型錠剤（特許文献５：特開平１０−２９８０６２号公報参照）、マンニトールと、崩壊剤と、セルロース類と、滑沢剤と、澱粉又は乳糖とを含有する口腔内崩壊性組成物（特許文献６：特開２０００−２７３０３９号公報参照）が提案されている。これらは、主に賦形剤の種類等を特定して解決していることが特徴であるが、いずれも唾液を急激に吸収して膨潤することから、舌に粉っぽさと粘りを感じる等、不快な舌触りとなりやすい。 In order to solve the above problems, a method has been proposed in which a wet sugar, a drug, and water are mixed and tableted, and then dried to obtain an orally disintegrating tablet (Patent Document 3: Japanese Patent Laid-Open No. 5-271044). However, the above method requires a drying process, requires special equipment, and has problems in manufacturability such as affecting the stability depending on drugs and perfumes. An oral-dissolving solid preparation containing a drug, erythritol, crystalline cellulose, and a disintegrant and excellent in strength and disintegration (see Patent Document 4: JP-A-10-182436), drug, and mannitol as a main excipient , An oral-dissolving tablet that is compression-molded by mixing wet granulated granules containing a disintegrant and a disintegrant (see Patent Document 5: JP-A-10-298062), mannitol, a disintegrant, cell An orally disintegrating composition (see Patent Document 6: Japanese Patent Laid-Open No. 2000-273039) containing a sesame, a lubricant, and starch or lactose has been proposed. It is characterized by solving the problem by specifying the type of agent, etc., but all of them absorb saliva rapidly and swell, so that the tongue tends to feel unpleasant, such as feeling powdery and sticky.
さらに、薬物と難溶性無機物と５０％以上が粒径２０〜３００μｍの糖／糖アルコールを含有する適切な強度を有する錠剤医薬組成物が提案されているが（特許文献７：特開２００１−３１６２４９号公報参照）、口腔内崩壊錠とした場合の崩壊性、舌触りにおいて改善の余地がある。アスピリンと制酸剤と単糖類、二糖類及び糖アルコールから選ばれる化合物とを含有する口中崩壊性アスピリン含有製剤に関する技術も提案されているが（特許文献８：特開２００２−８７９６５号公報参照）、崩壊時の舌触りの点で改善の余地がある。３０μｍ以下の生理活性成分と制酸剤を含有する口中で崩壊又は溶解させる固形医薬組成物に関する技術が提案されているが（特許文献９：特開２００２−２９９６４号公報参照）、咀嚼錠としてのざらつき感は改善されるものの、舌触り、崩壊性及び強度の全てを十分満足させるには改善の余地があった。 Furthermore, a tablet pharmaceutical composition having an appropriate strength containing a drug, a hardly soluble inorganic substance, and a sugar / sugar alcohol having a particle size of 20 to 300 μm of 50% or more has been proposed (Patent Document 7: JP 2001-316249 A). No.), and there is room for improvement in disintegration and mouthfeel when used as an orally disintegrating tablet. A technique relating to an orally disintegrating aspirin-containing preparation containing an aspirin, an antacid, and a compound selected from monosaccharides, disaccharides and sugar alcohols has also been proposed (see Patent Document 8: JP 2002-87965 A). There is room for improvement in terms of touch when collapsed. A technique related to a solid pharmaceutical composition that is disintegrated or dissolved in a mouth containing a physiologically active ingredient of 30 μm or less and an antacid is proposed (see Patent Document 9: Japanese Patent Laid-Open No. 2002-29964). Although the feeling of roughness was improved, there was room for improvement to sufficiently satisfy all of the touch, disintegration and strength.
口腔内崩壊時の舌触りを良くしようとすると崩壊時間が遅くなり、錠剤の強度と崩壊性を両立しようとすると舌触りが悪くなるため、これらを全て満足する錠剤を得ることは困難であった。そこで、舌触りがよく、適度な強度と口中崩壊性を有する口腔内崩壊錠が望
まれていた。
When trying to improve the mouthfeel when disintegrating in the oral cavity, the disintegration time is delayed, and when trying to achieve both tablet strength and disintegration, the mouthfeel becomes worse. Therefore, it has been difficult to obtain a tablet satisfying all of these. Therefore, an orally disintegrating tablet that has a good touch and has an appropriate strength and disintegrating property in the mouth has been desired.
本発明は、崩壊剤の吸水による粉っぽさを低減し、しかも適度な強度と口腔内での速やかな崩壊性を有する、舌触りが良好な口腔内崩壊錠を提供することを目的とする。 An object of the present invention is to provide an orally disintegrating tablet with a good tongue touch that has reduced powderiness due to water absorption of a disintegrant, and has an appropriate strength and quick disintegration in the oral cavity.
本発明者らは鋭意検討の結果、（ａ）部分α化デンプン、（ｂ）非膨潤性水難溶性無機塩及び（ｃ）水溶性賦形剤を、特定の割合で配合することにより、舌触りが良好な口腔内崩壊錠が得られることを知見した。さらに、（ｂ）／（ａ）（質量比）＝３〜７、（ｃ）／（ａ）（質量比）＝７〜１５、かつ（ａ）、（ｂ）及び（ｃ）成分の合計量が崩壊錠全体の６０質量％以上とすることで、舌触り良く、錠剤強度及び崩壊性が良好な口腔内崩壊錠が得られることを見出し、本発明をなすに至ったものである。即ち、本発明は、錠剤に通常使用される水不溶性セルロース類より膨潤度の低い（ａ）部分α化デンプンと、（ｂ）非膨潤性水難溶性無機塩と、（ｃ）水溶性賦形剤とを特定の比及び量で組み合わせることにより、強度を損なわずに崩壊性が大幅に向上して、しかも舌触りの良い口腔内崩壊錠を得ることができたものである。 As a result of intensive studies, the present inventors have (a) partially pregelatinized starch, (b) a non-swellable poorly water-soluble inorganic salt, and (c) a water-soluble excipient at a specific ratio, so that the tongue feel It was found that a good orally disintegrating tablet can be obtained. Furthermore, (b) / (a) (mass ratio) = 3-7, (c) / (a) (mass ratio) = 7-15, and the total amount of (a), (b) and (c) components Has been found to be an orally disintegrating tablet with good touch and good tablet strength and disintegration by making it 60% by mass or more of the entire disintegrating tablet, and has led to the present invention. That is, the present invention comprises (a) partially pregelatinized starch having a lower degree of swelling than water-insoluble celluloses usually used for tablets, (b) a non-swellable poorly water-soluble inorganic salt, and (c) a water-soluble excipient. Can be obtained in a specific ratio and amount, so that disintegration can be greatly improved without impairing strength, and an orally disintegrating tablet with good touch can be obtained.
すなわち、本発明は下記を提供する。
[１]．（ａ）部分α化デンプン、（ｂ）リン酸マグネシウム及び／又は焼成カルシウム、及び（ｃ）二糖類及び／又は糖アルコールを含有する口腔内崩壊錠であって、（ｂ）／（ａ）（質量比）＝３〜７、（ｃ）／（ａ）（質量比）＝７〜１５、かつ（ａ）、（ｂ）及び（ｃ）成分の合計量が崩壊錠全体の６０質量％以上である口腔内崩壊錠。
[２]．（ａ）部分α化デンプンが、外層と内層とからなる粒子であって、外層がβデンプンからなり、内層の一部又は全部がα化デンプンからなる粒子であることを特徴とする[１]記載の口腔内崩壊錠。
[３]．（ｃ）水溶性賦形剤の全部又は一部が造粒物であることを特徴とする[１]又は[２]記載の口腔内崩壊錠。
[４]．口臭除去用であることを特徴とする[１]〜[３]のいずれかに記載の口腔内崩壊錠。
[５]．口腔内崩壊錠に対する配合量が、（ａ）成分が２〜９質量％、（ｂ）成分が１０〜５０質量％、（ｃ）成分が２０〜７０質量％である[１]〜[４]のいずれかに記載の口腔内崩壊錠。
That is, the present invention provides the following.
[1]. An orally disintegrating tablet comprising (a) partially pregelatinized starch, (b) magnesium phosphate and / or calcined calcium, and (c) a disaccharide and / or a sugar alcohol , wherein (b) / (a) ( (Mass ratio) = 3-7, (c) / (a) (mass ratio) = 7-15, and the total amount of components (a), (b) and (c) is 60% by mass or more of the entire disintegrating tablet. An orally disintegrating tablet.
[2]. (A) The partially pregelatinized starch is particles composed of an outer layer and an inner layer, the outer layer is composed of β starch, and part or all of the inner layer is composed of particles pregelatinized [1] The orally disintegrating tablet described.
[3]. (C) The orally disintegrating tablet according to [1] or [2], wherein all or part of the water-soluble excipient is a granulated product.
[ 4 ]. The orally disintegrating tablet according to any one of [1] to [ 3 ], which is used for removing bad breath.
[ 5 ]. [1] to [ 4 ] with respect to the orally disintegrating tablet, the component (a) is 2 to 9% by mass, the component (b) is 10 to 50% by mass, and the component (c) is 20 to 70% by mass. Orally disintegrating tablet according to any one of the above.
本発明によれば、舌触り、錠剤強度及び崩壊性が良好な口腔内崩壊錠を提供することができる。 ADVANTAGE OF THE INVENTION According to this invention, an orally disintegrating tablet with favorable touch, tablet strength, and disintegration property can be provided.
本発明の（ａ）部分α化デンプンは１種単独で又は２種以上を適宜組み合わせて用いることができ、この中でも、外層と内層とからなる粒子であって、外層がβデンプンからなり、内層の一部又は全部がα化デンプンからなる粒子が好ましい。このように、粒子表面がβデンプンで内部の一部又は全部がα化された層状粒子とすることで、粉の流動性と崩壊性が向上する。外層と内層とからなる粒子であって、外層がβデンプンからなり、内層の一部又は全部がα化デンプンからなる粒子としては、旭化成製「製品名ＰＣＳ」等が挙げられる。また、粒子全体としてのα化度が９０％以上のものが好ましく、部分α化デンプンは、崩壊性の面から、造粒しないで直打用を配合して直接打錠する方が好ましい。 The (a) partially pregelatinized starch of the present invention can be used singly or in appropriate combination of two or more, and among these, particles comprising an outer layer and an inner layer, the outer layer comprising β starch, Particulate or partially composed of pregelatinized starch is preferred. Thus, the fluidity | liquidity and disintegration property of a powder improve by making the particle | grain surface into the layered particle | grains by which the inside or part of (beta) starch was made into (beta) starch. Examples of particles composed of an outer layer and an inner layer, in which the outer layer is made of β starch and a part or all of the inner layer is made of pregelatinized starch, include “Product Name PCS” manufactured by Asahi Kasei. Further, it is preferable that the degree of pregelatinization of the particles as a whole is 90% or more. From the viewpoint of disintegration, partially pregelatinized starch is preferably directly tableted by blending for direct compression without granulation.
本発明の（ｂ）非膨潤性水難溶性無機塩は、常温での溶解度が１ｇ／１００ｍＬ以下、好ましくは０．１ｇ／１００ｍＬ以下で、膨潤容積が２以下の無機塩である。膨潤容積とは、予め嵩密度を測定した無機塩に過剰量の水を入れ、そのときの沈降体積を測定し、その倍率を表す。 The (b) non-swellable poorly water-soluble inorganic salt of the present invention is an inorganic salt having a solubility at room temperature of 1 g / 100 mL or less, preferably 0.1 g / 100 mL or less and a swelling volume of 2 or less. The swelling volume refers to the magnification obtained by adding an excessive amount of water to an inorganic salt whose bulk density has been measured in advance and measuring the sedimentation volume at that time.
（ｂ）非膨潤性水難溶性無機塩としては、合成ヒドロタルサイト、水酸化カルシウム、炭酸カルシウム、炭酸マグネシウム、リン酸カルシウム、リン酸マグネシウム、リン酸一水素カルシウム、焼成カルシウム等が挙げられ、１種単独で又は２種以上を適宜組み合わせて用いることができる。この中でも、リン酸カルシウム、リン酸マグネシウム、リン酸一水素カルシウム等のリン酸塩、焼成カルシウムが好ましく、最も好ましい非膨潤性水難溶性無機塩はリン酸マグネシウム、焼成カルシウムである。非膨潤性水難溶性無機塩の粒径は、好ましくは平均粒径１００μｍ以下とすると、ざらつきがなく、また本発明の効果も優れている。また、非膨潤性水難溶性無機塩は、崩壊性の面から、造粒しないで直接打錠する方が好ましい。 (B) Non-swellable poorly water-soluble inorganic salts include synthetic hydrotalcite, calcium hydroxide, calcium carbonate, magnesium carbonate, calcium phosphate, magnesium phosphate, calcium monohydrogen phosphate, calcined calcium, etc. Or two or more can be used in appropriate combination. Among these, phosphates such as calcium phosphate, magnesium phosphate, and calcium monohydrogen phosphate, and calcined calcium are preferable, and the most preferable non-swellable poorly water-soluble inorganic salt is magnesium phosphate and calcined calcium. When the particle diameter of the non-swellable poorly water-soluble inorganic salt is preferably an average particle diameter of 100 μm or less, there is no roughness and the effect of the present invention is excellent. The non-swellable poorly water-soluble inorganic salt is preferably compressed directly without granulation from the viewpoint of disintegration.
なお、本発明において平均粒径は、第１５改正日局一般試験法 第２法にて粒子径分布を評価して、平均粒子径（累積５０％（重量）粒径）を算出する。 In the present invention, the average particle size is calculated by evaluating the particle size distribution according to the second method of the 15th revised JP General Test Method and calculating the average particle size (cumulative 50% (weight) particle size).
本発明の（ｃ）水溶性賦形剤は１種単独で又は２種以上を適宜組み合わせて用いることができ、二糖類及び／又は糖アルコールが好ましい。二糖類としては、乳糖、トレハロース、パラチノース等が好ましく、糖アルコールとしては、ソルビトール、エリスリトール、キシリトール、マンニトール、マルチトール、ラクチトール、パラチニット等が好ましい。この中でも、マルチトール、乳糖、ラクチトール、トレハロース、パラチノース、パラチニット、エリスリトールを用いることで、耐吸湿性を向上させることができる。二糖類及び／又は糖アルコールは直打用粒子又は造粒粒子が用いられ、これらの平均粒径（累積５０重量％粒径）は５０〜５００μｍ以下が好ましく、より好ましくは１００〜３００μｍである。５０μｍ未満では流動性が悪くなる場合があり、５００μｍを超えると口中でざらつきを生じる場合がある。 (C) The water-soluble excipient | filler of this invention can be used individually by 1 type or in combination of 2 or more types, A disaccharide and / or sugar alcohol are preferable. As the disaccharide, lactose, trehalose, palatinose and the like are preferable, and as the sugar alcohol, sorbitol, erythritol, xylitol, mannitol, maltitol, lactitol, palatinit and the like are preferable. Among these, moisture absorption resistance can be improved by using maltitol, lactose, lactitol, trehalose, palatinose, palatinit, and erythritol. As the disaccharide and / or sugar alcohol, direct hitting particles or granulated particles are used, and the average particle size (cumulative 50% by weight particle size) is preferably 50 to 500 μm or less, more preferably 100 to 300 μm. If it is less than 50 μm, the fluidity may be deteriorated, and if it exceeds 500 μm, roughness may occur in the mouth.
（ｃ）水溶性賦形剤は、結合力と流動性の面から、全部又は一部を造粒物とすることが好ましい。造粒に用いる結合剤としては、ヒドロキシプロピルセルロース（置換度５３．４〜７７．５％）、メチルセルロース、ゼラチン、ポリビニルピロリドン等が挙げられるが、好ましい結合剤はヒドロキシプロピルセルロース（置換度５３．４〜７７．５％）である。また、コーティング剤に着色剤を入れることにより色調を変えることもできる。着色剤としては、酸化チタン、色素が挙げられる。また、造粒時に造粒補助剤としてデンプン、薬効成分等他成分を一緒に造粒することも可能である。 (C) It is preferable that all or part of the water-soluble excipient is a granulated product from the viewpoints of binding strength and fluidity. Examples of the binder used for granulation include hydroxypropyl cellulose (substitution degree 53.4-77.5%), methyl cellulose, gelatin, polyvinyl pyrrolidone and the like. Preferred binder is hydroxypropyl cellulose (substitution degree 53.4). ~ 77.5%). The color tone can also be changed by adding a colorant to the coating agent. Examples of the colorant include titanium oxide and pigment. It is also possible to granulate together other ingredients such as starch and medicinal ingredients as a granulation aid during granulation.
特に、二糖類及び／又は糖アルコールの造粒は、例えば以下のように製造することができる。流動層造粒により、薬物を流動させ水溶性高分子水溶液を噴霧し、乾燥する方法、撹拌造粒機により、撹拌中の薬物に水溶性高分子水溶液を含浸させ、流動層造粒機で乾燥する方法等がある。 In particular, granulation of disaccharide and / or sugar alcohol can be produced, for example, as follows. Fluidized bed granulation allows the drug to flow, sprays water-soluble polymer aqueous solution, and drys. Stirring granulator impregnates the drug being stirred with water-soluble polymer aqueous solution, then dry in fluidized bed granulator There are ways to do this.
本発明における(ａ)部分α化デンプンと（ｂ）非膨潤性不溶性無機塩の質量比は、（ｂ）／（ａ）（質量比）＝３〜７であり、好ましくは４〜６である。（ａ）部分α化デンプンに対する（ｂ）非膨潤性不溶性無機塩の割合が少なすぎると、結合性が悪くなって、強度が弱くなり、（ａ）部分α化デンプンに対する（ｂ）非膨潤性不溶性無機塩が多すぎると崩壊性が悪くなる。また、(ａ)部分α化デンプンと（ｃ）水溶性賦形剤の質量比は、（ｃ）／（ａ）（質量比）＝７〜１５であり、８〜１２が好ましい。（ａ）部分α化デンプンに対する（ｃ）水溶性賦形剤の割合が少なすぎると、強度が弱くなり、（ａ）部分α化デンプンに対する（ｃ）水溶性賦形剤が多すぎると崩壊性が悪くなる。また、（ａ）、（ｂ）及び（ｃ）成分の合計量は崩壊錠全体の６０質量％以上であり、７０質量％以上が好ましい。６０質量％未満だと崩壊性が悪くなる。なお、（ａ）、（ｂ）及び（ｃ）成分の合計量の上限は特に限定されないが、９０質量％が好ましい。 The mass ratio of (a) partially pregelatinized starch and (b) non-swellable insoluble inorganic salt in the present invention is (b) / (a) (mass ratio) = 3-7, preferably 4-6. . (A) If the ratio of (b) non-swellable insoluble inorganic salt to the partially pregelatinized starch is too small, the bondability becomes poor and the strength becomes weak. (A) (b) nonswellable to the partially pregelatinized starch When there are too many insoluble inorganic salts, disintegration will worsen. Moreover, the mass ratio of (a) partially pregelatinized starch and (c) water-soluble excipient is (c) / (a) (mass ratio) = 7 to 15, preferably 8 to 12. (A) If the ratio of the (c) water-soluble excipient to the partially pregelatinized starch is too small, the strength becomes weak, and (a) the amount of (c) the water-soluble excipient to the partially pregelatinized starch is too disintegrable. Becomes worse. Further, the total amount of the components (a), (b) and (c) is 60% by mass or more, and preferably 70% by mass or more of the entire disintegrating tablet. When it is less than 60% by mass, the disintegration property is deteriorated. In addition, the upper limit of the total amount of the components (a), (b) and (c) is not particularly limited, but 90% by mass is preferable.
また、（ａ）部分α化デンプン、（ｂ）非膨潤性水難溶性無機塩及び（ｃ）水溶性賦形剤の口腔内崩壊錠に対する配合量は、上記比率、（ａ）、（ｂ）及び（ｃ）成分の合計量を満たせば、特に限定されないが、（ａ）部分α化デンプンは２〜９質量％が好ましく、（ｂ）非膨潤性水難溶性無機塩は１０〜５０質量％が好ましく、（ｃ）水溶性賦形剤は２０〜７０質量％が好ましい。 The blending amount of (a) partially pregelatinized starch, (b) non-swelling poorly water-soluble inorganic salt and (c) water-soluble excipient with respect to the orally disintegrating tablet is the above ratio, (a), (b) and (C) Although it will not specifically limit if the total amount of a component is satisfy | filled, (a) Partially pregelatinized starch is preferable 2-9 mass%, (b) Non-swelling water sparingly soluble inorganic salt is preferable 10-50 mass%. (C) 20-70 mass% of water-soluble excipient | filler is preferable.
本発明の口腔内崩壊錠には、上記（ａ）〜（ｃ）成分の他に、各種薬物を配合することが好ましい。薬物としては、ビタミン、鎮痛薬、抗炎症薬、抗アレルギー薬、抗ヒスタミン薬、粘膜保護剤等の胃腸薬、眠気防止薬、生薬、グルクロノラクトン、グルクロン酸、口臭除去剤等の各種薬物を、単体粒子としてそのまま、又は造粒粒子として配合することができる。造粒粒子とする場合は（ｃ）の糖アルコールと共に造粒してもよい。 In the orally disintegrating tablet of the present invention, it is preferable to incorporate various drugs in addition to the components (a) to (c). Drugs include various drugs such as vitamins, analgesics, anti-inflammatory drugs, antiallergic drugs, antihistamines, mucosal protective agents, etc., gastrointestinal drugs, sleepiness prevention drugs, herbal medicines, glucuronolactone, glucuronic acid, bad breath removers, etc. It can be blended as single particles or as granulated particles. When it is set as granulated particles, it may be granulated with the sugar alcohol of (c).
ビタミンとしては、ビタミンＢ1群（例えばチアミン、硝酸チアミン、塩酸チアミン、ビタミンＢ1誘導体）、ビタミンＢ2群（例えばリボフラビン、リン酸リボフラビンナト
リウム、酪酸リボフラビン等）、ビタミンＢ6群（例えばピリドキシン、ピリドキサル、ピリドキサミン及びこれらのリン酸あるいは塩酸塩等）、ビタミンＢ12群（例えばコバラミン、シアノコバラミン、メチルコバラミン等）、ビタミンＣ（アスコルビン酸、アスコルビン酸カルシウム等）、ビタミンＡ群、ビタミンＥ群等が挙げられ、そのほかに、ビタミン剤に配合できる成分としてパントテン酸類、Ｌ−システイン、グルクロノラクトン等が挙げられる。また、鎮痛薬としてはイブプロフェン、アセトアミノフェン等が挙げられる。抗ヒスタミン薬としては、マレイン酸クロルフェニラミン、マレイン酸カルビノキサミン、塩酸ジフェンヒドラミン等が挙げられる。粘膜保護剤としては、スクラルファート、アルジオキサ、アズレンスルホン酸ナトリウム、ｌ−グルタミン等が挙げられる。眠気防止薬としてはカフェイン、無水カフェインが挙げられる。
As vitamins, vitamin B 1 group (for example, thiamine, thiamine nitrate, thiamine hydrochloride, vitamin B 1 derivative), vitamin B 2 group (for example, riboflavin, sodium riboflavin phosphate, riboflavin butyrate, etc.), vitamin B 6 group (for example, pyridoxine, Pyridoxal, pyridoxamine and their phosphates or hydrochlorides), vitamin B 12 groups (eg cobalamin, cyanocobalamin, methylcobalamin etc.), vitamin C (ascorbic acid, calcium ascorbate etc.), vitamin A group, vitamin E group, etc. In addition, pantothenic acids, L-cysteine, glucuronolactone and the like can be mentioned as components that can be added to the vitamin preparation. Moreover, ibuprofen, acetaminophen, etc. are mentioned as an analgesic. Antihistamines include chlorpheniramine maleate, carbinoxamine maleate, diphenhydramine hydrochloride and the like. Examples of the mucosal protective agent include sucralfate, aldioxa, sodium azulene sulfonate, l-glutamine and the like. Caffeine and anhydrous caffeine are mentioned as a sleepiness prevention drug.
上記薬物は、各々目的とする薬効に応じて適切な処方とすることができる。例えば、口臭除去剤とする場合は、口中で口臭除去・抑制効果を発揮する口臭除去成分を配合することが好ましい。
口臭除去成分としては、サイクロデキストリン、クエン酸、酒石酸、リンゴ酸等の有機酸及びその塩、ゼオライト、活性炭、シリカゲル、銅クロロフィリンナトリウム、カテキン、ポリフェノール、フラボノイド、グルコン酸銅、クエン酸銅、リンゴ酸銅等の銅塩、ローズマリー、セージ、タイム、オレガノ、マジョラム、シソ、セーボリー等のシソ科植物、コラエキス、サンショウエキス、チョウジ、オウレン、レンギョウ、タンニン酸、没食子酸、甜茶、車前草、ジコッピ、ニンドウ、ディル、オウゴン、メース、アラメ、カキノハ、ブルーベリー、ライチ、グアバ、アセロラ、アロニア、ブラックカラント、エルダベリー、ヤナギタデ、ローズヒップ、重曹、サラダ油、リノール酸、トリクロサン、ビオゾール、グルコン酸クロルヘキシジン、塩酸クロルヘキシジン、ＣＰＣ、塩化ベンザルコニウム等が挙げられる。口臭除去成分の口腔内崩壊錠に対する配合量は、０．００１〜４０質量％が好ましく、より好ましくは０．０１〜２０質量％である。
Each of the above drugs can be formulated appropriately according to the intended drug efficacy. For example, when it is used as a bad breath removing agent, it is preferable to blend a bad breath removing component that exhibits a bad breath removing / suppressing effect in the mouth.
As bad breath removing components, cyclodextrin, citric acid, tartaric acid, malic acid and other organic acids and salts thereof, zeolite, activated carbon, silica gel, copper chlorophyllin sodium, catechin, polyphenol, flavonoid, copper gluconate, copper citrate, malic acid Copper salts such as copper, rosemary, sage, thyme, oregano, marjoram, perilla, savory, etc. Nindo, Dill, Ogon, Mace, Alame, Persimmon, Blueberry, Lychee, Guava, Acerola, Aronia, Blackcurrant, Eldaberry, Willow, Rosehip, Baking Soda, Salad Oil, Linoleic Acid, Triclosan, Biosol, Chlorhexyl Gluconate Jin, chlorhexidine hydrochloride, CPC, etc. benzalkonium chloride. 0.001-40 mass% is preferable, and, as for the compounding quantity with respect to the orally disintegrating tablet of a bad breath removing component, More preferably, it is 0.01-20 mass%.
本発明の口腔内崩壊錠には、上記の他、矯味成分として、甘味剤、酸味剤、香味剤を配合することが好ましい。 In addition to the above, the orally disintegrating tablet of the present invention preferably contains a sweetening agent, a sour agent, and a flavoring agent.
甘味剤としては、アスパルテーム、アセスルファムカリウム、サッカリンナトリウム、スクラロース、ステビア、ソーマチン等が挙げられ、アスパルテーム、アセスルファムカリウムが好ましい。その配合量は、口腔内崩壊錠に対して０．３〜３質量％が好ましく、より好ましくは０．５〜１．５質量％である。酸味剤としては、クエン酸、酒石酸、リンゴ酸、コハク酸、フマル酸等が挙げられ、クエン酸が好ましい。その配合量は、口腔内崩壊錠に対して０．２〜１０質量％が好ましく、より好ましくは１〜５質量％である。香味剤としては、メントール、カンフル、ボルネオール、リモネン等のモノテルペン類、それらを含有する精油が挙げられ、この中でもメントール（精油としてはハッカ油、ペパーミント油、スペアミント油等）、リモネン（オレンジ油等）が好ましい。その配合量は、口腔内崩壊錠に対して０．１〜５質量％が好ましく、より好ましくは１〜３質量％である。香料は、そのまま添加しても、各種担体に担持させたものを用いても良い。 Examples of the sweetener include aspartame, acesulfame potassium, saccharin sodium, sucralose, stevia, thaumatin and the like, and aspartame and acesulfame potassium are preferable. The blending amount is preferably 0.3 to 3% by mass, more preferably 0.5 to 1.5% by mass with respect to the orally disintegrating tablet. Examples of the sour agent include citric acid, tartaric acid, malic acid, succinic acid, fumaric acid and the like, and citric acid is preferable. The blending amount is preferably 0.2 to 10% by mass, more preferably 1 to 5% by mass with respect to the orally disintegrating tablet. Examples of flavoring agents include monoterpenes such as menthol, camphor, borneol, limonene, and essential oils containing them, among which menthol (such as mint oil, peppermint oil, spearmint oil, etc.), limonene (orange oil, etc.) ) Is preferred. The blending amount is preferably 0.1 to 5% by mass, more preferably 1 to 3% by mass with respect to the orally disintegrating tablet. The fragrance may be added as it is or may be carried on various carriers.
本発明の口腔内崩壊錠には、上記の他、本発明の効果を損なわない範囲で、他の任意成分（例えば、（ａ）成分以外の崩壊剤、（ｃ）成分以外の賦形剤、滑沢剤、崩壊剤、色素等）を配合することができる。 In the orally disintegrating tablet of the present invention, in addition to the above, other optional components (for example, a disintegrant other than the component (a), an excipient other than the component (c), Lubricants, disintegrants, pigments, and the like).
（ａ）成分以外の崩壊剤として、例えばクロスカルメロースナトリウム、カルボキシメチルセルロース、結晶セルロース等を、本発明の効果を損なわない程度に配合することができるが、その量は口腔内崩壊錠に対して４質量％以下が好ましく、より好ましくは２質量％以下、さらに好ましくは１質量％以下であり、含まないことが最も好ましい。これは、クロスカルメロースナトリウム、カルボキシメチルセルロース、結晶セルロースは、口中の唾液を急激に吸収することから、口腔内崩壊時の舌触りが悪くなるためである。 As disintegrants other than the component (a), for example, croscarmellose sodium, carboxymethylcellulose, crystalline cellulose, and the like can be blended to such an extent that the effects of the present invention are not impaired. 4 mass% or less is preferable, More preferably, it is 2 mass% or less, More preferably, it is 1 mass% or less, and it is most preferable not to contain. This is because croscarmellose sodium, carboxymethylcellulose, and crystalline cellulose absorb saliva in the mouth rapidly, and thus the tongue feels bad during oral disintegration.
（ｃ）成分以外の賦形剤としては、トウモロコシデンプン、バレイショデンプン、コムギデンプン、タルク、カオリン等が挙げられる。滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、ポリエチレングリコール、タルク、ステアリン酸等が挙げられる。 Examples of excipients other than component (c) include corn starch, potato starch, wheat starch, talc, and kaolin. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.
本発明の口腔内崩壊錠の製造は、例えば、（ａ）部分α化デンプン、（ｂ）非膨潤性水難溶性無機塩、（ｃ）水溶性賦形剤、その他錠剤に配合する各粒子を、所定の割合となるように混合し、その混合粉体を打錠して得ることができる。打錠には、一般に錠剤の成型に用いられる装置が用いられる。例えば、単発錠剤機（菊水製作所製等）、ロータリー式錠剤機（菊水製作所製等）等が用いられる。打錠の際の成型圧力は、成型物の硬度、口腔内の崩壊性から調整し設定することが好ましい。口腔内崩壊剤としての硬度と崩壊性を適度に調整するため、打錠圧力は、好ましくは４００〜３０００ｋｇ／ｃｍ2、より好ましくは６００〜２０００ｋｇ／ｃｍ2、さらに好ましくは８００〜１８００ｋｇ／ｃｍ2とするとよい。 Production of the orally disintegrating tablet of the present invention includes, for example, (a) partially pregelatinized starch, (b) a non-swelling poorly water-soluble inorganic salt, (c) a water-soluble excipient, and other particles to be blended in a tablet. It can be obtained by mixing so as to be a predetermined ratio and tableting the mixed powder. For tableting, an apparatus generally used for tablet formation is used. For example, a single tablet machine (manufactured by Kikusui Seisakusho, etc.), a rotary tablet machine (manufactured by Kikusui Seisakusho, etc.) and the like are used. The molding pressure at the time of tableting is preferably adjusted and set from the hardness of the molded product and the disintegration property in the oral cavity. The tableting pressure is preferably 400 to 3000 kg / cm 2 , more preferably 600 to 2000 kg / cm 2 , and still more preferably 800 to 1800 kg / cm 2 in order to appropriately adjust the hardness and disintegration property as an oral disintegrant. It is good to do.
本発明の口腔内崩壊錠の硬度は、２〜１０ｋｇｆが好ましく、より好ましくは４〜７ｋｇｆである。なお、錠剤硬度は、モンサント型の錠剤強度試験機を使用し、常法に従って測定することができる。また、強度の指標として、摩損度は０．４％以下が好ましい。これ以上では、搬送時、携帯時に錠剤が欠ける可能性がある。摩損試験は、日本薬局方参考情報の錠剤の摩損度試験法により測定できる。崩壊性は、錠剤を口腔内に入れて噛まずに舌で継続的に転がし、錠剤が完全に崩壊するまでの時間が１８０秒以内が好ましく、より好ましくは１２０秒以内、さらに好ましくは９０秒以内のものが好ましい。また、必要応じて錠剤は多層錠とすることもできる。 The hardness of the orally disintegrating tablet of the present invention is preferably 2 to 10 kgf, more preferably 4 to 7 kgf. The tablet hardness can be measured according to a conventional method using a Monsanto type tablet strength tester. As a strength indicator, the friability is preferably 0.4% or less. Above this, there is a possibility that the tablet may be missing during transportation or carrying. The friability test can be measured by the friability test method for tablets in Japanese Pharmacopoeia Reference Information. The disintegration is preferably within 180 seconds, more preferably within 120 seconds, and even more preferably within 90 seconds until the tablet is completely rolled with the tongue without being chewed after being put into the oral cavity. Are preferred. Moreover, a tablet can also be used as a multilayer tablet as needed.
本発明の口腔内崩壊錠は、崩壊剤による唾液の吸収による粉っぽさや粘り感を生じず服用性が良好で、錠剤強度と口中崩壊性、舌触りに優れた口腔内崩壊錠であるため、噛まずに口腔内で崩壊させる服用方法である錠剤とすることが好ましい。特に、口臭除去用等の口腔用錠剤を目的とする場合に優れた効果を得ることができる。 The orally disintegrating tablet of the present invention is an orally disintegrating tablet excellent in tablet strength and disintegration property in the mouth and in the touch, with good dosage without causing powderiness and stickiness due to absorption of saliva by the disintegrant, It is preferable to use a tablet which is a method for taking the medicine in the oral cavity without chewing. In particular, an excellent effect can be obtained when an oral tablet for removing bad breath is intended.
以下、調製例、実施例及び比較例を示し、本発明を具体的に説明するが、本発明は下記の実施例に制限されるものではない。 EXAMPLES Hereinafter, although a preparation example, an Example, and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example.
［調製例１：造粒品１］
ローズマリーエキス４５０ｇ、グァバ葉エキス３００ｇ、サンショウエキス１５ｇ、エリスリトール１９３５ｇ、コーンスターチ３００ｇにヒドロキシプロピルセルロース６質量％水溶液４０００ｇを加えて造粒物を製造し、平均粒径２９０μｍの造粒品１を得た。造粒にはスパイラルフロー（ＦＬＯ−５型：フロイント産業（株）製）を用いた。
[Preparation Example 1: Granulated product 1]
450 g of rosemary extract, 300 g of guava leaf extract, 15 g of sunflower extract, 1935 g of erythritol and 300 g of corn starch are added with 4000 g of a 6% by weight aqueous solution of hydroxypropylcellulose to produce a granulated product, and a granulated product 1 having an average particle size of 290 μm is obtained. It was. Spiral flow (FLO-5 type: manufactured by Freund Sangyo Co., Ltd.) was used for granulation.
［調製例２：造粒品２］
セイジエキス４５０ｇ、ピクノジェノール３０ｇ、サンショウエキス１５ｇ、塩化セチルピリジニウム３０ｇ、キシリトール２１７５ｇ、コーンスターチ３００ｇにヒドロキシプロピルセルロース６％水溶液４０００ｇを加えて造粒物を製造し、平均粒径３１０μｍの造粒品２を得た。造粒にはスパイラルフロー（ＦＬＯ−５型：フロイント産業（株）製）を用いた。
[Preparation Example 2: Granulated product 2]
450 g of sage extract, 30 g of Pycnogenol, 15 g of salamander extract, 30 g of cetylpyridinium chloride, 2175 g of xylitol, and 300 g of corn starch are added with 4000 g of a 6% aqueous solution of hydroxypropylcellulose to produce a granulated product. Obtained. Spiral flow (FLO-5 type: manufactured by Freund Sangyo Co., Ltd.) was used for granulation.
［調製例３：造粒品３］
リボフラビン６０ｇ、塩酸ピリドキシン３００ｇ、ベンフォチアミン３００ｇ、マンニトール２０４０ｇコーンスターチ３００ｇにヒドロキシプロピルセルロース６％水溶液４０００ｇを加えて造粒物を製造し、平均粒径の２９０μｍの造粒品３を得た。造粒にはスパイラルフロー（ＦＬＯ−５型：フロイント産業（株）製）を用いた。
[Preparation Example 3: Granulated product 3]
A granulated product was prepared by adding 4000 g of 6% aqueous solution of hydroxypropylcellulose to 300 g of riboflavin 60 g, pyridoxine hydrochloride 300 g, benfotiamine 300 g, mannitol 2040 g corn starch, and a granulated product 3 having an average particle size of 290 μm was obtained. Spiral flow (FLO-5 type: manufactured by Freund Sangyo Co., Ltd.) was used for granulation.
［実施例１〜１９、比較例１〜１０］
表１〜５の組成の１万倍量を量り、Ｖ型混合機Ｖ−５型（徳寿製作所製）にて均一に混合した。部分α化デンプンは製品名ＰＣＳ（旭化成製）、リン酸マグネシウムは製品名リン酸三マグネシウム（太平化学産業製）を使用した。前記混合物を、ロータリー式錠剤機（畑鐵工所製）で表１の質量となるように打錠し、直径９．５ｍｍの錠剤を得た。打錠にあたっては、錠剤硬度が４〜６ｋｇｆとなるように打錠圧を調整した。なお、表１〜３のソルビトール、マンニトール、キシリトール、マルチトール、乳糖、ラクチトール、トレハロース、パラチノース、パラチニット、エリスリトールの平均粒子径は２００μｍ、リン酸マグネシウム、焼成カルシウムの平均粒子径は６０μｍのものを使用した。
[Examples 1 to 19, Comparative Examples 1 to 10]
The amount of 10,000 times the composition of Tables 1-5 was measured, and it mixed uniformly with the V type mixer V-5 type (made by Tokuju Seisakusho). The partially pregelatinized starch used the product name PCS (manufactured by Asahi Kasei), and the magnesium phosphate used the product name trimagnesium phosphate (manufactured by Taihei Chemical Industry). The mixture was tableted with a rotary tablet machine (manufactured by Hata Kogyo Co., Ltd.) so as to have the mass shown in Table 1 to obtain tablets with a diameter of 9.5 mm. In tableting, the tableting pressure was adjusted so that the tablet hardness was 4 to 6 kgf. In Tables 1 to 3, sorbitol, mannitol, xylitol, maltitol, lactose, lactitol, trehalose, palatinose, palatinit, erythritol have an average particle diameter of 200 μm, and magnesium phosphate and calcined calcium have an average particle diameter of 60 μm. did.
［実施例２０］
下記口臭除去用口腔内崩壊錠を得た。
ローズマリーエキス９００ｇ、グァバ葉エキス６００ｇ、ピクノジェノール６０ｇ、エリスリトール１１４０ｇ、コーンスターチ３００ｇにヒドロキシプロピルセルロース６質量％水溶液４０００ｇを加えて造粒物を製造し、造粒品４を得た。造粒にはスパイラルフロー（ＦＬＯ−５型：フロイント産業（株）製）を用いた。
サンショウエキス３０ｇ、キシリトール４００ｇ、エリスリトール２２７０ｇ、コーンスターチ３００ｇにヒドロキシプロピルセルロース６質量％水溶液４０００ｇを加えて造粒物を製造し、造粒品５を得た。造粒にはスパイラルフロー（ＦＬＯ−５型：フロイント産業（株）社製）を用いた。
造粒品４を７００ｇ、部分α化デンプン１００ｇ、ソルビトール７００ｇ、リン酸マグネシウム４５０ｇ、微粒二酸化ケイ素２５ｇ、メントールミクロン２４０ｇ、アスパルテーム３０ｇ、ステアリン酸カルシウム２０ｇ、紅花色素粉末３５ｇをＶ型混合機Ｖ−５型（徳寿製作所）にて均一に混合し、混合品Ａを得た。
造粒品５を９００ｇ、部分α化デンプン１２０ｇ、ソルビトール８００ｇ、リン酸マグネシウム６００ｇ、微粒二酸化ケイ素３０ｇ、メントールミクロン２００ｇ、アスパルテーム３０ｇ、ステアリン酸カルシウム２０ｇをＶ型混合機Ｖ−５型（徳寿製作所）にて均一に混合し、混合品Ｂを得た。
ロータリー式錠剤機（畑鐵工所製）で第１層として混合品Ａを２３０ｍｇ、第２層として混合品Ｂを１３５ｍｇとなるように打錠し、直径９．５ｍｍの２層錠の錠剤を得た。第１層の（ｂ）／（ａ）は４．７、（ｃ）／（ａ）は９．５、（ａ）、（ｂ）及び（ｃ）成分の合計量は６５．９質量％であった。第２層の（ｂ）／（ａ）は３．２、（ｃ）／（ａ）は７．２、（ａ）、（ｂ）及び（ｃ）成分の合計量は８３．７質量％であった。
この錠剤は、硬度は５ｋｇ、摩損度は０．１％、口中崩壊評価は６９秒、舌触りは４．３点であった。
この製剤による下記評価方法（６）によるメチルメルカプタンの抑制率（対無処置）は５１％であった。
[Example 20]
The following orally disintegrating tablets for removing bad breath were obtained.
A granulated product was obtained by adding 4000 g of a 6% by weight aqueous solution of hydroxypropylcellulose to 900 g of rosemary extract, 600 g of guava leaf extract, 60 g of pycnogenol, 1140 g of erythritol, and 300 g of corn starch. Spiral flow (FLO-5 type: manufactured by Freund Sangyo Co., Ltd.) was used for granulation.
A granulated product was obtained by adding 4000 g of a 6% by weight aqueous solution of hydroxypropylcellulose to 30 g of a salamander extract, 400 g of xylitol, 2270 g of erythritol, and 300 g of corn starch. Spiral flow (FLO-5 type: manufactured by Freund Sangyo Co., Ltd.) was used for granulation.
700 g of granulated product 4, 100 g of partially pregelatinized starch, 700 g of sorbitol, 450 g of magnesium phosphate, 25 g of fine silicon dioxide, 240 g of mentholmicron, 30 g of aspartame, 20 g of calcium stearate, 35 g of safflower pigment powder, V type mixer V-5 type (Tokusu Seisakusho) was mixed uniformly to obtain a mixture A.
900 g of granulated product 5, 120 g of partially pregelatinized starch, 800 g of sorbitol, 600 g of magnesium phosphate, 30 g of finely divided silicon dioxide, 200 g of menthol micron, 30 g of aspartame, 20 g of calcium stearate are added to a V type mixer V-5 type (Tokuju Seisakusho) And mixed uniformly to obtain a mixture B.
Using a rotary tablet machine (manufactured by Hata Kogyo), the mixture A was compressed to 230 mg for the first layer and the mixture B to 135 mg for the second layer, and a 9.5 mm diameter double layer tablet was prepared. Obtained. (B) / (a) of the first layer is 4.7, (c) / (a) is 9.5, and the total amount of the components (a), (b) and (c) is 65.9% by mass. there were. The second layer (b) / (a) is 3.2, (c) / (a) is 7.2, and the total amount of the components (a), (b) and (c) is 83.7% by mass. there were.
This tablet had a hardness of 5 kg, a friability of 0.1%, an evaluation of disintegration in the mouth of 69 seconds, and a touch of 4.3 points.
The inhibition rate (vs. no treatment) of methyl mercaptan by the following evaluation method (6) with this preparation was 51%.
<評価>
（１）錠剤硬度試験
硬度は、モンサント型の錠剤強度試験機を用いて、常法に従って測定した（ｎ＝２０）。
（２）錠剤摩損度
摩損度は、日本薬局方参考情報の錠剤の摩損度試験法により錠剤２０錠で試験を行った。
<Evaluation>
(1) Tablet hardness test Hardness was measured according to a conventional method using a Monsanto type tablet strength tester (n = 20).
(2) Tablet friability The friability was tested with 20 tablets according to the tablet friability test method of the Japanese Pharmacopoeia Reference Information.
（３）口中崩壊試験
成人男性６人により、口中崩壊性を評価した。錠剤を口腔内に入れ、噛まずに舌で転がしながら錠剤を崩壊させ、錠剤が完全に崩壊するまでの時間を測定した。時間の平均値（小数点以下を四捨五入）から結果を下記基準で示した。
基準
９０秒以内に崩壊（又は溶解）した場合を○
９０秒超１８０秒以内に崩壊（又は溶解）した場合を△
１８０秒で崩壊（又は溶解）しない場合を×
(3) Oral disintegration test Oral disintegration was evaluated by 6 adult men. The tablet was put into the oral cavity, the tablet was disintegrated while rolling with the tongue without chewing, and the time until the tablet was completely disintegrated was measured. The result was shown on the following reference | standard from the average value (rounded off the decimal point) of time.
The case where it collapses (or dissolves) within the standard 90 seconds ○
△ When it disintegrates (or dissolves) within 90 seconds and 180 seconds
When not disintegrating (or dissolving) in 180 seconds x
（４）舌触り
成人男性６人により、舌触りを評価した。錠剤を口腔内に入れ、舌で転がしながら錠剤を崩壊させ、舌触りを下記基準で評価した。結果を６人の平均値（小数点第２位を四捨五入）で示す。
基準
粉っぽさ、粘り感がない：５点
わずかに粉っぽい又は粘り感がある：４点
やや粉っぽい又は粘り感がある：３点
粉っぽい又は粘り感がある：２点
非常に粉っぽい又は粘り感がある：１点
(4) Tongue feel Tongue feel was evaluated by 6 adult men. The tablet was put into the oral cavity, the tablet was disintegrated while rolling with the tongue, and the touch of the tongue was evaluated according to the following criteria. Results are shown as the average of 6 people (rounded to the first decimal place).
Standard powdery, no stickiness: 5 points Slightly powdery or sticky: 4 points Slightly powdery or sticky: 3 points Powdery or sticky: 2 points Has a powdery or sticky feel: 1 point
（５）耐吸湿性
通気性を有するプラスチック（ポリプロピレン）製のフタつき容器（５５ｍｍ×３５ｍｍ×２０ｍｍ、直方体）に試験錠剤１錠を入れ、３５℃７５％ＲＨの恒温槽中に２４時間放置し、吸湿による質量増加率（対初期錠剤質量）を評価した。質量増加率が３％以下であれば耐吸湿性が良好であり、３％超７％以下であれば耐吸湿性が少し悪く、７％超であれば耐吸湿性が悪い。
(5) Moisture absorption resistance Put one test tablet in a container (55 mm x 35 mm x 20 mm, rectangular parallelepiped) made of plastic (polypropylene) with air permeability and let it stand in a thermostatic bath at 35 ° C and 75% RH for 24 hours. The mass increase rate due to moisture absorption (vs. initial tablet mass) was evaluated. If the mass increase rate is 3% or less, the moisture absorption resistance is good, if it exceeds 3% and 7% or less, the moisture absorption resistance is a little bad, and if it exceeds 7%, the moisture absorption resistance is bad.
（６）メチルメルカプタンの抑制率
昼食１時間後にサンプル１粒を口中で完全に溶かして飲み込んだ。一時間経過後、テドラーバッグに呼気（約２００ｍＬ）を採取し、ＰＴＲ−ＭＳ（プロトン移動反応質量分析器）にてメチルメルカプタンガス濃度を測定した。得られたメチルメルカプタンガス濃度から、対無処置に対するメチルメルカプタンの抑制率（％）を算出した。
(6) Inhibition rate of methyl mercaptan One hour after lunch, one sample was completely dissolved in the mouth and swallowed. After one hour, exhaled air (about 200 mL) was collected in a Tedlar bag, and the methyl mercaptan gas concentration was measured with PTR-MS (proton transfer reaction mass spectrometer). From the obtained methyl mercaptan gas concentration, the inhibition rate (%) of methyl mercaptan relative to no treatment was calculated.
実施例１〜２０は、摩損度も低く、崩壊時間もはやい。比較例１は（ａ）部分α化デンプンに対する（ｂ）非膨潤性不溶性無機塩の割合が少なすぎ、比較例５は（ａ）部分α化デンプンに対する（ｃ）水溶性賦形剤の割合が少なすぎることから、崩壊はするものの摩損度が高い。比較例２は、（ａ）部分α化デンプンに対する（ｂ）非膨潤性不溶性無機塩が多すぎ、比較例３は（ａ）、（ｂ）及び（ｃ）成分の合計量が少なく、比較例４は（ａ）部分α化デンプンに対する（ｃ）水溶性賦形剤の割合が多すぎることから、崩壊性が悪い。比較例６は、崩壊するものの摩損度が高い上に舌触りが悪い。また、実施例１３〜１９は耐吸湿性にも優れている。 Examples 1-20 have low friability and no longer decay time. In Comparative Example 1, (a) the ratio of (b) non-swellable insoluble inorganic salt to the partially pregelatinized starch is too small, and in Comparative Example 5, the ratio of (c) the water-soluble excipient to the partially pregelatinized starch Since there is too little, although it collapses, it is highly friable. Comparative Example 2 has (a) too much (b) non-swellable insoluble inorganic salt for partially pregelatinized starch, and Comparative Example 3 has a small total amount of components (a), (b) and (c). 4 has poor disintegration because the ratio of (c) water-soluble excipient to (a) partially pregelatinized starch is too large. Although the comparative example 6 is disintegrated, it has a high degree of wear and a poor touch. Examples 13 to 19 are also excellent in moisture absorption resistance.
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